Eldad J Dann MDRambam Health Care Campus

and Bruce Rappaport faculty of medicineTechnionIsrael technical institute Haifa Israel

Hodgkin Lymphoma Questions and Answers

102017

Conflict of interest Takeda Research grant honorarium consultation fees

INTRODUCTION

The current aim of treatment for Hodgkin lymphoma (HL) is tomaximize response to therapy while minimizing long-term toxicitySeveral studies have been recently conducted tailoring therapybased on interim PET (PET-2) findings which may result in a newstandard of care for HL Should therapy be escalated in patients with positive PET-2 Could therapy be de-escalated based on negative PET-2 Could RT be omitted in early-stage HL and negative PET

SF is a 26-y old male ndash a medical student ndash who noticed a lump in his Rt neck base in 72017He had no weight loss night sweat or feverESR -4PETCT at diagnosis Pathologic uptake in the lower neck SCN and ICN 3X6X31 (SUV-109)Rt paratracheal and anterior mediastinum uptake of up to 6 cmStage IIa early favorable HL 3 sites of disease non-bulkyPt started with ABVDx2 persistent coughing was noticed following 15 cyclesBleomycin was excluded and

coughing subsided DLCO and lung function were within normal limitsPET-2 Deauville Score -1 Further therapy was discussed with the Pt and family

Hodgkinrsquos Lymphomas I and II untreated 15-70 yrs

Risk factors age ge 50 mediastinal mass B symptoms and ESRgt30

ESRgt50 if no B symptoms gt3 sitesAndrersquo et al JCO 2017

Q Can RT be omitted in early favorable HLA Probably not unless more chemotherapy is givenQIs RT really necessary in patients with early unfavorable HL and negative interim PET-2(negative PET-2 was defined as DS 12)

A RT may be substituted with 4xABVD

Favorable HD Un-favorable

Andrersquo et al JCO 2017

PET-2 positive pts Effect of therapy escalationwith 2 EB

The H10 shows that when ePET is positive after 2 cycles of ABVD intensification with 2 cycles of EB +INRT should be considered as the best treatment optionIn ePET negative patients the overall outcome is excellent either after combined modality treatment or after chemotherapy onlyIn the favorable group CMT is a better immediate disease control (5yPFS 99 versus 87) however in the unfavorable group benefit of CMT seems to be less clinically relevant and treatment with chemotherapy only is defensible in individual patients(5yPFS 921 versus 896)

The 5-year PFS for ED patients was 091 and 068 for negative and positive interim PETCT respectively (p=009)

Dann EJ BJH 2017

In the RT group 3-year PFS was 94middot6(95 CI 91middot5-97middot7) compared to90middot8 (95 CI 86middot9-94middot8) in the no-further-treatment groupFor PFS the HR was 1middot57 (95 CI 0middot84- 2middot97 p=0middot16) the 3-year absolute risk difference was minus3middot8 (95 CI minus8middot8-1middot3)

HL deaths

4

1

0

3-year PFS and overall survival rates 908 and 990 respectively

However the per-protocol analysis showed a greater 3-year PFS rate than the intention-to-treat analysis in the RT group 971 (95 CI 947 to 996)with a hazard ratio of 236 (95 CI 113-495P = 002) because 26 patients did not receive the assigned RT and 6 events occurred among those patients

Initial results of the US Intergroup trial of response-adapted chemotherapy or chemotherapyradiation therapy based on PET for non-bulky stage I and II Hodgkin

lymphomaStraus DJ et al Blood 2015

David J Straus et al Blood 2015126578copy2015 by American Society of Hematology

PETCT after 2xABVD identified 91 of PET-2 negative pts who were treated with additional 2xABVD with an estimated 3-yr PFS of 92Defining PET-2 negative pts by DS 1-3 (91) rather than DS 1-2(75) allows maintaining PFS gt90 and reducing the number of patients receiving IFRT

Treating PET-2 positive pts (9) with 2x escalated BEACOPP+IFRT may not result in clinically important improvement in PFS HR-604(1822008) at 2 yrs

Kaplan-Meier plot showing progression-free survival according to IPS group and PET results

after two cycles of ABVD

Andrea Gallamini et al Haematologica 2014991107-1113

copy2014 by Ferrata Storti Foundation

The 3-year PFS rate was 83 for the whole study population 28 for patients with positive interim scans and 95 for patients with negative interim scans (Plt00001)

Advanced Hodgkin Lymphoma

Central PET review bull Standardized protocol drawn up by expert panel

bull Only full-ring dedicated PET-CT scanners

bull Documented daily quality control procedure

bull Tested and secure method to transfer anonymised scan data betweenscanning facilities and the central reporting facility in each country andagreed file naming convention

bull It must be demonstrated that image quality is comparable between centres and standard uptake values can be reliably determined from the PETCT imagesStandardized Deauville 5PS criteria (1-3 negative 4-5 positive)

SCORE 1 NO UPTAKE

SCORE 2 UPTAKE le MEDIASTINUM

SCORE 3 UPTAKE gt MEDIASTINUM BUT le LIVER

SCORE 4 MODERATELY UPTAKE gt LIVER

SCORE 5 MARKEDLY UPTAKE gt LIVER

Johnson P Federico M et al NEJM2016

Flow chart showing the clinical outcome of patients according to IPS group

and PET results after two cycles of ABVD

CR continued complete remission PRO primary refractory to chemotherapyprogression within 6

months after completion of therapy REL late relapse

Andrea Gallamini et al Haematologica 2014991107-1113

copy2014 by Ferrata Storti Foundation

87 69

ProgressionPos 3345 73Neg 12215 5

2 cycles ABVD

Full dose on schedule

PET 2 -vePET 2 +ve

4 cycles ABVD

PET2

PET 1(Staging)

IPS 0-7

Randomize

4 cycles AVD

Follow-up (no RT)

4 cycles BEACOPP-14

or 3 eBEACOPP

PET3

PET 3 -vePET 3 +ve

RT or salvage

regimen

2 cycles BEACOPP-14 or

1 eBEACOPP

No RT

RATHL study Chairman Peter Johnson

Johnson P Federico M et al NEJM2016

Outcomes at 1 year according to PET score after ABVD x 2

PET 2 Score Total Number

Number Assessable

at 1 yr

Progressions Deaths PFS events

1 114 88 7 0 80

2 493 375 25 6 72

3 347 239 20 4 96

4 144 102 14 7 167

5 38 25 10 5 520PET Missing 78 22 0 2 91

Total 1214 851 76 24 105

Johnson P Federico M et al NEJM2016

PET-2 +PFS

PET-2 ndashPFS ()

PET-2- PET-2+

PET-2 DS 1-3 negativeDS 4-5 positive

NStageTrial

69 (4y)87 (4y)81192xABVD ndash 4xABVD+ 4xEB+4xSB

2xABVD ndash 4xAVD+ 4xEB or 6xSB

2xABVD ndash 4xABVD+ 6xEB

780IIB-IVB

GITIL 0607Gallamini A

(in press)

675 (3y)85 (3y)84161119IIB-IVB

NCRI RATHLJohnson P

NEJM 2016

64 (2y)82 (2y)8218336III-IVSWOG S0816Press O

JCO 2016

668582182235TOTALMEAN

Gallamini A Kostakoglu L Ann Oncol 2015

Positive interim PETCT is an adverse prognostic marker and treatment intensification improves prognosis However it is inferior to that observed pts with negative PET-2

68 (5y)82 (5y)88 8112 19IPS 0-2ge 3 ABVDEB

185IIB-IVH2 BJH 2017

73 (2y)93 (2y)87132xEB - 4x ABVDEB+4x EB

810IIB-IVGELLA AHL 2011

A Gallamini C Tarella S Viviani A Rossi C Patti M Picardi A Romano M Cantonetti G La Nasa L Trentin SBolis D Rapezzi V Zoli D Gottardi P Gavarotti P Corradini M Cimminiello C Schiavotto G Parvis RZanotti G Gini A JM Ferreri P Viero A Biggi F Fallanca U Ficola G Prosperini F Bergesio S Chauvie CPavoni A M Gianni and A Rambaldi

Early chemotherapy intensification with escalated BEACOPP in advanced-stage Hodgkin Lymphoma patients with a positive interim PET-CT after 2 ABVD cycles long-term results of the GITILFIL HD 0607 trial

Pts enrolledregistered 783785

Pt enrollment 62008- 62014Median fu for pts completing treatment 1303 (2-2857) days

0

02

04

06

08

1

0 2 4 6 8

DS 4

DS 5

0

02

04

06

08

1

0 2 4 6 8

DS 4

DS 5

DS 4 101 (5) 82 (2) 29 (1) 3 (0) 0

DS 5 49 (5) 34 (2) 8 (1) 1 (0) 0

Years from registration

P = 00696

DS 4 101 (15) 75 (2) 26 (0) 3 (0) 0

DS 5 49 (25) 19 (1) 5 (0) 1 (0) 0

Years from registration

P lt 0001

Overall Survival Progression-free Survival

OS and PFS according to Deauville Score

4-Y OS 92 (95CI 84-96)

4-Y OS 83 (95CI 67-92)

4-Y PFS 81 (95CI 71-88)

4-Y PFS 46 (95CI 31-59)

PET-2 positive patient with a DS 4 switching to BEACOPP have a 3-Y PFS similar to the entire cohort of patients (4-Y PFS 81 95 CI 71-88)Patients with a DS 5 which are a small subset of the entire population (63) still represent an unmet therapeutic need awaiting new treatment strategies

Gallamini A et al EHA 2017

0

02

04

06

08

1

0 2 4 6 8

No RX

RX

No RX 148 (1) 141 (2) 40 (0) 0 (0) 0

RX 148 (0) 144 (0) 40 (0) 0 (0) 0

Years from registration

P = 00790

4-Y OS 100

4-Y OS 98 (95CI 92-99)

0

02

04

06

08

1

0 2 4 6 8

No RX

RX

No RX 148 (9) 133 (1) 35 (0) 14 (0) 0

RX 148 (5) 139 (1) 39 (0) 10 (0) 0

Years from registration

P = 02882

4-Y PFS 96 (95CI 91-98)

4-Y PFS 93 (95CI 87-96)

Overall Survival Progression-free Survival

OS and PFS in PET2- randomized to RXNFT

Consolidation radiotherapy in the region where a large nodal mass was recorded at baseline did not improve treatment result in negative PET-2 and PET-6 patients irrespective of the dimension of the lesion at baseline

Gallamini A et al EHA 2017

BEACOPP esc x 2

Standard Arm Experimental Arm

Neg Pos

Salvagetherapy

Pos Neg

PET4

PET2

Neg Pos Neg Pos Neg

BEACOPP esc x 2

IPS 0-7BEACOPP esc x 2 BEACOPP esc x 2

BEACOPP esc x 2

R

ABVD x 2

Non inferiority of the experimental arm

ABVD x 2

BEACOPP esc x 2

Courtesy of O Casasnovas

Kairos

Gela ahl2011Stage IIIIV and high risk IIB Hodgkin Lymphoma

Salvagetherapy

Primary Endpoint Planned accrual Date start Date end

5-yr PFS 810 Pts May 2011 May 2015

Abs 577 Randomized phase III study comparing an early PET driven treatment de-escalation to non-PET monitored strategy in patients with advanced HL

O Casasnovas ASH 2015

There was no significant difference between the experimental and standard arms Reduction of therapy based on negative interim PET is safe

Randomized phase III study comparing an early PET driven treatment de-escalation to non pet monitored strategy in patients with advanced HL

O Casanovas ASH 2015

Positive interim PET is a risk factor for HL progression even if EB is continued

Casanovas 2016

There is a value to perform PET-4 if PET-2 is positive Consider change of therapy if PET-4 is positive

Casanovas 2016

Is there a role for PET-4 if treatment was escalated based on PET-2

Casanovas 2016

Progression 90 PtsProgression 157 Pts

ABVD x2

PET-2

BEACOPP ESC x4

PET-6ABVD x4

IPS 0-2

NEGATIVE

POSITIVEBEACOPP ESC x2

IPS 3-7

PET-6ISRT to bulky MM

+

Israeli H2 protocol for advanced Hodgkin lymphoma

B symptoms Stage III IV

The study prospectively evaluated the outcome of HL patients whose therapy waschosen based on initial prognostic factors and tailored based on results of PETCTperformed after 2 cycles of chemotherapy

This multicenter study was initiated in 2006 and ended in 72013 enrolling 355 patientswith stages I-IV HL aged 18-60 years

Conclusions

bull Both baseline PETCT and PET-2 are recommendedbull Deauville scores 1-3 should be considered a negative PET resultbull Positive PET-2 (DS 4-5) is a poor prognostic sign when treatment is initiated

with ABVD or even with EB (Gallamini Johnson Casasnovas)bull Escalation of therapy in PET-2 positive patients improves the outcomebull Escalation of therapy to EB in early-stage HL Pts with positive PET-2 (DS 4-5)

improves PFS (Andrersquo M Straus D)bull Pts with high IPS or bulky mediastinal mass have a worse outcome if

therapy is initiated with ABVD and a higher probability of a positive PET-2 (Johnson)

bull If therapy is initiated with escalated BEACOPP de-escalation of therapy to ABVD does not impair the outcome (Casasnovas)

bull The same percentage of PET-2 negativity was found in patients with IPS 0-2 who initiated therapy with ABVD (5-y PFS 079) and in patients with IPS 3-7 whose initial therapy was escalated BEACOPP (5-y PFS 081) (Dann)

bull Salvage therapy should be considered in PET-2 (DS-5) or PET-4 (DS 4-5) positive patients (Johnson Casasnovas )

Thank You e_dannrambamhealthgovil

Should BLEOMYCIN be omitted at age ge 65

RAPID trial toxicity

Bleomycin in older early-stage favorable Hodgkin lymphoma patients analysis of the German Hodgkin Study Group (GHSG) HD10 and HD13 trialsBoris Bumloll et al German Hodgkin Study Group

Two cycles of ABVD or AVD were equally tolerable in older early-stage favorable HL patients Excessive toxicity including severe bleomycin-induced lung toxicity occurred in older HL patients receiving 4 cycles of ABVD Doxorubicin bleomycin vinblastine sulfate and dacarbazine (ABVD) is associated with severe toxicity in older patients particularly from bleomycin-induced lung toxicity (BLT) Therefore using bleomycin has been questioned in older Hodgkin lymphoma (HL) patients especially in early-stage HL We therefore analyzed feasibility toxicity and efficacy of ABVD or AVD in 287 older early-stage favorable HL patients We included patients ge60 years of age in the German Hodgkin Study Group HD10 and HD13 trials randomized to either 2 cycles of ABVD (2XABVD n = 137) or AVD (2xAVD n = 82) each followed by involved-field radiotherapy (IF-RT) with patients randomized to 4xABVD+IFRT (n =68) Patientsrsquo median age was 65 years (range 60-75) with comparable patient and disease characteristics Grade III-IV adverse event rates were similar in patients receiving 2xAVD and 2xABVD (40 and 39 respectively) but considerably higher in patients receiving 4xABVD (65) Similarly BLT was rare in patients receiving 2xABVDAVD but occurred in 769 (10) of patients randomized to 4xABVD with 3 lethal events In conclusion no effects of bleomycin on toxicity rates were detectable in older patients receiving 2 cycles of chemotherapy However we found a high risk of severe toxicity of bleomycin in older HL patients receiving more than 2 cycles of ABVD (Blood 2016 127(18)2189-2192)

Forty-four advanced-stage older HL patients (aged ge60 years) were treated on the randomized study E2496 Toxicities were mostly similar between chemotherapy regimens although 24 of older patients developed bleomycin lung toxicity (BLT) which occurred mainly with ABVD (91) Further the BLT-related mortality rate was 18 The overall treatment-related mortality for older HL patients was 9 versus 03 for patients aged lt60 years (plt0001) Among older patients there were no survival differences between ABVD and SV According to age outcomes were significantly inferior for older versus younger patients (5-year FFS 48 vs 74 respectively p=0002 5-year OS 58 and 90 respectively plt00001)Among the 45 older HL patients enrolled 11 (24) developed BLT of whom 211 (18) died due to acute pulmonary fibrosisrespiratory failure) Furthermore 1011 (91) BLT cases occurred withduring ABVD (BLT incidence 43 with ABVD vs 5 Stanford V p=004) This toxicity appeared to occur later in the chemotherapy course however the two BLT-related deaths occurred during cycle 3 of ABVD We did not identify any factors that predicted the development of BLT or death due to BLT Granulocyte growth factor was given the vast majority of patients thus it was not analyzed as a risk factor

The Efficacy and Tolerability of ABVD and Stanford V in Older Hodgkin Lymphoma Patients A Comprehensive Analysis from the North American Intergroup Trial E2496 Andrew M Evens et al BJH 2013

INTRODUCTION

The current aim of treatment for Hodgkin lymphoma (HL) is tomaximize response to therapy while minimizing long-term toxicitySeveral studies have been recently conducted tailoring therapybased on interim PET (PET-2) findings which may result in a newstandard of care for HL Should therapy be escalated in patients with positive PET-2 Could therapy be de-escalated based on negative PET-2 Could RT be omitted in early-stage HL and negative PET

SF is a 26-y old male ndash a medical student ndash who noticed a lump in his Rt neck base in 72017He had no weight loss night sweat or feverESR -4PETCT at diagnosis Pathologic uptake in the lower neck SCN and ICN 3X6X31 (SUV-109)Rt paratracheal and anterior mediastinum uptake of up to 6 cmStage IIa early favorable HL 3 sites of disease non-bulkyPt started with ABVDx2 persistent coughing was noticed following 15 cyclesBleomycin was excluded and

coughing subsided DLCO and lung function were within normal limitsPET-2 Deauville Score -1 Further therapy was discussed with the Pt and family

Hodgkinrsquos Lymphomas I and II untreated 15-70 yrs

Risk factors age ge 50 mediastinal mass B symptoms and ESRgt30

ESRgt50 if no B symptoms gt3 sitesAndrersquo et al JCO 2017

Q Can RT be omitted in early favorable HLA Probably not unless more chemotherapy is givenQIs RT really necessary in patients with early unfavorable HL and negative interim PET-2(negative PET-2 was defined as DS 12)

A RT may be substituted with 4xABVD

Favorable HD Un-favorable

Andrersquo et al JCO 2017

PET-2 positive pts Effect of therapy escalationwith 2 EB

The H10 shows that when ePET is positive after 2 cycles of ABVD intensification with 2 cycles of EB +INRT should be considered as the best treatment optionIn ePET negative patients the overall outcome is excellent either after combined modality treatment or after chemotherapy onlyIn the favorable group CMT is a better immediate disease control (5yPFS 99 versus 87) however in the unfavorable group benefit of CMT seems to be less clinically relevant and treatment with chemotherapy only is defensible in individual patients(5yPFS 921 versus 896)

The 5-year PFS for ED patients was 091 and 068 for negative and positive interim PETCT respectively (p=009)

Dann EJ BJH 2017

In the RT group 3-year PFS was 94middot6(95 CI 91middot5-97middot7) compared to90middot8 (95 CI 86middot9-94middot8) in the no-further-treatment groupFor PFS the HR was 1middot57 (95 CI 0middot84- 2middot97 p=0middot16) the 3-year absolute risk difference was minus3middot8 (95 CI minus8middot8-1middot3)

HL deaths

4

1

0

3-year PFS and overall survival rates 908 and 990 respectively

However the per-protocol analysis showed a greater 3-year PFS rate than the intention-to-treat analysis in the RT group 971 (95 CI 947 to 996)with a hazard ratio of 236 (95 CI 113-495P = 002) because 26 patients did not receive the assigned RT and 6 events occurred among those patients

Initial results of the US Intergroup trial of response-adapted chemotherapy or chemotherapyradiation therapy based on PET for non-bulky stage I and II Hodgkin

lymphomaStraus DJ et al Blood 2015

David J Straus et al Blood 2015126578copy2015 by American Society of Hematology

PETCT after 2xABVD identified 91 of PET-2 negative pts who were treated with additional 2xABVD with an estimated 3-yr PFS of 92Defining PET-2 negative pts by DS 1-3 (91) rather than DS 1-2(75) allows maintaining PFS gt90 and reducing the number of patients receiving IFRT

Treating PET-2 positive pts (9) with 2x escalated BEACOPP+IFRT may not result in clinically important improvement in PFS HR-604(1822008) at 2 yrs

Kaplan-Meier plot showing progression-free survival according to IPS group and PET results

after two cycles of ABVD

Andrea Gallamini et al Haematologica 2014991107-1113

copy2014 by Ferrata Storti Foundation

The 3-year PFS rate was 83 for the whole study population 28 for patients with positive interim scans and 95 for patients with negative interim scans (Plt00001)

Advanced Hodgkin Lymphoma

Central PET review bull Standardized protocol drawn up by expert panel

bull Only full-ring dedicated PET-CT scanners

bull Documented daily quality control procedure

bull Tested and secure method to transfer anonymised scan data betweenscanning facilities and the central reporting facility in each country andagreed file naming convention

bull It must be demonstrated that image quality is comparable between centres and standard uptake values can be reliably determined from the PETCT imagesStandardized Deauville 5PS criteria (1-3 negative 4-5 positive)

SCORE 1 NO UPTAKE

SCORE 2 UPTAKE le MEDIASTINUM

SCORE 3 UPTAKE gt MEDIASTINUM BUT le LIVER

SCORE 4 MODERATELY UPTAKE gt LIVER

SCORE 5 MARKEDLY UPTAKE gt LIVER

Johnson P Federico M et al NEJM2016

Flow chart showing the clinical outcome of patients according to IPS group

and PET results after two cycles of ABVD

CR continued complete remission PRO primary refractory to chemotherapyprogression within 6

months after completion of therapy REL late relapse

Andrea Gallamini et al Haematologica 2014991107-1113

copy2014 by Ferrata Storti Foundation

87 69

ProgressionPos 3345 73Neg 12215 5

2 cycles ABVD

Full dose on schedule

PET 2 -vePET 2 +ve

4 cycles ABVD

PET2

PET 1(Staging)

IPS 0-7

Randomize

4 cycles AVD

Follow-up (no RT)

4 cycles BEACOPP-14

or 3 eBEACOPP

PET3

PET 3 -vePET 3 +ve

RT or salvage

regimen

2 cycles BEACOPP-14 or

1 eBEACOPP

No RT

RATHL study Chairman Peter Johnson

Johnson P Federico M et al NEJM2016

Outcomes at 1 year according to PET score after ABVD x 2

PET 2 Score Total Number

Number Assessable

at 1 yr

Progressions Deaths PFS events

1 114 88 7 0 80

2 493 375 25 6 72

3 347 239 20 4 96

4 144 102 14 7 167

5 38 25 10 5 520PET Missing 78 22 0 2 91

Total 1214 851 76 24 105

Johnson P Federico M et al NEJM2016

PET-2 +PFS

PET-2 ndashPFS ()

PET-2- PET-2+

PET-2 DS 1-3 negativeDS 4-5 positive

NStageTrial

69 (4y)87 (4y)81192xABVD ndash 4xABVD+ 4xEB+4xSB

2xABVD ndash 4xAVD+ 4xEB or 6xSB

2xABVD ndash 4xABVD+ 6xEB

780IIB-IVB

GITIL 0607Gallamini A

(in press)

675 (3y)85 (3y)84161119IIB-IVB

NCRI RATHLJohnson P

NEJM 2016

64 (2y)82 (2y)8218336III-IVSWOG S0816Press O

JCO 2016

668582182235TOTALMEAN

Gallamini A Kostakoglu L Ann Oncol 2015

Positive interim PETCT is an adverse prognostic marker and treatment intensification improves prognosis However it is inferior to that observed pts with negative PET-2

68 (5y)82 (5y)88 8112 19IPS 0-2ge 3 ABVDEB

185IIB-IVH2 BJH 2017

73 (2y)93 (2y)87132xEB - 4x ABVDEB+4x EB

810IIB-IVGELLA AHL 2011

A Gallamini C Tarella S Viviani A Rossi C Patti M Picardi A Romano M Cantonetti G La Nasa L Trentin SBolis D Rapezzi V Zoli D Gottardi P Gavarotti P Corradini M Cimminiello C Schiavotto G Parvis RZanotti G Gini A JM Ferreri P Viero A Biggi F Fallanca U Ficola G Prosperini F Bergesio S Chauvie CPavoni A M Gianni and A Rambaldi

Early chemotherapy intensification with escalated BEACOPP in advanced-stage Hodgkin Lymphoma patients with a positive interim PET-CT after 2 ABVD cycles long-term results of the GITILFIL HD 0607 trial

Pts enrolledregistered 783785

Pt enrollment 62008- 62014Median fu for pts completing treatment 1303 (2-2857) days

0

02

04

06

08

1

0 2 4 6 8

DS 4

DS 5

0

02

04

06

08

1

0 2 4 6 8

DS 4

DS 5

DS 4 101 (5) 82 (2) 29 (1) 3 (0) 0

DS 5 49 (5) 34 (2) 8 (1) 1 (0) 0

Years from registration

P = 00696

DS 4 101 (15) 75 (2) 26 (0) 3 (0) 0

DS 5 49 (25) 19 (1) 5 (0) 1 (0) 0

Years from registration

P lt 0001

Overall Survival Progression-free Survival

OS and PFS according to Deauville Score

4-Y OS 92 (95CI 84-96)

4-Y OS 83 (95CI 67-92)

4-Y PFS 81 (95CI 71-88)

4-Y PFS 46 (95CI 31-59)

PET-2 positive patient with a DS 4 switching to BEACOPP have a 3-Y PFS similar to the entire cohort of patients (4-Y PFS 81 95 CI 71-88)Patients with a DS 5 which are a small subset of the entire population (63) still represent an unmet therapeutic need awaiting new treatment strategies

Gallamini A et al EHA 2017

0

02

04

06

08

1

0 2 4 6 8

No RX

RX

No RX 148 (1) 141 (2) 40 (0) 0 (0) 0

RX 148 (0) 144 (0) 40 (0) 0 (0) 0

Years from registration

P = 00790

4-Y OS 100

4-Y OS 98 (95CI 92-99)

0

02

04

06

08

1

0 2 4 6 8

No RX

RX

No RX 148 (9) 133 (1) 35 (0) 14 (0) 0

RX 148 (5) 139 (1) 39 (0) 10 (0) 0

Years from registration

P = 02882

4-Y PFS 96 (95CI 91-98)

4-Y PFS 93 (95CI 87-96)

Overall Survival Progression-free Survival

OS and PFS in PET2- randomized to RXNFT

Consolidation radiotherapy in the region where a large nodal mass was recorded at baseline did not improve treatment result in negative PET-2 and PET-6 patients irrespective of the dimension of the lesion at baseline

Gallamini A et al EHA 2017

BEACOPP esc x 2

Standard Arm Experimental Arm

Neg Pos

Salvagetherapy

Pos Neg

PET4

PET2

Neg Pos Neg Pos Neg

BEACOPP esc x 2

IPS 0-7BEACOPP esc x 2 BEACOPP esc x 2

BEACOPP esc x 2

R

ABVD x 2

Non inferiority of the experimental arm

ABVD x 2

BEACOPP esc x 2

Courtesy of O Casasnovas

Kairos

Gela ahl2011Stage IIIIV and high risk IIB Hodgkin Lymphoma

Salvagetherapy

Primary Endpoint Planned accrual Date start Date end

5-yr PFS 810 Pts May 2011 May 2015

Abs 577 Randomized phase III study comparing an early PET driven treatment de-escalation to non-PET monitored strategy in patients with advanced HL

O Casasnovas ASH 2015

There was no significant difference between the experimental and standard arms Reduction of therapy based on negative interim PET is safe

Randomized phase III study comparing an early PET driven treatment de-escalation to non pet monitored strategy in patients with advanced HL

O Casanovas ASH 2015

Positive interim PET is a risk factor for HL progression even if EB is continued

Casanovas 2016

There is a value to perform PET-4 if PET-2 is positive Consider change of therapy if PET-4 is positive

Casanovas 2016

Is there a role for PET-4 if treatment was escalated based on PET-2

Casanovas 2016

Progression 90 PtsProgression 157 Pts

ABVD x2

PET-2

BEACOPP ESC x4

PET-6ABVD x4

IPS 0-2

NEGATIVE

POSITIVEBEACOPP ESC x2

IPS 3-7

PET-6ISRT to bulky MM

+

Israeli H2 protocol for advanced Hodgkin lymphoma

B symptoms Stage III IV

The study prospectively evaluated the outcome of HL patients whose therapy waschosen based on initial prognostic factors and tailored based on results of PETCTperformed after 2 cycles of chemotherapy

This multicenter study was initiated in 2006 and ended in 72013 enrolling 355 patientswith stages I-IV HL aged 18-60 years

Conclusions

bull Both baseline PETCT and PET-2 are recommendedbull Deauville scores 1-3 should be considered a negative PET resultbull Positive PET-2 (DS 4-5) is a poor prognostic sign when treatment is initiated

with ABVD or even with EB (Gallamini Johnson Casasnovas)bull Escalation of therapy in PET-2 positive patients improves the outcomebull Escalation of therapy to EB in early-stage HL Pts with positive PET-2 (DS 4-5)

improves PFS (Andrersquo M Straus D)bull Pts with high IPS or bulky mediastinal mass have a worse outcome if

therapy is initiated with ABVD and a higher probability of a positive PET-2 (Johnson)

bull If therapy is initiated with escalated BEACOPP de-escalation of therapy to ABVD does not impair the outcome (Casasnovas)

bull The same percentage of PET-2 negativity was found in patients with IPS 0-2 who initiated therapy with ABVD (5-y PFS 079) and in patients with IPS 3-7 whose initial therapy was escalated BEACOPP (5-y PFS 081) (Dann)

bull Salvage therapy should be considered in PET-2 (DS-5) or PET-4 (DS 4-5) positive patients (Johnson Casasnovas )

Thank You e_dannrambamhealthgovil

Should BLEOMYCIN be omitted at age ge 65

RAPID trial toxicity

Bleomycin in older early-stage favorable Hodgkin lymphoma patients analysis of the German Hodgkin Study Group (GHSG) HD10 and HD13 trialsBoris Bumloll et al German Hodgkin Study Group

Two cycles of ABVD or AVD were equally tolerable in older early-stage favorable HL patients Excessive toxicity including severe bleomycin-induced lung toxicity occurred in older HL patients receiving 4 cycles of ABVD Doxorubicin bleomycin vinblastine sulfate and dacarbazine (ABVD) is associated with severe toxicity in older patients particularly from bleomycin-induced lung toxicity (BLT) Therefore using bleomycin has been questioned in older Hodgkin lymphoma (HL) patients especially in early-stage HL We therefore analyzed feasibility toxicity and efficacy of ABVD or AVD in 287 older early-stage favorable HL patients We included patients ge60 years of age in the German Hodgkin Study Group HD10 and HD13 trials randomized to either 2 cycles of ABVD (2XABVD n = 137) or AVD (2xAVD n = 82) each followed by involved-field radiotherapy (IF-RT) with patients randomized to 4xABVD+IFRT (n =68) Patientsrsquo median age was 65 years (range 60-75) with comparable patient and disease characteristics Grade III-IV adverse event rates were similar in patients receiving 2xAVD and 2xABVD (40 and 39 respectively) but considerably higher in patients receiving 4xABVD (65) Similarly BLT was rare in patients receiving 2xABVDAVD but occurred in 769 (10) of patients randomized to 4xABVD with 3 lethal events In conclusion no effects of bleomycin on toxicity rates were detectable in older patients receiving 2 cycles of chemotherapy However we found a high risk of severe toxicity of bleomycin in older HL patients receiving more than 2 cycles of ABVD (Blood 2016 127(18)2189-2192)

Forty-four advanced-stage older HL patients (aged ge60 years) were treated on the randomized study E2496 Toxicities were mostly similar between chemotherapy regimens although 24 of older patients developed bleomycin lung toxicity (BLT) which occurred mainly with ABVD (91) Further the BLT-related mortality rate was 18 The overall treatment-related mortality for older HL patients was 9 versus 03 for patients aged lt60 years (plt0001) Among older patients there were no survival differences between ABVD and SV According to age outcomes were significantly inferior for older versus younger patients (5-year FFS 48 vs 74 respectively p=0002 5-year OS 58 and 90 respectively plt00001)Among the 45 older HL patients enrolled 11 (24) developed BLT of whom 211 (18) died due to acute pulmonary fibrosisrespiratory failure) Furthermore 1011 (91) BLT cases occurred withduring ABVD (BLT incidence 43 with ABVD vs 5 Stanford V p=004) This toxicity appeared to occur later in the chemotherapy course however the two BLT-related deaths occurred during cycle 3 of ABVD We did not identify any factors that predicted the development of BLT or death due to BLT Granulocyte growth factor was given the vast majority of patients thus it was not analyzed as a risk factor

The Efficacy and Tolerability of ABVD and Stanford V in Older Hodgkin Lymphoma Patients A Comprehensive Analysis from the North American Intergroup Trial E2496 Andrew M Evens et al BJH 2013

SF is a 26-y old male ndash a medical student ndash who noticed a lump in his Rt neck base in 72017He had no weight loss night sweat or feverESR -4PETCT at diagnosis Pathologic uptake in the lower neck SCN and ICN 3X6X31 (SUV-109)Rt paratracheal and anterior mediastinum uptake of up to 6 cmStage IIa early favorable HL 3 sites of disease non-bulkyPt started with ABVDx2 persistent coughing was noticed following 15 cyclesBleomycin was excluded and

coughing subsided DLCO and lung function were within normal limitsPET-2 Deauville Score -1 Further therapy was discussed with the Pt and family

Hodgkinrsquos Lymphomas I and II untreated 15-70 yrs

Risk factors age ge 50 mediastinal mass B symptoms and ESRgt30

ESRgt50 if no B symptoms gt3 sitesAndrersquo et al JCO 2017

Q Can RT be omitted in early favorable HLA Probably not unless more chemotherapy is givenQIs RT really necessary in patients with early unfavorable HL and negative interim PET-2(negative PET-2 was defined as DS 12)

A RT may be substituted with 4xABVD

Favorable HD Un-favorable

Andrersquo et al JCO 2017

PET-2 positive pts Effect of therapy escalationwith 2 EB

The H10 shows that when ePET is positive after 2 cycles of ABVD intensification with 2 cycles of EB +INRT should be considered as the best treatment optionIn ePET negative patients the overall outcome is excellent either after combined modality treatment or after chemotherapy onlyIn the favorable group CMT is a better immediate disease control (5yPFS 99 versus 87) however in the unfavorable group benefit of CMT seems to be less clinically relevant and treatment with chemotherapy only is defensible in individual patients(5yPFS 921 versus 896)

The 5-year PFS for ED patients was 091 and 068 for negative and positive interim PETCT respectively (p=009)

Dann EJ BJH 2017

In the RT group 3-year PFS was 94middot6(95 CI 91middot5-97middot7) compared to90middot8 (95 CI 86middot9-94middot8) in the no-further-treatment groupFor PFS the HR was 1middot57 (95 CI 0middot84- 2middot97 p=0middot16) the 3-year absolute risk difference was minus3middot8 (95 CI minus8middot8-1middot3)

HL deaths

4

1

0

3-year PFS and overall survival rates 908 and 990 respectively

However the per-protocol analysis showed a greater 3-year PFS rate than the intention-to-treat analysis in the RT group 971 (95 CI 947 to 996)with a hazard ratio of 236 (95 CI 113-495P = 002) because 26 patients did not receive the assigned RT and 6 events occurred among those patients

Initial results of the US Intergroup trial of response-adapted chemotherapy or chemotherapyradiation therapy based on PET for non-bulky stage I and II Hodgkin

lymphomaStraus DJ et al Blood 2015

David J Straus et al Blood 2015126578copy2015 by American Society of Hematology

PETCT after 2xABVD identified 91 of PET-2 negative pts who were treated with additional 2xABVD with an estimated 3-yr PFS of 92Defining PET-2 negative pts by DS 1-3 (91) rather than DS 1-2(75) allows maintaining PFS gt90 and reducing the number of patients receiving IFRT

Treating PET-2 positive pts (9) with 2x escalated BEACOPP+IFRT may not result in clinically important improvement in PFS HR-604(1822008) at 2 yrs

Kaplan-Meier plot showing progression-free survival according to IPS group and PET results

after two cycles of ABVD

Andrea Gallamini et al Haematologica 2014991107-1113

copy2014 by Ferrata Storti Foundation

The 3-year PFS rate was 83 for the whole study population 28 for patients with positive interim scans and 95 for patients with negative interim scans (Plt00001)

Advanced Hodgkin Lymphoma

Central PET review bull Standardized protocol drawn up by expert panel

bull Only full-ring dedicated PET-CT scanners

bull Documented daily quality control procedure

bull Tested and secure method to transfer anonymised scan data betweenscanning facilities and the central reporting facility in each country andagreed file naming convention

bull It must be demonstrated that image quality is comparable between centres and standard uptake values can be reliably determined from the PETCT imagesStandardized Deauville 5PS criteria (1-3 negative 4-5 positive)

SCORE 1 NO UPTAKE

SCORE 2 UPTAKE le MEDIASTINUM

SCORE 3 UPTAKE gt MEDIASTINUM BUT le LIVER

SCORE 4 MODERATELY UPTAKE gt LIVER

SCORE 5 MARKEDLY UPTAKE gt LIVER

Johnson P Federico M et al NEJM2016

Flow chart showing the clinical outcome of patients according to IPS group

and PET results after two cycles of ABVD

CR continued complete remission PRO primary refractory to chemotherapyprogression within 6

months after completion of therapy REL late relapse

Andrea Gallamini et al Haematologica 2014991107-1113

copy2014 by Ferrata Storti Foundation

87 69

ProgressionPos 3345 73Neg 12215 5

2 cycles ABVD

Full dose on schedule

PET 2 -vePET 2 +ve

4 cycles ABVD

PET2

PET 1(Staging)

IPS 0-7

Randomize

4 cycles AVD

Follow-up (no RT)

4 cycles BEACOPP-14

or 3 eBEACOPP

PET3

PET 3 -vePET 3 +ve

RT or salvage

regimen

2 cycles BEACOPP-14 or

1 eBEACOPP

No RT

RATHL study Chairman Peter Johnson

Johnson P Federico M et al NEJM2016

Outcomes at 1 year according to PET score after ABVD x 2

PET 2 Score Total Number

Number Assessable

at 1 yr

Progressions Deaths PFS events

1 114 88 7 0 80

2 493 375 25 6 72

3 347 239 20 4 96

4 144 102 14 7 167

5 38 25 10 5 520PET Missing 78 22 0 2 91

Total 1214 851 76 24 105

Johnson P Federico M et al NEJM2016

PET-2 +PFS

PET-2 ndashPFS ()

PET-2- PET-2+

PET-2 DS 1-3 negativeDS 4-5 positive

NStageTrial

69 (4y)87 (4y)81192xABVD ndash 4xABVD+ 4xEB+4xSB

2xABVD ndash 4xAVD+ 4xEB or 6xSB

2xABVD ndash 4xABVD+ 6xEB

780IIB-IVB

GITIL 0607Gallamini A

(in press)

675 (3y)85 (3y)84161119IIB-IVB

NCRI RATHLJohnson P

NEJM 2016

64 (2y)82 (2y)8218336III-IVSWOG S0816Press O

JCO 2016

668582182235TOTALMEAN

Gallamini A Kostakoglu L Ann Oncol 2015

Positive interim PETCT is an adverse prognostic marker and treatment intensification improves prognosis However it is inferior to that observed pts with negative PET-2

68 (5y)82 (5y)88 8112 19IPS 0-2ge 3 ABVDEB

185IIB-IVH2 BJH 2017

73 (2y)93 (2y)87132xEB - 4x ABVDEB+4x EB

810IIB-IVGELLA AHL 2011

A Gallamini C Tarella S Viviani A Rossi C Patti M Picardi A Romano M Cantonetti G La Nasa L Trentin SBolis D Rapezzi V Zoli D Gottardi P Gavarotti P Corradini M Cimminiello C Schiavotto G Parvis RZanotti G Gini A JM Ferreri P Viero A Biggi F Fallanca U Ficola G Prosperini F Bergesio S Chauvie CPavoni A M Gianni and A Rambaldi

Early chemotherapy intensification with escalated BEACOPP in advanced-stage Hodgkin Lymphoma patients with a positive interim PET-CT after 2 ABVD cycles long-term results of the GITILFIL HD 0607 trial

Pts enrolledregistered 783785

Pt enrollment 62008- 62014Median fu for pts completing treatment 1303 (2-2857) days

0

02

04

06

08

1

0 2 4 6 8

DS 4

DS 5

0

02

04

06

08

1

0 2 4 6 8

DS 4

DS 5

DS 4 101 (5) 82 (2) 29 (1) 3 (0) 0

DS 5 49 (5) 34 (2) 8 (1) 1 (0) 0

Years from registration

P = 00696

DS 4 101 (15) 75 (2) 26 (0) 3 (0) 0

DS 5 49 (25) 19 (1) 5 (0) 1 (0) 0

Years from registration

P lt 0001

Overall Survival Progression-free Survival

OS and PFS according to Deauville Score

4-Y OS 92 (95CI 84-96)

4-Y OS 83 (95CI 67-92)

4-Y PFS 81 (95CI 71-88)

4-Y PFS 46 (95CI 31-59)

PET-2 positive patient with a DS 4 switching to BEACOPP have a 3-Y PFS similar to the entire cohort of patients (4-Y PFS 81 95 CI 71-88)Patients with a DS 5 which are a small subset of the entire population (63) still represent an unmet therapeutic need awaiting new treatment strategies

Gallamini A et al EHA 2017

0

02

04

06

08

1

0 2 4 6 8

No RX

RX

No RX 148 (1) 141 (2) 40 (0) 0 (0) 0

RX 148 (0) 144 (0) 40 (0) 0 (0) 0

Years from registration

P = 00790

4-Y OS 100

4-Y OS 98 (95CI 92-99)

0

02

04

06

08

1

0 2 4 6 8

No RX

RX

No RX 148 (9) 133 (1) 35 (0) 14 (0) 0

RX 148 (5) 139 (1) 39 (0) 10 (0) 0

Years from registration

P = 02882

4-Y PFS 96 (95CI 91-98)

4-Y PFS 93 (95CI 87-96)

Overall Survival Progression-free Survival

OS and PFS in PET2- randomized to RXNFT

Consolidation radiotherapy in the region where a large nodal mass was recorded at baseline did not improve treatment result in negative PET-2 and PET-6 patients irrespective of the dimension of the lesion at baseline

Gallamini A et al EHA 2017

BEACOPP esc x 2

Standard Arm Experimental Arm

Neg Pos

Salvagetherapy

Pos Neg

PET4

PET2

Neg Pos Neg Pos Neg

BEACOPP esc x 2

IPS 0-7BEACOPP esc x 2 BEACOPP esc x 2

BEACOPP esc x 2

R

ABVD x 2

Non inferiority of the experimental arm

ABVD x 2

BEACOPP esc x 2

Courtesy of O Casasnovas

Kairos

Gela ahl2011Stage IIIIV and high risk IIB Hodgkin Lymphoma

Salvagetherapy

Primary Endpoint Planned accrual Date start Date end

5-yr PFS 810 Pts May 2011 May 2015

Abs 577 Randomized phase III study comparing an early PET driven treatment de-escalation to non-PET monitored strategy in patients with advanced HL

O Casasnovas ASH 2015

There was no significant difference between the experimental and standard arms Reduction of therapy based on negative interim PET is safe

Randomized phase III study comparing an early PET driven treatment de-escalation to non pet monitored strategy in patients with advanced HL

O Casanovas ASH 2015

Positive interim PET is a risk factor for HL progression even if EB is continued

Casanovas 2016

There is a value to perform PET-4 if PET-2 is positive Consider change of therapy if PET-4 is positive

Casanovas 2016

Is there a role for PET-4 if treatment was escalated based on PET-2

Casanovas 2016

Progression 90 PtsProgression 157 Pts

ABVD x2

PET-2

BEACOPP ESC x4

PET-6ABVD x4

IPS 0-2

NEGATIVE

POSITIVEBEACOPP ESC x2

IPS 3-7

PET-6ISRT to bulky MM

+

Israeli H2 protocol for advanced Hodgkin lymphoma

B symptoms Stage III IV

The study prospectively evaluated the outcome of HL patients whose therapy waschosen based on initial prognostic factors and tailored based on results of PETCTperformed after 2 cycles of chemotherapy

This multicenter study was initiated in 2006 and ended in 72013 enrolling 355 patientswith stages I-IV HL aged 18-60 years

Conclusions

bull Both baseline PETCT and PET-2 are recommendedbull Deauville scores 1-3 should be considered a negative PET resultbull Positive PET-2 (DS 4-5) is a poor prognostic sign when treatment is initiated

with ABVD or even with EB (Gallamini Johnson Casasnovas)bull Escalation of therapy in PET-2 positive patients improves the outcomebull Escalation of therapy to EB in early-stage HL Pts with positive PET-2 (DS 4-5)

improves PFS (Andrersquo M Straus D)bull Pts with high IPS or bulky mediastinal mass have a worse outcome if

therapy is initiated with ABVD and a higher probability of a positive PET-2 (Johnson)

bull If therapy is initiated with escalated BEACOPP de-escalation of therapy to ABVD does not impair the outcome (Casasnovas)

bull The same percentage of PET-2 negativity was found in patients with IPS 0-2 who initiated therapy with ABVD (5-y PFS 079) and in patients with IPS 3-7 whose initial therapy was escalated BEACOPP (5-y PFS 081) (Dann)

bull Salvage therapy should be considered in PET-2 (DS-5) or PET-4 (DS 4-5) positive patients (Johnson Casasnovas )

Thank You e_dannrambamhealthgovil

Should BLEOMYCIN be omitted at age ge 65

RAPID trial toxicity

Bleomycin in older early-stage favorable Hodgkin lymphoma patients analysis of the German Hodgkin Study Group (GHSG) HD10 and HD13 trialsBoris Bumloll et al German Hodgkin Study Group

Two cycles of ABVD or AVD were equally tolerable in older early-stage favorable HL patients Excessive toxicity including severe bleomycin-induced lung toxicity occurred in older HL patients receiving 4 cycles of ABVD Doxorubicin bleomycin vinblastine sulfate and dacarbazine (ABVD) is associated with severe toxicity in older patients particularly from bleomycin-induced lung toxicity (BLT) Therefore using bleomycin has been questioned in older Hodgkin lymphoma (HL) patients especially in early-stage HL We therefore analyzed feasibility toxicity and efficacy of ABVD or AVD in 287 older early-stage favorable HL patients We included patients ge60 years of age in the German Hodgkin Study Group HD10 and HD13 trials randomized to either 2 cycles of ABVD (2XABVD n = 137) or AVD (2xAVD n = 82) each followed by involved-field radiotherapy (IF-RT) with patients randomized to 4xABVD+IFRT (n =68) Patientsrsquo median age was 65 years (range 60-75) with comparable patient and disease characteristics Grade III-IV adverse event rates were similar in patients receiving 2xAVD and 2xABVD (40 and 39 respectively) but considerably higher in patients receiving 4xABVD (65) Similarly BLT was rare in patients receiving 2xABVDAVD but occurred in 769 (10) of patients randomized to 4xABVD with 3 lethal events In conclusion no effects of bleomycin on toxicity rates were detectable in older patients receiving 2 cycles of chemotherapy However we found a high risk of severe toxicity of bleomycin in older HL patients receiving more than 2 cycles of ABVD (Blood 2016 127(18)2189-2192)

Forty-four advanced-stage older HL patients (aged ge60 years) were treated on the randomized study E2496 Toxicities were mostly similar between chemotherapy regimens although 24 of older patients developed bleomycin lung toxicity (BLT) which occurred mainly with ABVD (91) Further the BLT-related mortality rate was 18 The overall treatment-related mortality for older HL patients was 9 versus 03 for patients aged lt60 years (plt0001) Among older patients there were no survival differences between ABVD and SV According to age outcomes were significantly inferior for older versus younger patients (5-year FFS 48 vs 74 respectively p=0002 5-year OS 58 and 90 respectively plt00001)Among the 45 older HL patients enrolled 11 (24) developed BLT of whom 211 (18) died due to acute pulmonary fibrosisrespiratory failure) Furthermore 1011 (91) BLT cases occurred withduring ABVD (BLT incidence 43 with ABVD vs 5 Stanford V p=004) This toxicity appeared to occur later in the chemotherapy course however the two BLT-related deaths occurred during cycle 3 of ABVD We did not identify any factors that predicted the development of BLT or death due to BLT Granulocyte growth factor was given the vast majority of patients thus it was not analyzed as a risk factor

The Efficacy and Tolerability of ABVD and Stanford V in Older Hodgkin Lymphoma Patients A Comprehensive Analysis from the North American Intergroup Trial E2496 Andrew M Evens et al BJH 2013

Hodgkinrsquos Lymphomas I and II untreated 15-70 yrs

Risk factors age ge 50 mediastinal mass B symptoms and ESRgt30

ESRgt50 if no B symptoms gt3 sitesAndrersquo et al JCO 2017

Q Can RT be omitted in early favorable HLA Probably not unless more chemotherapy is givenQIs RT really necessary in patients with early unfavorable HL and negative interim PET-2(negative PET-2 was defined as DS 12)

A RT may be substituted with 4xABVD

Favorable HD Un-favorable

Andrersquo et al JCO 2017

PET-2 positive pts Effect of therapy escalationwith 2 EB

The H10 shows that when ePET is positive after 2 cycles of ABVD intensification with 2 cycles of EB +INRT should be considered as the best treatment optionIn ePET negative patients the overall outcome is excellent either after combined modality treatment or after chemotherapy onlyIn the favorable group CMT is a better immediate disease control (5yPFS 99 versus 87) however in the unfavorable group benefit of CMT seems to be less clinically relevant and treatment with chemotherapy only is defensible in individual patients(5yPFS 921 versus 896)

The 5-year PFS for ED patients was 091 and 068 for negative and positive interim PETCT respectively (p=009)

Dann EJ BJH 2017

In the RT group 3-year PFS was 94middot6(95 CI 91middot5-97middot7) compared to90middot8 (95 CI 86middot9-94middot8) in the no-further-treatment groupFor PFS the HR was 1middot57 (95 CI 0middot84- 2middot97 p=0middot16) the 3-year absolute risk difference was minus3middot8 (95 CI minus8middot8-1middot3)

HL deaths

4

1

0

3-year PFS and overall survival rates 908 and 990 respectively

However the per-protocol analysis showed a greater 3-year PFS rate than the intention-to-treat analysis in the RT group 971 (95 CI 947 to 996)with a hazard ratio of 236 (95 CI 113-495P = 002) because 26 patients did not receive the assigned RT and 6 events occurred among those patients

Initial results of the US Intergroup trial of response-adapted chemotherapy or chemotherapyradiation therapy based on PET for non-bulky stage I and II Hodgkin

lymphomaStraus DJ et al Blood 2015

David J Straus et al Blood 2015126578copy2015 by American Society of Hematology

PETCT after 2xABVD identified 91 of PET-2 negative pts who were treated with additional 2xABVD with an estimated 3-yr PFS of 92Defining PET-2 negative pts by DS 1-3 (91) rather than DS 1-2(75) allows maintaining PFS gt90 and reducing the number of patients receiving IFRT

Treating PET-2 positive pts (9) with 2x escalated BEACOPP+IFRT may not result in clinically important improvement in PFS HR-604(1822008) at 2 yrs

Kaplan-Meier plot showing progression-free survival according to IPS group and PET results

after two cycles of ABVD

Andrea Gallamini et al Haematologica 2014991107-1113

copy2014 by Ferrata Storti Foundation

The 3-year PFS rate was 83 for the whole study population 28 for patients with positive interim scans and 95 for patients with negative interim scans (Plt00001)

Advanced Hodgkin Lymphoma

Central PET review bull Standardized protocol drawn up by expert panel

bull Only full-ring dedicated PET-CT scanners

bull Documented daily quality control procedure

bull Tested and secure method to transfer anonymised scan data betweenscanning facilities and the central reporting facility in each country andagreed file naming convention

bull It must be demonstrated that image quality is comparable between centres and standard uptake values can be reliably determined from the PETCT imagesStandardized Deauville 5PS criteria (1-3 negative 4-5 positive)

SCORE 1 NO UPTAKE

SCORE 2 UPTAKE le MEDIASTINUM

SCORE 3 UPTAKE gt MEDIASTINUM BUT le LIVER

SCORE 4 MODERATELY UPTAKE gt LIVER

SCORE 5 MARKEDLY UPTAKE gt LIVER

Johnson P Federico M et al NEJM2016

Flow chart showing the clinical outcome of patients according to IPS group

and PET results after two cycles of ABVD

CR continued complete remission PRO primary refractory to chemotherapyprogression within 6

months after completion of therapy REL late relapse

Andrea Gallamini et al Haematologica 2014991107-1113

copy2014 by Ferrata Storti Foundation

87 69

ProgressionPos 3345 73Neg 12215 5

2 cycles ABVD

Full dose on schedule

PET 2 -vePET 2 +ve

4 cycles ABVD

PET2

PET 1(Staging)

IPS 0-7

Randomize

4 cycles AVD

Follow-up (no RT)

4 cycles BEACOPP-14

or 3 eBEACOPP

PET3

PET 3 -vePET 3 +ve

RT or salvage

regimen

2 cycles BEACOPP-14 or

1 eBEACOPP

No RT

RATHL study Chairman Peter Johnson

Johnson P Federico M et al NEJM2016

Outcomes at 1 year according to PET score after ABVD x 2

PET 2 Score Total Number

Number Assessable

at 1 yr

Progressions Deaths PFS events

1 114 88 7 0 80

2 493 375 25 6 72

3 347 239 20 4 96

4 144 102 14 7 167

5 38 25 10 5 520PET Missing 78 22 0 2 91

Total 1214 851 76 24 105

Johnson P Federico M et al NEJM2016

PET-2 +PFS

PET-2 ndashPFS ()

PET-2- PET-2+

PET-2 DS 1-3 negativeDS 4-5 positive

NStageTrial

69 (4y)87 (4y)81192xABVD ndash 4xABVD+ 4xEB+4xSB

2xABVD ndash 4xAVD+ 4xEB or 6xSB

2xABVD ndash 4xABVD+ 6xEB

780IIB-IVB

GITIL 0607Gallamini A

(in press)

675 (3y)85 (3y)84161119IIB-IVB

NCRI RATHLJohnson P

NEJM 2016

64 (2y)82 (2y)8218336III-IVSWOG S0816Press O

JCO 2016

668582182235TOTALMEAN

Gallamini A Kostakoglu L Ann Oncol 2015

Positive interim PETCT is an adverse prognostic marker and treatment intensification improves prognosis However it is inferior to that observed pts with negative PET-2

68 (5y)82 (5y)88 8112 19IPS 0-2ge 3 ABVDEB

185IIB-IVH2 BJH 2017

73 (2y)93 (2y)87132xEB - 4x ABVDEB+4x EB

810IIB-IVGELLA AHL 2011

A Gallamini C Tarella S Viviani A Rossi C Patti M Picardi A Romano M Cantonetti G La Nasa L Trentin SBolis D Rapezzi V Zoli D Gottardi P Gavarotti P Corradini M Cimminiello C Schiavotto G Parvis RZanotti G Gini A JM Ferreri P Viero A Biggi F Fallanca U Ficola G Prosperini F Bergesio S Chauvie CPavoni A M Gianni and A Rambaldi

Early chemotherapy intensification with escalated BEACOPP in advanced-stage Hodgkin Lymphoma patients with a positive interim PET-CT after 2 ABVD cycles long-term results of the GITILFIL HD 0607 trial

Pts enrolledregistered 783785

Pt enrollment 62008- 62014Median fu for pts completing treatment 1303 (2-2857) days

0

02

04

06

08

1

0 2 4 6 8

DS 4

DS 5

0

02

04

06

08

1

0 2 4 6 8

DS 4

DS 5

DS 4 101 (5) 82 (2) 29 (1) 3 (0) 0

DS 5 49 (5) 34 (2) 8 (1) 1 (0) 0

Years from registration

P = 00696

DS 4 101 (15) 75 (2) 26 (0) 3 (0) 0

DS 5 49 (25) 19 (1) 5 (0) 1 (0) 0

Years from registration

P lt 0001

Overall Survival Progression-free Survival

OS and PFS according to Deauville Score

4-Y OS 92 (95CI 84-96)

4-Y OS 83 (95CI 67-92)

4-Y PFS 81 (95CI 71-88)

4-Y PFS 46 (95CI 31-59)

PET-2 positive patient with a DS 4 switching to BEACOPP have a 3-Y PFS similar to the entire cohort of patients (4-Y PFS 81 95 CI 71-88)Patients with a DS 5 which are a small subset of the entire population (63) still represent an unmet therapeutic need awaiting new treatment strategies

Gallamini A et al EHA 2017

0

02

04

06

08

1

0 2 4 6 8

No RX

RX

No RX 148 (1) 141 (2) 40 (0) 0 (0) 0

RX 148 (0) 144 (0) 40 (0) 0 (0) 0

Years from registration

P = 00790

4-Y OS 100

4-Y OS 98 (95CI 92-99)

0

02

04

06

08

1

0 2 4 6 8

No RX

RX

No RX 148 (9) 133 (1) 35 (0) 14 (0) 0

RX 148 (5) 139 (1) 39 (0) 10 (0) 0

Years from registration

P = 02882

4-Y PFS 96 (95CI 91-98)

4-Y PFS 93 (95CI 87-96)

Overall Survival Progression-free Survival

OS and PFS in PET2- randomized to RXNFT

Consolidation radiotherapy in the region where a large nodal mass was recorded at baseline did not improve treatment result in negative PET-2 and PET-6 patients irrespective of the dimension of the lesion at baseline

Gallamini A et al EHA 2017

BEACOPP esc x 2

Standard Arm Experimental Arm

Neg Pos

Salvagetherapy

Pos Neg

PET4

PET2

Neg Pos Neg Pos Neg

BEACOPP esc x 2

IPS 0-7BEACOPP esc x 2 BEACOPP esc x 2

BEACOPP esc x 2

R

ABVD x 2

Non inferiority of the experimental arm

ABVD x 2

BEACOPP esc x 2

Courtesy of O Casasnovas

Kairos

Gela ahl2011Stage IIIIV and high risk IIB Hodgkin Lymphoma

Salvagetherapy

Primary Endpoint Planned accrual Date start Date end

5-yr PFS 810 Pts May 2011 May 2015

Abs 577 Randomized phase III study comparing an early PET driven treatment de-escalation to non-PET monitored strategy in patients with advanced HL

O Casasnovas ASH 2015

There was no significant difference between the experimental and standard arms Reduction of therapy based on negative interim PET is safe

Randomized phase III study comparing an early PET driven treatment de-escalation to non pet monitored strategy in patients with advanced HL

O Casanovas ASH 2015

Positive interim PET is a risk factor for HL progression even if EB is continued

Casanovas 2016

There is a value to perform PET-4 if PET-2 is positive Consider change of therapy if PET-4 is positive

Casanovas 2016

Is there a role for PET-4 if treatment was escalated based on PET-2

Casanovas 2016

Progression 90 PtsProgression 157 Pts

ABVD x2

PET-2

BEACOPP ESC x4

PET-6ABVD x4

IPS 0-2

NEGATIVE

POSITIVEBEACOPP ESC x2

IPS 3-7

PET-6ISRT to bulky MM

+

Israeli H2 protocol for advanced Hodgkin lymphoma

B symptoms Stage III IV

The study prospectively evaluated the outcome of HL patients whose therapy waschosen based on initial prognostic factors and tailored based on results of PETCTperformed after 2 cycles of chemotherapy

This multicenter study was initiated in 2006 and ended in 72013 enrolling 355 patientswith stages I-IV HL aged 18-60 years

Conclusions

bull Both baseline PETCT and PET-2 are recommendedbull Deauville scores 1-3 should be considered a negative PET resultbull Positive PET-2 (DS 4-5) is a poor prognostic sign when treatment is initiated

with ABVD or even with EB (Gallamini Johnson Casasnovas)bull Escalation of therapy in PET-2 positive patients improves the outcomebull Escalation of therapy to EB in early-stage HL Pts with positive PET-2 (DS 4-5)

improves PFS (Andrersquo M Straus D)bull Pts with high IPS or bulky mediastinal mass have a worse outcome if

therapy is initiated with ABVD and a higher probability of a positive PET-2 (Johnson)

bull If therapy is initiated with escalated BEACOPP de-escalation of therapy to ABVD does not impair the outcome (Casasnovas)

bull The same percentage of PET-2 negativity was found in patients with IPS 0-2 who initiated therapy with ABVD (5-y PFS 079) and in patients with IPS 3-7 whose initial therapy was escalated BEACOPP (5-y PFS 081) (Dann)

bull Salvage therapy should be considered in PET-2 (DS-5) or PET-4 (DS 4-5) positive patients (Johnson Casasnovas )

Thank You e_dannrambamhealthgovil

Should BLEOMYCIN be omitted at age ge 65

RAPID trial toxicity

Bleomycin in older early-stage favorable Hodgkin lymphoma patients analysis of the German Hodgkin Study Group (GHSG) HD10 and HD13 trialsBoris Bumloll et al German Hodgkin Study Group

Two cycles of ABVD or AVD were equally tolerable in older early-stage favorable HL patients Excessive toxicity including severe bleomycin-induced lung toxicity occurred in older HL patients receiving 4 cycles of ABVD Doxorubicin bleomycin vinblastine sulfate and dacarbazine (ABVD) is associated with severe toxicity in older patients particularly from bleomycin-induced lung toxicity (BLT) Therefore using bleomycin has been questioned in older Hodgkin lymphoma (HL) patients especially in early-stage HL We therefore analyzed feasibility toxicity and efficacy of ABVD or AVD in 287 older early-stage favorable HL patients We included patients ge60 years of age in the German Hodgkin Study Group HD10 and HD13 trials randomized to either 2 cycles of ABVD (2XABVD n = 137) or AVD (2xAVD n = 82) each followed by involved-field radiotherapy (IF-RT) with patients randomized to 4xABVD+IFRT (n =68) Patientsrsquo median age was 65 years (range 60-75) with comparable patient and disease characteristics Grade III-IV adverse event rates were similar in patients receiving 2xAVD and 2xABVD (40 and 39 respectively) but considerably higher in patients receiving 4xABVD (65) Similarly BLT was rare in patients receiving 2xABVDAVD but occurred in 769 (10) of patients randomized to 4xABVD with 3 lethal events In conclusion no effects of bleomycin on toxicity rates were detectable in older patients receiving 2 cycles of chemotherapy However we found a high risk of severe toxicity of bleomycin in older HL patients receiving more than 2 cycles of ABVD (Blood 2016 127(18)2189-2192)

Forty-four advanced-stage older HL patients (aged ge60 years) were treated on the randomized study E2496 Toxicities were mostly similar between chemotherapy regimens although 24 of older patients developed bleomycin lung toxicity (BLT) which occurred mainly with ABVD (91) Further the BLT-related mortality rate was 18 The overall treatment-related mortality for older HL patients was 9 versus 03 for patients aged lt60 years (plt0001) Among older patients there were no survival differences between ABVD and SV According to age outcomes were significantly inferior for older versus younger patients (5-year FFS 48 vs 74 respectively p=0002 5-year OS 58 and 90 respectively plt00001)Among the 45 older HL patients enrolled 11 (24) developed BLT of whom 211 (18) died due to acute pulmonary fibrosisrespiratory failure) Furthermore 1011 (91) BLT cases occurred withduring ABVD (BLT incidence 43 with ABVD vs 5 Stanford V p=004) This toxicity appeared to occur later in the chemotherapy course however the two BLT-related deaths occurred during cycle 3 of ABVD We did not identify any factors that predicted the development of BLT or death due to BLT Granulocyte growth factor was given the vast majority of patients thus it was not analyzed as a risk factor

The Efficacy and Tolerability of ABVD and Stanford V in Older Hodgkin Lymphoma Patients A Comprehensive Analysis from the North American Intergroup Trial E2496 Andrew M Evens et al BJH 2013

Q Can RT be omitted in early favorable HLA Probably not unless more chemotherapy is givenQIs RT really necessary in patients with early unfavorable HL and negative interim PET-2(negative PET-2 was defined as DS 12)

A RT may be substituted with 4xABVD

Favorable HD Un-favorable

Andrersquo et al JCO 2017

PET-2 positive pts Effect of therapy escalationwith 2 EB

The H10 shows that when ePET is positive after 2 cycles of ABVD intensification with 2 cycles of EB +INRT should be considered as the best treatment optionIn ePET negative patients the overall outcome is excellent either after combined modality treatment or after chemotherapy onlyIn the favorable group CMT is a better immediate disease control (5yPFS 99 versus 87) however in the unfavorable group benefit of CMT seems to be less clinically relevant and treatment with chemotherapy only is defensible in individual patients(5yPFS 921 versus 896)

The 5-year PFS for ED patients was 091 and 068 for negative and positive interim PETCT respectively (p=009)

Dann EJ BJH 2017

In the RT group 3-year PFS was 94middot6(95 CI 91middot5-97middot7) compared to90middot8 (95 CI 86middot9-94middot8) in the no-further-treatment groupFor PFS the HR was 1middot57 (95 CI 0middot84- 2middot97 p=0middot16) the 3-year absolute risk difference was minus3middot8 (95 CI minus8middot8-1middot3)

HL deaths

4

1

0

3-year PFS and overall survival rates 908 and 990 respectively

However the per-protocol analysis showed a greater 3-year PFS rate than the intention-to-treat analysis in the RT group 971 (95 CI 947 to 996)with a hazard ratio of 236 (95 CI 113-495P = 002) because 26 patients did not receive the assigned RT and 6 events occurred among those patients

Initial results of the US Intergroup trial of response-adapted chemotherapy or chemotherapyradiation therapy based on PET for non-bulky stage I and II Hodgkin

lymphomaStraus DJ et al Blood 2015

David J Straus et al Blood 2015126578copy2015 by American Society of Hematology

PETCT after 2xABVD identified 91 of PET-2 negative pts who were treated with additional 2xABVD with an estimated 3-yr PFS of 92Defining PET-2 negative pts by DS 1-3 (91) rather than DS 1-2(75) allows maintaining PFS gt90 and reducing the number of patients receiving IFRT

Treating PET-2 positive pts (9) with 2x escalated BEACOPP+IFRT may not result in clinically important improvement in PFS HR-604(1822008) at 2 yrs

Kaplan-Meier plot showing progression-free survival according to IPS group and PET results

after two cycles of ABVD

Andrea Gallamini et al Haematologica 2014991107-1113

copy2014 by Ferrata Storti Foundation

The 3-year PFS rate was 83 for the whole study population 28 for patients with positive interim scans and 95 for patients with negative interim scans (Plt00001)

Advanced Hodgkin Lymphoma

Central PET review bull Standardized protocol drawn up by expert panel

bull Only full-ring dedicated PET-CT scanners

bull Documented daily quality control procedure

bull Tested and secure method to transfer anonymised scan data betweenscanning facilities and the central reporting facility in each country andagreed file naming convention

bull It must be demonstrated that image quality is comparable between centres and standard uptake values can be reliably determined from the PETCT imagesStandardized Deauville 5PS criteria (1-3 negative 4-5 positive)

SCORE 1 NO UPTAKE

SCORE 2 UPTAKE le MEDIASTINUM

SCORE 3 UPTAKE gt MEDIASTINUM BUT le LIVER

SCORE 4 MODERATELY UPTAKE gt LIVER

SCORE 5 MARKEDLY UPTAKE gt LIVER

Johnson P Federico M et al NEJM2016

Flow chart showing the clinical outcome of patients according to IPS group

and PET results after two cycles of ABVD

CR continued complete remission PRO primary refractory to chemotherapyprogression within 6

months after completion of therapy REL late relapse

Andrea Gallamini et al Haematologica 2014991107-1113

copy2014 by Ferrata Storti Foundation

87 69

ProgressionPos 3345 73Neg 12215 5

2 cycles ABVD

Full dose on schedule

PET 2 -vePET 2 +ve

4 cycles ABVD

PET2

PET 1(Staging)

IPS 0-7

Randomize

4 cycles AVD

Follow-up (no RT)

4 cycles BEACOPP-14

or 3 eBEACOPP

PET3

PET 3 -vePET 3 +ve

RT or salvage

regimen

2 cycles BEACOPP-14 or

1 eBEACOPP

No RT

RATHL study Chairman Peter Johnson

Johnson P Federico M et al NEJM2016

Outcomes at 1 year according to PET score after ABVD x 2

PET 2 Score Total Number

Number Assessable

at 1 yr

Progressions Deaths PFS events

1 114 88 7 0 80

2 493 375 25 6 72

3 347 239 20 4 96

4 144 102 14 7 167

5 38 25 10 5 520PET Missing 78 22 0 2 91

Total 1214 851 76 24 105

Johnson P Federico M et al NEJM2016

PET-2 +PFS

PET-2 ndashPFS ()

PET-2- PET-2+

PET-2 DS 1-3 negativeDS 4-5 positive

NStageTrial

69 (4y)87 (4y)81192xABVD ndash 4xABVD+ 4xEB+4xSB

2xABVD ndash 4xAVD+ 4xEB or 6xSB

2xABVD ndash 4xABVD+ 6xEB

780IIB-IVB

GITIL 0607Gallamini A

(in press)

675 (3y)85 (3y)84161119IIB-IVB

NCRI RATHLJohnson P

NEJM 2016

64 (2y)82 (2y)8218336III-IVSWOG S0816Press O

JCO 2016

668582182235TOTALMEAN

Gallamini A Kostakoglu L Ann Oncol 2015

Positive interim PETCT is an adverse prognostic marker and treatment intensification improves prognosis However it is inferior to that observed pts with negative PET-2

68 (5y)82 (5y)88 8112 19IPS 0-2ge 3 ABVDEB

185IIB-IVH2 BJH 2017

73 (2y)93 (2y)87132xEB - 4x ABVDEB+4x EB

810IIB-IVGELLA AHL 2011

A Gallamini C Tarella S Viviani A Rossi C Patti M Picardi A Romano M Cantonetti G La Nasa L Trentin SBolis D Rapezzi V Zoli D Gottardi P Gavarotti P Corradini M Cimminiello C Schiavotto G Parvis RZanotti G Gini A JM Ferreri P Viero A Biggi F Fallanca U Ficola G Prosperini F Bergesio S Chauvie CPavoni A M Gianni and A Rambaldi

Early chemotherapy intensification with escalated BEACOPP in advanced-stage Hodgkin Lymphoma patients with a positive interim PET-CT after 2 ABVD cycles long-term results of the GITILFIL HD 0607 trial

Pts enrolledregistered 783785

Pt enrollment 62008- 62014Median fu for pts completing treatment 1303 (2-2857) days

0

02

04

06

08

1

0 2 4 6 8

DS 4

DS 5

0

02

04

06

08

1

0 2 4 6 8

DS 4

DS 5

DS 4 101 (5) 82 (2) 29 (1) 3 (0) 0

DS 5 49 (5) 34 (2) 8 (1) 1 (0) 0

Years from registration

P = 00696

DS 4 101 (15) 75 (2) 26 (0) 3 (0) 0

DS 5 49 (25) 19 (1) 5 (0) 1 (0) 0

Years from registration

P lt 0001

Overall Survival Progression-free Survival

OS and PFS according to Deauville Score

4-Y OS 92 (95CI 84-96)

4-Y OS 83 (95CI 67-92)

4-Y PFS 81 (95CI 71-88)

4-Y PFS 46 (95CI 31-59)

PET-2 positive patient with a DS 4 switching to BEACOPP have a 3-Y PFS similar to the entire cohort of patients (4-Y PFS 81 95 CI 71-88)Patients with a DS 5 which are a small subset of the entire population (63) still represent an unmet therapeutic need awaiting new treatment strategies

Gallamini A et al EHA 2017

0

02

04

06

08

1

0 2 4 6 8

No RX

RX

No RX 148 (1) 141 (2) 40 (0) 0 (0) 0

RX 148 (0) 144 (0) 40 (0) 0 (0) 0

Years from registration

P = 00790

4-Y OS 100

4-Y OS 98 (95CI 92-99)

0

02

04

06

08

1

0 2 4 6 8

No RX

RX

No RX 148 (9) 133 (1) 35 (0) 14 (0) 0

RX 148 (5) 139 (1) 39 (0) 10 (0) 0

Years from registration

P = 02882

4-Y PFS 96 (95CI 91-98)

4-Y PFS 93 (95CI 87-96)

Overall Survival Progression-free Survival

OS and PFS in PET2- randomized to RXNFT

Consolidation radiotherapy in the region where a large nodal mass was recorded at baseline did not improve treatment result in negative PET-2 and PET-6 patients irrespective of the dimension of the lesion at baseline

Gallamini A et al EHA 2017

BEACOPP esc x 2

Standard Arm Experimental Arm

Neg Pos

Salvagetherapy

Pos Neg

PET4

PET2

Neg Pos Neg Pos Neg

BEACOPP esc x 2

IPS 0-7BEACOPP esc x 2 BEACOPP esc x 2

BEACOPP esc x 2

R

ABVD x 2

Non inferiority of the experimental arm

ABVD x 2

BEACOPP esc x 2

Courtesy of O Casasnovas

Kairos

Gela ahl2011Stage IIIIV and high risk IIB Hodgkin Lymphoma

Salvagetherapy

Primary Endpoint Planned accrual Date start Date end

5-yr PFS 810 Pts May 2011 May 2015

Abs 577 Randomized phase III study comparing an early PET driven treatment de-escalation to non-PET monitored strategy in patients with advanced HL

O Casasnovas ASH 2015

There was no significant difference between the experimental and standard arms Reduction of therapy based on negative interim PET is safe

Randomized phase III study comparing an early PET driven treatment de-escalation to non pet monitored strategy in patients with advanced HL

O Casanovas ASH 2015

Positive interim PET is a risk factor for HL progression even if EB is continued

Casanovas 2016

There is a value to perform PET-4 if PET-2 is positive Consider change of therapy if PET-4 is positive

Casanovas 2016

Is there a role for PET-4 if treatment was escalated based on PET-2

Casanovas 2016

Progression 90 PtsProgression 157 Pts

ABVD x2

PET-2

BEACOPP ESC x4

PET-6ABVD x4

IPS 0-2

NEGATIVE

POSITIVEBEACOPP ESC x2

IPS 3-7

PET-6ISRT to bulky MM

+

Israeli H2 protocol for advanced Hodgkin lymphoma

B symptoms Stage III IV

The study prospectively evaluated the outcome of HL patients whose therapy waschosen based on initial prognostic factors and tailored based on results of PETCTperformed after 2 cycles of chemotherapy

This multicenter study was initiated in 2006 and ended in 72013 enrolling 355 patientswith stages I-IV HL aged 18-60 years

Conclusions

bull Both baseline PETCT and PET-2 are recommendedbull Deauville scores 1-3 should be considered a negative PET resultbull Positive PET-2 (DS 4-5) is a poor prognostic sign when treatment is initiated

with ABVD or even with EB (Gallamini Johnson Casasnovas)bull Escalation of therapy in PET-2 positive patients improves the outcomebull Escalation of therapy to EB in early-stage HL Pts with positive PET-2 (DS 4-5)

improves PFS (Andrersquo M Straus D)bull Pts with high IPS or bulky mediastinal mass have a worse outcome if

therapy is initiated with ABVD and a higher probability of a positive PET-2 (Johnson)

bull If therapy is initiated with escalated BEACOPP de-escalation of therapy to ABVD does not impair the outcome (Casasnovas)

bull The same percentage of PET-2 negativity was found in patients with IPS 0-2 who initiated therapy with ABVD (5-y PFS 079) and in patients with IPS 3-7 whose initial therapy was escalated BEACOPP (5-y PFS 081) (Dann)

bull Salvage therapy should be considered in PET-2 (DS-5) or PET-4 (DS 4-5) positive patients (Johnson Casasnovas )

Thank You e_dannrambamhealthgovil

Should BLEOMYCIN be omitted at age ge 65

RAPID trial toxicity

Bleomycin in older early-stage favorable Hodgkin lymphoma patients analysis of the German Hodgkin Study Group (GHSG) HD10 and HD13 trialsBoris Bumloll et al German Hodgkin Study Group

Two cycles of ABVD or AVD were equally tolerable in older early-stage favorable HL patients Excessive toxicity including severe bleomycin-induced lung toxicity occurred in older HL patients receiving 4 cycles of ABVD Doxorubicin bleomycin vinblastine sulfate and dacarbazine (ABVD) is associated with severe toxicity in older patients particularly from bleomycin-induced lung toxicity (BLT) Therefore using bleomycin has been questioned in older Hodgkin lymphoma (HL) patients especially in early-stage HL We therefore analyzed feasibility toxicity and efficacy of ABVD or AVD in 287 older early-stage favorable HL patients We included patients ge60 years of age in the German Hodgkin Study Group HD10 and HD13 trials randomized to either 2 cycles of ABVD (2XABVD n = 137) or AVD (2xAVD n = 82) each followed by involved-field radiotherapy (IF-RT) with patients randomized to 4xABVD+IFRT (n =68) Patientsrsquo median age was 65 years (range 60-75) with comparable patient and disease characteristics Grade III-IV adverse event rates were similar in patients receiving 2xAVD and 2xABVD (40 and 39 respectively) but considerably higher in patients receiving 4xABVD (65) Similarly BLT was rare in patients receiving 2xABVDAVD but occurred in 769 (10) of patients randomized to 4xABVD with 3 lethal events In conclusion no effects of bleomycin on toxicity rates were detectable in older patients receiving 2 cycles of chemotherapy However we found a high risk of severe toxicity of bleomycin in older HL patients receiving more than 2 cycles of ABVD (Blood 2016 127(18)2189-2192)

Forty-four advanced-stage older HL patients (aged ge60 years) were treated on the randomized study E2496 Toxicities were mostly similar between chemotherapy regimens although 24 of older patients developed bleomycin lung toxicity (BLT) which occurred mainly with ABVD (91) Further the BLT-related mortality rate was 18 The overall treatment-related mortality for older HL patients was 9 versus 03 for patients aged lt60 years (plt0001) Among older patients there were no survival differences between ABVD and SV According to age outcomes were significantly inferior for older versus younger patients (5-year FFS 48 vs 74 respectively p=0002 5-year OS 58 and 90 respectively plt00001)Among the 45 older HL patients enrolled 11 (24) developed BLT of whom 211 (18) died due to acute pulmonary fibrosisrespiratory failure) Furthermore 1011 (91) BLT cases occurred withduring ABVD (BLT incidence 43 with ABVD vs 5 Stanford V p=004) This toxicity appeared to occur later in the chemotherapy course however the two BLT-related deaths occurred during cycle 3 of ABVD We did not identify any factors that predicted the development of BLT or death due to BLT Granulocyte growth factor was given the vast majority of patients thus it was not analyzed as a risk factor

The Efficacy and Tolerability of ABVD and Stanford V in Older Hodgkin Lymphoma Patients A Comprehensive Analysis from the North American Intergroup Trial E2496 Andrew M Evens et al BJH 2013

Andrersquo et al JCO 2017

PET-2 positive pts Effect of therapy escalationwith 2 EB

The H10 shows that when ePET is positive after 2 cycles of ABVD intensification with 2 cycles of EB +INRT should be considered as the best treatment optionIn ePET negative patients the overall outcome is excellent either after combined modality treatment or after chemotherapy onlyIn the favorable group CMT is a better immediate disease control (5yPFS 99 versus 87) however in the unfavorable group benefit of CMT seems to be less clinically relevant and treatment with chemotherapy only is defensible in individual patients(5yPFS 921 versus 896)

The 5-year PFS for ED patients was 091 and 068 for negative and positive interim PETCT respectively (p=009)

Dann EJ BJH 2017

In the RT group 3-year PFS was 94middot6(95 CI 91middot5-97middot7) compared to90middot8 (95 CI 86middot9-94middot8) in the no-further-treatment groupFor PFS the HR was 1middot57 (95 CI 0middot84- 2middot97 p=0middot16) the 3-year absolute risk difference was minus3middot8 (95 CI minus8middot8-1middot3)

HL deaths

4

1

0

3-year PFS and overall survival rates 908 and 990 respectively

However the per-protocol analysis showed a greater 3-year PFS rate than the intention-to-treat analysis in the RT group 971 (95 CI 947 to 996)with a hazard ratio of 236 (95 CI 113-495P = 002) because 26 patients did not receive the assigned RT and 6 events occurred among those patients

Initial results of the US Intergroup trial of response-adapted chemotherapy or chemotherapyradiation therapy based on PET for non-bulky stage I and II Hodgkin

lymphomaStraus DJ et al Blood 2015

David J Straus et al Blood 2015126578copy2015 by American Society of Hematology

PETCT after 2xABVD identified 91 of PET-2 negative pts who were treated with additional 2xABVD with an estimated 3-yr PFS of 92Defining PET-2 negative pts by DS 1-3 (91) rather than DS 1-2(75) allows maintaining PFS gt90 and reducing the number of patients receiving IFRT

Treating PET-2 positive pts (9) with 2x escalated BEACOPP+IFRT may not result in clinically important improvement in PFS HR-604(1822008) at 2 yrs

Kaplan-Meier plot showing progression-free survival according to IPS group and PET results

after two cycles of ABVD

Andrea Gallamini et al Haematologica 2014991107-1113

copy2014 by Ferrata Storti Foundation

The 3-year PFS rate was 83 for the whole study population 28 for patients with positive interim scans and 95 for patients with negative interim scans (Plt00001)

Advanced Hodgkin Lymphoma

Central PET review bull Standardized protocol drawn up by expert panel

bull Only full-ring dedicated PET-CT scanners

bull Documented daily quality control procedure

bull Tested and secure method to transfer anonymised scan data betweenscanning facilities and the central reporting facility in each country andagreed file naming convention

bull It must be demonstrated that image quality is comparable between centres and standard uptake values can be reliably determined from the PETCT imagesStandardized Deauville 5PS criteria (1-3 negative 4-5 positive)

SCORE 1 NO UPTAKE

SCORE 2 UPTAKE le MEDIASTINUM

SCORE 3 UPTAKE gt MEDIASTINUM BUT le LIVER

SCORE 4 MODERATELY UPTAKE gt LIVER

SCORE 5 MARKEDLY UPTAKE gt LIVER

Johnson P Federico M et al NEJM2016

Flow chart showing the clinical outcome of patients according to IPS group

and PET results after two cycles of ABVD

CR continued complete remission PRO primary refractory to chemotherapyprogression within 6

months after completion of therapy REL late relapse

Andrea Gallamini et al Haematologica 2014991107-1113

copy2014 by Ferrata Storti Foundation

87 69

ProgressionPos 3345 73Neg 12215 5

2 cycles ABVD

Full dose on schedule

PET 2 -vePET 2 +ve

4 cycles ABVD

PET2

PET 1(Staging)

IPS 0-7

Randomize

4 cycles AVD

Follow-up (no RT)

4 cycles BEACOPP-14

or 3 eBEACOPP

PET3

PET 3 -vePET 3 +ve

RT or salvage

regimen

2 cycles BEACOPP-14 or

1 eBEACOPP

No RT

RATHL study Chairman Peter Johnson

Johnson P Federico M et al NEJM2016

Outcomes at 1 year according to PET score after ABVD x 2

PET 2 Score Total Number

Number Assessable

at 1 yr

Progressions Deaths PFS events

1 114 88 7 0 80

2 493 375 25 6 72

3 347 239 20 4 96

4 144 102 14 7 167

5 38 25 10 5 520PET Missing 78 22 0 2 91

Total 1214 851 76 24 105

Johnson P Federico M et al NEJM2016

PET-2 +PFS

PET-2 ndashPFS ()

PET-2- PET-2+

PET-2 DS 1-3 negativeDS 4-5 positive

NStageTrial

69 (4y)87 (4y)81192xABVD ndash 4xABVD+ 4xEB+4xSB

2xABVD ndash 4xAVD+ 4xEB or 6xSB

2xABVD ndash 4xABVD+ 6xEB

780IIB-IVB

GITIL 0607Gallamini A

(in press)

675 (3y)85 (3y)84161119IIB-IVB

NCRI RATHLJohnson P

NEJM 2016

64 (2y)82 (2y)8218336III-IVSWOG S0816Press O

JCO 2016

668582182235TOTALMEAN

Gallamini A Kostakoglu L Ann Oncol 2015

Positive interim PETCT is an adverse prognostic marker and treatment intensification improves prognosis However it is inferior to that observed pts with negative PET-2

68 (5y)82 (5y)88 8112 19IPS 0-2ge 3 ABVDEB

185IIB-IVH2 BJH 2017

73 (2y)93 (2y)87132xEB - 4x ABVDEB+4x EB

810IIB-IVGELLA AHL 2011

A Gallamini C Tarella S Viviani A Rossi C Patti M Picardi A Romano M Cantonetti G La Nasa L Trentin SBolis D Rapezzi V Zoli D Gottardi P Gavarotti P Corradini M Cimminiello C Schiavotto G Parvis RZanotti G Gini A JM Ferreri P Viero A Biggi F Fallanca U Ficola G Prosperini F Bergesio S Chauvie CPavoni A M Gianni and A Rambaldi

Early chemotherapy intensification with escalated BEACOPP in advanced-stage Hodgkin Lymphoma patients with a positive interim PET-CT after 2 ABVD cycles long-term results of the GITILFIL HD 0607 trial

Pts enrolledregistered 783785

Pt enrollment 62008- 62014Median fu for pts completing treatment 1303 (2-2857) days

0

02

04

06

08

1

0 2 4 6 8

DS 4

DS 5

0

02

04

06

08

1

0 2 4 6 8

DS 4

DS 5

DS 4 101 (5) 82 (2) 29 (1) 3 (0) 0

DS 5 49 (5) 34 (2) 8 (1) 1 (0) 0

Years from registration

P = 00696

DS 4 101 (15) 75 (2) 26 (0) 3 (0) 0

DS 5 49 (25) 19 (1) 5 (0) 1 (0) 0

Years from registration

P lt 0001

Overall Survival Progression-free Survival

OS and PFS according to Deauville Score

4-Y OS 92 (95CI 84-96)

4-Y OS 83 (95CI 67-92)

4-Y PFS 81 (95CI 71-88)

4-Y PFS 46 (95CI 31-59)

PET-2 positive patient with a DS 4 switching to BEACOPP have a 3-Y PFS similar to the entire cohort of patients (4-Y PFS 81 95 CI 71-88)Patients with a DS 5 which are a small subset of the entire population (63) still represent an unmet therapeutic need awaiting new treatment strategies

Gallamini A et al EHA 2017

0

02

04

06

08

1

0 2 4 6 8

No RX

RX

No RX 148 (1) 141 (2) 40 (0) 0 (0) 0

RX 148 (0) 144 (0) 40 (0) 0 (0) 0

Years from registration

P = 00790

4-Y OS 100

4-Y OS 98 (95CI 92-99)

0

02

04

06

08

1

0 2 4 6 8

No RX

RX

No RX 148 (9) 133 (1) 35 (0) 14 (0) 0

RX 148 (5) 139 (1) 39 (0) 10 (0) 0

Years from registration

P = 02882

4-Y PFS 96 (95CI 91-98)

4-Y PFS 93 (95CI 87-96)

Overall Survival Progression-free Survival

OS and PFS in PET2- randomized to RXNFT

Consolidation radiotherapy in the region where a large nodal mass was recorded at baseline did not improve treatment result in negative PET-2 and PET-6 patients irrespective of the dimension of the lesion at baseline

Gallamini A et al EHA 2017

BEACOPP esc x 2

Standard Arm Experimental Arm

Neg Pos

Salvagetherapy

Pos Neg

PET4

PET2

Neg Pos Neg Pos Neg

BEACOPP esc x 2

IPS 0-7BEACOPP esc x 2 BEACOPP esc x 2

BEACOPP esc x 2

R

ABVD x 2

Non inferiority of the experimental arm

ABVD x 2

BEACOPP esc x 2

Courtesy of O Casasnovas

Kairos

Gela ahl2011Stage IIIIV and high risk IIB Hodgkin Lymphoma

Salvagetherapy

Primary Endpoint Planned accrual Date start Date end

5-yr PFS 810 Pts May 2011 May 2015

Abs 577 Randomized phase III study comparing an early PET driven treatment de-escalation to non-PET monitored strategy in patients with advanced HL

O Casasnovas ASH 2015

There was no significant difference between the experimental and standard arms Reduction of therapy based on negative interim PET is safe

Randomized phase III study comparing an early PET driven treatment de-escalation to non pet monitored strategy in patients with advanced HL

O Casanovas ASH 2015

Positive interim PET is a risk factor for HL progression even if EB is continued

Casanovas 2016

There is a value to perform PET-4 if PET-2 is positive Consider change of therapy if PET-4 is positive

Casanovas 2016

Is there a role for PET-4 if treatment was escalated based on PET-2

Casanovas 2016

Progression 90 PtsProgression 157 Pts

ABVD x2

PET-2

BEACOPP ESC x4

PET-6ABVD x4

IPS 0-2

NEGATIVE

POSITIVEBEACOPP ESC x2

IPS 3-7

PET-6ISRT to bulky MM

+

Israeli H2 protocol for advanced Hodgkin lymphoma

B symptoms Stage III IV

The study prospectively evaluated the outcome of HL patients whose therapy waschosen based on initial prognostic factors and tailored based on results of PETCTperformed after 2 cycles of chemotherapy

This multicenter study was initiated in 2006 and ended in 72013 enrolling 355 patientswith stages I-IV HL aged 18-60 years

Conclusions

bull Both baseline PETCT and PET-2 are recommendedbull Deauville scores 1-3 should be considered a negative PET resultbull Positive PET-2 (DS 4-5) is a poor prognostic sign when treatment is initiated

with ABVD or even with EB (Gallamini Johnson Casasnovas)bull Escalation of therapy in PET-2 positive patients improves the outcomebull Escalation of therapy to EB in early-stage HL Pts with positive PET-2 (DS 4-5)

improves PFS (Andrersquo M Straus D)bull Pts with high IPS or bulky mediastinal mass have a worse outcome if

therapy is initiated with ABVD and a higher probability of a positive PET-2 (Johnson)

bull If therapy is initiated with escalated BEACOPP de-escalation of therapy to ABVD does not impair the outcome (Casasnovas)

bull The same percentage of PET-2 negativity was found in patients with IPS 0-2 who initiated therapy with ABVD (5-y PFS 079) and in patients with IPS 3-7 whose initial therapy was escalated BEACOPP (5-y PFS 081) (Dann)

bull Salvage therapy should be considered in PET-2 (DS-5) or PET-4 (DS 4-5) positive patients (Johnson Casasnovas )

Thank You e_dannrambamhealthgovil

Should BLEOMYCIN be omitted at age ge 65

RAPID trial toxicity

Bleomycin in older early-stage favorable Hodgkin lymphoma patients analysis of the German Hodgkin Study Group (GHSG) HD10 and HD13 trialsBoris Bumloll et al German Hodgkin Study Group

Two cycles of ABVD or AVD were equally tolerable in older early-stage favorable HL patients Excessive toxicity including severe bleomycin-induced lung toxicity occurred in older HL patients receiving 4 cycles of ABVD Doxorubicin bleomycin vinblastine sulfate and dacarbazine (ABVD) is associated with severe toxicity in older patients particularly from bleomycin-induced lung toxicity (BLT) Therefore using bleomycin has been questioned in older Hodgkin lymphoma (HL) patients especially in early-stage HL We therefore analyzed feasibility toxicity and efficacy of ABVD or AVD in 287 older early-stage favorable HL patients We included patients ge60 years of age in the German Hodgkin Study Group HD10 and HD13 trials randomized to either 2 cycles of ABVD (2XABVD n = 137) or AVD (2xAVD n = 82) each followed by involved-field radiotherapy (IF-RT) with patients randomized to 4xABVD+IFRT (n =68) Patientsrsquo median age was 65 years (range 60-75) with comparable patient and disease characteristics Grade III-IV adverse event rates were similar in patients receiving 2xAVD and 2xABVD (40 and 39 respectively) but considerably higher in patients receiving 4xABVD (65) Similarly BLT was rare in patients receiving 2xABVDAVD but occurred in 769 (10) of patients randomized to 4xABVD with 3 lethal events In conclusion no effects of bleomycin on toxicity rates were detectable in older patients receiving 2 cycles of chemotherapy However we found a high risk of severe toxicity of bleomycin in older HL patients receiving more than 2 cycles of ABVD (Blood 2016 127(18)2189-2192)

Forty-four advanced-stage older HL patients (aged ge60 years) were treated on the randomized study E2496 Toxicities were mostly similar between chemotherapy regimens although 24 of older patients developed bleomycin lung toxicity (BLT) which occurred mainly with ABVD (91) Further the BLT-related mortality rate was 18 The overall treatment-related mortality for older HL patients was 9 versus 03 for patients aged lt60 years (plt0001) Among older patients there were no survival differences between ABVD and SV According to age outcomes were significantly inferior for older versus younger patients (5-year FFS 48 vs 74 respectively p=0002 5-year OS 58 and 90 respectively plt00001)Among the 45 older HL patients enrolled 11 (24) developed BLT of whom 211 (18) died due to acute pulmonary fibrosisrespiratory failure) Furthermore 1011 (91) BLT cases occurred withduring ABVD (BLT incidence 43 with ABVD vs 5 Stanford V p=004) This toxicity appeared to occur later in the chemotherapy course however the two BLT-related deaths occurred during cycle 3 of ABVD We did not identify any factors that predicted the development of BLT or death due to BLT Granulocyte growth factor was given the vast majority of patients thus it was not analyzed as a risk factor

The Efficacy and Tolerability of ABVD and Stanford V in Older Hodgkin Lymphoma Patients A Comprehensive Analysis from the North American Intergroup Trial E2496 Andrew M Evens et al BJH 2013

The 5-year PFS for ED patients was 091 and 068 for negative and positive interim PETCT respectively (p=009)

Dann EJ BJH 2017

In the RT group 3-year PFS was 94middot6(95 CI 91middot5-97middot7) compared to90middot8 (95 CI 86middot9-94middot8) in the no-further-treatment groupFor PFS the HR was 1middot57 (95 CI 0middot84- 2middot97 p=0middot16) the 3-year absolute risk difference was minus3middot8 (95 CI minus8middot8-1middot3)

HL deaths

4

1

0

3-year PFS and overall survival rates 908 and 990 respectively

However the per-protocol analysis showed a greater 3-year PFS rate than the intention-to-treat analysis in the RT group 971 (95 CI 947 to 996)with a hazard ratio of 236 (95 CI 113-495P = 002) because 26 patients did not receive the assigned RT and 6 events occurred among those patients

Initial results of the US Intergroup trial of response-adapted chemotherapy or chemotherapyradiation therapy based on PET for non-bulky stage I and II Hodgkin

lymphomaStraus DJ et al Blood 2015

David J Straus et al Blood 2015126578copy2015 by American Society of Hematology

PETCT after 2xABVD identified 91 of PET-2 negative pts who were treated with additional 2xABVD with an estimated 3-yr PFS of 92Defining PET-2 negative pts by DS 1-3 (91) rather than DS 1-2(75) allows maintaining PFS gt90 and reducing the number of patients receiving IFRT

Treating PET-2 positive pts (9) with 2x escalated BEACOPP+IFRT may not result in clinically important improvement in PFS HR-604(1822008) at 2 yrs

Kaplan-Meier plot showing progression-free survival according to IPS group and PET results

after two cycles of ABVD

Andrea Gallamini et al Haematologica 2014991107-1113

copy2014 by Ferrata Storti Foundation

The 3-year PFS rate was 83 for the whole study population 28 for patients with positive interim scans and 95 for patients with negative interim scans (Plt00001)

Advanced Hodgkin Lymphoma

Central PET review bull Standardized protocol drawn up by expert panel

bull Only full-ring dedicated PET-CT scanners

bull Documented daily quality control procedure

bull Tested and secure method to transfer anonymised scan data betweenscanning facilities and the central reporting facility in each country andagreed file naming convention

bull It must be demonstrated that image quality is comparable between centres and standard uptake values can be reliably determined from the PETCT imagesStandardized Deauville 5PS criteria (1-3 negative 4-5 positive)

SCORE 1 NO UPTAKE

SCORE 2 UPTAKE le MEDIASTINUM

SCORE 3 UPTAKE gt MEDIASTINUM BUT le LIVER

SCORE 4 MODERATELY UPTAKE gt LIVER

SCORE 5 MARKEDLY UPTAKE gt LIVER

Johnson P Federico M et al NEJM2016

Flow chart showing the clinical outcome of patients according to IPS group

and PET results after two cycles of ABVD

CR continued complete remission PRO primary refractory to chemotherapyprogression within 6

months after completion of therapy REL late relapse

Andrea Gallamini et al Haematologica 2014991107-1113

copy2014 by Ferrata Storti Foundation

87 69

ProgressionPos 3345 73Neg 12215 5

2 cycles ABVD

Full dose on schedule

PET 2 -vePET 2 +ve

4 cycles ABVD

PET2

PET 1(Staging)

IPS 0-7

Randomize

4 cycles AVD

Follow-up (no RT)

4 cycles BEACOPP-14

or 3 eBEACOPP

PET3

PET 3 -vePET 3 +ve

RT or salvage

regimen

2 cycles BEACOPP-14 or

1 eBEACOPP

No RT

RATHL study Chairman Peter Johnson

Johnson P Federico M et al NEJM2016

Outcomes at 1 year according to PET score after ABVD x 2

PET 2 Score Total Number

Number Assessable

at 1 yr

Progressions Deaths PFS events

1 114 88 7 0 80

2 493 375 25 6 72

3 347 239 20 4 96

4 144 102 14 7 167

5 38 25 10 5 520PET Missing 78 22 0 2 91

Total 1214 851 76 24 105

Johnson P Federico M et al NEJM2016

PET-2 +PFS

PET-2 ndashPFS ()

PET-2- PET-2+

PET-2 DS 1-3 negativeDS 4-5 positive

NStageTrial

69 (4y)87 (4y)81192xABVD ndash 4xABVD+ 4xEB+4xSB

2xABVD ndash 4xAVD+ 4xEB or 6xSB

2xABVD ndash 4xABVD+ 6xEB

780IIB-IVB

GITIL 0607Gallamini A

(in press)

675 (3y)85 (3y)84161119IIB-IVB

NCRI RATHLJohnson P

NEJM 2016

64 (2y)82 (2y)8218336III-IVSWOG S0816Press O

JCO 2016

668582182235TOTALMEAN

Gallamini A Kostakoglu L Ann Oncol 2015

Positive interim PETCT is an adverse prognostic marker and treatment intensification improves prognosis However it is inferior to that observed pts with negative PET-2

68 (5y)82 (5y)88 8112 19IPS 0-2ge 3 ABVDEB

185IIB-IVH2 BJH 2017

73 (2y)93 (2y)87132xEB - 4x ABVDEB+4x EB

810IIB-IVGELLA AHL 2011

A Gallamini C Tarella S Viviani A Rossi C Patti M Picardi A Romano M Cantonetti G La Nasa L Trentin SBolis D Rapezzi V Zoli D Gottardi P Gavarotti P Corradini M Cimminiello C Schiavotto G Parvis RZanotti G Gini A JM Ferreri P Viero A Biggi F Fallanca U Ficola G Prosperini F Bergesio S Chauvie CPavoni A M Gianni and A Rambaldi

Early chemotherapy intensification with escalated BEACOPP in advanced-stage Hodgkin Lymphoma patients with a positive interim PET-CT after 2 ABVD cycles long-term results of the GITILFIL HD 0607 trial

Pts enrolledregistered 783785

Pt enrollment 62008- 62014Median fu for pts completing treatment 1303 (2-2857) days

0

02

04

06

08

1

0 2 4 6 8

DS 4

DS 5

0

02

04

06

08

1

0 2 4 6 8

DS 4

DS 5

DS 4 101 (5) 82 (2) 29 (1) 3 (0) 0

DS 5 49 (5) 34 (2) 8 (1) 1 (0) 0

Years from registration

P = 00696

DS 4 101 (15) 75 (2) 26 (0) 3 (0) 0

DS 5 49 (25) 19 (1) 5 (0) 1 (0) 0

Years from registration

P lt 0001

Overall Survival Progression-free Survival

OS and PFS according to Deauville Score

4-Y OS 92 (95CI 84-96)

4-Y OS 83 (95CI 67-92)

4-Y PFS 81 (95CI 71-88)

4-Y PFS 46 (95CI 31-59)

PET-2 positive patient with a DS 4 switching to BEACOPP have a 3-Y PFS similar to the entire cohort of patients (4-Y PFS 81 95 CI 71-88)Patients with a DS 5 which are a small subset of the entire population (63) still represent an unmet therapeutic need awaiting new treatment strategies

Gallamini A et al EHA 2017

0

02

04

06

08

1

0 2 4 6 8

No RX

RX

No RX 148 (1) 141 (2) 40 (0) 0 (0) 0

RX 148 (0) 144 (0) 40 (0) 0 (0) 0

Years from registration

P = 00790

4-Y OS 100

4-Y OS 98 (95CI 92-99)

0

02

04

06

08

1

0 2 4 6 8

No RX

RX

No RX 148 (9) 133 (1) 35 (0) 14 (0) 0

RX 148 (5) 139 (1) 39 (0) 10 (0) 0

Years from registration

P = 02882

4-Y PFS 96 (95CI 91-98)

4-Y PFS 93 (95CI 87-96)

Overall Survival Progression-free Survival

OS and PFS in PET2- randomized to RXNFT

Consolidation radiotherapy in the region where a large nodal mass was recorded at baseline did not improve treatment result in negative PET-2 and PET-6 patients irrespective of the dimension of the lesion at baseline

Gallamini A et al EHA 2017

BEACOPP esc x 2

Standard Arm Experimental Arm

Neg Pos

Salvagetherapy

Pos Neg

PET4

PET2

Neg Pos Neg Pos Neg

BEACOPP esc x 2

IPS 0-7BEACOPP esc x 2 BEACOPP esc x 2

BEACOPP esc x 2

R

ABVD x 2

Non inferiority of the experimental arm

ABVD x 2

BEACOPP esc x 2

Courtesy of O Casasnovas

Kairos

Gela ahl2011Stage IIIIV and high risk IIB Hodgkin Lymphoma

Salvagetherapy

Primary Endpoint Planned accrual Date start Date end

5-yr PFS 810 Pts May 2011 May 2015

Abs 577 Randomized phase III study comparing an early PET driven treatment de-escalation to non-PET monitored strategy in patients with advanced HL

O Casasnovas ASH 2015

There was no significant difference between the experimental and standard arms Reduction of therapy based on negative interim PET is safe

Randomized phase III study comparing an early PET driven treatment de-escalation to non pet monitored strategy in patients with advanced HL

O Casanovas ASH 2015

Positive interim PET is a risk factor for HL progression even if EB is continued

Casanovas 2016

There is a value to perform PET-4 if PET-2 is positive Consider change of therapy if PET-4 is positive

Casanovas 2016

Is there a role for PET-4 if treatment was escalated based on PET-2

Casanovas 2016

Progression 90 PtsProgression 157 Pts

ABVD x2

PET-2

BEACOPP ESC x4

PET-6ABVD x4

IPS 0-2

NEGATIVE

POSITIVEBEACOPP ESC x2

IPS 3-7

PET-6ISRT to bulky MM

+

Israeli H2 protocol for advanced Hodgkin lymphoma

B symptoms Stage III IV

The study prospectively evaluated the outcome of HL patients whose therapy waschosen based on initial prognostic factors and tailored based on results of PETCTperformed after 2 cycles of chemotherapy

This multicenter study was initiated in 2006 and ended in 72013 enrolling 355 patientswith stages I-IV HL aged 18-60 years

Conclusions

bull Both baseline PETCT and PET-2 are recommendedbull Deauville scores 1-3 should be considered a negative PET resultbull Positive PET-2 (DS 4-5) is a poor prognostic sign when treatment is initiated

with ABVD or even with EB (Gallamini Johnson Casasnovas)bull Escalation of therapy in PET-2 positive patients improves the outcomebull Escalation of therapy to EB in early-stage HL Pts with positive PET-2 (DS 4-5)

improves PFS (Andrersquo M Straus D)bull Pts with high IPS or bulky mediastinal mass have a worse outcome if

therapy is initiated with ABVD and a higher probability of a positive PET-2 (Johnson)

bull If therapy is initiated with escalated BEACOPP de-escalation of therapy to ABVD does not impair the outcome (Casasnovas)

bull The same percentage of PET-2 negativity was found in patients with IPS 0-2 who initiated therapy with ABVD (5-y PFS 079) and in patients with IPS 3-7 whose initial therapy was escalated BEACOPP (5-y PFS 081) (Dann)

bull Salvage therapy should be considered in PET-2 (DS-5) or PET-4 (DS 4-5) positive patients (Johnson Casasnovas )

Thank You e_dannrambamhealthgovil

Should BLEOMYCIN be omitted at age ge 65

RAPID trial toxicity

Bleomycin in older early-stage favorable Hodgkin lymphoma patients analysis of the German Hodgkin Study Group (GHSG) HD10 and HD13 trialsBoris Bumloll et al German Hodgkin Study Group

Two cycles of ABVD or AVD were equally tolerable in older early-stage favorable HL patients Excessive toxicity including severe bleomycin-induced lung toxicity occurred in older HL patients receiving 4 cycles of ABVD Doxorubicin bleomycin vinblastine sulfate and dacarbazine (ABVD) is associated with severe toxicity in older patients particularly from bleomycin-induced lung toxicity (BLT) Therefore using bleomycin has been questioned in older Hodgkin lymphoma (HL) patients especially in early-stage HL We therefore analyzed feasibility toxicity and efficacy of ABVD or AVD in 287 older early-stage favorable HL patients We included patients ge60 years of age in the German Hodgkin Study Group HD10 and HD13 trials randomized to either 2 cycles of ABVD (2XABVD n = 137) or AVD (2xAVD n = 82) each followed by involved-field radiotherapy (IF-RT) with patients randomized to 4xABVD+IFRT (n =68) Patientsrsquo median age was 65 years (range 60-75) with comparable patient and disease characteristics Grade III-IV adverse event rates were similar in patients receiving 2xAVD and 2xABVD (40 and 39 respectively) but considerably higher in patients receiving 4xABVD (65) Similarly BLT was rare in patients receiving 2xABVDAVD but occurred in 769 (10) of patients randomized to 4xABVD with 3 lethal events In conclusion no effects of bleomycin on toxicity rates were detectable in older patients receiving 2 cycles of chemotherapy However we found a high risk of severe toxicity of bleomycin in older HL patients receiving more than 2 cycles of ABVD (Blood 2016 127(18)2189-2192)

Forty-four advanced-stage older HL patients (aged ge60 years) were treated on the randomized study E2496 Toxicities were mostly similar between chemotherapy regimens although 24 of older patients developed bleomycin lung toxicity (BLT) which occurred mainly with ABVD (91) Further the BLT-related mortality rate was 18 The overall treatment-related mortality for older HL patients was 9 versus 03 for patients aged lt60 years (plt0001) Among older patients there were no survival differences between ABVD and SV According to age outcomes were significantly inferior for older versus younger patients (5-year FFS 48 vs 74 respectively p=0002 5-year OS 58 and 90 respectively plt00001)Among the 45 older HL patients enrolled 11 (24) developed BLT of whom 211 (18) died due to acute pulmonary fibrosisrespiratory failure) Furthermore 1011 (91) BLT cases occurred withduring ABVD (BLT incidence 43 with ABVD vs 5 Stanford V p=004) This toxicity appeared to occur later in the chemotherapy course however the two BLT-related deaths occurred during cycle 3 of ABVD We did not identify any factors that predicted the development of BLT or death due to BLT Granulocyte growth factor was given the vast majority of patients thus it was not analyzed as a risk factor

The Efficacy and Tolerability of ABVD and Stanford V in Older Hodgkin Lymphoma Patients A Comprehensive Analysis from the North American Intergroup Trial E2496 Andrew M Evens et al BJH 2013

In the RT group 3-year PFS was 94middot6(95 CI 91middot5-97middot7) compared to90middot8 (95 CI 86middot9-94middot8) in the no-further-treatment groupFor PFS the HR was 1middot57 (95 CI 0middot84- 2middot97 p=0middot16) the 3-year absolute risk difference was minus3middot8 (95 CI minus8middot8-1middot3)

HL deaths

4

1

0

3-year PFS and overall survival rates 908 and 990 respectively

However the per-protocol analysis showed a greater 3-year PFS rate than the intention-to-treat analysis in the RT group 971 (95 CI 947 to 996)with a hazard ratio of 236 (95 CI 113-495P = 002) because 26 patients did not receive the assigned RT and 6 events occurred among those patients

Initial results of the US Intergroup trial of response-adapted chemotherapy or chemotherapyradiation therapy based on PET for non-bulky stage I and II Hodgkin

lymphomaStraus DJ et al Blood 2015

David J Straus et al Blood 2015126578copy2015 by American Society of Hematology

PETCT after 2xABVD identified 91 of PET-2 negative pts who were treated with additional 2xABVD with an estimated 3-yr PFS of 92Defining PET-2 negative pts by DS 1-3 (91) rather than DS 1-2(75) allows maintaining PFS gt90 and reducing the number of patients receiving IFRT

Treating PET-2 positive pts (9) with 2x escalated BEACOPP+IFRT may not result in clinically important improvement in PFS HR-604(1822008) at 2 yrs

Kaplan-Meier plot showing progression-free survival according to IPS group and PET results

after two cycles of ABVD

Andrea Gallamini et al Haematologica 2014991107-1113

copy2014 by Ferrata Storti Foundation

The 3-year PFS rate was 83 for the whole study population 28 for patients with positive interim scans and 95 for patients with negative interim scans (Plt00001)

Advanced Hodgkin Lymphoma

Central PET review bull Standardized protocol drawn up by expert panel

bull Only full-ring dedicated PET-CT scanners

bull Documented daily quality control procedure

bull Tested and secure method to transfer anonymised scan data betweenscanning facilities and the central reporting facility in each country andagreed file naming convention

bull It must be demonstrated that image quality is comparable between centres and standard uptake values can be reliably determined from the PETCT imagesStandardized Deauville 5PS criteria (1-3 negative 4-5 positive)

SCORE 1 NO UPTAKE

SCORE 2 UPTAKE le MEDIASTINUM

SCORE 3 UPTAKE gt MEDIASTINUM BUT le LIVER

SCORE 4 MODERATELY UPTAKE gt LIVER

SCORE 5 MARKEDLY UPTAKE gt LIVER

Johnson P Federico M et al NEJM2016

Flow chart showing the clinical outcome of patients according to IPS group

and PET results after two cycles of ABVD

CR continued complete remission PRO primary refractory to chemotherapyprogression within 6

months after completion of therapy REL late relapse

Andrea Gallamini et al Haematologica 2014991107-1113

copy2014 by Ferrata Storti Foundation

87 69

ProgressionPos 3345 73Neg 12215 5

2 cycles ABVD

Full dose on schedule

PET 2 -vePET 2 +ve

4 cycles ABVD

PET2

PET 1(Staging)

IPS 0-7

Randomize

4 cycles AVD

Follow-up (no RT)

4 cycles BEACOPP-14

or 3 eBEACOPP

PET3

PET 3 -vePET 3 +ve

RT or salvage

regimen

2 cycles BEACOPP-14 or

1 eBEACOPP

No RT

RATHL study Chairman Peter Johnson

Johnson P Federico M et al NEJM2016

Outcomes at 1 year according to PET score after ABVD x 2

PET 2 Score Total Number

Number Assessable

at 1 yr

Progressions Deaths PFS events

1 114 88 7 0 80

2 493 375 25 6 72

3 347 239 20 4 96

4 144 102 14 7 167

5 38 25 10 5 520PET Missing 78 22 0 2 91

Total 1214 851 76 24 105

Johnson P Federico M et al NEJM2016

PET-2 +PFS

PET-2 ndashPFS ()

PET-2- PET-2+

PET-2 DS 1-3 negativeDS 4-5 positive

NStageTrial

69 (4y)87 (4y)81192xABVD ndash 4xABVD+ 4xEB+4xSB

2xABVD ndash 4xAVD+ 4xEB or 6xSB

2xABVD ndash 4xABVD+ 6xEB

780IIB-IVB

GITIL 0607Gallamini A

(in press)

675 (3y)85 (3y)84161119IIB-IVB

NCRI RATHLJohnson P

NEJM 2016

64 (2y)82 (2y)8218336III-IVSWOG S0816Press O

JCO 2016

668582182235TOTALMEAN

Gallamini A Kostakoglu L Ann Oncol 2015

Positive interim PETCT is an adverse prognostic marker and treatment intensification improves prognosis However it is inferior to that observed pts with negative PET-2

68 (5y)82 (5y)88 8112 19IPS 0-2ge 3 ABVDEB

185IIB-IVH2 BJH 2017

73 (2y)93 (2y)87132xEB - 4x ABVDEB+4x EB

810IIB-IVGELLA AHL 2011

A Gallamini C Tarella S Viviani A Rossi C Patti M Picardi A Romano M Cantonetti G La Nasa L Trentin SBolis D Rapezzi V Zoli D Gottardi P Gavarotti P Corradini M Cimminiello C Schiavotto G Parvis RZanotti G Gini A JM Ferreri P Viero A Biggi F Fallanca U Ficola G Prosperini F Bergesio S Chauvie CPavoni A M Gianni and A Rambaldi

Early chemotherapy intensification with escalated BEACOPP in advanced-stage Hodgkin Lymphoma patients with a positive interim PET-CT after 2 ABVD cycles long-term results of the GITILFIL HD 0607 trial

Pts enrolledregistered 783785

Pt enrollment 62008- 62014Median fu for pts completing treatment 1303 (2-2857) days

0

02

04

06

08

1

0 2 4 6 8

DS 4

DS 5

0

02

04

06

08

1

0 2 4 6 8

DS 4

DS 5

DS 4 101 (5) 82 (2) 29 (1) 3 (0) 0

DS 5 49 (5) 34 (2) 8 (1) 1 (0) 0

Years from registration

P = 00696

DS 4 101 (15) 75 (2) 26 (0) 3 (0) 0

DS 5 49 (25) 19 (1) 5 (0) 1 (0) 0

Years from registration

P lt 0001

Overall Survival Progression-free Survival

OS and PFS according to Deauville Score

4-Y OS 92 (95CI 84-96)

4-Y OS 83 (95CI 67-92)

4-Y PFS 81 (95CI 71-88)

4-Y PFS 46 (95CI 31-59)

PET-2 positive patient with a DS 4 switching to BEACOPP have a 3-Y PFS similar to the entire cohort of patients (4-Y PFS 81 95 CI 71-88)Patients with a DS 5 which are a small subset of the entire population (63) still represent an unmet therapeutic need awaiting new treatment strategies

Gallamini A et al EHA 2017

0

02

04

06

08

1

0 2 4 6 8

No RX

RX

No RX 148 (1) 141 (2) 40 (0) 0 (0) 0

RX 148 (0) 144 (0) 40 (0) 0 (0) 0

Years from registration

P = 00790

4-Y OS 100

4-Y OS 98 (95CI 92-99)

0

02

04

06

08

1

0 2 4 6 8

No RX

RX

No RX 148 (9) 133 (1) 35 (0) 14 (0) 0

RX 148 (5) 139 (1) 39 (0) 10 (0) 0

Years from registration

P = 02882

4-Y PFS 96 (95CI 91-98)

4-Y PFS 93 (95CI 87-96)

Overall Survival Progression-free Survival

OS and PFS in PET2- randomized to RXNFT

Consolidation radiotherapy in the region where a large nodal mass was recorded at baseline did not improve treatment result in negative PET-2 and PET-6 patients irrespective of the dimension of the lesion at baseline

Gallamini A et al EHA 2017

BEACOPP esc x 2

Standard Arm Experimental Arm

Neg Pos

Salvagetherapy

Pos Neg

PET4

PET2

Neg Pos Neg Pos Neg

BEACOPP esc x 2

IPS 0-7BEACOPP esc x 2 BEACOPP esc x 2

BEACOPP esc x 2

R

ABVD x 2

Non inferiority of the experimental arm

ABVD x 2

BEACOPP esc x 2

Courtesy of O Casasnovas

Kairos

Gela ahl2011Stage IIIIV and high risk IIB Hodgkin Lymphoma

Salvagetherapy

Primary Endpoint Planned accrual Date start Date end

5-yr PFS 810 Pts May 2011 May 2015

Abs 577 Randomized phase III study comparing an early PET driven treatment de-escalation to non-PET monitored strategy in patients with advanced HL

O Casasnovas ASH 2015

There was no significant difference between the experimental and standard arms Reduction of therapy based on negative interim PET is safe

Randomized phase III study comparing an early PET driven treatment de-escalation to non pet monitored strategy in patients with advanced HL

O Casanovas ASH 2015

Positive interim PET is a risk factor for HL progression even if EB is continued

Casanovas 2016

There is a value to perform PET-4 if PET-2 is positive Consider change of therapy if PET-4 is positive

Casanovas 2016

Is there a role for PET-4 if treatment was escalated based on PET-2

Casanovas 2016

Progression 90 PtsProgression 157 Pts

ABVD x2

PET-2

BEACOPP ESC x4

PET-6ABVD x4

IPS 0-2

NEGATIVE

POSITIVEBEACOPP ESC x2

IPS 3-7

PET-6ISRT to bulky MM

+

Israeli H2 protocol for advanced Hodgkin lymphoma

B symptoms Stage III IV

The study prospectively evaluated the outcome of HL patients whose therapy waschosen based on initial prognostic factors and tailored based on results of PETCTperformed after 2 cycles of chemotherapy

This multicenter study was initiated in 2006 and ended in 72013 enrolling 355 patientswith stages I-IV HL aged 18-60 years

Conclusions

bull Both baseline PETCT and PET-2 are recommendedbull Deauville scores 1-3 should be considered a negative PET resultbull Positive PET-2 (DS 4-5) is a poor prognostic sign when treatment is initiated

with ABVD or even with EB (Gallamini Johnson Casasnovas)bull Escalation of therapy in PET-2 positive patients improves the outcomebull Escalation of therapy to EB in early-stage HL Pts with positive PET-2 (DS 4-5)

improves PFS (Andrersquo M Straus D)bull Pts with high IPS or bulky mediastinal mass have a worse outcome if

therapy is initiated with ABVD and a higher probability of a positive PET-2 (Johnson)

bull If therapy is initiated with escalated BEACOPP de-escalation of therapy to ABVD does not impair the outcome (Casasnovas)

bull The same percentage of PET-2 negativity was found in patients with IPS 0-2 who initiated therapy with ABVD (5-y PFS 079) and in patients with IPS 3-7 whose initial therapy was escalated BEACOPP (5-y PFS 081) (Dann)

bull Salvage therapy should be considered in PET-2 (DS-5) or PET-4 (DS 4-5) positive patients (Johnson Casasnovas )

Thank You e_dannrambamhealthgovil

Should BLEOMYCIN be omitted at age ge 65

RAPID trial toxicity

Bleomycin in older early-stage favorable Hodgkin lymphoma patients analysis of the German Hodgkin Study Group (GHSG) HD10 and HD13 trialsBoris Bumloll et al German Hodgkin Study Group

Two cycles of ABVD or AVD were equally tolerable in older early-stage favorable HL patients Excessive toxicity including severe bleomycin-induced lung toxicity occurred in older HL patients receiving 4 cycles of ABVD Doxorubicin bleomycin vinblastine sulfate and dacarbazine (ABVD) is associated with severe toxicity in older patients particularly from bleomycin-induced lung toxicity (BLT) Therefore using bleomycin has been questioned in older Hodgkin lymphoma (HL) patients especially in early-stage HL We therefore analyzed feasibility toxicity and efficacy of ABVD or AVD in 287 older early-stage favorable HL patients We included patients ge60 years of age in the German Hodgkin Study Group HD10 and HD13 trials randomized to either 2 cycles of ABVD (2XABVD n = 137) or AVD (2xAVD n = 82) each followed by involved-field radiotherapy (IF-RT) with patients randomized to 4xABVD+IFRT (n =68) Patientsrsquo median age was 65 years (range 60-75) with comparable patient and disease characteristics Grade III-IV adverse event rates were similar in patients receiving 2xAVD and 2xABVD (40 and 39 respectively) but considerably higher in patients receiving 4xABVD (65) Similarly BLT was rare in patients receiving 2xABVDAVD but occurred in 769 (10) of patients randomized to 4xABVD with 3 lethal events In conclusion no effects of bleomycin on toxicity rates were detectable in older patients receiving 2 cycles of chemotherapy However we found a high risk of severe toxicity of bleomycin in older HL patients receiving more than 2 cycles of ABVD (Blood 2016 127(18)2189-2192)

Forty-four advanced-stage older HL patients (aged ge60 years) were treated on the randomized study E2496 Toxicities were mostly similar between chemotherapy regimens although 24 of older patients developed bleomycin lung toxicity (BLT) which occurred mainly with ABVD (91) Further the BLT-related mortality rate was 18 The overall treatment-related mortality for older HL patients was 9 versus 03 for patients aged lt60 years (plt0001) Among older patients there were no survival differences between ABVD and SV According to age outcomes were significantly inferior for older versus younger patients (5-year FFS 48 vs 74 respectively p=0002 5-year OS 58 and 90 respectively plt00001)Among the 45 older HL patients enrolled 11 (24) developed BLT of whom 211 (18) died due to acute pulmonary fibrosisrespiratory failure) Furthermore 1011 (91) BLT cases occurred withduring ABVD (BLT incidence 43 with ABVD vs 5 Stanford V p=004) This toxicity appeared to occur later in the chemotherapy course however the two BLT-related deaths occurred during cycle 3 of ABVD We did not identify any factors that predicted the development of BLT or death due to BLT Granulocyte growth factor was given the vast majority of patients thus it was not analyzed as a risk factor

The Efficacy and Tolerability of ABVD and Stanford V in Older Hodgkin Lymphoma Patients A Comprehensive Analysis from the North American Intergroup Trial E2496 Andrew M Evens et al BJH 2013

3-year PFS and overall survival rates 908 and 990 respectively

However the per-protocol analysis showed a greater 3-year PFS rate than the intention-to-treat analysis in the RT group 971 (95 CI 947 to 996)with a hazard ratio of 236 (95 CI 113-495P = 002) because 26 patients did not receive the assigned RT and 6 events occurred among those patients

Initial results of the US Intergroup trial of response-adapted chemotherapy or chemotherapyradiation therapy based on PET for non-bulky stage I and II Hodgkin

lymphomaStraus DJ et al Blood 2015

David J Straus et al Blood 2015126578copy2015 by American Society of Hematology

PETCT after 2xABVD identified 91 of PET-2 negative pts who were treated with additional 2xABVD with an estimated 3-yr PFS of 92Defining PET-2 negative pts by DS 1-3 (91) rather than DS 1-2(75) allows maintaining PFS gt90 and reducing the number of patients receiving IFRT

Treating PET-2 positive pts (9) with 2x escalated BEACOPP+IFRT may not result in clinically important improvement in PFS HR-604(1822008) at 2 yrs

Kaplan-Meier plot showing progression-free survival according to IPS group and PET results

after two cycles of ABVD

Andrea Gallamini et al Haematologica 2014991107-1113

copy2014 by Ferrata Storti Foundation

The 3-year PFS rate was 83 for the whole study population 28 for patients with positive interim scans and 95 for patients with negative interim scans (Plt00001)

Advanced Hodgkin Lymphoma

Central PET review bull Standardized protocol drawn up by expert panel

bull Only full-ring dedicated PET-CT scanners

bull Documented daily quality control procedure

bull Tested and secure method to transfer anonymised scan data betweenscanning facilities and the central reporting facility in each country andagreed file naming convention

bull It must be demonstrated that image quality is comparable between centres and standard uptake values can be reliably determined from the PETCT imagesStandardized Deauville 5PS criteria (1-3 negative 4-5 positive)

SCORE 1 NO UPTAKE

SCORE 2 UPTAKE le MEDIASTINUM

SCORE 3 UPTAKE gt MEDIASTINUM BUT le LIVER

SCORE 4 MODERATELY UPTAKE gt LIVER

SCORE 5 MARKEDLY UPTAKE gt LIVER

Johnson P Federico M et al NEJM2016

Flow chart showing the clinical outcome of patients according to IPS group

and PET results after two cycles of ABVD

CR continued complete remission PRO primary refractory to chemotherapyprogression within 6

months after completion of therapy REL late relapse

Andrea Gallamini et al Haematologica 2014991107-1113

copy2014 by Ferrata Storti Foundation

87 69

ProgressionPos 3345 73Neg 12215 5

2 cycles ABVD

Full dose on schedule

PET 2 -vePET 2 +ve

4 cycles ABVD

PET2

PET 1(Staging)

IPS 0-7

Randomize

4 cycles AVD

Follow-up (no RT)

4 cycles BEACOPP-14

or 3 eBEACOPP

PET3

PET 3 -vePET 3 +ve

RT or salvage

regimen

2 cycles BEACOPP-14 or

1 eBEACOPP

No RT

RATHL study Chairman Peter Johnson

Johnson P Federico M et al NEJM2016

Outcomes at 1 year according to PET score after ABVD x 2

PET 2 Score Total Number

Number Assessable

at 1 yr

Progressions Deaths PFS events

1 114 88 7 0 80

2 493 375 25 6 72

3 347 239 20 4 96

4 144 102 14 7 167

5 38 25 10 5 520PET Missing 78 22 0 2 91

Total 1214 851 76 24 105

Johnson P Federico M et al NEJM2016

PET-2 +PFS

PET-2 ndashPFS ()

PET-2- PET-2+

PET-2 DS 1-3 negativeDS 4-5 positive

NStageTrial

69 (4y)87 (4y)81192xABVD ndash 4xABVD+ 4xEB+4xSB

2xABVD ndash 4xAVD+ 4xEB or 6xSB

2xABVD ndash 4xABVD+ 6xEB

780IIB-IVB

GITIL 0607Gallamini A

(in press)

675 (3y)85 (3y)84161119IIB-IVB

NCRI RATHLJohnson P

NEJM 2016

64 (2y)82 (2y)8218336III-IVSWOG S0816Press O

JCO 2016

668582182235TOTALMEAN

Gallamini A Kostakoglu L Ann Oncol 2015

Positive interim PETCT is an adverse prognostic marker and treatment intensification improves prognosis However it is inferior to that observed pts with negative PET-2

68 (5y)82 (5y)88 8112 19IPS 0-2ge 3 ABVDEB

185IIB-IVH2 BJH 2017

73 (2y)93 (2y)87132xEB - 4x ABVDEB+4x EB

810IIB-IVGELLA AHL 2011

A Gallamini C Tarella S Viviani A Rossi C Patti M Picardi A Romano M Cantonetti G La Nasa L Trentin SBolis D Rapezzi V Zoli D Gottardi P Gavarotti P Corradini M Cimminiello C Schiavotto G Parvis RZanotti G Gini A JM Ferreri P Viero A Biggi F Fallanca U Ficola G Prosperini F Bergesio S Chauvie CPavoni A M Gianni and A Rambaldi

Early chemotherapy intensification with escalated BEACOPP in advanced-stage Hodgkin Lymphoma patients with a positive interim PET-CT after 2 ABVD cycles long-term results of the GITILFIL HD 0607 trial

Pts enrolledregistered 783785

Pt enrollment 62008- 62014Median fu for pts completing treatment 1303 (2-2857) days

0

02

04

06

08

1

0 2 4 6 8

DS 4

DS 5

0

02

04

06

08

1

0 2 4 6 8

DS 4

DS 5

DS 4 101 (5) 82 (2) 29 (1) 3 (0) 0

DS 5 49 (5) 34 (2) 8 (1) 1 (0) 0

Years from registration

P = 00696

DS 4 101 (15) 75 (2) 26 (0) 3 (0) 0

DS 5 49 (25) 19 (1) 5 (0) 1 (0) 0

Years from registration

P lt 0001

Overall Survival Progression-free Survival

OS and PFS according to Deauville Score

4-Y OS 92 (95CI 84-96)

4-Y OS 83 (95CI 67-92)

4-Y PFS 81 (95CI 71-88)

4-Y PFS 46 (95CI 31-59)

PET-2 positive patient with a DS 4 switching to BEACOPP have a 3-Y PFS similar to the entire cohort of patients (4-Y PFS 81 95 CI 71-88)Patients with a DS 5 which are a small subset of the entire population (63) still represent an unmet therapeutic need awaiting new treatment strategies

Gallamini A et al EHA 2017

0

02

04

06

08

1

0 2 4 6 8

No RX

RX

No RX 148 (1) 141 (2) 40 (0) 0 (0) 0

RX 148 (0) 144 (0) 40 (0) 0 (0) 0

Years from registration

P = 00790

4-Y OS 100

4-Y OS 98 (95CI 92-99)

0

02

04

06

08

1

0 2 4 6 8

No RX

RX

No RX 148 (9) 133 (1) 35 (0) 14 (0) 0

RX 148 (5) 139 (1) 39 (0) 10 (0) 0

Years from registration

P = 02882

4-Y PFS 96 (95CI 91-98)

4-Y PFS 93 (95CI 87-96)

Overall Survival Progression-free Survival

OS and PFS in PET2- randomized to RXNFT

Consolidation radiotherapy in the region where a large nodal mass was recorded at baseline did not improve treatment result in negative PET-2 and PET-6 patients irrespective of the dimension of the lesion at baseline

Gallamini A et al EHA 2017

BEACOPP esc x 2

Standard Arm Experimental Arm

Neg Pos

Salvagetherapy

Pos Neg

PET4

PET2

Neg Pos Neg Pos Neg

BEACOPP esc x 2

IPS 0-7BEACOPP esc x 2 BEACOPP esc x 2

BEACOPP esc x 2

R

ABVD x 2

Non inferiority of the experimental arm

ABVD x 2

BEACOPP esc x 2

Courtesy of O Casasnovas

Kairos

Gela ahl2011Stage IIIIV and high risk IIB Hodgkin Lymphoma

Salvagetherapy

Primary Endpoint Planned accrual Date start Date end

5-yr PFS 810 Pts May 2011 May 2015

Abs 577 Randomized phase III study comparing an early PET driven treatment de-escalation to non-PET monitored strategy in patients with advanced HL

O Casasnovas ASH 2015

There was no significant difference between the experimental and standard arms Reduction of therapy based on negative interim PET is safe

Randomized phase III study comparing an early PET driven treatment de-escalation to non pet monitored strategy in patients with advanced HL

O Casanovas ASH 2015

Positive interim PET is a risk factor for HL progression even if EB is continued

Casanovas 2016

There is a value to perform PET-4 if PET-2 is positive Consider change of therapy if PET-4 is positive

Casanovas 2016

Is there a role for PET-4 if treatment was escalated based on PET-2

Casanovas 2016

Progression 90 PtsProgression 157 Pts

ABVD x2

PET-2

BEACOPP ESC x4

PET-6ABVD x4

IPS 0-2

NEGATIVE

POSITIVEBEACOPP ESC x2

IPS 3-7

PET-6ISRT to bulky MM

+

Israeli H2 protocol for advanced Hodgkin lymphoma

B symptoms Stage III IV

The study prospectively evaluated the outcome of HL patients whose therapy waschosen based on initial prognostic factors and tailored based on results of PETCTperformed after 2 cycles of chemotherapy

This multicenter study was initiated in 2006 and ended in 72013 enrolling 355 patientswith stages I-IV HL aged 18-60 years

Conclusions

bull Both baseline PETCT and PET-2 are recommendedbull Deauville scores 1-3 should be considered a negative PET resultbull Positive PET-2 (DS 4-5) is a poor prognostic sign when treatment is initiated

with ABVD or even with EB (Gallamini Johnson Casasnovas)bull Escalation of therapy in PET-2 positive patients improves the outcomebull Escalation of therapy to EB in early-stage HL Pts with positive PET-2 (DS 4-5)

improves PFS (Andrersquo M Straus D)bull Pts with high IPS or bulky mediastinal mass have a worse outcome if

therapy is initiated with ABVD and a higher probability of a positive PET-2 (Johnson)

bull If therapy is initiated with escalated BEACOPP de-escalation of therapy to ABVD does not impair the outcome (Casasnovas)

bull The same percentage of PET-2 negativity was found in patients with IPS 0-2 who initiated therapy with ABVD (5-y PFS 079) and in patients with IPS 3-7 whose initial therapy was escalated BEACOPP (5-y PFS 081) (Dann)

bull Salvage therapy should be considered in PET-2 (DS-5) or PET-4 (DS 4-5) positive patients (Johnson Casasnovas )

Thank You e_dannrambamhealthgovil

Should BLEOMYCIN be omitted at age ge 65

RAPID trial toxicity

Bleomycin in older early-stage favorable Hodgkin lymphoma patients analysis of the German Hodgkin Study Group (GHSG) HD10 and HD13 trialsBoris Bumloll et al German Hodgkin Study Group

Two cycles of ABVD or AVD were equally tolerable in older early-stage favorable HL patients Excessive toxicity including severe bleomycin-induced lung toxicity occurred in older HL patients receiving 4 cycles of ABVD Doxorubicin bleomycin vinblastine sulfate and dacarbazine (ABVD) is associated with severe toxicity in older patients particularly from bleomycin-induced lung toxicity (BLT) Therefore using bleomycin has been questioned in older Hodgkin lymphoma (HL) patients especially in early-stage HL We therefore analyzed feasibility toxicity and efficacy of ABVD or AVD in 287 older early-stage favorable HL patients We included patients ge60 years of age in the German Hodgkin Study Group HD10 and HD13 trials randomized to either 2 cycles of ABVD (2XABVD n = 137) or AVD (2xAVD n = 82) each followed by involved-field radiotherapy (IF-RT) with patients randomized to 4xABVD+IFRT (n =68) Patientsrsquo median age was 65 years (range 60-75) with comparable patient and disease characteristics Grade III-IV adverse event rates were similar in patients receiving 2xAVD and 2xABVD (40 and 39 respectively) but considerably higher in patients receiving 4xABVD (65) Similarly BLT was rare in patients receiving 2xABVDAVD but occurred in 769 (10) of patients randomized to 4xABVD with 3 lethal events In conclusion no effects of bleomycin on toxicity rates were detectable in older patients receiving 2 cycles of chemotherapy However we found a high risk of severe toxicity of bleomycin in older HL patients receiving more than 2 cycles of ABVD (Blood 2016 127(18)2189-2192)

Forty-four advanced-stage older HL patients (aged ge60 years) were treated on the randomized study E2496 Toxicities were mostly similar between chemotherapy regimens although 24 of older patients developed bleomycin lung toxicity (BLT) which occurred mainly with ABVD (91) Further the BLT-related mortality rate was 18 The overall treatment-related mortality for older HL patients was 9 versus 03 for patients aged lt60 years (plt0001) Among older patients there were no survival differences between ABVD and SV According to age outcomes were significantly inferior for older versus younger patients (5-year FFS 48 vs 74 respectively p=0002 5-year OS 58 and 90 respectively plt00001)Among the 45 older HL patients enrolled 11 (24) developed BLT of whom 211 (18) died due to acute pulmonary fibrosisrespiratory failure) Furthermore 1011 (91) BLT cases occurred withduring ABVD (BLT incidence 43 with ABVD vs 5 Stanford V p=004) This toxicity appeared to occur later in the chemotherapy course however the two BLT-related deaths occurred during cycle 3 of ABVD We did not identify any factors that predicted the development of BLT or death due to BLT Granulocyte growth factor was given the vast majority of patients thus it was not analyzed as a risk factor

The Efficacy and Tolerability of ABVD and Stanford V in Older Hodgkin Lymphoma Patients A Comprehensive Analysis from the North American Intergroup Trial E2496 Andrew M Evens et al BJH 2013

Initial results of the US Intergroup trial of response-adapted chemotherapy or chemotherapyradiation therapy based on PET for non-bulky stage I and II Hodgkin

lymphomaStraus DJ et al Blood 2015

David J Straus et al Blood 2015126578copy2015 by American Society of Hematology

PETCT after 2xABVD identified 91 of PET-2 negative pts who were treated with additional 2xABVD with an estimated 3-yr PFS of 92Defining PET-2 negative pts by DS 1-3 (91) rather than DS 1-2(75) allows maintaining PFS gt90 and reducing the number of patients receiving IFRT

Treating PET-2 positive pts (9) with 2x escalated BEACOPP+IFRT may not result in clinically important improvement in PFS HR-604(1822008) at 2 yrs

Kaplan-Meier plot showing progression-free survival according to IPS group and PET results

after two cycles of ABVD

Andrea Gallamini et al Haematologica 2014991107-1113

copy2014 by Ferrata Storti Foundation

The 3-year PFS rate was 83 for the whole study population 28 for patients with positive interim scans and 95 for patients with negative interim scans (Plt00001)

Advanced Hodgkin Lymphoma

Central PET review bull Standardized protocol drawn up by expert panel

bull Only full-ring dedicated PET-CT scanners

bull Documented daily quality control procedure

bull Tested and secure method to transfer anonymised scan data betweenscanning facilities and the central reporting facility in each country andagreed file naming convention

bull It must be demonstrated that image quality is comparable between centres and standard uptake values can be reliably determined from the PETCT imagesStandardized Deauville 5PS criteria (1-3 negative 4-5 positive)

SCORE 1 NO UPTAKE

SCORE 2 UPTAKE le MEDIASTINUM

SCORE 3 UPTAKE gt MEDIASTINUM BUT le LIVER

SCORE 4 MODERATELY UPTAKE gt LIVER

SCORE 5 MARKEDLY UPTAKE gt LIVER

Johnson P Federico M et al NEJM2016

Flow chart showing the clinical outcome of patients according to IPS group

and PET results after two cycles of ABVD

CR continued complete remission PRO primary refractory to chemotherapyprogression within 6

months after completion of therapy REL late relapse

Andrea Gallamini et al Haematologica 2014991107-1113

copy2014 by Ferrata Storti Foundation

87 69

ProgressionPos 3345 73Neg 12215 5

2 cycles ABVD

Full dose on schedule

PET 2 -vePET 2 +ve

4 cycles ABVD

PET2

PET 1(Staging)

IPS 0-7

Randomize

4 cycles AVD

Follow-up (no RT)

4 cycles BEACOPP-14

or 3 eBEACOPP

PET3

PET 3 -vePET 3 +ve

RT or salvage

regimen

2 cycles BEACOPP-14 or

1 eBEACOPP

No RT

RATHL study Chairman Peter Johnson

Johnson P Federico M et al NEJM2016

Outcomes at 1 year according to PET score after ABVD x 2

PET 2 Score Total Number

Number Assessable

at 1 yr

Progressions Deaths PFS events

1 114 88 7 0 80

2 493 375 25 6 72

3 347 239 20 4 96

4 144 102 14 7 167

5 38 25 10 5 520PET Missing 78 22 0 2 91

Total 1214 851 76 24 105

Johnson P Federico M et al NEJM2016

PET-2 +PFS

PET-2 ndashPFS ()

PET-2- PET-2+

PET-2 DS 1-3 negativeDS 4-5 positive

NStageTrial

69 (4y)87 (4y)81192xABVD ndash 4xABVD+ 4xEB+4xSB

2xABVD ndash 4xAVD+ 4xEB or 6xSB

2xABVD ndash 4xABVD+ 6xEB

780IIB-IVB

GITIL 0607Gallamini A

(in press)

675 (3y)85 (3y)84161119IIB-IVB

NCRI RATHLJohnson P

NEJM 2016

64 (2y)82 (2y)8218336III-IVSWOG S0816Press O

JCO 2016

668582182235TOTALMEAN

Gallamini A Kostakoglu L Ann Oncol 2015

Positive interim PETCT is an adverse prognostic marker and treatment intensification improves prognosis However it is inferior to that observed pts with negative PET-2

68 (5y)82 (5y)88 8112 19IPS 0-2ge 3 ABVDEB

185IIB-IVH2 BJH 2017

73 (2y)93 (2y)87132xEB - 4x ABVDEB+4x EB

810IIB-IVGELLA AHL 2011

A Gallamini C Tarella S Viviani A Rossi C Patti M Picardi A Romano M Cantonetti G La Nasa L Trentin SBolis D Rapezzi V Zoli D Gottardi P Gavarotti P Corradini M Cimminiello C Schiavotto G Parvis RZanotti G Gini A JM Ferreri P Viero A Biggi F Fallanca U Ficola G Prosperini F Bergesio S Chauvie CPavoni A M Gianni and A Rambaldi

Early chemotherapy intensification with escalated BEACOPP in advanced-stage Hodgkin Lymphoma patients with a positive interim PET-CT after 2 ABVD cycles long-term results of the GITILFIL HD 0607 trial

Pts enrolledregistered 783785

Pt enrollment 62008- 62014Median fu for pts completing treatment 1303 (2-2857) days

0

02

04

06

08

1

0 2 4 6 8

DS 4

DS 5

0

02

04

06

08

1

0 2 4 6 8

DS 4

DS 5

DS 4 101 (5) 82 (2) 29 (1) 3 (0) 0

DS 5 49 (5) 34 (2) 8 (1) 1 (0) 0

Years from registration

P = 00696

DS 4 101 (15) 75 (2) 26 (0) 3 (0) 0

DS 5 49 (25) 19 (1) 5 (0) 1 (0) 0

Years from registration

P lt 0001

Overall Survival Progression-free Survival

OS and PFS according to Deauville Score

4-Y OS 92 (95CI 84-96)

4-Y OS 83 (95CI 67-92)

4-Y PFS 81 (95CI 71-88)

4-Y PFS 46 (95CI 31-59)

PET-2 positive patient with a DS 4 switching to BEACOPP have a 3-Y PFS similar to the entire cohort of patients (4-Y PFS 81 95 CI 71-88)Patients with a DS 5 which are a small subset of the entire population (63) still represent an unmet therapeutic need awaiting new treatment strategies

Gallamini A et al EHA 2017

0

02

04

06

08

1

0 2 4 6 8

No RX

RX

No RX 148 (1) 141 (2) 40 (0) 0 (0) 0

RX 148 (0) 144 (0) 40 (0) 0 (0) 0

Years from registration

P = 00790

4-Y OS 100

4-Y OS 98 (95CI 92-99)

0

02

04

06

08

1

0 2 4 6 8

No RX

RX

No RX 148 (9) 133 (1) 35 (0) 14 (0) 0

RX 148 (5) 139 (1) 39 (0) 10 (0) 0

Years from registration

P = 02882

4-Y PFS 96 (95CI 91-98)

4-Y PFS 93 (95CI 87-96)

Overall Survival Progression-free Survival

OS and PFS in PET2- randomized to RXNFT

Consolidation radiotherapy in the region where a large nodal mass was recorded at baseline did not improve treatment result in negative PET-2 and PET-6 patients irrespective of the dimension of the lesion at baseline

Gallamini A et al EHA 2017

BEACOPP esc x 2

Standard Arm Experimental Arm

Neg Pos

Salvagetherapy

Pos Neg

PET4

PET2

Neg Pos Neg Pos Neg

BEACOPP esc x 2

IPS 0-7BEACOPP esc x 2 BEACOPP esc x 2

BEACOPP esc x 2

R

ABVD x 2

Non inferiority of the experimental arm

ABVD x 2

BEACOPP esc x 2

Courtesy of O Casasnovas

Kairos

Gela ahl2011Stage IIIIV and high risk IIB Hodgkin Lymphoma

Salvagetherapy

Primary Endpoint Planned accrual Date start Date end

5-yr PFS 810 Pts May 2011 May 2015

Abs 577 Randomized phase III study comparing an early PET driven treatment de-escalation to non-PET monitored strategy in patients with advanced HL

O Casasnovas ASH 2015

There was no significant difference between the experimental and standard arms Reduction of therapy based on negative interim PET is safe

Randomized phase III study comparing an early PET driven treatment de-escalation to non pet monitored strategy in patients with advanced HL

O Casanovas ASH 2015

Positive interim PET is a risk factor for HL progression even if EB is continued

Casanovas 2016

There is a value to perform PET-4 if PET-2 is positive Consider change of therapy if PET-4 is positive

Casanovas 2016

Is there a role for PET-4 if treatment was escalated based on PET-2

Casanovas 2016

Progression 90 PtsProgression 157 Pts

ABVD x2

PET-2

BEACOPP ESC x4

PET-6ABVD x4

IPS 0-2

NEGATIVE

POSITIVEBEACOPP ESC x2

IPS 3-7

PET-6ISRT to bulky MM

+

Israeli H2 protocol for advanced Hodgkin lymphoma

B symptoms Stage III IV

The study prospectively evaluated the outcome of HL patients whose therapy waschosen based on initial prognostic factors and tailored based on results of PETCTperformed after 2 cycles of chemotherapy

This multicenter study was initiated in 2006 and ended in 72013 enrolling 355 patientswith stages I-IV HL aged 18-60 years

Conclusions

bull Both baseline PETCT and PET-2 are recommendedbull Deauville scores 1-3 should be considered a negative PET resultbull Positive PET-2 (DS 4-5) is a poor prognostic sign when treatment is initiated

with ABVD or even with EB (Gallamini Johnson Casasnovas)bull Escalation of therapy in PET-2 positive patients improves the outcomebull Escalation of therapy to EB in early-stage HL Pts with positive PET-2 (DS 4-5)

improves PFS (Andrersquo M Straus D)bull Pts with high IPS or bulky mediastinal mass have a worse outcome if

therapy is initiated with ABVD and a higher probability of a positive PET-2 (Johnson)

bull If therapy is initiated with escalated BEACOPP de-escalation of therapy to ABVD does not impair the outcome (Casasnovas)

bull The same percentage of PET-2 negativity was found in patients with IPS 0-2 who initiated therapy with ABVD (5-y PFS 079) and in patients with IPS 3-7 whose initial therapy was escalated BEACOPP (5-y PFS 081) (Dann)

bull Salvage therapy should be considered in PET-2 (DS-5) or PET-4 (DS 4-5) positive patients (Johnson Casasnovas )

Thank You e_dannrambamhealthgovil

Should BLEOMYCIN be omitted at age ge 65

RAPID trial toxicity

Bleomycin in older early-stage favorable Hodgkin lymphoma patients analysis of the German Hodgkin Study Group (GHSG) HD10 and HD13 trialsBoris Bumloll et al German Hodgkin Study Group

Two cycles of ABVD or AVD were equally tolerable in older early-stage favorable HL patients Excessive toxicity including severe bleomycin-induced lung toxicity occurred in older HL patients receiving 4 cycles of ABVD Doxorubicin bleomycin vinblastine sulfate and dacarbazine (ABVD) is associated with severe toxicity in older patients particularly from bleomycin-induced lung toxicity (BLT) Therefore using bleomycin has been questioned in older Hodgkin lymphoma (HL) patients especially in early-stage HL We therefore analyzed feasibility toxicity and efficacy of ABVD or AVD in 287 older early-stage favorable HL patients We included patients ge60 years of age in the German Hodgkin Study Group HD10 and HD13 trials randomized to either 2 cycles of ABVD (2XABVD n = 137) or AVD (2xAVD n = 82) each followed by involved-field radiotherapy (IF-RT) with patients randomized to 4xABVD+IFRT (n =68) Patientsrsquo median age was 65 years (range 60-75) with comparable patient and disease characteristics Grade III-IV adverse event rates were similar in patients receiving 2xAVD and 2xABVD (40 and 39 respectively) but considerably higher in patients receiving 4xABVD (65) Similarly BLT was rare in patients receiving 2xABVDAVD but occurred in 769 (10) of patients randomized to 4xABVD with 3 lethal events In conclusion no effects of bleomycin on toxicity rates were detectable in older patients receiving 2 cycles of chemotherapy However we found a high risk of severe toxicity of bleomycin in older HL patients receiving more than 2 cycles of ABVD (Blood 2016 127(18)2189-2192)

Forty-four advanced-stage older HL patients (aged ge60 years) were treated on the randomized study E2496 Toxicities were mostly similar between chemotherapy regimens although 24 of older patients developed bleomycin lung toxicity (BLT) which occurred mainly with ABVD (91) Further the BLT-related mortality rate was 18 The overall treatment-related mortality for older HL patients was 9 versus 03 for patients aged lt60 years (plt0001) Among older patients there were no survival differences between ABVD and SV According to age outcomes were significantly inferior for older versus younger patients (5-year FFS 48 vs 74 respectively p=0002 5-year OS 58 and 90 respectively plt00001)Among the 45 older HL patients enrolled 11 (24) developed BLT of whom 211 (18) died due to acute pulmonary fibrosisrespiratory failure) Furthermore 1011 (91) BLT cases occurred withduring ABVD (BLT incidence 43 with ABVD vs 5 Stanford V p=004) This toxicity appeared to occur later in the chemotherapy course however the two BLT-related deaths occurred during cycle 3 of ABVD We did not identify any factors that predicted the development of BLT or death due to BLT Granulocyte growth factor was given the vast majority of patients thus it was not analyzed as a risk factor

The Efficacy and Tolerability of ABVD and Stanford V in Older Hodgkin Lymphoma Patients A Comprehensive Analysis from the North American Intergroup Trial E2496 Andrew M Evens et al BJH 2013

David J Straus et al Blood 2015126578copy2015 by American Society of Hematology

PETCT after 2xABVD identified 91 of PET-2 negative pts who were treated with additional 2xABVD with an estimated 3-yr PFS of 92Defining PET-2 negative pts by DS 1-3 (91) rather than DS 1-2(75) allows maintaining PFS gt90 and reducing the number of patients receiving IFRT

Treating PET-2 positive pts (9) with 2x escalated BEACOPP+IFRT may not result in clinically important improvement in PFS HR-604(1822008) at 2 yrs

Kaplan-Meier plot showing progression-free survival according to IPS group and PET results

after two cycles of ABVD

Andrea Gallamini et al Haematologica 2014991107-1113

copy2014 by Ferrata Storti Foundation

The 3-year PFS rate was 83 for the whole study population 28 for patients with positive interim scans and 95 for patients with negative interim scans (Plt00001)

Advanced Hodgkin Lymphoma

Central PET review bull Standardized protocol drawn up by expert panel

bull Only full-ring dedicated PET-CT scanners

bull Documented daily quality control procedure

bull Tested and secure method to transfer anonymised scan data betweenscanning facilities and the central reporting facility in each country andagreed file naming convention

bull It must be demonstrated that image quality is comparable between centres and standard uptake values can be reliably determined from the PETCT imagesStandardized Deauville 5PS criteria (1-3 negative 4-5 positive)

SCORE 1 NO UPTAKE

SCORE 2 UPTAKE le MEDIASTINUM

SCORE 3 UPTAKE gt MEDIASTINUM BUT le LIVER

SCORE 4 MODERATELY UPTAKE gt LIVER

SCORE 5 MARKEDLY UPTAKE gt LIVER

Johnson P Federico M et al NEJM2016

Flow chart showing the clinical outcome of patients according to IPS group

and PET results after two cycles of ABVD

CR continued complete remission PRO primary refractory to chemotherapyprogression within 6

months after completion of therapy REL late relapse

Andrea Gallamini et al Haematologica 2014991107-1113

copy2014 by Ferrata Storti Foundation

87 69

ProgressionPos 3345 73Neg 12215 5

2 cycles ABVD

Full dose on schedule

PET 2 -vePET 2 +ve

4 cycles ABVD

PET2

PET 1(Staging)

IPS 0-7

Randomize

4 cycles AVD

Follow-up (no RT)

4 cycles BEACOPP-14

or 3 eBEACOPP

PET3

PET 3 -vePET 3 +ve

RT or salvage

regimen

2 cycles BEACOPP-14 or

1 eBEACOPP

No RT

RATHL study Chairman Peter Johnson

Johnson P Federico M et al NEJM2016

Outcomes at 1 year according to PET score after ABVD x 2

PET 2 Score Total Number

Number Assessable

at 1 yr

Progressions Deaths PFS events

1 114 88 7 0 80

2 493 375 25 6 72

3 347 239 20 4 96

4 144 102 14 7 167

5 38 25 10 5 520PET Missing 78 22 0 2 91

Total 1214 851 76 24 105

Johnson P Federico M et al NEJM2016

PET-2 +PFS

PET-2 ndashPFS ()

PET-2- PET-2+

PET-2 DS 1-3 negativeDS 4-5 positive

NStageTrial

69 (4y)87 (4y)81192xABVD ndash 4xABVD+ 4xEB+4xSB

2xABVD ndash 4xAVD+ 4xEB or 6xSB

2xABVD ndash 4xABVD+ 6xEB

780IIB-IVB

GITIL 0607Gallamini A

(in press)

675 (3y)85 (3y)84161119IIB-IVB

NCRI RATHLJohnson P

NEJM 2016

64 (2y)82 (2y)8218336III-IVSWOG S0816Press O

JCO 2016

668582182235TOTALMEAN

Gallamini A Kostakoglu L Ann Oncol 2015

Positive interim PETCT is an adverse prognostic marker and treatment intensification improves prognosis However it is inferior to that observed pts with negative PET-2

68 (5y)82 (5y)88 8112 19IPS 0-2ge 3 ABVDEB

185IIB-IVH2 BJH 2017

73 (2y)93 (2y)87132xEB - 4x ABVDEB+4x EB

810IIB-IVGELLA AHL 2011

A Gallamini C Tarella S Viviani A Rossi C Patti M Picardi A Romano M Cantonetti G La Nasa L Trentin SBolis D Rapezzi V Zoli D Gottardi P Gavarotti P Corradini M Cimminiello C Schiavotto G Parvis RZanotti G Gini A JM Ferreri P Viero A Biggi F Fallanca U Ficola G Prosperini F Bergesio S Chauvie CPavoni A M Gianni and A Rambaldi

Early chemotherapy intensification with escalated BEACOPP in advanced-stage Hodgkin Lymphoma patients with a positive interim PET-CT after 2 ABVD cycles long-term results of the GITILFIL HD 0607 trial

Pts enrolledregistered 783785

Pt enrollment 62008- 62014Median fu for pts completing treatment 1303 (2-2857) days

0

02

04

06

08

1

0 2 4 6 8

DS 4

DS 5

0

02

04

06

08

1

0 2 4 6 8

DS 4

DS 5

DS 4 101 (5) 82 (2) 29 (1) 3 (0) 0

DS 5 49 (5) 34 (2) 8 (1) 1 (0) 0

Years from registration

P = 00696

DS 4 101 (15) 75 (2) 26 (0) 3 (0) 0

DS 5 49 (25) 19 (1) 5 (0) 1 (0) 0

Years from registration

P lt 0001

Overall Survival Progression-free Survival

OS and PFS according to Deauville Score

4-Y OS 92 (95CI 84-96)

4-Y OS 83 (95CI 67-92)

4-Y PFS 81 (95CI 71-88)

4-Y PFS 46 (95CI 31-59)

PET-2 positive patient with a DS 4 switching to BEACOPP have a 3-Y PFS similar to the entire cohort of patients (4-Y PFS 81 95 CI 71-88)Patients with a DS 5 which are a small subset of the entire population (63) still represent an unmet therapeutic need awaiting new treatment strategies

Gallamini A et al EHA 2017

0

02

04

06

08

1

0 2 4 6 8

No RX

RX

No RX 148 (1) 141 (2) 40 (0) 0 (0) 0

RX 148 (0) 144 (0) 40 (0) 0 (0) 0

Years from registration

P = 00790

4-Y OS 100

4-Y OS 98 (95CI 92-99)

0

02

04

06

08

1

0 2 4 6 8

No RX

RX

No RX 148 (9) 133 (1) 35 (0) 14 (0) 0

RX 148 (5) 139 (1) 39 (0) 10 (0) 0

Years from registration

P = 02882

4-Y PFS 96 (95CI 91-98)

4-Y PFS 93 (95CI 87-96)

Overall Survival Progression-free Survival

OS and PFS in PET2- randomized to RXNFT

Consolidation radiotherapy in the region where a large nodal mass was recorded at baseline did not improve treatment result in negative PET-2 and PET-6 patients irrespective of the dimension of the lesion at baseline

Gallamini A et al EHA 2017

BEACOPP esc x 2

Standard Arm Experimental Arm

Neg Pos

Salvagetherapy

Pos Neg

PET4

PET2

Neg Pos Neg Pos Neg

BEACOPP esc x 2

IPS 0-7BEACOPP esc x 2 BEACOPP esc x 2

BEACOPP esc x 2

R

ABVD x 2

Non inferiority of the experimental arm

ABVD x 2

BEACOPP esc x 2

Courtesy of O Casasnovas

Kairos

Gela ahl2011Stage IIIIV and high risk IIB Hodgkin Lymphoma

Salvagetherapy

Primary Endpoint Planned accrual Date start Date end

5-yr PFS 810 Pts May 2011 May 2015

Abs 577 Randomized phase III study comparing an early PET driven treatment de-escalation to non-PET monitored strategy in patients with advanced HL

O Casasnovas ASH 2015

There was no significant difference between the experimental and standard arms Reduction of therapy based on negative interim PET is safe

Randomized phase III study comparing an early PET driven treatment de-escalation to non pet monitored strategy in patients with advanced HL

O Casanovas ASH 2015

Positive interim PET is a risk factor for HL progression even if EB is continued

Casanovas 2016

There is a value to perform PET-4 if PET-2 is positive Consider change of therapy if PET-4 is positive

Casanovas 2016

Is there a role for PET-4 if treatment was escalated based on PET-2

Casanovas 2016

Progression 90 PtsProgression 157 Pts

ABVD x2

PET-2

BEACOPP ESC x4

PET-6ABVD x4

IPS 0-2

NEGATIVE

POSITIVEBEACOPP ESC x2

IPS 3-7

PET-6ISRT to bulky MM

+

Israeli H2 protocol for advanced Hodgkin lymphoma

B symptoms Stage III IV

The study prospectively evaluated the outcome of HL patients whose therapy waschosen based on initial prognostic factors and tailored based on results of PETCTperformed after 2 cycles of chemotherapy

This multicenter study was initiated in 2006 and ended in 72013 enrolling 355 patientswith stages I-IV HL aged 18-60 years

Conclusions

bull Both baseline PETCT and PET-2 are recommendedbull Deauville scores 1-3 should be considered a negative PET resultbull Positive PET-2 (DS 4-5) is a poor prognostic sign when treatment is initiated

with ABVD or even with EB (Gallamini Johnson Casasnovas)bull Escalation of therapy in PET-2 positive patients improves the outcomebull Escalation of therapy to EB in early-stage HL Pts with positive PET-2 (DS 4-5)

improves PFS (Andrersquo M Straus D)bull Pts with high IPS or bulky mediastinal mass have a worse outcome if

therapy is initiated with ABVD and a higher probability of a positive PET-2 (Johnson)

bull If therapy is initiated with escalated BEACOPP de-escalation of therapy to ABVD does not impair the outcome (Casasnovas)

bull The same percentage of PET-2 negativity was found in patients with IPS 0-2 who initiated therapy with ABVD (5-y PFS 079) and in patients with IPS 3-7 whose initial therapy was escalated BEACOPP (5-y PFS 081) (Dann)

bull Salvage therapy should be considered in PET-2 (DS-5) or PET-4 (DS 4-5) positive patients (Johnson Casasnovas )

Thank You e_dannrambamhealthgovil

Should BLEOMYCIN be omitted at age ge 65

RAPID trial toxicity

Bleomycin in older early-stage favorable Hodgkin lymphoma patients analysis of the German Hodgkin Study Group (GHSG) HD10 and HD13 trialsBoris Bumloll et al German Hodgkin Study Group

Two cycles of ABVD or AVD were equally tolerable in older early-stage favorable HL patients Excessive toxicity including severe bleomycin-induced lung toxicity occurred in older HL patients receiving 4 cycles of ABVD Doxorubicin bleomycin vinblastine sulfate and dacarbazine (ABVD) is associated with severe toxicity in older patients particularly from bleomycin-induced lung toxicity (BLT) Therefore using bleomycin has been questioned in older Hodgkin lymphoma (HL) patients especially in early-stage HL We therefore analyzed feasibility toxicity and efficacy of ABVD or AVD in 287 older early-stage favorable HL patients We included patients ge60 years of age in the German Hodgkin Study Group HD10 and HD13 trials randomized to either 2 cycles of ABVD (2XABVD n = 137) or AVD (2xAVD n = 82) each followed by involved-field radiotherapy (IF-RT) with patients randomized to 4xABVD+IFRT (n =68) Patientsrsquo median age was 65 years (range 60-75) with comparable patient and disease characteristics Grade III-IV adverse event rates were similar in patients receiving 2xAVD and 2xABVD (40 and 39 respectively) but considerably higher in patients receiving 4xABVD (65) Similarly BLT was rare in patients receiving 2xABVDAVD but occurred in 769 (10) of patients randomized to 4xABVD with 3 lethal events In conclusion no effects of bleomycin on toxicity rates were detectable in older patients receiving 2 cycles of chemotherapy However we found a high risk of severe toxicity of bleomycin in older HL patients receiving more than 2 cycles of ABVD (Blood 2016 127(18)2189-2192)

Forty-four advanced-stage older HL patients (aged ge60 years) were treated on the randomized study E2496 Toxicities were mostly similar between chemotherapy regimens although 24 of older patients developed bleomycin lung toxicity (BLT) which occurred mainly with ABVD (91) Further the BLT-related mortality rate was 18 The overall treatment-related mortality for older HL patients was 9 versus 03 for patients aged lt60 years (plt0001) Among older patients there were no survival differences between ABVD and SV According to age outcomes were significantly inferior for older versus younger patients (5-year FFS 48 vs 74 respectively p=0002 5-year OS 58 and 90 respectively plt00001)Among the 45 older HL patients enrolled 11 (24) developed BLT of whom 211 (18) died due to acute pulmonary fibrosisrespiratory failure) Furthermore 1011 (91) BLT cases occurred withduring ABVD (BLT incidence 43 with ABVD vs 5 Stanford V p=004) This toxicity appeared to occur later in the chemotherapy course however the two BLT-related deaths occurred during cycle 3 of ABVD We did not identify any factors that predicted the development of BLT or death due to BLT Granulocyte growth factor was given the vast majority of patients thus it was not analyzed as a risk factor

The Efficacy and Tolerability of ABVD and Stanford V in Older Hodgkin Lymphoma Patients A Comprehensive Analysis from the North American Intergroup Trial E2496 Andrew M Evens et al BJH 2013

Kaplan-Meier plot showing progression-free survival according to IPS group and PET results

after two cycles of ABVD

Andrea Gallamini et al Haematologica 2014991107-1113

copy2014 by Ferrata Storti Foundation

The 3-year PFS rate was 83 for the whole study population 28 for patients with positive interim scans and 95 for patients with negative interim scans (Plt00001)

Advanced Hodgkin Lymphoma

Central PET review bull Standardized protocol drawn up by expert panel

bull Only full-ring dedicated PET-CT scanners

bull Documented daily quality control procedure

bull Tested and secure method to transfer anonymised scan data betweenscanning facilities and the central reporting facility in each country andagreed file naming convention

bull It must be demonstrated that image quality is comparable between centres and standard uptake values can be reliably determined from the PETCT imagesStandardized Deauville 5PS criteria (1-3 negative 4-5 positive)

SCORE 1 NO UPTAKE

SCORE 2 UPTAKE le MEDIASTINUM

SCORE 3 UPTAKE gt MEDIASTINUM BUT le LIVER

SCORE 4 MODERATELY UPTAKE gt LIVER

SCORE 5 MARKEDLY UPTAKE gt LIVER

Johnson P Federico M et al NEJM2016

Flow chart showing the clinical outcome of patients according to IPS group

and PET results after two cycles of ABVD

CR continued complete remission PRO primary refractory to chemotherapyprogression within 6

months after completion of therapy REL late relapse

Andrea Gallamini et al Haematologica 2014991107-1113

copy2014 by Ferrata Storti Foundation

87 69

ProgressionPos 3345 73Neg 12215 5

2 cycles ABVD

Full dose on schedule

PET 2 -vePET 2 +ve

4 cycles ABVD

PET2

PET 1(Staging)

IPS 0-7

Randomize

4 cycles AVD

Follow-up (no RT)

4 cycles BEACOPP-14

or 3 eBEACOPP

PET3

PET 3 -vePET 3 +ve

RT or salvage

regimen

2 cycles BEACOPP-14 or

1 eBEACOPP

No RT

RATHL study Chairman Peter Johnson

Johnson P Federico M et al NEJM2016

Outcomes at 1 year according to PET score after ABVD x 2

PET 2 Score Total Number

Number Assessable

at 1 yr

Progressions Deaths PFS events

1 114 88 7 0 80

2 493 375 25 6 72

3 347 239 20 4 96

4 144 102 14 7 167

5 38 25 10 5 520PET Missing 78 22 0 2 91

Total 1214 851 76 24 105

Johnson P Federico M et al NEJM2016

PET-2 +PFS

PET-2 ndashPFS ()

PET-2- PET-2+

PET-2 DS 1-3 negativeDS 4-5 positive

NStageTrial

69 (4y)87 (4y)81192xABVD ndash 4xABVD+ 4xEB+4xSB

2xABVD ndash 4xAVD+ 4xEB or 6xSB

2xABVD ndash 4xABVD+ 6xEB

780IIB-IVB

GITIL 0607Gallamini A

(in press)

675 (3y)85 (3y)84161119IIB-IVB

NCRI RATHLJohnson P

NEJM 2016

64 (2y)82 (2y)8218336III-IVSWOG S0816Press O

JCO 2016

668582182235TOTALMEAN

Gallamini A Kostakoglu L Ann Oncol 2015

Positive interim PETCT is an adverse prognostic marker and treatment intensification improves prognosis However it is inferior to that observed pts with negative PET-2

68 (5y)82 (5y)88 8112 19IPS 0-2ge 3 ABVDEB

185IIB-IVH2 BJH 2017

73 (2y)93 (2y)87132xEB - 4x ABVDEB+4x EB

810IIB-IVGELLA AHL 2011

A Gallamini C Tarella S Viviani A Rossi C Patti M Picardi A Romano M Cantonetti G La Nasa L Trentin SBolis D Rapezzi V Zoli D Gottardi P Gavarotti P Corradini M Cimminiello C Schiavotto G Parvis RZanotti G Gini A JM Ferreri P Viero A Biggi F Fallanca U Ficola G Prosperini F Bergesio S Chauvie CPavoni A M Gianni and A Rambaldi

Early chemotherapy intensification with escalated BEACOPP in advanced-stage Hodgkin Lymphoma patients with a positive interim PET-CT after 2 ABVD cycles long-term results of the GITILFIL HD 0607 trial

Pts enrolledregistered 783785

Pt enrollment 62008- 62014Median fu for pts completing treatment 1303 (2-2857) days

0

02

04

06

08

1

0 2 4 6 8

DS 4

DS 5

0

02

04

06

08

1

0 2 4 6 8

DS 4

DS 5

DS 4 101 (5) 82 (2) 29 (1) 3 (0) 0

DS 5 49 (5) 34 (2) 8 (1) 1 (0) 0

Years from registration

P = 00696

DS 4 101 (15) 75 (2) 26 (0) 3 (0) 0

DS 5 49 (25) 19 (1) 5 (0) 1 (0) 0

Years from registration

P lt 0001

Overall Survival Progression-free Survival

OS and PFS according to Deauville Score

4-Y OS 92 (95CI 84-96)

4-Y OS 83 (95CI 67-92)

4-Y PFS 81 (95CI 71-88)

4-Y PFS 46 (95CI 31-59)

PET-2 positive patient with a DS 4 switching to BEACOPP have a 3-Y PFS similar to the entire cohort of patients (4-Y PFS 81 95 CI 71-88)Patients with a DS 5 which are a small subset of the entire population (63) still represent an unmet therapeutic need awaiting new treatment strategies

Gallamini A et al EHA 2017

0

02

04

06

08

1

0 2 4 6 8

No RX

RX

No RX 148 (1) 141 (2) 40 (0) 0 (0) 0

RX 148 (0) 144 (0) 40 (0) 0 (0) 0

Years from registration

P = 00790

4-Y OS 100

4-Y OS 98 (95CI 92-99)

0

02

04

06

08

1

0 2 4 6 8

No RX

RX

No RX 148 (9) 133 (1) 35 (0) 14 (0) 0

RX 148 (5) 139 (1) 39 (0) 10 (0) 0

Years from registration

P = 02882

4-Y PFS 96 (95CI 91-98)

4-Y PFS 93 (95CI 87-96)

Overall Survival Progression-free Survival

OS and PFS in PET2- randomized to RXNFT

Consolidation radiotherapy in the region where a large nodal mass was recorded at baseline did not improve treatment result in negative PET-2 and PET-6 patients irrespective of the dimension of the lesion at baseline

Gallamini A et al EHA 2017

BEACOPP esc x 2

Standard Arm Experimental Arm

Neg Pos

Salvagetherapy

Pos Neg

PET4

PET2

Neg Pos Neg Pos Neg

BEACOPP esc x 2

IPS 0-7BEACOPP esc x 2 BEACOPP esc x 2

BEACOPP esc x 2

R

ABVD x 2

Non inferiority of the experimental arm

ABVD x 2

BEACOPP esc x 2

Courtesy of O Casasnovas

Kairos

Gela ahl2011Stage IIIIV and high risk IIB Hodgkin Lymphoma

Salvagetherapy

Primary Endpoint Planned accrual Date start Date end

5-yr PFS 810 Pts May 2011 May 2015

Abs 577 Randomized phase III study comparing an early PET driven treatment de-escalation to non-PET monitored strategy in patients with advanced HL

O Casasnovas ASH 2015

There was no significant difference between the experimental and standard arms Reduction of therapy based on negative interim PET is safe

Randomized phase III study comparing an early PET driven treatment de-escalation to non pet monitored strategy in patients with advanced HL

O Casanovas ASH 2015

Positive interim PET is a risk factor for HL progression even if EB is continued

Casanovas 2016

There is a value to perform PET-4 if PET-2 is positive Consider change of therapy if PET-4 is positive

Casanovas 2016

Is there a role for PET-4 if treatment was escalated based on PET-2

Casanovas 2016

Progression 90 PtsProgression 157 Pts

ABVD x2

PET-2

BEACOPP ESC x4

PET-6ABVD x4

IPS 0-2

NEGATIVE

POSITIVEBEACOPP ESC x2

IPS 3-7

PET-6ISRT to bulky MM

+

Israeli H2 protocol for advanced Hodgkin lymphoma

B symptoms Stage III IV

The study prospectively evaluated the outcome of HL patients whose therapy waschosen based on initial prognostic factors and tailored based on results of PETCTperformed after 2 cycles of chemotherapy

This multicenter study was initiated in 2006 and ended in 72013 enrolling 355 patientswith stages I-IV HL aged 18-60 years

Conclusions

bull Both baseline PETCT and PET-2 are recommendedbull Deauville scores 1-3 should be considered a negative PET resultbull Positive PET-2 (DS 4-5) is a poor prognostic sign when treatment is initiated

with ABVD or even with EB (Gallamini Johnson Casasnovas)bull Escalation of therapy in PET-2 positive patients improves the outcomebull Escalation of therapy to EB in early-stage HL Pts with positive PET-2 (DS 4-5)

improves PFS (Andrersquo M Straus D)bull Pts with high IPS or bulky mediastinal mass have a worse outcome if

therapy is initiated with ABVD and a higher probability of a positive PET-2 (Johnson)

bull If therapy is initiated with escalated BEACOPP de-escalation of therapy to ABVD does not impair the outcome (Casasnovas)

bull The same percentage of PET-2 negativity was found in patients with IPS 0-2 who initiated therapy with ABVD (5-y PFS 079) and in patients with IPS 3-7 whose initial therapy was escalated BEACOPP (5-y PFS 081) (Dann)

bull Salvage therapy should be considered in PET-2 (DS-5) or PET-4 (DS 4-5) positive patients (Johnson Casasnovas )

Thank You e_dannrambamhealthgovil

Should BLEOMYCIN be omitted at age ge 65

RAPID trial toxicity

Bleomycin in older early-stage favorable Hodgkin lymphoma patients analysis of the German Hodgkin Study Group (GHSG) HD10 and HD13 trialsBoris Bumloll et al German Hodgkin Study Group

Two cycles of ABVD or AVD were equally tolerable in older early-stage favorable HL patients Excessive toxicity including severe bleomycin-induced lung toxicity occurred in older HL patients receiving 4 cycles of ABVD Doxorubicin bleomycin vinblastine sulfate and dacarbazine (ABVD) is associated with severe toxicity in older patients particularly from bleomycin-induced lung toxicity (BLT) Therefore using bleomycin has been questioned in older Hodgkin lymphoma (HL) patients especially in early-stage HL We therefore analyzed feasibility toxicity and efficacy of ABVD or AVD in 287 older early-stage favorable HL patients We included patients ge60 years of age in the German Hodgkin Study Group HD10 and HD13 trials randomized to either 2 cycles of ABVD (2XABVD n = 137) or AVD (2xAVD n = 82) each followed by involved-field radiotherapy (IF-RT) with patients randomized to 4xABVD+IFRT (n =68) Patientsrsquo median age was 65 years (range 60-75) with comparable patient and disease characteristics Grade III-IV adverse event rates were similar in patients receiving 2xAVD and 2xABVD (40 and 39 respectively) but considerably higher in patients receiving 4xABVD (65) Similarly BLT was rare in patients receiving 2xABVDAVD but occurred in 769 (10) of patients randomized to 4xABVD with 3 lethal events In conclusion no effects of bleomycin on toxicity rates were detectable in older patients receiving 2 cycles of chemotherapy However we found a high risk of severe toxicity of bleomycin in older HL patients receiving more than 2 cycles of ABVD (Blood 2016 127(18)2189-2192)

Forty-four advanced-stage older HL patients (aged ge60 years) were treated on the randomized study E2496 Toxicities were mostly similar between chemotherapy regimens although 24 of older patients developed bleomycin lung toxicity (BLT) which occurred mainly with ABVD (91) Further the BLT-related mortality rate was 18 The overall treatment-related mortality for older HL patients was 9 versus 03 for patients aged lt60 years (plt0001) Among older patients there were no survival differences between ABVD and SV According to age outcomes were significantly inferior for older versus younger patients (5-year FFS 48 vs 74 respectively p=0002 5-year OS 58 and 90 respectively plt00001)Among the 45 older HL patients enrolled 11 (24) developed BLT of whom 211 (18) died due to acute pulmonary fibrosisrespiratory failure) Furthermore 1011 (91) BLT cases occurred withduring ABVD (BLT incidence 43 with ABVD vs 5 Stanford V p=004) This toxicity appeared to occur later in the chemotherapy course however the two BLT-related deaths occurred during cycle 3 of ABVD We did not identify any factors that predicted the development of BLT or death due to BLT Granulocyte growth factor was given the vast majority of patients thus it was not analyzed as a risk factor

The Efficacy and Tolerability of ABVD and Stanford V in Older Hodgkin Lymphoma Patients A Comprehensive Analysis from the North American Intergroup Trial E2496 Andrew M Evens et al BJH 2013

Central PET review bull Standardized protocol drawn up by expert panel

bull Only full-ring dedicated PET-CT scanners

bull Documented daily quality control procedure

bull Tested and secure method to transfer anonymised scan data betweenscanning facilities and the central reporting facility in each country andagreed file naming convention

bull It must be demonstrated that image quality is comparable between centres and standard uptake values can be reliably determined from the PETCT imagesStandardized Deauville 5PS criteria (1-3 negative 4-5 positive)

SCORE 1 NO UPTAKE

SCORE 2 UPTAKE le MEDIASTINUM

SCORE 3 UPTAKE gt MEDIASTINUM BUT le LIVER

SCORE 4 MODERATELY UPTAKE gt LIVER

SCORE 5 MARKEDLY UPTAKE gt LIVER

Johnson P Federico M et al NEJM2016

Flow chart showing the clinical outcome of patients according to IPS group

and PET results after two cycles of ABVD

CR continued complete remission PRO primary refractory to chemotherapyprogression within 6

months after completion of therapy REL late relapse

Andrea Gallamini et al Haematologica 2014991107-1113

copy2014 by Ferrata Storti Foundation

87 69

ProgressionPos 3345 73Neg 12215 5

2 cycles ABVD

Full dose on schedule

PET 2 -vePET 2 +ve

4 cycles ABVD

PET2

PET 1(Staging)

IPS 0-7

Randomize

4 cycles AVD

Follow-up (no RT)

4 cycles BEACOPP-14

or 3 eBEACOPP

PET3

PET 3 -vePET 3 +ve

RT or salvage

regimen

2 cycles BEACOPP-14 or

1 eBEACOPP

No RT

RATHL study Chairman Peter Johnson

Johnson P Federico M et al NEJM2016

Outcomes at 1 year according to PET score after ABVD x 2

PET 2 Score Total Number

Number Assessable

at 1 yr

Progressions Deaths PFS events

1 114 88 7 0 80

2 493 375 25 6 72

3 347 239 20 4 96

4 144 102 14 7 167

5 38 25 10 5 520PET Missing 78 22 0 2 91

Total 1214 851 76 24 105

Johnson P Federico M et al NEJM2016

PET-2 +PFS

PET-2 ndashPFS ()

PET-2- PET-2+

PET-2 DS 1-3 negativeDS 4-5 positive

NStageTrial

69 (4y)87 (4y)81192xABVD ndash 4xABVD+ 4xEB+4xSB

2xABVD ndash 4xAVD+ 4xEB or 6xSB

2xABVD ndash 4xABVD+ 6xEB

780IIB-IVB

GITIL 0607Gallamini A

(in press)

675 (3y)85 (3y)84161119IIB-IVB

NCRI RATHLJohnson P

NEJM 2016

64 (2y)82 (2y)8218336III-IVSWOG S0816Press O

JCO 2016

668582182235TOTALMEAN

Gallamini A Kostakoglu L Ann Oncol 2015

Positive interim PETCT is an adverse prognostic marker and treatment intensification improves prognosis However it is inferior to that observed pts with negative PET-2

68 (5y)82 (5y)88 8112 19IPS 0-2ge 3 ABVDEB

185IIB-IVH2 BJH 2017

73 (2y)93 (2y)87132xEB - 4x ABVDEB+4x EB

810IIB-IVGELLA AHL 2011

A Gallamini C Tarella S Viviani A Rossi C Patti M Picardi A Romano M Cantonetti G La Nasa L Trentin SBolis D Rapezzi V Zoli D Gottardi P Gavarotti P Corradini M Cimminiello C Schiavotto G Parvis RZanotti G Gini A JM Ferreri P Viero A Biggi F Fallanca U Ficola G Prosperini F Bergesio S Chauvie CPavoni A M Gianni and A Rambaldi

Early chemotherapy intensification with escalated BEACOPP in advanced-stage Hodgkin Lymphoma patients with a positive interim PET-CT after 2 ABVD cycles long-term results of the GITILFIL HD 0607 trial

Pts enrolledregistered 783785

Pt enrollment 62008- 62014Median fu for pts completing treatment 1303 (2-2857) days

0

02

04

06

08

1

0 2 4 6 8

DS 4

DS 5

0

02

04

06

08

1

0 2 4 6 8

DS 4

DS 5

DS 4 101 (5) 82 (2) 29 (1) 3 (0) 0

DS 5 49 (5) 34 (2) 8 (1) 1 (0) 0

Years from registration

P = 00696

DS 4 101 (15) 75 (2) 26 (0) 3 (0) 0

DS 5 49 (25) 19 (1) 5 (0) 1 (0) 0

Years from registration

P lt 0001

Overall Survival Progression-free Survival

OS and PFS according to Deauville Score

4-Y OS 92 (95CI 84-96)

4-Y OS 83 (95CI 67-92)

4-Y PFS 81 (95CI 71-88)

4-Y PFS 46 (95CI 31-59)

PET-2 positive patient with a DS 4 switching to BEACOPP have a 3-Y PFS similar to the entire cohort of patients (4-Y PFS 81 95 CI 71-88)Patients with a DS 5 which are a small subset of the entire population (63) still represent an unmet therapeutic need awaiting new treatment strategies

Gallamini A et al EHA 2017

0

02

04

06

08

1

0 2 4 6 8

No RX

RX

No RX 148 (1) 141 (2) 40 (0) 0 (0) 0

RX 148 (0) 144 (0) 40 (0) 0 (0) 0

Years from registration

P = 00790

4-Y OS 100

4-Y OS 98 (95CI 92-99)

0

02

04

06

08

1

0 2 4 6 8

No RX

RX

No RX 148 (9) 133 (1) 35 (0) 14 (0) 0

RX 148 (5) 139 (1) 39 (0) 10 (0) 0

Years from registration

P = 02882

4-Y PFS 96 (95CI 91-98)

4-Y PFS 93 (95CI 87-96)

Overall Survival Progression-free Survival

OS and PFS in PET2- randomized to RXNFT

Consolidation radiotherapy in the region where a large nodal mass was recorded at baseline did not improve treatment result in negative PET-2 and PET-6 patients irrespective of the dimension of the lesion at baseline

Gallamini A et al EHA 2017

BEACOPP esc x 2

Standard Arm Experimental Arm

Neg Pos

Salvagetherapy

Pos Neg

PET4

PET2

Neg Pos Neg Pos Neg

BEACOPP esc x 2

IPS 0-7BEACOPP esc x 2 BEACOPP esc x 2

BEACOPP esc x 2

R

ABVD x 2

Non inferiority of the experimental arm

ABVD x 2

BEACOPP esc x 2

Courtesy of O Casasnovas

Kairos

Gela ahl2011Stage IIIIV and high risk IIB Hodgkin Lymphoma

Salvagetherapy

Primary Endpoint Planned accrual Date start Date end

5-yr PFS 810 Pts May 2011 May 2015

Abs 577 Randomized phase III study comparing an early PET driven treatment de-escalation to non-PET monitored strategy in patients with advanced HL

O Casasnovas ASH 2015

There was no significant difference between the experimental and standard arms Reduction of therapy based on negative interim PET is safe

Randomized phase III study comparing an early PET driven treatment de-escalation to non pet monitored strategy in patients with advanced HL

O Casanovas ASH 2015

Positive interim PET is a risk factor for HL progression even if EB is continued

Casanovas 2016

There is a value to perform PET-4 if PET-2 is positive Consider change of therapy if PET-4 is positive

Casanovas 2016

Is there a role for PET-4 if treatment was escalated based on PET-2

Casanovas 2016

Progression 90 PtsProgression 157 Pts

ABVD x2

PET-2

BEACOPP ESC x4

PET-6ABVD x4

IPS 0-2

NEGATIVE

POSITIVEBEACOPP ESC x2

IPS 3-7

PET-6ISRT to bulky MM

+

Israeli H2 protocol for advanced Hodgkin lymphoma

B symptoms Stage III IV

The study prospectively evaluated the outcome of HL patients whose therapy waschosen based on initial prognostic factors and tailored based on results of PETCTperformed after 2 cycles of chemotherapy

This multicenter study was initiated in 2006 and ended in 72013 enrolling 355 patientswith stages I-IV HL aged 18-60 years

Conclusions

bull Both baseline PETCT and PET-2 are recommendedbull Deauville scores 1-3 should be considered a negative PET resultbull Positive PET-2 (DS 4-5) is a poor prognostic sign when treatment is initiated

with ABVD or even with EB (Gallamini Johnson Casasnovas)bull Escalation of therapy in PET-2 positive patients improves the outcomebull Escalation of therapy to EB in early-stage HL Pts with positive PET-2 (DS 4-5)

improves PFS (Andrersquo M Straus D)bull Pts with high IPS or bulky mediastinal mass have a worse outcome if

therapy is initiated with ABVD and a higher probability of a positive PET-2 (Johnson)

bull If therapy is initiated with escalated BEACOPP de-escalation of therapy to ABVD does not impair the outcome (Casasnovas)

bull The same percentage of PET-2 negativity was found in patients with IPS 0-2 who initiated therapy with ABVD (5-y PFS 079) and in patients with IPS 3-7 whose initial therapy was escalated BEACOPP (5-y PFS 081) (Dann)

bull Salvage therapy should be considered in PET-2 (DS-5) or PET-4 (DS 4-5) positive patients (Johnson Casasnovas )

Thank You e_dannrambamhealthgovil

Should BLEOMYCIN be omitted at age ge 65

RAPID trial toxicity

Bleomycin in older early-stage favorable Hodgkin lymphoma patients analysis of the German Hodgkin Study Group (GHSG) HD10 and HD13 trialsBoris Bumloll et al German Hodgkin Study Group

Two cycles of ABVD or AVD were equally tolerable in older early-stage favorable HL patients Excessive toxicity including severe bleomycin-induced lung toxicity occurred in older HL patients receiving 4 cycles of ABVD Doxorubicin bleomycin vinblastine sulfate and dacarbazine (ABVD) is associated with severe toxicity in older patients particularly from bleomycin-induced lung toxicity (BLT) Therefore using bleomycin has been questioned in older Hodgkin lymphoma (HL) patients especially in early-stage HL We therefore analyzed feasibility toxicity and efficacy of ABVD or AVD in 287 older early-stage favorable HL patients We included patients ge60 years of age in the German Hodgkin Study Group HD10 and HD13 trials randomized to either 2 cycles of ABVD (2XABVD n = 137) or AVD (2xAVD n = 82) each followed by involved-field radiotherapy (IF-RT) with patients randomized to 4xABVD+IFRT (n =68) Patientsrsquo median age was 65 years (range 60-75) with comparable patient and disease characteristics Grade III-IV adverse event rates were similar in patients receiving 2xAVD and 2xABVD (40 and 39 respectively) but considerably higher in patients receiving 4xABVD (65) Similarly BLT was rare in patients receiving 2xABVDAVD but occurred in 769 (10) of patients randomized to 4xABVD with 3 lethal events In conclusion no effects of bleomycin on toxicity rates were detectable in older patients receiving 2 cycles of chemotherapy However we found a high risk of severe toxicity of bleomycin in older HL patients receiving more than 2 cycles of ABVD (Blood 2016 127(18)2189-2192)

Forty-four advanced-stage older HL patients (aged ge60 years) were treated on the randomized study E2496 Toxicities were mostly similar between chemotherapy regimens although 24 of older patients developed bleomycin lung toxicity (BLT) which occurred mainly with ABVD (91) Further the BLT-related mortality rate was 18 The overall treatment-related mortality for older HL patients was 9 versus 03 for patients aged lt60 years (plt0001) Among older patients there were no survival differences between ABVD and SV According to age outcomes were significantly inferior for older versus younger patients (5-year FFS 48 vs 74 respectively p=0002 5-year OS 58 and 90 respectively plt00001)Among the 45 older HL patients enrolled 11 (24) developed BLT of whom 211 (18) died due to acute pulmonary fibrosisrespiratory failure) Furthermore 1011 (91) BLT cases occurred withduring ABVD (BLT incidence 43 with ABVD vs 5 Stanford V p=004) This toxicity appeared to occur later in the chemotherapy course however the two BLT-related deaths occurred during cycle 3 of ABVD We did not identify any factors that predicted the development of BLT or death due to BLT Granulocyte growth factor was given the vast majority of patients thus it was not analyzed as a risk factor

The Efficacy and Tolerability of ABVD and Stanford V in Older Hodgkin Lymphoma Patients A Comprehensive Analysis from the North American Intergroup Trial E2496 Andrew M Evens et al BJH 2013

Flow chart showing the clinical outcome of patients according to IPS group

and PET results after two cycles of ABVD

CR continued complete remission PRO primary refractory to chemotherapyprogression within 6

months after completion of therapy REL late relapse

Andrea Gallamini et al Haematologica 2014991107-1113

copy2014 by Ferrata Storti Foundation

87 69

ProgressionPos 3345 73Neg 12215 5

2 cycles ABVD

Full dose on schedule

PET 2 -vePET 2 +ve

4 cycles ABVD

PET2

PET 1(Staging)

IPS 0-7

Randomize

4 cycles AVD

Follow-up (no RT)

4 cycles BEACOPP-14

or 3 eBEACOPP

PET3

PET 3 -vePET 3 +ve

RT or salvage

regimen

2 cycles BEACOPP-14 or

1 eBEACOPP

No RT

RATHL study Chairman Peter Johnson

Johnson P Federico M et al NEJM2016

Outcomes at 1 year according to PET score after ABVD x 2

PET 2 Score Total Number

Number Assessable

at 1 yr

Progressions Deaths PFS events

1 114 88 7 0 80

2 493 375 25 6 72

3 347 239 20 4 96

4 144 102 14 7 167

5 38 25 10 5 520PET Missing 78 22 0 2 91

Total 1214 851 76 24 105

Johnson P Federico M et al NEJM2016

PET-2 +PFS

PET-2 ndashPFS ()

PET-2- PET-2+

PET-2 DS 1-3 negativeDS 4-5 positive

NStageTrial

69 (4y)87 (4y)81192xABVD ndash 4xABVD+ 4xEB+4xSB

2xABVD ndash 4xAVD+ 4xEB or 6xSB

2xABVD ndash 4xABVD+ 6xEB

780IIB-IVB

GITIL 0607Gallamini A

(in press)

675 (3y)85 (3y)84161119IIB-IVB

NCRI RATHLJohnson P

NEJM 2016

64 (2y)82 (2y)8218336III-IVSWOG S0816Press O

JCO 2016

668582182235TOTALMEAN

Gallamini A Kostakoglu L Ann Oncol 2015

Positive interim PETCT is an adverse prognostic marker and treatment intensification improves prognosis However it is inferior to that observed pts with negative PET-2

68 (5y)82 (5y)88 8112 19IPS 0-2ge 3 ABVDEB

185IIB-IVH2 BJH 2017

73 (2y)93 (2y)87132xEB - 4x ABVDEB+4x EB

810IIB-IVGELLA AHL 2011

A Gallamini C Tarella S Viviani A Rossi C Patti M Picardi A Romano M Cantonetti G La Nasa L Trentin SBolis D Rapezzi V Zoli D Gottardi P Gavarotti P Corradini M Cimminiello C Schiavotto G Parvis RZanotti G Gini A JM Ferreri P Viero A Biggi F Fallanca U Ficola G Prosperini F Bergesio S Chauvie CPavoni A M Gianni and A Rambaldi

Early chemotherapy intensification with escalated BEACOPP in advanced-stage Hodgkin Lymphoma patients with a positive interim PET-CT after 2 ABVD cycles long-term results of the GITILFIL HD 0607 trial

Pts enrolledregistered 783785

Pt enrollment 62008- 62014Median fu for pts completing treatment 1303 (2-2857) days

0

02

04

06

08

1

0 2 4 6 8

DS 4

DS 5

0

02

04

06

08

1

0 2 4 6 8

DS 4

DS 5

DS 4 101 (5) 82 (2) 29 (1) 3 (0) 0

DS 5 49 (5) 34 (2) 8 (1) 1 (0) 0

Years from registration

P = 00696

DS 4 101 (15) 75 (2) 26 (0) 3 (0) 0

DS 5 49 (25) 19 (1) 5 (0) 1 (0) 0

Years from registration

P lt 0001

Overall Survival Progression-free Survival

OS and PFS according to Deauville Score

4-Y OS 92 (95CI 84-96)

4-Y OS 83 (95CI 67-92)

4-Y PFS 81 (95CI 71-88)

4-Y PFS 46 (95CI 31-59)

PET-2 positive patient with a DS 4 switching to BEACOPP have a 3-Y PFS similar to the entire cohort of patients (4-Y PFS 81 95 CI 71-88)Patients with a DS 5 which are a small subset of the entire population (63) still represent an unmet therapeutic need awaiting new treatment strategies

Gallamini A et al EHA 2017

0

02

04

06

08

1

0 2 4 6 8

No RX

RX

No RX 148 (1) 141 (2) 40 (0) 0 (0) 0

RX 148 (0) 144 (0) 40 (0) 0 (0) 0

Years from registration

P = 00790

4-Y OS 100

4-Y OS 98 (95CI 92-99)

0

02

04

06

08

1

0 2 4 6 8

No RX

RX

No RX 148 (9) 133 (1) 35 (0) 14 (0) 0

RX 148 (5) 139 (1) 39 (0) 10 (0) 0

Years from registration

P = 02882

4-Y PFS 96 (95CI 91-98)

4-Y PFS 93 (95CI 87-96)

Overall Survival Progression-free Survival

OS and PFS in PET2- randomized to RXNFT

Consolidation radiotherapy in the region where a large nodal mass was recorded at baseline did not improve treatment result in negative PET-2 and PET-6 patients irrespective of the dimension of the lesion at baseline

Gallamini A et al EHA 2017

BEACOPP esc x 2

Standard Arm Experimental Arm

Neg Pos

Salvagetherapy

Pos Neg

PET4

PET2

Neg Pos Neg Pos Neg

BEACOPP esc x 2

IPS 0-7BEACOPP esc x 2 BEACOPP esc x 2

BEACOPP esc x 2

R

ABVD x 2

Non inferiority of the experimental arm

ABVD x 2

BEACOPP esc x 2

Courtesy of O Casasnovas

Kairos

Gela ahl2011Stage IIIIV and high risk IIB Hodgkin Lymphoma

Salvagetherapy

Primary Endpoint Planned accrual Date start Date end

5-yr PFS 810 Pts May 2011 May 2015

Abs 577 Randomized phase III study comparing an early PET driven treatment de-escalation to non-PET monitored strategy in patients with advanced HL

O Casasnovas ASH 2015

There was no significant difference between the experimental and standard arms Reduction of therapy based on negative interim PET is safe

Randomized phase III study comparing an early PET driven treatment de-escalation to non pet monitored strategy in patients with advanced HL

O Casanovas ASH 2015

Positive interim PET is a risk factor for HL progression even if EB is continued

Casanovas 2016

There is a value to perform PET-4 if PET-2 is positive Consider change of therapy if PET-4 is positive

Casanovas 2016

Is there a role for PET-4 if treatment was escalated based on PET-2

Casanovas 2016

Progression 90 PtsProgression 157 Pts

ABVD x2

PET-2

BEACOPP ESC x4

PET-6ABVD x4

IPS 0-2

NEGATIVE

POSITIVEBEACOPP ESC x2

IPS 3-7

PET-6ISRT to bulky MM

+

Israeli H2 protocol for advanced Hodgkin lymphoma

B symptoms Stage III IV

The study prospectively evaluated the outcome of HL patients whose therapy waschosen based on initial prognostic factors and tailored based on results of PETCTperformed after 2 cycles of chemotherapy

This multicenter study was initiated in 2006 and ended in 72013 enrolling 355 patientswith stages I-IV HL aged 18-60 years

Conclusions

bull Both baseline PETCT and PET-2 are recommendedbull Deauville scores 1-3 should be considered a negative PET resultbull Positive PET-2 (DS 4-5) is a poor prognostic sign when treatment is initiated

with ABVD or even with EB (Gallamini Johnson Casasnovas)bull Escalation of therapy in PET-2 positive patients improves the outcomebull Escalation of therapy to EB in early-stage HL Pts with positive PET-2 (DS 4-5)

improves PFS (Andrersquo M Straus D)bull Pts with high IPS or bulky mediastinal mass have a worse outcome if

therapy is initiated with ABVD and a higher probability of a positive PET-2 (Johnson)

bull If therapy is initiated with escalated BEACOPP de-escalation of therapy to ABVD does not impair the outcome (Casasnovas)

bull The same percentage of PET-2 negativity was found in patients with IPS 0-2 who initiated therapy with ABVD (5-y PFS 079) and in patients with IPS 3-7 whose initial therapy was escalated BEACOPP (5-y PFS 081) (Dann)

bull Salvage therapy should be considered in PET-2 (DS-5) or PET-4 (DS 4-5) positive patients (Johnson Casasnovas )

Thank You e_dannrambamhealthgovil

Should BLEOMYCIN be omitted at age ge 65

RAPID trial toxicity

Bleomycin in older early-stage favorable Hodgkin lymphoma patients analysis of the German Hodgkin Study Group (GHSG) HD10 and HD13 trialsBoris Bumloll et al German Hodgkin Study Group

Two cycles of ABVD or AVD were equally tolerable in older early-stage favorable HL patients Excessive toxicity including severe bleomycin-induced lung toxicity occurred in older HL patients receiving 4 cycles of ABVD Doxorubicin bleomycin vinblastine sulfate and dacarbazine (ABVD) is associated with severe toxicity in older patients particularly from bleomycin-induced lung toxicity (BLT) Therefore using bleomycin has been questioned in older Hodgkin lymphoma (HL) patients especially in early-stage HL We therefore analyzed feasibility toxicity and efficacy of ABVD or AVD in 287 older early-stage favorable HL patients We included patients ge60 years of age in the German Hodgkin Study Group HD10 and HD13 trials randomized to either 2 cycles of ABVD (2XABVD n = 137) or AVD (2xAVD n = 82) each followed by involved-field radiotherapy (IF-RT) with patients randomized to 4xABVD+IFRT (n =68) Patientsrsquo median age was 65 years (range 60-75) with comparable patient and disease characteristics Grade III-IV adverse event rates were similar in patients receiving 2xAVD and 2xABVD (40 and 39 respectively) but considerably higher in patients receiving 4xABVD (65) Similarly BLT was rare in patients receiving 2xABVDAVD but occurred in 769 (10) of patients randomized to 4xABVD with 3 lethal events In conclusion no effects of bleomycin on toxicity rates were detectable in older patients receiving 2 cycles of chemotherapy However we found a high risk of severe toxicity of bleomycin in older HL patients receiving more than 2 cycles of ABVD (Blood 2016 127(18)2189-2192)

Forty-four advanced-stage older HL patients (aged ge60 years) were treated on the randomized study E2496 Toxicities were mostly similar between chemotherapy regimens although 24 of older patients developed bleomycin lung toxicity (BLT) which occurred mainly with ABVD (91) Further the BLT-related mortality rate was 18 The overall treatment-related mortality for older HL patients was 9 versus 03 for patients aged lt60 years (plt0001) Among older patients there were no survival differences between ABVD and SV According to age outcomes were significantly inferior for older versus younger patients (5-year FFS 48 vs 74 respectively p=0002 5-year OS 58 and 90 respectively plt00001)Among the 45 older HL patients enrolled 11 (24) developed BLT of whom 211 (18) died due to acute pulmonary fibrosisrespiratory failure) Furthermore 1011 (91) BLT cases occurred withduring ABVD (BLT incidence 43 with ABVD vs 5 Stanford V p=004) This toxicity appeared to occur later in the chemotherapy course however the two BLT-related deaths occurred during cycle 3 of ABVD We did not identify any factors that predicted the development of BLT or death due to BLT Granulocyte growth factor was given the vast majority of patients thus it was not analyzed as a risk factor

The Efficacy and Tolerability of ABVD and Stanford V in Older Hodgkin Lymphoma Patients A Comprehensive Analysis from the North American Intergroup Trial E2496 Andrew M Evens et al BJH 2013

2 cycles ABVD

Full dose on schedule

PET 2 -vePET 2 +ve

4 cycles ABVD

PET2

PET 1(Staging)

IPS 0-7

Randomize

4 cycles AVD

Follow-up (no RT)

4 cycles BEACOPP-14

or 3 eBEACOPP

PET3

PET 3 -vePET 3 +ve

RT or salvage

regimen

2 cycles BEACOPP-14 or

1 eBEACOPP

No RT

RATHL study Chairman Peter Johnson

Johnson P Federico M et al NEJM2016

Outcomes at 1 year according to PET score after ABVD x 2

PET 2 Score Total Number

Number Assessable

at 1 yr

Progressions Deaths PFS events

1 114 88 7 0 80

2 493 375 25 6 72

3 347 239 20 4 96

4 144 102 14 7 167

5 38 25 10 5 520PET Missing 78 22 0 2 91

Total 1214 851 76 24 105

Johnson P Federico M et al NEJM2016

PET-2 +PFS

PET-2 ndashPFS ()

PET-2- PET-2+

PET-2 DS 1-3 negativeDS 4-5 positive

NStageTrial

69 (4y)87 (4y)81192xABVD ndash 4xABVD+ 4xEB+4xSB

2xABVD ndash 4xAVD+ 4xEB or 6xSB

2xABVD ndash 4xABVD+ 6xEB

780IIB-IVB

GITIL 0607Gallamini A

(in press)

675 (3y)85 (3y)84161119IIB-IVB

NCRI RATHLJohnson P

NEJM 2016

64 (2y)82 (2y)8218336III-IVSWOG S0816Press O

JCO 2016

668582182235TOTALMEAN

Gallamini A Kostakoglu L Ann Oncol 2015

Positive interim PETCT is an adverse prognostic marker and treatment intensification improves prognosis However it is inferior to that observed pts with negative PET-2

68 (5y)82 (5y)88 8112 19IPS 0-2ge 3 ABVDEB

185IIB-IVH2 BJH 2017

73 (2y)93 (2y)87132xEB - 4x ABVDEB+4x EB

810IIB-IVGELLA AHL 2011

A Gallamini C Tarella S Viviani A Rossi C Patti M Picardi A Romano M Cantonetti G La Nasa L Trentin SBolis D Rapezzi V Zoli D Gottardi P Gavarotti P Corradini M Cimminiello C Schiavotto G Parvis RZanotti G Gini A JM Ferreri P Viero A Biggi F Fallanca U Ficola G Prosperini F Bergesio S Chauvie CPavoni A M Gianni and A Rambaldi

Early chemotherapy intensification with escalated BEACOPP in advanced-stage Hodgkin Lymphoma patients with a positive interim PET-CT after 2 ABVD cycles long-term results of the GITILFIL HD 0607 trial

Pts enrolledregistered 783785

Pt enrollment 62008- 62014Median fu for pts completing treatment 1303 (2-2857) days

0

02

04

06

08

1

0 2 4 6 8

DS 4

DS 5

0

02

04

06

08

1

0 2 4 6 8

DS 4

DS 5

DS 4 101 (5) 82 (2) 29 (1) 3 (0) 0

DS 5 49 (5) 34 (2) 8 (1) 1 (0) 0

Years from registration

P = 00696

DS 4 101 (15) 75 (2) 26 (0) 3 (0) 0

DS 5 49 (25) 19 (1) 5 (0) 1 (0) 0

Years from registration

P lt 0001

Overall Survival Progression-free Survival

OS and PFS according to Deauville Score

4-Y OS 92 (95CI 84-96)

4-Y OS 83 (95CI 67-92)

4-Y PFS 81 (95CI 71-88)

4-Y PFS 46 (95CI 31-59)

PET-2 positive patient with a DS 4 switching to BEACOPP have a 3-Y PFS similar to the entire cohort of patients (4-Y PFS 81 95 CI 71-88)Patients with a DS 5 which are a small subset of the entire population (63) still represent an unmet therapeutic need awaiting new treatment strategies

Gallamini A et al EHA 2017

0

02

04

06

08

1

0 2 4 6 8

No RX

RX

No RX 148 (1) 141 (2) 40 (0) 0 (0) 0

RX 148 (0) 144 (0) 40 (0) 0 (0) 0

Years from registration

P = 00790

4-Y OS 100

4-Y OS 98 (95CI 92-99)

0

02

04

06

08

1

0 2 4 6 8

No RX

RX

No RX 148 (9) 133 (1) 35 (0) 14 (0) 0

RX 148 (5) 139 (1) 39 (0) 10 (0) 0

Years from registration

P = 02882

4-Y PFS 96 (95CI 91-98)

4-Y PFS 93 (95CI 87-96)

Overall Survival Progression-free Survival

OS and PFS in PET2- randomized to RXNFT

Consolidation radiotherapy in the region where a large nodal mass was recorded at baseline did not improve treatment result in negative PET-2 and PET-6 patients irrespective of the dimension of the lesion at baseline

Gallamini A et al EHA 2017

BEACOPP esc x 2

Standard Arm Experimental Arm

Neg Pos

Salvagetherapy

Pos Neg

PET4

PET2

Neg Pos Neg Pos Neg

BEACOPP esc x 2

IPS 0-7BEACOPP esc x 2 BEACOPP esc x 2

BEACOPP esc x 2

R

ABVD x 2

Non inferiority of the experimental arm

ABVD x 2

BEACOPP esc x 2

Courtesy of O Casasnovas

Kairos

Gela ahl2011Stage IIIIV and high risk IIB Hodgkin Lymphoma

Salvagetherapy

Primary Endpoint Planned accrual Date start Date end

5-yr PFS 810 Pts May 2011 May 2015

Abs 577 Randomized phase III study comparing an early PET driven treatment de-escalation to non-PET monitored strategy in patients with advanced HL

O Casasnovas ASH 2015

There was no significant difference between the experimental and standard arms Reduction of therapy based on negative interim PET is safe

Randomized phase III study comparing an early PET driven treatment de-escalation to non pet monitored strategy in patients with advanced HL

O Casanovas ASH 2015

Positive interim PET is a risk factor for HL progression even if EB is continued

Casanovas 2016

There is a value to perform PET-4 if PET-2 is positive Consider change of therapy if PET-4 is positive

Casanovas 2016

Is there a role for PET-4 if treatment was escalated based on PET-2

Casanovas 2016

Progression 90 PtsProgression 157 Pts

ABVD x2

PET-2

BEACOPP ESC x4

PET-6ABVD x4

IPS 0-2

NEGATIVE

POSITIVEBEACOPP ESC x2

IPS 3-7

PET-6ISRT to bulky MM

+

Israeli H2 protocol for advanced Hodgkin lymphoma

B symptoms Stage III IV

The study prospectively evaluated the outcome of HL patients whose therapy waschosen based on initial prognostic factors and tailored based on results of PETCTperformed after 2 cycles of chemotherapy

This multicenter study was initiated in 2006 and ended in 72013 enrolling 355 patientswith stages I-IV HL aged 18-60 years

Conclusions

bull Both baseline PETCT and PET-2 are recommendedbull Deauville scores 1-3 should be considered a negative PET resultbull Positive PET-2 (DS 4-5) is a poor prognostic sign when treatment is initiated

with ABVD or even with EB (Gallamini Johnson Casasnovas)bull Escalation of therapy in PET-2 positive patients improves the outcomebull Escalation of therapy to EB in early-stage HL Pts with positive PET-2 (DS 4-5)

improves PFS (Andrersquo M Straus D)bull Pts with high IPS or bulky mediastinal mass have a worse outcome if

therapy is initiated with ABVD and a higher probability of a positive PET-2 (Johnson)

bull If therapy is initiated with escalated BEACOPP de-escalation of therapy to ABVD does not impair the outcome (Casasnovas)

bull The same percentage of PET-2 negativity was found in patients with IPS 0-2 who initiated therapy with ABVD (5-y PFS 079) and in patients with IPS 3-7 whose initial therapy was escalated BEACOPP (5-y PFS 081) (Dann)

bull Salvage therapy should be considered in PET-2 (DS-5) or PET-4 (DS 4-5) positive patients (Johnson Casasnovas )

Thank You e_dannrambamhealthgovil

Should BLEOMYCIN be omitted at age ge 65

RAPID trial toxicity

Bleomycin in older early-stage favorable Hodgkin lymphoma patients analysis of the German Hodgkin Study Group (GHSG) HD10 and HD13 trialsBoris Bumloll et al German Hodgkin Study Group

Two cycles of ABVD or AVD were equally tolerable in older early-stage favorable HL patients Excessive toxicity including severe bleomycin-induced lung toxicity occurred in older HL patients receiving 4 cycles of ABVD Doxorubicin bleomycin vinblastine sulfate and dacarbazine (ABVD) is associated with severe toxicity in older patients particularly from bleomycin-induced lung toxicity (BLT) Therefore using bleomycin has been questioned in older Hodgkin lymphoma (HL) patients especially in early-stage HL We therefore analyzed feasibility toxicity and efficacy of ABVD or AVD in 287 older early-stage favorable HL patients We included patients ge60 years of age in the German Hodgkin Study Group HD10 and HD13 trials randomized to either 2 cycles of ABVD (2XABVD n = 137) or AVD (2xAVD n = 82) each followed by involved-field radiotherapy (IF-RT) with patients randomized to 4xABVD+IFRT (n =68) Patientsrsquo median age was 65 years (range 60-75) with comparable patient and disease characteristics Grade III-IV adverse event rates were similar in patients receiving 2xAVD and 2xABVD (40 and 39 respectively) but considerably higher in patients receiving 4xABVD (65) Similarly BLT was rare in patients receiving 2xABVDAVD but occurred in 769 (10) of patients randomized to 4xABVD with 3 lethal events In conclusion no effects of bleomycin on toxicity rates were detectable in older patients receiving 2 cycles of chemotherapy However we found a high risk of severe toxicity of bleomycin in older HL patients receiving more than 2 cycles of ABVD (Blood 2016 127(18)2189-2192)

Forty-four advanced-stage older HL patients (aged ge60 years) were treated on the randomized study E2496 Toxicities were mostly similar between chemotherapy regimens although 24 of older patients developed bleomycin lung toxicity (BLT) which occurred mainly with ABVD (91) Further the BLT-related mortality rate was 18 The overall treatment-related mortality for older HL patients was 9 versus 03 for patients aged lt60 years (plt0001) Among older patients there were no survival differences between ABVD and SV According to age outcomes were significantly inferior for older versus younger patients (5-year FFS 48 vs 74 respectively p=0002 5-year OS 58 and 90 respectively plt00001)Among the 45 older HL patients enrolled 11 (24) developed BLT of whom 211 (18) died due to acute pulmonary fibrosisrespiratory failure) Furthermore 1011 (91) BLT cases occurred withduring ABVD (BLT incidence 43 with ABVD vs 5 Stanford V p=004) This toxicity appeared to occur later in the chemotherapy course however the two BLT-related deaths occurred during cycle 3 of ABVD We did not identify any factors that predicted the development of BLT or death due to BLT Granulocyte growth factor was given the vast majority of patients thus it was not analyzed as a risk factor

The Efficacy and Tolerability of ABVD and Stanford V in Older Hodgkin Lymphoma Patients A Comprehensive Analysis from the North American Intergroup Trial E2496 Andrew M Evens et al BJH 2013

Outcomes at 1 year according to PET score after ABVD x 2

PET 2 Score Total Number

Number Assessable

at 1 yr

Progressions Deaths PFS events

1 114 88 7 0 80

2 493 375 25 6 72

3 347 239 20 4 96

4 144 102 14 7 167

5 38 25 10 5 520PET Missing 78 22 0 2 91

Total 1214 851 76 24 105

Johnson P Federico M et al NEJM2016

PET-2 +PFS

PET-2 ndashPFS ()

PET-2- PET-2+

PET-2 DS 1-3 negativeDS 4-5 positive

NStageTrial

69 (4y)87 (4y)81192xABVD ndash 4xABVD+ 4xEB+4xSB

2xABVD ndash 4xAVD+ 4xEB or 6xSB

2xABVD ndash 4xABVD+ 6xEB

780IIB-IVB

GITIL 0607Gallamini A

(in press)

675 (3y)85 (3y)84161119IIB-IVB

NCRI RATHLJohnson P

NEJM 2016

64 (2y)82 (2y)8218336III-IVSWOG S0816Press O

JCO 2016

668582182235TOTALMEAN

Gallamini A Kostakoglu L Ann Oncol 2015

Positive interim PETCT is an adverse prognostic marker and treatment intensification improves prognosis However it is inferior to that observed pts with negative PET-2

68 (5y)82 (5y)88 8112 19IPS 0-2ge 3 ABVDEB

185IIB-IVH2 BJH 2017

73 (2y)93 (2y)87132xEB - 4x ABVDEB+4x EB

810IIB-IVGELLA AHL 2011

A Gallamini C Tarella S Viviani A Rossi C Patti M Picardi A Romano M Cantonetti G La Nasa L Trentin SBolis D Rapezzi V Zoli D Gottardi P Gavarotti P Corradini M Cimminiello C Schiavotto G Parvis RZanotti G Gini A JM Ferreri P Viero A Biggi F Fallanca U Ficola G Prosperini F Bergesio S Chauvie CPavoni A M Gianni and A Rambaldi

Early chemotherapy intensification with escalated BEACOPP in advanced-stage Hodgkin Lymphoma patients with a positive interim PET-CT after 2 ABVD cycles long-term results of the GITILFIL HD 0607 trial

Pts enrolledregistered 783785

Pt enrollment 62008- 62014Median fu for pts completing treatment 1303 (2-2857) days

0

02

04

06

08

1

0 2 4 6 8

DS 4

DS 5

0

02

04

06

08

1

0 2 4 6 8

DS 4

DS 5

DS 4 101 (5) 82 (2) 29 (1) 3 (0) 0

DS 5 49 (5) 34 (2) 8 (1) 1 (0) 0

Years from registration

P = 00696

DS 4 101 (15) 75 (2) 26 (0) 3 (0) 0

DS 5 49 (25) 19 (1) 5 (0) 1 (0) 0

Years from registration

P lt 0001

Overall Survival Progression-free Survival

OS and PFS according to Deauville Score

4-Y OS 92 (95CI 84-96)

4-Y OS 83 (95CI 67-92)

4-Y PFS 81 (95CI 71-88)

4-Y PFS 46 (95CI 31-59)

PET-2 positive patient with a DS 4 switching to BEACOPP have a 3-Y PFS similar to the entire cohort of patients (4-Y PFS 81 95 CI 71-88)Patients with a DS 5 which are a small subset of the entire population (63) still represent an unmet therapeutic need awaiting new treatment strategies

Gallamini A et al EHA 2017

0

02

04

06

08

1

0 2 4 6 8

No RX

RX

No RX 148 (1) 141 (2) 40 (0) 0 (0) 0

RX 148 (0) 144 (0) 40 (0) 0 (0) 0

Years from registration

P = 00790

4-Y OS 100

4-Y OS 98 (95CI 92-99)

0

02

04

06

08

1

0 2 4 6 8

No RX

RX

No RX 148 (9) 133 (1) 35 (0) 14 (0) 0

RX 148 (5) 139 (1) 39 (0) 10 (0) 0

Years from registration

P = 02882

4-Y PFS 96 (95CI 91-98)

4-Y PFS 93 (95CI 87-96)

Overall Survival Progression-free Survival

OS and PFS in PET2- randomized to RXNFT

Consolidation radiotherapy in the region where a large nodal mass was recorded at baseline did not improve treatment result in negative PET-2 and PET-6 patients irrespective of the dimension of the lesion at baseline

Gallamini A et al EHA 2017

BEACOPP esc x 2

Standard Arm Experimental Arm

Neg Pos

Salvagetherapy

Pos Neg

PET4

PET2

Neg Pos Neg Pos Neg

BEACOPP esc x 2

IPS 0-7BEACOPP esc x 2 BEACOPP esc x 2

BEACOPP esc x 2

R

ABVD x 2

Non inferiority of the experimental arm

ABVD x 2

BEACOPP esc x 2

Courtesy of O Casasnovas

Kairos

Gela ahl2011Stage IIIIV and high risk IIB Hodgkin Lymphoma

Salvagetherapy

Primary Endpoint Planned accrual Date start Date end

5-yr PFS 810 Pts May 2011 May 2015

Abs 577 Randomized phase III study comparing an early PET driven treatment de-escalation to non-PET monitored strategy in patients with advanced HL

O Casasnovas ASH 2015

There was no significant difference between the experimental and standard arms Reduction of therapy based on negative interim PET is safe

Randomized phase III study comparing an early PET driven treatment de-escalation to non pet monitored strategy in patients with advanced HL

O Casanovas ASH 2015

Positive interim PET is a risk factor for HL progression even if EB is continued

Casanovas 2016

There is a value to perform PET-4 if PET-2 is positive Consider change of therapy if PET-4 is positive

Casanovas 2016

Is there a role for PET-4 if treatment was escalated based on PET-2

Casanovas 2016

Progression 90 PtsProgression 157 Pts

ABVD x2

PET-2

BEACOPP ESC x4

PET-6ABVD x4

IPS 0-2

NEGATIVE

POSITIVEBEACOPP ESC x2

IPS 3-7

PET-6ISRT to bulky MM

+

Israeli H2 protocol for advanced Hodgkin lymphoma

B symptoms Stage III IV

The study prospectively evaluated the outcome of HL patients whose therapy waschosen based on initial prognostic factors and tailored based on results of PETCTperformed after 2 cycles of chemotherapy

This multicenter study was initiated in 2006 and ended in 72013 enrolling 355 patientswith stages I-IV HL aged 18-60 years

Conclusions

bull Both baseline PETCT and PET-2 are recommendedbull Deauville scores 1-3 should be considered a negative PET resultbull Positive PET-2 (DS 4-5) is a poor prognostic sign when treatment is initiated

with ABVD or even with EB (Gallamini Johnson Casasnovas)bull Escalation of therapy in PET-2 positive patients improves the outcomebull Escalation of therapy to EB in early-stage HL Pts with positive PET-2 (DS 4-5)

improves PFS (Andrersquo M Straus D)bull Pts with high IPS or bulky mediastinal mass have a worse outcome if

therapy is initiated with ABVD and a higher probability of a positive PET-2 (Johnson)

bull If therapy is initiated with escalated BEACOPP de-escalation of therapy to ABVD does not impair the outcome (Casasnovas)

bull The same percentage of PET-2 negativity was found in patients with IPS 0-2 who initiated therapy with ABVD (5-y PFS 079) and in patients with IPS 3-7 whose initial therapy was escalated BEACOPP (5-y PFS 081) (Dann)

bull Salvage therapy should be considered in PET-2 (DS-5) or PET-4 (DS 4-5) positive patients (Johnson Casasnovas )

Thank You e_dannrambamhealthgovil

Should BLEOMYCIN be omitted at age ge 65

RAPID trial toxicity

Bleomycin in older early-stage favorable Hodgkin lymphoma patients analysis of the German Hodgkin Study Group (GHSG) HD10 and HD13 trialsBoris Bumloll et al German Hodgkin Study Group

Two cycles of ABVD or AVD were equally tolerable in older early-stage favorable HL patients Excessive toxicity including severe bleomycin-induced lung toxicity occurred in older HL patients receiving 4 cycles of ABVD Doxorubicin bleomycin vinblastine sulfate and dacarbazine (ABVD) is associated with severe toxicity in older patients particularly from bleomycin-induced lung toxicity (BLT) Therefore using bleomycin has been questioned in older Hodgkin lymphoma (HL) patients especially in early-stage HL We therefore analyzed feasibility toxicity and efficacy of ABVD or AVD in 287 older early-stage favorable HL patients We included patients ge60 years of age in the German Hodgkin Study Group HD10 and HD13 trials randomized to either 2 cycles of ABVD (2XABVD n = 137) or AVD (2xAVD n = 82) each followed by involved-field radiotherapy (IF-RT) with patients randomized to 4xABVD+IFRT (n =68) Patientsrsquo median age was 65 years (range 60-75) with comparable patient and disease characteristics Grade III-IV adverse event rates were similar in patients receiving 2xAVD and 2xABVD (40 and 39 respectively) but considerably higher in patients receiving 4xABVD (65) Similarly BLT was rare in patients receiving 2xABVDAVD but occurred in 769 (10) of patients randomized to 4xABVD with 3 lethal events In conclusion no effects of bleomycin on toxicity rates were detectable in older patients receiving 2 cycles of chemotherapy However we found a high risk of severe toxicity of bleomycin in older HL patients receiving more than 2 cycles of ABVD (Blood 2016 127(18)2189-2192)

Forty-four advanced-stage older HL patients (aged ge60 years) were treated on the randomized study E2496 Toxicities were mostly similar between chemotherapy regimens although 24 of older patients developed bleomycin lung toxicity (BLT) which occurred mainly with ABVD (91) Further the BLT-related mortality rate was 18 The overall treatment-related mortality for older HL patients was 9 versus 03 for patients aged lt60 years (plt0001) Among older patients there were no survival differences between ABVD and SV According to age outcomes were significantly inferior for older versus younger patients (5-year FFS 48 vs 74 respectively p=0002 5-year OS 58 and 90 respectively plt00001)Among the 45 older HL patients enrolled 11 (24) developed BLT of whom 211 (18) died due to acute pulmonary fibrosisrespiratory failure) Furthermore 1011 (91) BLT cases occurred withduring ABVD (BLT incidence 43 with ABVD vs 5 Stanford V p=004) This toxicity appeared to occur later in the chemotherapy course however the two BLT-related deaths occurred during cycle 3 of ABVD We did not identify any factors that predicted the development of BLT or death due to BLT Granulocyte growth factor was given the vast majority of patients thus it was not analyzed as a risk factor

The Efficacy and Tolerability of ABVD and Stanford V in Older Hodgkin Lymphoma Patients A Comprehensive Analysis from the North American Intergroup Trial E2496 Andrew M Evens et al BJH 2013

Johnson P Federico M et al NEJM2016

PET-2 +PFS

PET-2 ndashPFS ()

PET-2- PET-2+

PET-2 DS 1-3 negativeDS 4-5 positive

NStageTrial

69 (4y)87 (4y)81192xABVD ndash 4xABVD+ 4xEB+4xSB

2xABVD ndash 4xAVD+ 4xEB or 6xSB

2xABVD ndash 4xABVD+ 6xEB

780IIB-IVB

GITIL 0607Gallamini A

(in press)

675 (3y)85 (3y)84161119IIB-IVB

NCRI RATHLJohnson P

NEJM 2016

64 (2y)82 (2y)8218336III-IVSWOG S0816Press O

JCO 2016

668582182235TOTALMEAN

Gallamini A Kostakoglu L Ann Oncol 2015

Positive interim PETCT is an adverse prognostic marker and treatment intensification improves prognosis However it is inferior to that observed pts with negative PET-2

68 (5y)82 (5y)88 8112 19IPS 0-2ge 3 ABVDEB

185IIB-IVH2 BJH 2017

73 (2y)93 (2y)87132xEB - 4x ABVDEB+4x EB

810IIB-IVGELLA AHL 2011

A Gallamini C Tarella S Viviani A Rossi C Patti M Picardi A Romano M Cantonetti G La Nasa L Trentin SBolis D Rapezzi V Zoli D Gottardi P Gavarotti P Corradini M Cimminiello C Schiavotto G Parvis RZanotti G Gini A JM Ferreri P Viero A Biggi F Fallanca U Ficola G Prosperini F Bergesio S Chauvie CPavoni A M Gianni and A Rambaldi

Early chemotherapy intensification with escalated BEACOPP in advanced-stage Hodgkin Lymphoma patients with a positive interim PET-CT after 2 ABVD cycles long-term results of the GITILFIL HD 0607 trial

Pts enrolledregistered 783785

Pt enrollment 62008- 62014Median fu for pts completing treatment 1303 (2-2857) days

0

02

04

06

08

1

0 2 4 6 8

DS 4

DS 5

0

02

04

06

08

1

0 2 4 6 8

DS 4

DS 5

DS 4 101 (5) 82 (2) 29 (1) 3 (0) 0

DS 5 49 (5) 34 (2) 8 (1) 1 (0) 0

Years from registration

P = 00696

DS 4 101 (15) 75 (2) 26 (0) 3 (0) 0

DS 5 49 (25) 19 (1) 5 (0) 1 (0) 0

Years from registration

P lt 0001

Overall Survival Progression-free Survival

OS and PFS according to Deauville Score

4-Y OS 92 (95CI 84-96)

4-Y OS 83 (95CI 67-92)

4-Y PFS 81 (95CI 71-88)

4-Y PFS 46 (95CI 31-59)

PET-2 positive patient with a DS 4 switching to BEACOPP have a 3-Y PFS similar to the entire cohort of patients (4-Y PFS 81 95 CI 71-88)Patients with a DS 5 which are a small subset of the entire population (63) still represent an unmet therapeutic need awaiting new treatment strategies

Gallamini A et al EHA 2017

0

02

04

06

08

1

0 2 4 6 8

No RX

RX

No RX 148 (1) 141 (2) 40 (0) 0 (0) 0

RX 148 (0) 144 (0) 40 (0) 0 (0) 0

Years from registration

P = 00790

4-Y OS 100

4-Y OS 98 (95CI 92-99)

0

02

04

06

08

1

0 2 4 6 8

No RX

RX

No RX 148 (9) 133 (1) 35 (0) 14 (0) 0

RX 148 (5) 139 (1) 39 (0) 10 (0) 0

Years from registration

P = 02882

4-Y PFS 96 (95CI 91-98)

4-Y PFS 93 (95CI 87-96)

Overall Survival Progression-free Survival

OS and PFS in PET2- randomized to RXNFT

Consolidation radiotherapy in the region where a large nodal mass was recorded at baseline did not improve treatment result in negative PET-2 and PET-6 patients irrespective of the dimension of the lesion at baseline

Gallamini A et al EHA 2017

BEACOPP esc x 2

Standard Arm Experimental Arm

Neg Pos

Salvagetherapy

Pos Neg

PET4

PET2

Neg Pos Neg Pos Neg

BEACOPP esc x 2

IPS 0-7BEACOPP esc x 2 BEACOPP esc x 2

BEACOPP esc x 2

R

ABVD x 2

Non inferiority of the experimental arm

ABVD x 2

BEACOPP esc x 2

Courtesy of O Casasnovas

Kairos

Gela ahl2011Stage IIIIV and high risk IIB Hodgkin Lymphoma

Salvagetherapy

Primary Endpoint Planned accrual Date start Date end

5-yr PFS 810 Pts May 2011 May 2015

Abs 577 Randomized phase III study comparing an early PET driven treatment de-escalation to non-PET monitored strategy in patients with advanced HL

O Casasnovas ASH 2015

There was no significant difference between the experimental and standard arms Reduction of therapy based on negative interim PET is safe

Randomized phase III study comparing an early PET driven treatment de-escalation to non pet monitored strategy in patients with advanced HL

O Casanovas ASH 2015

Positive interim PET is a risk factor for HL progression even if EB is continued

Casanovas 2016

There is a value to perform PET-4 if PET-2 is positive Consider change of therapy if PET-4 is positive

Casanovas 2016

Is there a role for PET-4 if treatment was escalated based on PET-2

Casanovas 2016

Progression 90 PtsProgression 157 Pts

ABVD x2

PET-2

BEACOPP ESC x4

PET-6ABVD x4

IPS 0-2

NEGATIVE

POSITIVEBEACOPP ESC x2

IPS 3-7

PET-6ISRT to bulky MM

+

Israeli H2 protocol for advanced Hodgkin lymphoma

B symptoms Stage III IV

The study prospectively evaluated the outcome of HL patients whose therapy waschosen based on initial prognostic factors and tailored based on results of PETCTperformed after 2 cycles of chemotherapy

This multicenter study was initiated in 2006 and ended in 72013 enrolling 355 patientswith stages I-IV HL aged 18-60 years

Conclusions

bull Both baseline PETCT and PET-2 are recommendedbull Deauville scores 1-3 should be considered a negative PET resultbull Positive PET-2 (DS 4-5) is a poor prognostic sign when treatment is initiated

with ABVD or even with EB (Gallamini Johnson Casasnovas)bull Escalation of therapy in PET-2 positive patients improves the outcomebull Escalation of therapy to EB in early-stage HL Pts with positive PET-2 (DS 4-5)

improves PFS (Andrersquo M Straus D)bull Pts with high IPS or bulky mediastinal mass have a worse outcome if

therapy is initiated with ABVD and a higher probability of a positive PET-2 (Johnson)

bull If therapy is initiated with escalated BEACOPP de-escalation of therapy to ABVD does not impair the outcome (Casasnovas)

bull The same percentage of PET-2 negativity was found in patients with IPS 0-2 who initiated therapy with ABVD (5-y PFS 079) and in patients with IPS 3-7 whose initial therapy was escalated BEACOPP (5-y PFS 081) (Dann)

bull Salvage therapy should be considered in PET-2 (DS-5) or PET-4 (DS 4-5) positive patients (Johnson Casasnovas )

Thank You e_dannrambamhealthgovil

Should BLEOMYCIN be omitted at age ge 65

RAPID trial toxicity

Bleomycin in older early-stage favorable Hodgkin lymphoma patients analysis of the German Hodgkin Study Group (GHSG) HD10 and HD13 trialsBoris Bumloll et al German Hodgkin Study Group

Two cycles of ABVD or AVD were equally tolerable in older early-stage favorable HL patients Excessive toxicity including severe bleomycin-induced lung toxicity occurred in older HL patients receiving 4 cycles of ABVD Doxorubicin bleomycin vinblastine sulfate and dacarbazine (ABVD) is associated with severe toxicity in older patients particularly from bleomycin-induced lung toxicity (BLT) Therefore using bleomycin has been questioned in older Hodgkin lymphoma (HL) patients especially in early-stage HL We therefore analyzed feasibility toxicity and efficacy of ABVD or AVD in 287 older early-stage favorable HL patients We included patients ge60 years of age in the German Hodgkin Study Group HD10 and HD13 trials randomized to either 2 cycles of ABVD (2XABVD n = 137) or AVD (2xAVD n = 82) each followed by involved-field radiotherapy (IF-RT) with patients randomized to 4xABVD+IFRT (n =68) Patientsrsquo median age was 65 years (range 60-75) with comparable patient and disease characteristics Grade III-IV adverse event rates were similar in patients receiving 2xAVD and 2xABVD (40 and 39 respectively) but considerably higher in patients receiving 4xABVD (65) Similarly BLT was rare in patients receiving 2xABVDAVD but occurred in 769 (10) of patients randomized to 4xABVD with 3 lethal events In conclusion no effects of bleomycin on toxicity rates were detectable in older patients receiving 2 cycles of chemotherapy However we found a high risk of severe toxicity of bleomycin in older HL patients receiving more than 2 cycles of ABVD (Blood 2016 127(18)2189-2192)

Forty-four advanced-stage older HL patients (aged ge60 years) were treated on the randomized study E2496 Toxicities were mostly similar between chemotherapy regimens although 24 of older patients developed bleomycin lung toxicity (BLT) which occurred mainly with ABVD (91) Further the BLT-related mortality rate was 18 The overall treatment-related mortality for older HL patients was 9 versus 03 for patients aged lt60 years (plt0001) Among older patients there were no survival differences between ABVD and SV According to age outcomes were significantly inferior for older versus younger patients (5-year FFS 48 vs 74 respectively p=0002 5-year OS 58 and 90 respectively plt00001)Among the 45 older HL patients enrolled 11 (24) developed BLT of whom 211 (18) died due to acute pulmonary fibrosisrespiratory failure) Furthermore 1011 (91) BLT cases occurred withduring ABVD (BLT incidence 43 with ABVD vs 5 Stanford V p=004) This toxicity appeared to occur later in the chemotherapy course however the two BLT-related deaths occurred during cycle 3 of ABVD We did not identify any factors that predicted the development of BLT or death due to BLT Granulocyte growth factor was given the vast majority of patients thus it was not analyzed as a risk factor

The Efficacy and Tolerability of ABVD and Stanford V in Older Hodgkin Lymphoma Patients A Comprehensive Analysis from the North American Intergroup Trial E2496 Andrew M Evens et al BJH 2013

PET-2 +PFS

PET-2 ndashPFS ()

PET-2- PET-2+

PET-2 DS 1-3 negativeDS 4-5 positive

NStageTrial

69 (4y)87 (4y)81192xABVD ndash 4xABVD+ 4xEB+4xSB

2xABVD ndash 4xAVD+ 4xEB or 6xSB

2xABVD ndash 4xABVD+ 6xEB

780IIB-IVB

GITIL 0607Gallamini A

(in press)

675 (3y)85 (3y)84161119IIB-IVB

NCRI RATHLJohnson P

NEJM 2016

64 (2y)82 (2y)8218336III-IVSWOG S0816Press O

JCO 2016

668582182235TOTALMEAN

Gallamini A Kostakoglu L Ann Oncol 2015

Positive interim PETCT is an adverse prognostic marker and treatment intensification improves prognosis However it is inferior to that observed pts with negative PET-2

68 (5y)82 (5y)88 8112 19IPS 0-2ge 3 ABVDEB

185IIB-IVH2 BJH 2017

73 (2y)93 (2y)87132xEB - 4x ABVDEB+4x EB

810IIB-IVGELLA AHL 2011

A Gallamini C Tarella S Viviani A Rossi C Patti M Picardi A Romano M Cantonetti G La Nasa L Trentin SBolis D Rapezzi V Zoli D Gottardi P Gavarotti P Corradini M Cimminiello C Schiavotto G Parvis RZanotti G Gini A JM Ferreri P Viero A Biggi F Fallanca U Ficola G Prosperini F Bergesio S Chauvie CPavoni A M Gianni and A Rambaldi

Early chemotherapy intensification with escalated BEACOPP in advanced-stage Hodgkin Lymphoma patients with a positive interim PET-CT after 2 ABVD cycles long-term results of the GITILFIL HD 0607 trial

Pts enrolledregistered 783785

Pt enrollment 62008- 62014Median fu for pts completing treatment 1303 (2-2857) days

0

02

04

06

08

1

0 2 4 6 8

DS 4

DS 5

0

02

04

06

08

1

0 2 4 6 8

DS 4

DS 5

DS 4 101 (5) 82 (2) 29 (1) 3 (0) 0

DS 5 49 (5) 34 (2) 8 (1) 1 (0) 0

Years from registration

P = 00696

DS 4 101 (15) 75 (2) 26 (0) 3 (0) 0

DS 5 49 (25) 19 (1) 5 (0) 1 (0) 0

Years from registration

P lt 0001

Overall Survival Progression-free Survival

OS and PFS according to Deauville Score

4-Y OS 92 (95CI 84-96)

4-Y OS 83 (95CI 67-92)

4-Y PFS 81 (95CI 71-88)

4-Y PFS 46 (95CI 31-59)

PET-2 positive patient with a DS 4 switching to BEACOPP have a 3-Y PFS similar to the entire cohort of patients (4-Y PFS 81 95 CI 71-88)Patients with a DS 5 which are a small subset of the entire population (63) still represent an unmet therapeutic need awaiting new treatment strategies

Gallamini A et al EHA 2017

0

02

04

06

08

1

0 2 4 6 8

No RX

RX

No RX 148 (1) 141 (2) 40 (0) 0 (0) 0

RX 148 (0) 144 (0) 40 (0) 0 (0) 0

Years from registration

P = 00790

4-Y OS 100

4-Y OS 98 (95CI 92-99)

0

02

04

06

08

1

0 2 4 6 8

No RX

RX

No RX 148 (9) 133 (1) 35 (0) 14 (0) 0

RX 148 (5) 139 (1) 39 (0) 10 (0) 0

Years from registration

P = 02882

4-Y PFS 96 (95CI 91-98)

4-Y PFS 93 (95CI 87-96)

Overall Survival Progression-free Survival

OS and PFS in PET2- randomized to RXNFT

Consolidation radiotherapy in the region where a large nodal mass was recorded at baseline did not improve treatment result in negative PET-2 and PET-6 patients irrespective of the dimension of the lesion at baseline

Gallamini A et al EHA 2017

BEACOPP esc x 2

Standard Arm Experimental Arm

Neg Pos

Salvagetherapy

Pos Neg

PET4

PET2

Neg Pos Neg Pos Neg

BEACOPP esc x 2

IPS 0-7BEACOPP esc x 2 BEACOPP esc x 2

BEACOPP esc x 2

R

ABVD x 2

Non inferiority of the experimental arm

ABVD x 2

BEACOPP esc x 2

Courtesy of O Casasnovas

Kairos

Gela ahl2011Stage IIIIV and high risk IIB Hodgkin Lymphoma

Salvagetherapy

Primary Endpoint Planned accrual Date start Date end

5-yr PFS 810 Pts May 2011 May 2015

Abs 577 Randomized phase III study comparing an early PET driven treatment de-escalation to non-PET monitored strategy in patients with advanced HL

O Casasnovas ASH 2015

There was no significant difference between the experimental and standard arms Reduction of therapy based on negative interim PET is safe

Randomized phase III study comparing an early PET driven treatment de-escalation to non pet monitored strategy in patients with advanced HL

O Casanovas ASH 2015

Positive interim PET is a risk factor for HL progression even if EB is continued

Casanovas 2016

There is a value to perform PET-4 if PET-2 is positive Consider change of therapy if PET-4 is positive

Casanovas 2016

Is there a role for PET-4 if treatment was escalated based on PET-2

Casanovas 2016

Progression 90 PtsProgression 157 Pts

ABVD x2

PET-2

BEACOPP ESC x4

PET-6ABVD x4

IPS 0-2

NEGATIVE

POSITIVEBEACOPP ESC x2

IPS 3-7

PET-6ISRT to bulky MM

+

Israeli H2 protocol for advanced Hodgkin lymphoma

B symptoms Stage III IV

The study prospectively evaluated the outcome of HL patients whose therapy waschosen based on initial prognostic factors and tailored based on results of PETCTperformed after 2 cycles of chemotherapy

This multicenter study was initiated in 2006 and ended in 72013 enrolling 355 patientswith stages I-IV HL aged 18-60 years

Conclusions

bull Both baseline PETCT and PET-2 are recommendedbull Deauville scores 1-3 should be considered a negative PET resultbull Positive PET-2 (DS 4-5) is a poor prognostic sign when treatment is initiated

with ABVD or even with EB (Gallamini Johnson Casasnovas)bull Escalation of therapy in PET-2 positive patients improves the outcomebull Escalation of therapy to EB in early-stage HL Pts with positive PET-2 (DS 4-5)

improves PFS (Andrersquo M Straus D)bull Pts with high IPS or bulky mediastinal mass have a worse outcome if

therapy is initiated with ABVD and a higher probability of a positive PET-2 (Johnson)

bull If therapy is initiated with escalated BEACOPP de-escalation of therapy to ABVD does not impair the outcome (Casasnovas)

bull The same percentage of PET-2 negativity was found in patients with IPS 0-2 who initiated therapy with ABVD (5-y PFS 079) and in patients with IPS 3-7 whose initial therapy was escalated BEACOPP (5-y PFS 081) (Dann)

bull Salvage therapy should be considered in PET-2 (DS-5) or PET-4 (DS 4-5) positive patients (Johnson Casasnovas )

Thank You e_dannrambamhealthgovil

Should BLEOMYCIN be omitted at age ge 65

RAPID trial toxicity

Bleomycin in older early-stage favorable Hodgkin lymphoma patients analysis of the German Hodgkin Study Group (GHSG) HD10 and HD13 trialsBoris Bumloll et al German Hodgkin Study Group

Two cycles of ABVD or AVD were equally tolerable in older early-stage favorable HL patients Excessive toxicity including severe bleomycin-induced lung toxicity occurred in older HL patients receiving 4 cycles of ABVD Doxorubicin bleomycin vinblastine sulfate and dacarbazine (ABVD) is associated with severe toxicity in older patients particularly from bleomycin-induced lung toxicity (BLT) Therefore using bleomycin has been questioned in older Hodgkin lymphoma (HL) patients especially in early-stage HL We therefore analyzed feasibility toxicity and efficacy of ABVD or AVD in 287 older early-stage favorable HL patients We included patients ge60 years of age in the German Hodgkin Study Group HD10 and HD13 trials randomized to either 2 cycles of ABVD (2XABVD n = 137) or AVD (2xAVD n = 82) each followed by involved-field radiotherapy (IF-RT) with patients randomized to 4xABVD+IFRT (n =68) Patientsrsquo median age was 65 years (range 60-75) with comparable patient and disease characteristics Grade III-IV adverse event rates were similar in patients receiving 2xAVD and 2xABVD (40 and 39 respectively) but considerably higher in patients receiving 4xABVD (65) Similarly BLT was rare in patients receiving 2xABVDAVD but occurred in 769 (10) of patients randomized to 4xABVD with 3 lethal events In conclusion no effects of bleomycin on toxicity rates were detectable in older patients receiving 2 cycles of chemotherapy However we found a high risk of severe toxicity of bleomycin in older HL patients receiving more than 2 cycles of ABVD (Blood 2016 127(18)2189-2192)

Forty-four advanced-stage older HL patients (aged ge60 years) were treated on the randomized study E2496 Toxicities were mostly similar between chemotherapy regimens although 24 of older patients developed bleomycin lung toxicity (BLT) which occurred mainly with ABVD (91) Further the BLT-related mortality rate was 18 The overall treatment-related mortality for older HL patients was 9 versus 03 for patients aged lt60 years (plt0001) Among older patients there were no survival differences between ABVD and SV According to age outcomes were significantly inferior for older versus younger patients (5-year FFS 48 vs 74 respectively p=0002 5-year OS 58 and 90 respectively plt00001)Among the 45 older HL patients enrolled 11 (24) developed BLT of whom 211 (18) died due to acute pulmonary fibrosisrespiratory failure) Furthermore 1011 (91) BLT cases occurred withduring ABVD (BLT incidence 43 with ABVD vs 5 Stanford V p=004) This toxicity appeared to occur later in the chemotherapy course however the two BLT-related deaths occurred during cycle 3 of ABVD We did not identify any factors that predicted the development of BLT or death due to BLT Granulocyte growth factor was given the vast majority of patients thus it was not analyzed as a risk factor

The Efficacy and Tolerability of ABVD and Stanford V in Older Hodgkin Lymphoma Patients A Comprehensive Analysis from the North American Intergroup Trial E2496 Andrew M Evens et al BJH 2013

A Gallamini C Tarella S Viviani A Rossi C Patti M Picardi A Romano M Cantonetti G La Nasa L Trentin SBolis D Rapezzi V Zoli D Gottardi P Gavarotti P Corradini M Cimminiello C Schiavotto G Parvis RZanotti G Gini A JM Ferreri P Viero A Biggi F Fallanca U Ficola G Prosperini F Bergesio S Chauvie CPavoni A M Gianni and A Rambaldi

Early chemotherapy intensification with escalated BEACOPP in advanced-stage Hodgkin Lymphoma patients with a positive interim PET-CT after 2 ABVD cycles long-term results of the GITILFIL HD 0607 trial

Pts enrolledregistered 783785

Pt enrollment 62008- 62014Median fu for pts completing treatment 1303 (2-2857) days

0

02

04

06

08

1

0 2 4 6 8

DS 4

DS 5

0

02

04

06

08

1

0 2 4 6 8

DS 4

DS 5

DS 4 101 (5) 82 (2) 29 (1) 3 (0) 0

DS 5 49 (5) 34 (2) 8 (1) 1 (0) 0

Years from registration

P = 00696

DS 4 101 (15) 75 (2) 26 (0) 3 (0) 0

DS 5 49 (25) 19 (1) 5 (0) 1 (0) 0

Years from registration

P lt 0001

Overall Survival Progression-free Survival

OS and PFS according to Deauville Score

4-Y OS 92 (95CI 84-96)

4-Y OS 83 (95CI 67-92)

4-Y PFS 81 (95CI 71-88)

4-Y PFS 46 (95CI 31-59)

PET-2 positive patient with a DS 4 switching to BEACOPP have a 3-Y PFS similar to the entire cohort of patients (4-Y PFS 81 95 CI 71-88)Patients with a DS 5 which are a small subset of the entire population (63) still represent an unmet therapeutic need awaiting new treatment strategies

Gallamini A et al EHA 2017

0

02

04

06

08

1

0 2 4 6 8

No RX

RX

No RX 148 (1) 141 (2) 40 (0) 0 (0) 0

RX 148 (0) 144 (0) 40 (0) 0 (0) 0

Years from registration

P = 00790

4-Y OS 100

4-Y OS 98 (95CI 92-99)

0

02

04

06

08

1

0 2 4 6 8

No RX

RX

No RX 148 (9) 133 (1) 35 (0) 14 (0) 0

RX 148 (5) 139 (1) 39 (0) 10 (0) 0

Years from registration

P = 02882

4-Y PFS 96 (95CI 91-98)

4-Y PFS 93 (95CI 87-96)

Overall Survival Progression-free Survival

OS and PFS in PET2- randomized to RXNFT

Consolidation radiotherapy in the region where a large nodal mass was recorded at baseline did not improve treatment result in negative PET-2 and PET-6 patients irrespective of the dimension of the lesion at baseline

Gallamini A et al EHA 2017

BEACOPP esc x 2

Standard Arm Experimental Arm

Neg Pos

Salvagetherapy

Pos Neg

PET4

PET2

Neg Pos Neg Pos Neg

BEACOPP esc x 2

IPS 0-7BEACOPP esc x 2 BEACOPP esc x 2

BEACOPP esc x 2

R

ABVD x 2

Non inferiority of the experimental arm

ABVD x 2

BEACOPP esc x 2

Courtesy of O Casasnovas

Kairos

Gela ahl2011Stage IIIIV and high risk IIB Hodgkin Lymphoma

Salvagetherapy

Primary Endpoint Planned accrual Date start Date end

5-yr PFS 810 Pts May 2011 May 2015

Abs 577 Randomized phase III study comparing an early PET driven treatment de-escalation to non-PET monitored strategy in patients with advanced HL

O Casasnovas ASH 2015

There was no significant difference between the experimental and standard arms Reduction of therapy based on negative interim PET is safe

Randomized phase III study comparing an early PET driven treatment de-escalation to non pet monitored strategy in patients with advanced HL

O Casanovas ASH 2015

Positive interim PET is a risk factor for HL progression even if EB is continued

Casanovas 2016

There is a value to perform PET-4 if PET-2 is positive Consider change of therapy if PET-4 is positive

Casanovas 2016

Is there a role for PET-4 if treatment was escalated based on PET-2

Casanovas 2016

Progression 90 PtsProgression 157 Pts

ABVD x2

PET-2

BEACOPP ESC x4

PET-6ABVD x4

IPS 0-2

NEGATIVE

POSITIVEBEACOPP ESC x2

IPS 3-7

PET-6ISRT to bulky MM

+

Israeli H2 protocol for advanced Hodgkin lymphoma

B symptoms Stage III IV

The study prospectively evaluated the outcome of HL patients whose therapy waschosen based on initial prognostic factors and tailored based on results of PETCTperformed after 2 cycles of chemotherapy

This multicenter study was initiated in 2006 and ended in 72013 enrolling 355 patientswith stages I-IV HL aged 18-60 years

Conclusions

bull Both baseline PETCT and PET-2 are recommendedbull Deauville scores 1-3 should be considered a negative PET resultbull Positive PET-2 (DS 4-5) is a poor prognostic sign when treatment is initiated

with ABVD or even with EB (Gallamini Johnson Casasnovas)bull Escalation of therapy in PET-2 positive patients improves the outcomebull Escalation of therapy to EB in early-stage HL Pts with positive PET-2 (DS 4-5)

improves PFS (Andrersquo M Straus D)bull Pts with high IPS or bulky mediastinal mass have a worse outcome if

therapy is initiated with ABVD and a higher probability of a positive PET-2 (Johnson)

bull If therapy is initiated with escalated BEACOPP de-escalation of therapy to ABVD does not impair the outcome (Casasnovas)

bull The same percentage of PET-2 negativity was found in patients with IPS 0-2 who initiated therapy with ABVD (5-y PFS 079) and in patients with IPS 3-7 whose initial therapy was escalated BEACOPP (5-y PFS 081) (Dann)

bull Salvage therapy should be considered in PET-2 (DS-5) or PET-4 (DS 4-5) positive patients (Johnson Casasnovas )

Thank You e_dannrambamhealthgovil

Should BLEOMYCIN be omitted at age ge 65

RAPID trial toxicity

Bleomycin in older early-stage favorable Hodgkin lymphoma patients analysis of the German Hodgkin Study Group (GHSG) HD10 and HD13 trialsBoris Bumloll et al German Hodgkin Study Group

Two cycles of ABVD or AVD were equally tolerable in older early-stage favorable HL patients Excessive toxicity including severe bleomycin-induced lung toxicity occurred in older HL patients receiving 4 cycles of ABVD Doxorubicin bleomycin vinblastine sulfate and dacarbazine (ABVD) is associated with severe toxicity in older patients particularly from bleomycin-induced lung toxicity (BLT) Therefore using bleomycin has been questioned in older Hodgkin lymphoma (HL) patients especially in early-stage HL We therefore analyzed feasibility toxicity and efficacy of ABVD or AVD in 287 older early-stage favorable HL patients We included patients ge60 years of age in the German Hodgkin Study Group HD10 and HD13 trials randomized to either 2 cycles of ABVD (2XABVD n = 137) or AVD (2xAVD n = 82) each followed by involved-field radiotherapy (IF-RT) with patients randomized to 4xABVD+IFRT (n =68) Patientsrsquo median age was 65 years (range 60-75) with comparable patient and disease characteristics Grade III-IV adverse event rates were similar in patients receiving 2xAVD and 2xABVD (40 and 39 respectively) but considerably higher in patients receiving 4xABVD (65) Similarly BLT was rare in patients receiving 2xABVDAVD but occurred in 769 (10) of patients randomized to 4xABVD with 3 lethal events In conclusion no effects of bleomycin on toxicity rates were detectable in older patients receiving 2 cycles of chemotherapy However we found a high risk of severe toxicity of bleomycin in older HL patients receiving more than 2 cycles of ABVD (Blood 2016 127(18)2189-2192)

Forty-four advanced-stage older HL patients (aged ge60 years) were treated on the randomized study E2496 Toxicities were mostly similar between chemotherapy regimens although 24 of older patients developed bleomycin lung toxicity (BLT) which occurred mainly with ABVD (91) Further the BLT-related mortality rate was 18 The overall treatment-related mortality for older HL patients was 9 versus 03 for patients aged lt60 years (plt0001) Among older patients there were no survival differences between ABVD and SV According to age outcomes were significantly inferior for older versus younger patients (5-year FFS 48 vs 74 respectively p=0002 5-year OS 58 and 90 respectively plt00001)Among the 45 older HL patients enrolled 11 (24) developed BLT of whom 211 (18) died due to acute pulmonary fibrosisrespiratory failure) Furthermore 1011 (91) BLT cases occurred withduring ABVD (BLT incidence 43 with ABVD vs 5 Stanford V p=004) This toxicity appeared to occur later in the chemotherapy course however the two BLT-related deaths occurred during cycle 3 of ABVD We did not identify any factors that predicted the development of BLT or death due to BLT Granulocyte growth factor was given the vast majority of patients thus it was not analyzed as a risk factor

The Efficacy and Tolerability of ABVD and Stanford V in Older Hodgkin Lymphoma Patients A Comprehensive Analysis from the North American Intergroup Trial E2496 Andrew M Evens et al BJH 2013

0

02

04

06

08

1

0 2 4 6 8

DS 4

DS 5

0

02

04

06

08

1

0 2 4 6 8

DS 4

DS 5

DS 4 101 (5) 82 (2) 29 (1) 3 (0) 0

DS 5 49 (5) 34 (2) 8 (1) 1 (0) 0

Years from registration

P = 00696

DS 4 101 (15) 75 (2) 26 (0) 3 (0) 0

DS 5 49 (25) 19 (1) 5 (0) 1 (0) 0

Years from registration

P lt 0001

Overall Survival Progression-free Survival

OS and PFS according to Deauville Score

4-Y OS 92 (95CI 84-96)

4-Y OS 83 (95CI 67-92)

4-Y PFS 81 (95CI 71-88)

4-Y PFS 46 (95CI 31-59)

PET-2 positive patient with a DS 4 switching to BEACOPP have a 3-Y PFS similar to the entire cohort of patients (4-Y PFS 81 95 CI 71-88)Patients with a DS 5 which are a small subset of the entire population (63) still represent an unmet therapeutic need awaiting new treatment strategies

Gallamini A et al EHA 2017

0

02

04

06

08

1

0 2 4 6 8

No RX

RX

No RX 148 (1) 141 (2) 40 (0) 0 (0) 0

RX 148 (0) 144 (0) 40 (0) 0 (0) 0

Years from registration

P = 00790

4-Y OS 100

4-Y OS 98 (95CI 92-99)

0

02

04

06

08

1

0 2 4 6 8

No RX

RX

No RX 148 (9) 133 (1) 35 (0) 14 (0) 0

RX 148 (5) 139 (1) 39 (0) 10 (0) 0

Years from registration

P = 02882

4-Y PFS 96 (95CI 91-98)

4-Y PFS 93 (95CI 87-96)

Overall Survival Progression-free Survival

OS and PFS in PET2- randomized to RXNFT

Consolidation radiotherapy in the region where a large nodal mass was recorded at baseline did not improve treatment result in negative PET-2 and PET-6 patients irrespective of the dimension of the lesion at baseline

Gallamini A et al EHA 2017

BEACOPP esc x 2

Standard Arm Experimental Arm

Neg Pos

Salvagetherapy

Pos Neg

PET4

PET2

Neg Pos Neg Pos Neg

BEACOPP esc x 2

IPS 0-7BEACOPP esc x 2 BEACOPP esc x 2

BEACOPP esc x 2

R

ABVD x 2

Non inferiority of the experimental arm

ABVD x 2

BEACOPP esc x 2

Courtesy of O Casasnovas

Kairos

Gela ahl2011Stage IIIIV and high risk IIB Hodgkin Lymphoma

Salvagetherapy

Primary Endpoint Planned accrual Date start Date end

5-yr PFS 810 Pts May 2011 May 2015

Abs 577 Randomized phase III study comparing an early PET driven treatment de-escalation to non-PET monitored strategy in patients with advanced HL

O Casasnovas ASH 2015

There was no significant difference between the experimental and standard arms Reduction of therapy based on negative interim PET is safe

Randomized phase III study comparing an early PET driven treatment de-escalation to non pet monitored strategy in patients with advanced HL

O Casanovas ASH 2015

Positive interim PET is a risk factor for HL progression even if EB is continued

Casanovas 2016

There is a value to perform PET-4 if PET-2 is positive Consider change of therapy if PET-4 is positive

Casanovas 2016

Is there a role for PET-4 if treatment was escalated based on PET-2

Casanovas 2016

Progression 90 PtsProgression 157 Pts

ABVD x2

PET-2

BEACOPP ESC x4

PET-6ABVD x4

IPS 0-2

NEGATIVE

POSITIVEBEACOPP ESC x2

IPS 3-7

PET-6ISRT to bulky MM

+

Israeli H2 protocol for advanced Hodgkin lymphoma

B symptoms Stage III IV

The study prospectively evaluated the outcome of HL patients whose therapy waschosen based on initial prognostic factors and tailored based on results of PETCTperformed after 2 cycles of chemotherapy

This multicenter study was initiated in 2006 and ended in 72013 enrolling 355 patientswith stages I-IV HL aged 18-60 years

Conclusions

bull Both baseline PETCT and PET-2 are recommendedbull Deauville scores 1-3 should be considered a negative PET resultbull Positive PET-2 (DS 4-5) is a poor prognostic sign when treatment is initiated

with ABVD or even with EB (Gallamini Johnson Casasnovas)bull Escalation of therapy in PET-2 positive patients improves the outcomebull Escalation of therapy to EB in early-stage HL Pts with positive PET-2 (DS 4-5)

improves PFS (Andrersquo M Straus D)bull Pts with high IPS or bulky mediastinal mass have a worse outcome if

therapy is initiated with ABVD and a higher probability of a positive PET-2 (Johnson)

bull If therapy is initiated with escalated BEACOPP de-escalation of therapy to ABVD does not impair the outcome (Casasnovas)

bull The same percentage of PET-2 negativity was found in patients with IPS 0-2 who initiated therapy with ABVD (5-y PFS 079) and in patients with IPS 3-7 whose initial therapy was escalated BEACOPP (5-y PFS 081) (Dann)

bull Salvage therapy should be considered in PET-2 (DS-5) or PET-4 (DS 4-5) positive patients (Johnson Casasnovas )

Thank You e_dannrambamhealthgovil

Should BLEOMYCIN be omitted at age ge 65

RAPID trial toxicity

Bleomycin in older early-stage favorable Hodgkin lymphoma patients analysis of the German Hodgkin Study Group (GHSG) HD10 and HD13 trialsBoris Bumloll et al German Hodgkin Study Group

Two cycles of ABVD or AVD were equally tolerable in older early-stage favorable HL patients Excessive toxicity including severe bleomycin-induced lung toxicity occurred in older HL patients receiving 4 cycles of ABVD Doxorubicin bleomycin vinblastine sulfate and dacarbazine (ABVD) is associated with severe toxicity in older patients particularly from bleomycin-induced lung toxicity (BLT) Therefore using bleomycin has been questioned in older Hodgkin lymphoma (HL) patients especially in early-stage HL We therefore analyzed feasibility toxicity and efficacy of ABVD or AVD in 287 older early-stage favorable HL patients We included patients ge60 years of age in the German Hodgkin Study Group HD10 and HD13 trials randomized to either 2 cycles of ABVD (2XABVD n = 137) or AVD (2xAVD n = 82) each followed by involved-field radiotherapy (IF-RT) with patients randomized to 4xABVD+IFRT (n =68) Patientsrsquo median age was 65 years (range 60-75) with comparable patient and disease characteristics Grade III-IV adverse event rates were similar in patients receiving 2xAVD and 2xABVD (40 and 39 respectively) but considerably higher in patients receiving 4xABVD (65) Similarly BLT was rare in patients receiving 2xABVDAVD but occurred in 769 (10) of patients randomized to 4xABVD with 3 lethal events In conclusion no effects of bleomycin on toxicity rates were detectable in older patients receiving 2 cycles of chemotherapy However we found a high risk of severe toxicity of bleomycin in older HL patients receiving more than 2 cycles of ABVD (Blood 2016 127(18)2189-2192)

Forty-four advanced-stage older HL patients (aged ge60 years) were treated on the randomized study E2496 Toxicities were mostly similar between chemotherapy regimens although 24 of older patients developed bleomycin lung toxicity (BLT) which occurred mainly with ABVD (91) Further the BLT-related mortality rate was 18 The overall treatment-related mortality for older HL patients was 9 versus 03 for patients aged lt60 years (plt0001) Among older patients there were no survival differences between ABVD and SV According to age outcomes were significantly inferior for older versus younger patients (5-year FFS 48 vs 74 respectively p=0002 5-year OS 58 and 90 respectively plt00001)Among the 45 older HL patients enrolled 11 (24) developed BLT of whom 211 (18) died due to acute pulmonary fibrosisrespiratory failure) Furthermore 1011 (91) BLT cases occurred withduring ABVD (BLT incidence 43 with ABVD vs 5 Stanford V p=004) This toxicity appeared to occur later in the chemotherapy course however the two BLT-related deaths occurred during cycle 3 of ABVD We did not identify any factors that predicted the development of BLT or death due to BLT Granulocyte growth factor was given the vast majority of patients thus it was not analyzed as a risk factor

The Efficacy and Tolerability of ABVD and Stanford V in Older Hodgkin Lymphoma Patients A Comprehensive Analysis from the North American Intergroup Trial E2496 Andrew M Evens et al BJH 2013

0

02

04

06

08

1

0 2 4 6 8

No RX

RX

No RX 148 (1) 141 (2) 40 (0) 0 (0) 0

RX 148 (0) 144 (0) 40 (0) 0 (0) 0

Years from registration

P = 00790

4-Y OS 100

4-Y OS 98 (95CI 92-99)

0

02

04

06

08

1

0 2 4 6 8

No RX

RX

No RX 148 (9) 133 (1) 35 (0) 14 (0) 0

RX 148 (5) 139 (1) 39 (0) 10 (0) 0

Years from registration

P = 02882

4-Y PFS 96 (95CI 91-98)

4-Y PFS 93 (95CI 87-96)

Overall Survival Progression-free Survival

OS and PFS in PET2- randomized to RXNFT

Consolidation radiotherapy in the region where a large nodal mass was recorded at baseline did not improve treatment result in negative PET-2 and PET-6 patients irrespective of the dimension of the lesion at baseline

Gallamini A et al EHA 2017

BEACOPP esc x 2

Standard Arm Experimental Arm

Neg Pos

Salvagetherapy

Pos Neg

PET4

PET2

Neg Pos Neg Pos Neg

BEACOPP esc x 2

IPS 0-7BEACOPP esc x 2 BEACOPP esc x 2

BEACOPP esc x 2

R

ABVD x 2

Non inferiority of the experimental arm

ABVD x 2

BEACOPP esc x 2

Courtesy of O Casasnovas

Kairos

Gela ahl2011Stage IIIIV and high risk IIB Hodgkin Lymphoma

Salvagetherapy

Primary Endpoint Planned accrual Date start Date end

5-yr PFS 810 Pts May 2011 May 2015

Abs 577 Randomized phase III study comparing an early PET driven treatment de-escalation to non-PET monitored strategy in patients with advanced HL

O Casasnovas ASH 2015

There was no significant difference between the experimental and standard arms Reduction of therapy based on negative interim PET is safe

Randomized phase III study comparing an early PET driven treatment de-escalation to non pet monitored strategy in patients with advanced HL

O Casanovas ASH 2015

Positive interim PET is a risk factor for HL progression even if EB is continued

Casanovas 2016

There is a value to perform PET-4 if PET-2 is positive Consider change of therapy if PET-4 is positive

Casanovas 2016

Is there a role for PET-4 if treatment was escalated based on PET-2

Casanovas 2016

Progression 90 PtsProgression 157 Pts

ABVD x2

PET-2

BEACOPP ESC x4

PET-6ABVD x4

IPS 0-2

NEGATIVE

POSITIVEBEACOPP ESC x2

IPS 3-7

PET-6ISRT to bulky MM

+

Israeli H2 protocol for advanced Hodgkin lymphoma

B symptoms Stage III IV

The study prospectively evaluated the outcome of HL patients whose therapy waschosen based on initial prognostic factors and tailored based on results of PETCTperformed after 2 cycles of chemotherapy

This multicenter study was initiated in 2006 and ended in 72013 enrolling 355 patientswith stages I-IV HL aged 18-60 years

Conclusions

bull Both baseline PETCT and PET-2 are recommendedbull Deauville scores 1-3 should be considered a negative PET resultbull Positive PET-2 (DS 4-5) is a poor prognostic sign when treatment is initiated

with ABVD or even with EB (Gallamini Johnson Casasnovas)bull Escalation of therapy in PET-2 positive patients improves the outcomebull Escalation of therapy to EB in early-stage HL Pts with positive PET-2 (DS 4-5)

improves PFS (Andrersquo M Straus D)bull Pts with high IPS or bulky mediastinal mass have a worse outcome if

therapy is initiated with ABVD and a higher probability of a positive PET-2 (Johnson)

bull If therapy is initiated with escalated BEACOPP de-escalation of therapy to ABVD does not impair the outcome (Casasnovas)

bull The same percentage of PET-2 negativity was found in patients with IPS 0-2 who initiated therapy with ABVD (5-y PFS 079) and in patients with IPS 3-7 whose initial therapy was escalated BEACOPP (5-y PFS 081) (Dann)

bull Salvage therapy should be considered in PET-2 (DS-5) or PET-4 (DS 4-5) positive patients (Johnson Casasnovas )

Thank You e_dannrambamhealthgovil

Should BLEOMYCIN be omitted at age ge 65

RAPID trial toxicity

Bleomycin in older early-stage favorable Hodgkin lymphoma patients analysis of the German Hodgkin Study Group (GHSG) HD10 and HD13 trialsBoris Bumloll et al German Hodgkin Study Group

Two cycles of ABVD or AVD were equally tolerable in older early-stage favorable HL patients Excessive toxicity including severe bleomycin-induced lung toxicity occurred in older HL patients receiving 4 cycles of ABVD Doxorubicin bleomycin vinblastine sulfate and dacarbazine (ABVD) is associated with severe toxicity in older patients particularly from bleomycin-induced lung toxicity (BLT) Therefore using bleomycin has been questioned in older Hodgkin lymphoma (HL) patients especially in early-stage HL We therefore analyzed feasibility toxicity and efficacy of ABVD or AVD in 287 older early-stage favorable HL patients We included patients ge60 years of age in the German Hodgkin Study Group HD10 and HD13 trials randomized to either 2 cycles of ABVD (2XABVD n = 137) or AVD (2xAVD n = 82) each followed by involved-field radiotherapy (IF-RT) with patients randomized to 4xABVD+IFRT (n =68) Patientsrsquo median age was 65 years (range 60-75) with comparable patient and disease characteristics Grade III-IV adverse event rates were similar in patients receiving 2xAVD and 2xABVD (40 and 39 respectively) but considerably higher in patients receiving 4xABVD (65) Similarly BLT was rare in patients receiving 2xABVDAVD but occurred in 769 (10) of patients randomized to 4xABVD with 3 lethal events In conclusion no effects of bleomycin on toxicity rates were detectable in older patients receiving 2 cycles of chemotherapy However we found a high risk of severe toxicity of bleomycin in older HL patients receiving more than 2 cycles of ABVD (Blood 2016 127(18)2189-2192)

Forty-four advanced-stage older HL patients (aged ge60 years) were treated on the randomized study E2496 Toxicities were mostly similar between chemotherapy regimens although 24 of older patients developed bleomycin lung toxicity (BLT) which occurred mainly with ABVD (91) Further the BLT-related mortality rate was 18 The overall treatment-related mortality for older HL patients was 9 versus 03 for patients aged lt60 years (plt0001) Among older patients there were no survival differences between ABVD and SV According to age outcomes were significantly inferior for older versus younger patients (5-year FFS 48 vs 74 respectively p=0002 5-year OS 58 and 90 respectively plt00001)Among the 45 older HL patients enrolled 11 (24) developed BLT of whom 211 (18) died due to acute pulmonary fibrosisrespiratory failure) Furthermore 1011 (91) BLT cases occurred withduring ABVD (BLT incidence 43 with ABVD vs 5 Stanford V p=004) This toxicity appeared to occur later in the chemotherapy course however the two BLT-related deaths occurred during cycle 3 of ABVD We did not identify any factors that predicted the development of BLT or death due to BLT Granulocyte growth factor was given the vast majority of patients thus it was not analyzed as a risk factor

The Efficacy and Tolerability of ABVD and Stanford V in Older Hodgkin Lymphoma Patients A Comprehensive Analysis from the North American Intergroup Trial E2496 Andrew M Evens et al BJH 2013

BEACOPP esc x 2

Standard Arm Experimental Arm

Neg Pos

Salvagetherapy

Pos Neg

PET4

PET2

Neg Pos Neg Pos Neg

BEACOPP esc x 2

IPS 0-7BEACOPP esc x 2 BEACOPP esc x 2

BEACOPP esc x 2

R

ABVD x 2

Non inferiority of the experimental arm

ABVD x 2

BEACOPP esc x 2

Courtesy of O Casasnovas

Kairos

Gela ahl2011Stage IIIIV and high risk IIB Hodgkin Lymphoma

Salvagetherapy

Primary Endpoint Planned accrual Date start Date end

5-yr PFS 810 Pts May 2011 May 2015

Abs 577 Randomized phase III study comparing an early PET driven treatment de-escalation to non-PET monitored strategy in patients with advanced HL

O Casasnovas ASH 2015

There was no significant difference between the experimental and standard arms Reduction of therapy based on negative interim PET is safe

Randomized phase III study comparing an early PET driven treatment de-escalation to non pet monitored strategy in patients with advanced HL

O Casanovas ASH 2015

Positive interim PET is a risk factor for HL progression even if EB is continued

Casanovas 2016

There is a value to perform PET-4 if PET-2 is positive Consider change of therapy if PET-4 is positive

Casanovas 2016

Is there a role for PET-4 if treatment was escalated based on PET-2

Casanovas 2016

Progression 90 PtsProgression 157 Pts

ABVD x2

PET-2

BEACOPP ESC x4

PET-6ABVD x4

IPS 0-2

NEGATIVE

POSITIVEBEACOPP ESC x2

IPS 3-7

PET-6ISRT to bulky MM

+

Israeli H2 protocol for advanced Hodgkin lymphoma

B symptoms Stage III IV

The study prospectively evaluated the outcome of HL patients whose therapy waschosen based on initial prognostic factors and tailored based on results of PETCTperformed after 2 cycles of chemotherapy

This multicenter study was initiated in 2006 and ended in 72013 enrolling 355 patientswith stages I-IV HL aged 18-60 years

Conclusions

bull Both baseline PETCT and PET-2 are recommendedbull Deauville scores 1-3 should be considered a negative PET resultbull Positive PET-2 (DS 4-5) is a poor prognostic sign when treatment is initiated

with ABVD or even with EB (Gallamini Johnson Casasnovas)bull Escalation of therapy in PET-2 positive patients improves the outcomebull Escalation of therapy to EB in early-stage HL Pts with positive PET-2 (DS 4-5)

improves PFS (Andrersquo M Straus D)bull Pts with high IPS or bulky mediastinal mass have a worse outcome if

therapy is initiated with ABVD and a higher probability of a positive PET-2 (Johnson)

bull If therapy is initiated with escalated BEACOPP de-escalation of therapy to ABVD does not impair the outcome (Casasnovas)

bull The same percentage of PET-2 negativity was found in patients with IPS 0-2 who initiated therapy with ABVD (5-y PFS 079) and in patients with IPS 3-7 whose initial therapy was escalated BEACOPP (5-y PFS 081) (Dann)

bull Salvage therapy should be considered in PET-2 (DS-5) or PET-4 (DS 4-5) positive patients (Johnson Casasnovas )

Thank You e_dannrambamhealthgovil

Should BLEOMYCIN be omitted at age ge 65

RAPID trial toxicity

Bleomycin in older early-stage favorable Hodgkin lymphoma patients analysis of the German Hodgkin Study Group (GHSG) HD10 and HD13 trialsBoris Bumloll et al German Hodgkin Study Group

Two cycles of ABVD or AVD were equally tolerable in older early-stage favorable HL patients Excessive toxicity including severe bleomycin-induced lung toxicity occurred in older HL patients receiving 4 cycles of ABVD Doxorubicin bleomycin vinblastine sulfate and dacarbazine (ABVD) is associated with severe toxicity in older patients particularly from bleomycin-induced lung toxicity (BLT) Therefore using bleomycin has been questioned in older Hodgkin lymphoma (HL) patients especially in early-stage HL We therefore analyzed feasibility toxicity and efficacy of ABVD or AVD in 287 older early-stage favorable HL patients We included patients ge60 years of age in the German Hodgkin Study Group HD10 and HD13 trials randomized to either 2 cycles of ABVD (2XABVD n = 137) or AVD (2xAVD n = 82) each followed by involved-field radiotherapy (IF-RT) with patients randomized to 4xABVD+IFRT (n =68) Patientsrsquo median age was 65 years (range 60-75) with comparable patient and disease characteristics Grade III-IV adverse event rates were similar in patients receiving 2xAVD and 2xABVD (40 and 39 respectively) but considerably higher in patients receiving 4xABVD (65) Similarly BLT was rare in patients receiving 2xABVDAVD but occurred in 769 (10) of patients randomized to 4xABVD with 3 lethal events In conclusion no effects of bleomycin on toxicity rates were detectable in older patients receiving 2 cycles of chemotherapy However we found a high risk of severe toxicity of bleomycin in older HL patients receiving more than 2 cycles of ABVD (Blood 2016 127(18)2189-2192)

Forty-four advanced-stage older HL patients (aged ge60 years) were treated on the randomized study E2496 Toxicities were mostly similar between chemotherapy regimens although 24 of older patients developed bleomycin lung toxicity (BLT) which occurred mainly with ABVD (91) Further the BLT-related mortality rate was 18 The overall treatment-related mortality for older HL patients was 9 versus 03 for patients aged lt60 years (plt0001) Among older patients there were no survival differences between ABVD and SV According to age outcomes were significantly inferior for older versus younger patients (5-year FFS 48 vs 74 respectively p=0002 5-year OS 58 and 90 respectively plt00001)Among the 45 older HL patients enrolled 11 (24) developed BLT of whom 211 (18) died due to acute pulmonary fibrosisrespiratory failure) Furthermore 1011 (91) BLT cases occurred withduring ABVD (BLT incidence 43 with ABVD vs 5 Stanford V p=004) This toxicity appeared to occur later in the chemotherapy course however the two BLT-related deaths occurred during cycle 3 of ABVD We did not identify any factors that predicted the development of BLT or death due to BLT Granulocyte growth factor was given the vast majority of patients thus it was not analyzed as a risk factor

The Efficacy and Tolerability of ABVD and Stanford V in Older Hodgkin Lymphoma Patients A Comprehensive Analysis from the North American Intergroup Trial E2496 Andrew M Evens et al BJH 2013

There was no significant difference between the experimental and standard arms Reduction of therapy based on negative interim PET is safe

Randomized phase III study comparing an early PET driven treatment de-escalation to non pet monitored strategy in patients with advanced HL

O Casanovas ASH 2015

Positive interim PET is a risk factor for HL progression even if EB is continued

Casanovas 2016

There is a value to perform PET-4 if PET-2 is positive Consider change of therapy if PET-4 is positive

Casanovas 2016

Is there a role for PET-4 if treatment was escalated based on PET-2

Casanovas 2016

Progression 90 PtsProgression 157 Pts

ABVD x2

PET-2

BEACOPP ESC x4

PET-6ABVD x4

IPS 0-2

NEGATIVE

POSITIVEBEACOPP ESC x2

IPS 3-7

PET-6ISRT to bulky MM

+

Israeli H2 protocol for advanced Hodgkin lymphoma

B symptoms Stage III IV

The study prospectively evaluated the outcome of HL patients whose therapy waschosen based on initial prognostic factors and tailored based on results of PETCTperformed after 2 cycles of chemotherapy

This multicenter study was initiated in 2006 and ended in 72013 enrolling 355 patientswith stages I-IV HL aged 18-60 years

Conclusions

bull Both baseline PETCT and PET-2 are recommendedbull Deauville scores 1-3 should be considered a negative PET resultbull Positive PET-2 (DS 4-5) is a poor prognostic sign when treatment is initiated

with ABVD or even with EB (Gallamini Johnson Casasnovas)bull Escalation of therapy in PET-2 positive patients improves the outcomebull Escalation of therapy to EB in early-stage HL Pts with positive PET-2 (DS 4-5)

improves PFS (Andrersquo M Straus D)bull Pts with high IPS or bulky mediastinal mass have a worse outcome if

therapy is initiated with ABVD and a higher probability of a positive PET-2 (Johnson)

bull If therapy is initiated with escalated BEACOPP de-escalation of therapy to ABVD does not impair the outcome (Casasnovas)

bull The same percentage of PET-2 negativity was found in patients with IPS 0-2 who initiated therapy with ABVD (5-y PFS 079) and in patients with IPS 3-7 whose initial therapy was escalated BEACOPP (5-y PFS 081) (Dann)

bull Salvage therapy should be considered in PET-2 (DS-5) or PET-4 (DS 4-5) positive patients (Johnson Casasnovas )

Thank You e_dannrambamhealthgovil

Should BLEOMYCIN be omitted at age ge 65

RAPID trial toxicity

Bleomycin in older early-stage favorable Hodgkin lymphoma patients analysis of the German Hodgkin Study Group (GHSG) HD10 and HD13 trialsBoris Bumloll et al German Hodgkin Study Group

Two cycles of ABVD or AVD were equally tolerable in older early-stage favorable HL patients Excessive toxicity including severe bleomycin-induced lung toxicity occurred in older HL patients receiving 4 cycles of ABVD Doxorubicin bleomycin vinblastine sulfate and dacarbazine (ABVD) is associated with severe toxicity in older patients particularly from bleomycin-induced lung toxicity (BLT) Therefore using bleomycin has been questioned in older Hodgkin lymphoma (HL) patients especially in early-stage HL We therefore analyzed feasibility toxicity and efficacy of ABVD or AVD in 287 older early-stage favorable HL patients We included patients ge60 years of age in the German Hodgkin Study Group HD10 and HD13 trials randomized to either 2 cycles of ABVD (2XABVD n = 137) or AVD (2xAVD n = 82) each followed by involved-field radiotherapy (IF-RT) with patients randomized to 4xABVD+IFRT (n =68) Patientsrsquo median age was 65 years (range 60-75) with comparable patient and disease characteristics Grade III-IV adverse event rates were similar in patients receiving 2xAVD and 2xABVD (40 and 39 respectively) but considerably higher in patients receiving 4xABVD (65) Similarly BLT was rare in patients receiving 2xABVDAVD but occurred in 769 (10) of patients randomized to 4xABVD with 3 lethal events In conclusion no effects of bleomycin on toxicity rates were detectable in older patients receiving 2 cycles of chemotherapy However we found a high risk of severe toxicity of bleomycin in older HL patients receiving more than 2 cycles of ABVD (Blood 2016 127(18)2189-2192)

Forty-four advanced-stage older HL patients (aged ge60 years) were treated on the randomized study E2496 Toxicities were mostly similar between chemotherapy regimens although 24 of older patients developed bleomycin lung toxicity (BLT) which occurred mainly with ABVD (91) Further the BLT-related mortality rate was 18 The overall treatment-related mortality for older HL patients was 9 versus 03 for patients aged lt60 years (plt0001) Among older patients there were no survival differences between ABVD and SV According to age outcomes were significantly inferior for older versus younger patients (5-year FFS 48 vs 74 respectively p=0002 5-year OS 58 and 90 respectively plt00001)Among the 45 older HL patients enrolled 11 (24) developed BLT of whom 211 (18) died due to acute pulmonary fibrosisrespiratory failure) Furthermore 1011 (91) BLT cases occurred withduring ABVD (BLT incidence 43 with ABVD vs 5 Stanford V p=004) This toxicity appeared to occur later in the chemotherapy course however the two BLT-related deaths occurred during cycle 3 of ABVD We did not identify any factors that predicted the development of BLT or death due to BLT Granulocyte growth factor was given the vast majority of patients thus it was not analyzed as a risk factor

The Efficacy and Tolerability of ABVD and Stanford V in Older Hodgkin Lymphoma Patients A Comprehensive Analysis from the North American Intergroup Trial E2496 Andrew M Evens et al BJH 2013

Positive interim PET is a risk factor for HL progression even if EB is continued

Casanovas 2016

There is a value to perform PET-4 if PET-2 is positive Consider change of therapy if PET-4 is positive

Casanovas 2016

Is there a role for PET-4 if treatment was escalated based on PET-2

Casanovas 2016

Progression 90 PtsProgression 157 Pts

ABVD x2

PET-2

BEACOPP ESC x4

PET-6ABVD x4

IPS 0-2

NEGATIVE

POSITIVEBEACOPP ESC x2

IPS 3-7

PET-6ISRT to bulky MM

+

Israeli H2 protocol for advanced Hodgkin lymphoma

B symptoms Stage III IV

The study prospectively evaluated the outcome of HL patients whose therapy waschosen based on initial prognostic factors and tailored based on results of PETCTperformed after 2 cycles of chemotherapy

This multicenter study was initiated in 2006 and ended in 72013 enrolling 355 patientswith stages I-IV HL aged 18-60 years

Conclusions

bull Both baseline PETCT and PET-2 are recommendedbull Deauville scores 1-3 should be considered a negative PET resultbull Positive PET-2 (DS 4-5) is a poor prognostic sign when treatment is initiated

with ABVD or even with EB (Gallamini Johnson Casasnovas)bull Escalation of therapy in PET-2 positive patients improves the outcomebull Escalation of therapy to EB in early-stage HL Pts with positive PET-2 (DS 4-5)

improves PFS (Andrersquo M Straus D)bull Pts with high IPS or bulky mediastinal mass have a worse outcome if

therapy is initiated with ABVD and a higher probability of a positive PET-2 (Johnson)

bull If therapy is initiated with escalated BEACOPP de-escalation of therapy to ABVD does not impair the outcome (Casasnovas)

bull The same percentage of PET-2 negativity was found in patients with IPS 0-2 who initiated therapy with ABVD (5-y PFS 079) and in patients with IPS 3-7 whose initial therapy was escalated BEACOPP (5-y PFS 081) (Dann)

bull Salvage therapy should be considered in PET-2 (DS-5) or PET-4 (DS 4-5) positive patients (Johnson Casasnovas )

Thank You e_dannrambamhealthgovil

Should BLEOMYCIN be omitted at age ge 65

RAPID trial toxicity

Bleomycin in older early-stage favorable Hodgkin lymphoma patients analysis of the German Hodgkin Study Group (GHSG) HD10 and HD13 trialsBoris Bumloll et al German Hodgkin Study Group

Two cycles of ABVD or AVD were equally tolerable in older early-stage favorable HL patients Excessive toxicity including severe bleomycin-induced lung toxicity occurred in older HL patients receiving 4 cycles of ABVD Doxorubicin bleomycin vinblastine sulfate and dacarbazine (ABVD) is associated with severe toxicity in older patients particularly from bleomycin-induced lung toxicity (BLT) Therefore using bleomycin has been questioned in older Hodgkin lymphoma (HL) patients especially in early-stage HL We therefore analyzed feasibility toxicity and efficacy of ABVD or AVD in 287 older early-stage favorable HL patients We included patients ge60 years of age in the German Hodgkin Study Group HD10 and HD13 trials randomized to either 2 cycles of ABVD (2XABVD n = 137) or AVD (2xAVD n = 82) each followed by involved-field radiotherapy (IF-RT) with patients randomized to 4xABVD+IFRT (n =68) Patientsrsquo median age was 65 years (range 60-75) with comparable patient and disease characteristics Grade III-IV adverse event rates were similar in patients receiving 2xAVD and 2xABVD (40 and 39 respectively) but considerably higher in patients receiving 4xABVD (65) Similarly BLT was rare in patients receiving 2xABVDAVD but occurred in 769 (10) of patients randomized to 4xABVD with 3 lethal events In conclusion no effects of bleomycin on toxicity rates were detectable in older patients receiving 2 cycles of chemotherapy However we found a high risk of severe toxicity of bleomycin in older HL patients receiving more than 2 cycles of ABVD (Blood 2016 127(18)2189-2192)

Forty-four advanced-stage older HL patients (aged ge60 years) were treated on the randomized study E2496 Toxicities were mostly similar between chemotherapy regimens although 24 of older patients developed bleomycin lung toxicity (BLT) which occurred mainly with ABVD (91) Further the BLT-related mortality rate was 18 The overall treatment-related mortality for older HL patients was 9 versus 03 for patients aged lt60 years (plt0001) Among older patients there were no survival differences between ABVD and SV According to age outcomes were significantly inferior for older versus younger patients (5-year FFS 48 vs 74 respectively p=0002 5-year OS 58 and 90 respectively plt00001)Among the 45 older HL patients enrolled 11 (24) developed BLT of whom 211 (18) died due to acute pulmonary fibrosisrespiratory failure) Furthermore 1011 (91) BLT cases occurred withduring ABVD (BLT incidence 43 with ABVD vs 5 Stanford V p=004) This toxicity appeared to occur later in the chemotherapy course however the two BLT-related deaths occurred during cycle 3 of ABVD We did not identify any factors that predicted the development of BLT or death due to BLT Granulocyte growth factor was given the vast majority of patients thus it was not analyzed as a risk factor

The Efficacy and Tolerability of ABVD and Stanford V in Older Hodgkin Lymphoma Patients A Comprehensive Analysis from the North American Intergroup Trial E2496 Andrew M Evens et al BJH 2013

There is a value to perform PET-4 if PET-2 is positive Consider change of therapy if PET-4 is positive

Casanovas 2016

Is there a role for PET-4 if treatment was escalated based on PET-2

Casanovas 2016

Progression 90 PtsProgression 157 Pts

ABVD x2

PET-2

BEACOPP ESC x4

PET-6ABVD x4

IPS 0-2

NEGATIVE

POSITIVEBEACOPP ESC x2

IPS 3-7

PET-6ISRT to bulky MM

+

Israeli H2 protocol for advanced Hodgkin lymphoma

B symptoms Stage III IV

The study prospectively evaluated the outcome of HL patients whose therapy waschosen based on initial prognostic factors and tailored based on results of PETCTperformed after 2 cycles of chemotherapy

This multicenter study was initiated in 2006 and ended in 72013 enrolling 355 patientswith stages I-IV HL aged 18-60 years

Conclusions

bull Both baseline PETCT and PET-2 are recommendedbull Deauville scores 1-3 should be considered a negative PET resultbull Positive PET-2 (DS 4-5) is a poor prognostic sign when treatment is initiated

with ABVD or even with EB (Gallamini Johnson Casasnovas)bull Escalation of therapy in PET-2 positive patients improves the outcomebull Escalation of therapy to EB in early-stage HL Pts with positive PET-2 (DS 4-5)

improves PFS (Andrersquo M Straus D)bull Pts with high IPS or bulky mediastinal mass have a worse outcome if

therapy is initiated with ABVD and a higher probability of a positive PET-2 (Johnson)

bull If therapy is initiated with escalated BEACOPP de-escalation of therapy to ABVD does not impair the outcome (Casasnovas)

bull The same percentage of PET-2 negativity was found in patients with IPS 0-2 who initiated therapy with ABVD (5-y PFS 079) and in patients with IPS 3-7 whose initial therapy was escalated BEACOPP (5-y PFS 081) (Dann)

bull Salvage therapy should be considered in PET-2 (DS-5) or PET-4 (DS 4-5) positive patients (Johnson Casasnovas )

Thank You e_dannrambamhealthgovil

Should BLEOMYCIN be omitted at age ge 65

RAPID trial toxicity

Bleomycin in older early-stage favorable Hodgkin lymphoma patients analysis of the German Hodgkin Study Group (GHSG) HD10 and HD13 trialsBoris Bumloll et al German Hodgkin Study Group

Two cycles of ABVD or AVD were equally tolerable in older early-stage favorable HL patients Excessive toxicity including severe bleomycin-induced lung toxicity occurred in older HL patients receiving 4 cycles of ABVD Doxorubicin bleomycin vinblastine sulfate and dacarbazine (ABVD) is associated with severe toxicity in older patients particularly from bleomycin-induced lung toxicity (BLT) Therefore using bleomycin has been questioned in older Hodgkin lymphoma (HL) patients especially in early-stage HL We therefore analyzed feasibility toxicity and efficacy of ABVD or AVD in 287 older early-stage favorable HL patients We included patients ge60 years of age in the German Hodgkin Study Group HD10 and HD13 trials randomized to either 2 cycles of ABVD (2XABVD n = 137) or AVD (2xAVD n = 82) each followed by involved-field radiotherapy (IF-RT) with patients randomized to 4xABVD+IFRT (n =68) Patientsrsquo median age was 65 years (range 60-75) with comparable patient and disease characteristics Grade III-IV adverse event rates were similar in patients receiving 2xAVD and 2xABVD (40 and 39 respectively) but considerably higher in patients receiving 4xABVD (65) Similarly BLT was rare in patients receiving 2xABVDAVD but occurred in 769 (10) of patients randomized to 4xABVD with 3 lethal events In conclusion no effects of bleomycin on toxicity rates were detectable in older patients receiving 2 cycles of chemotherapy However we found a high risk of severe toxicity of bleomycin in older HL patients receiving more than 2 cycles of ABVD (Blood 2016 127(18)2189-2192)

Forty-four advanced-stage older HL patients (aged ge60 years) were treated on the randomized study E2496 Toxicities were mostly similar between chemotherapy regimens although 24 of older patients developed bleomycin lung toxicity (BLT) which occurred mainly with ABVD (91) Further the BLT-related mortality rate was 18 The overall treatment-related mortality for older HL patients was 9 versus 03 for patients aged lt60 years (plt0001) Among older patients there were no survival differences between ABVD and SV According to age outcomes were significantly inferior for older versus younger patients (5-year FFS 48 vs 74 respectively p=0002 5-year OS 58 and 90 respectively plt00001)Among the 45 older HL patients enrolled 11 (24) developed BLT of whom 211 (18) died due to acute pulmonary fibrosisrespiratory failure) Furthermore 1011 (91) BLT cases occurred withduring ABVD (BLT incidence 43 with ABVD vs 5 Stanford V p=004) This toxicity appeared to occur later in the chemotherapy course however the two BLT-related deaths occurred during cycle 3 of ABVD We did not identify any factors that predicted the development of BLT or death due to BLT Granulocyte growth factor was given the vast majority of patients thus it was not analyzed as a risk factor

The Efficacy and Tolerability of ABVD and Stanford V in Older Hodgkin Lymphoma Patients A Comprehensive Analysis from the North American Intergroup Trial E2496 Andrew M Evens et al BJH 2013

Casanovas 2016

Progression 90 PtsProgression 157 Pts

ABVD x2

PET-2

BEACOPP ESC x4

PET-6ABVD x4

IPS 0-2

NEGATIVE

POSITIVEBEACOPP ESC x2

IPS 3-7

PET-6ISRT to bulky MM

+

Israeli H2 protocol for advanced Hodgkin lymphoma

B symptoms Stage III IV

The study prospectively evaluated the outcome of HL patients whose therapy waschosen based on initial prognostic factors and tailored based on results of PETCTperformed after 2 cycles of chemotherapy

This multicenter study was initiated in 2006 and ended in 72013 enrolling 355 patientswith stages I-IV HL aged 18-60 years

Conclusions

bull Both baseline PETCT and PET-2 are recommendedbull Deauville scores 1-3 should be considered a negative PET resultbull Positive PET-2 (DS 4-5) is a poor prognostic sign when treatment is initiated

with ABVD or even with EB (Gallamini Johnson Casasnovas)bull Escalation of therapy in PET-2 positive patients improves the outcomebull Escalation of therapy to EB in early-stage HL Pts with positive PET-2 (DS 4-5)

improves PFS (Andrersquo M Straus D)bull Pts with high IPS or bulky mediastinal mass have a worse outcome if

therapy is initiated with ABVD and a higher probability of a positive PET-2 (Johnson)

bull If therapy is initiated with escalated BEACOPP de-escalation of therapy to ABVD does not impair the outcome (Casasnovas)

bull The same percentage of PET-2 negativity was found in patients with IPS 0-2 who initiated therapy with ABVD (5-y PFS 079) and in patients with IPS 3-7 whose initial therapy was escalated BEACOPP (5-y PFS 081) (Dann)

bull Salvage therapy should be considered in PET-2 (DS-5) or PET-4 (DS 4-5) positive patients (Johnson Casasnovas )

Thank You e_dannrambamhealthgovil

Should BLEOMYCIN be omitted at age ge 65

RAPID trial toxicity

Bleomycin in older early-stage favorable Hodgkin lymphoma patients analysis of the German Hodgkin Study Group (GHSG) HD10 and HD13 trialsBoris Bumloll et al German Hodgkin Study Group

Two cycles of ABVD or AVD were equally tolerable in older early-stage favorable HL patients Excessive toxicity including severe bleomycin-induced lung toxicity occurred in older HL patients receiving 4 cycles of ABVD Doxorubicin bleomycin vinblastine sulfate and dacarbazine (ABVD) is associated with severe toxicity in older patients particularly from bleomycin-induced lung toxicity (BLT) Therefore using bleomycin has been questioned in older Hodgkin lymphoma (HL) patients especially in early-stage HL We therefore analyzed feasibility toxicity and efficacy of ABVD or AVD in 287 older early-stage favorable HL patients We included patients ge60 years of age in the German Hodgkin Study Group HD10 and HD13 trials randomized to either 2 cycles of ABVD (2XABVD n = 137) or AVD (2xAVD n = 82) each followed by involved-field radiotherapy (IF-RT) with patients randomized to 4xABVD+IFRT (n =68) Patientsrsquo median age was 65 years (range 60-75) with comparable patient and disease characteristics Grade III-IV adverse event rates were similar in patients receiving 2xAVD and 2xABVD (40 and 39 respectively) but considerably higher in patients receiving 4xABVD (65) Similarly BLT was rare in patients receiving 2xABVDAVD but occurred in 769 (10) of patients randomized to 4xABVD with 3 lethal events In conclusion no effects of bleomycin on toxicity rates were detectable in older patients receiving 2 cycles of chemotherapy However we found a high risk of severe toxicity of bleomycin in older HL patients receiving more than 2 cycles of ABVD (Blood 2016 127(18)2189-2192)

Forty-four advanced-stage older HL patients (aged ge60 years) were treated on the randomized study E2496 Toxicities were mostly similar between chemotherapy regimens although 24 of older patients developed bleomycin lung toxicity (BLT) which occurred mainly with ABVD (91) Further the BLT-related mortality rate was 18 The overall treatment-related mortality for older HL patients was 9 versus 03 for patients aged lt60 years (plt0001) Among older patients there were no survival differences between ABVD and SV According to age outcomes were significantly inferior for older versus younger patients (5-year FFS 48 vs 74 respectively p=0002 5-year OS 58 and 90 respectively plt00001)Among the 45 older HL patients enrolled 11 (24) developed BLT of whom 211 (18) died due to acute pulmonary fibrosisrespiratory failure) Furthermore 1011 (91) BLT cases occurred withduring ABVD (BLT incidence 43 with ABVD vs 5 Stanford V p=004) This toxicity appeared to occur later in the chemotherapy course however the two BLT-related deaths occurred during cycle 3 of ABVD We did not identify any factors that predicted the development of BLT or death due to BLT Granulocyte growth factor was given the vast majority of patients thus it was not analyzed as a risk factor

The Efficacy and Tolerability of ABVD and Stanford V in Older Hodgkin Lymphoma Patients A Comprehensive Analysis from the North American Intergroup Trial E2496 Andrew M Evens et al BJH 2013

Progression 90 PtsProgression 157 Pts

ABVD x2

PET-2

BEACOPP ESC x4

PET-6ABVD x4

IPS 0-2

NEGATIVE

POSITIVEBEACOPP ESC x2

IPS 3-7

PET-6ISRT to bulky MM

+

Israeli H2 protocol for advanced Hodgkin lymphoma

B symptoms Stage III IV

The study prospectively evaluated the outcome of HL patients whose therapy waschosen based on initial prognostic factors and tailored based on results of PETCTperformed after 2 cycles of chemotherapy

This multicenter study was initiated in 2006 and ended in 72013 enrolling 355 patientswith stages I-IV HL aged 18-60 years

Conclusions

bull Both baseline PETCT and PET-2 are recommendedbull Deauville scores 1-3 should be considered a negative PET resultbull Positive PET-2 (DS 4-5) is a poor prognostic sign when treatment is initiated

with ABVD or even with EB (Gallamini Johnson Casasnovas)bull Escalation of therapy in PET-2 positive patients improves the outcomebull Escalation of therapy to EB in early-stage HL Pts with positive PET-2 (DS 4-5)

improves PFS (Andrersquo M Straus D)bull Pts with high IPS or bulky mediastinal mass have a worse outcome if

therapy is initiated with ABVD and a higher probability of a positive PET-2 (Johnson)

bull If therapy is initiated with escalated BEACOPP de-escalation of therapy to ABVD does not impair the outcome (Casasnovas)

bull The same percentage of PET-2 negativity was found in patients with IPS 0-2 who initiated therapy with ABVD (5-y PFS 079) and in patients with IPS 3-7 whose initial therapy was escalated BEACOPP (5-y PFS 081) (Dann)

bull Salvage therapy should be considered in PET-2 (DS-5) or PET-4 (DS 4-5) positive patients (Johnson Casasnovas )

Thank You e_dannrambamhealthgovil

Should BLEOMYCIN be omitted at age ge 65

RAPID trial toxicity

Bleomycin in older early-stage favorable Hodgkin lymphoma patients analysis of the German Hodgkin Study Group (GHSG) HD10 and HD13 trialsBoris Bumloll et al German Hodgkin Study Group

Two cycles of ABVD or AVD were equally tolerable in older early-stage favorable HL patients Excessive toxicity including severe bleomycin-induced lung toxicity occurred in older HL patients receiving 4 cycles of ABVD Doxorubicin bleomycin vinblastine sulfate and dacarbazine (ABVD) is associated with severe toxicity in older patients particularly from bleomycin-induced lung toxicity (BLT) Therefore using bleomycin has been questioned in older Hodgkin lymphoma (HL) patients especially in early-stage HL We therefore analyzed feasibility toxicity and efficacy of ABVD or AVD in 287 older early-stage favorable HL patients We included patients ge60 years of age in the German Hodgkin Study Group HD10 and HD13 trials randomized to either 2 cycles of ABVD (2XABVD n = 137) or AVD (2xAVD n = 82) each followed by involved-field radiotherapy (IF-RT) with patients randomized to 4xABVD+IFRT (n =68) Patientsrsquo median age was 65 years (range 60-75) with comparable patient and disease characteristics Grade III-IV adverse event rates were similar in patients receiving 2xAVD and 2xABVD (40 and 39 respectively) but considerably higher in patients receiving 4xABVD (65) Similarly BLT was rare in patients receiving 2xABVDAVD but occurred in 769 (10) of patients randomized to 4xABVD with 3 lethal events In conclusion no effects of bleomycin on toxicity rates were detectable in older patients receiving 2 cycles of chemotherapy However we found a high risk of severe toxicity of bleomycin in older HL patients receiving more than 2 cycles of ABVD (Blood 2016 127(18)2189-2192)

Forty-four advanced-stage older HL patients (aged ge60 years) were treated on the randomized study E2496 Toxicities were mostly similar between chemotherapy regimens although 24 of older patients developed bleomycin lung toxicity (BLT) which occurred mainly with ABVD (91) Further the BLT-related mortality rate was 18 The overall treatment-related mortality for older HL patients was 9 versus 03 for patients aged lt60 years (plt0001) Among older patients there were no survival differences between ABVD and SV According to age outcomes were significantly inferior for older versus younger patients (5-year FFS 48 vs 74 respectively p=0002 5-year OS 58 and 90 respectively plt00001)Among the 45 older HL patients enrolled 11 (24) developed BLT of whom 211 (18) died due to acute pulmonary fibrosisrespiratory failure) Furthermore 1011 (91) BLT cases occurred withduring ABVD (BLT incidence 43 with ABVD vs 5 Stanford V p=004) This toxicity appeared to occur later in the chemotherapy course however the two BLT-related deaths occurred during cycle 3 of ABVD We did not identify any factors that predicted the development of BLT or death due to BLT Granulocyte growth factor was given the vast majority of patients thus it was not analyzed as a risk factor

The Efficacy and Tolerability of ABVD and Stanford V in Older Hodgkin Lymphoma Patients A Comprehensive Analysis from the North American Intergroup Trial E2496 Andrew M Evens et al BJH 2013

ABVD x2

PET-2

BEACOPP ESC x4

PET-6ABVD x4

IPS 0-2

NEGATIVE

POSITIVEBEACOPP ESC x2

IPS 3-7

PET-6ISRT to bulky MM

+

Israeli H2 protocol for advanced Hodgkin lymphoma

B symptoms Stage III IV

The study prospectively evaluated the outcome of HL patients whose therapy waschosen based on initial prognostic factors and tailored based on results of PETCTperformed after 2 cycles of chemotherapy

This multicenter study was initiated in 2006 and ended in 72013 enrolling 355 patientswith stages I-IV HL aged 18-60 years

Conclusions

bull Both baseline PETCT and PET-2 are recommendedbull Deauville scores 1-3 should be considered a negative PET resultbull Positive PET-2 (DS 4-5) is a poor prognostic sign when treatment is initiated

with ABVD or even with EB (Gallamini Johnson Casasnovas)bull Escalation of therapy in PET-2 positive patients improves the outcomebull Escalation of therapy to EB in early-stage HL Pts with positive PET-2 (DS 4-5)

improves PFS (Andrersquo M Straus D)bull Pts with high IPS or bulky mediastinal mass have a worse outcome if

therapy is initiated with ABVD and a higher probability of a positive PET-2 (Johnson)

bull If therapy is initiated with escalated BEACOPP de-escalation of therapy to ABVD does not impair the outcome (Casasnovas)

bull The same percentage of PET-2 negativity was found in patients with IPS 0-2 who initiated therapy with ABVD (5-y PFS 079) and in patients with IPS 3-7 whose initial therapy was escalated BEACOPP (5-y PFS 081) (Dann)

bull Salvage therapy should be considered in PET-2 (DS-5) or PET-4 (DS 4-5) positive patients (Johnson Casasnovas )

Thank You e_dannrambamhealthgovil

Should BLEOMYCIN be omitted at age ge 65

RAPID trial toxicity

Bleomycin in older early-stage favorable Hodgkin lymphoma patients analysis of the German Hodgkin Study Group (GHSG) HD10 and HD13 trialsBoris Bumloll et al German Hodgkin Study Group

Two cycles of ABVD or AVD were equally tolerable in older early-stage favorable HL patients Excessive toxicity including severe bleomycin-induced lung toxicity occurred in older HL patients receiving 4 cycles of ABVD Doxorubicin bleomycin vinblastine sulfate and dacarbazine (ABVD) is associated with severe toxicity in older patients particularly from bleomycin-induced lung toxicity (BLT) Therefore using bleomycin has been questioned in older Hodgkin lymphoma (HL) patients especially in early-stage HL We therefore analyzed feasibility toxicity and efficacy of ABVD or AVD in 287 older early-stage favorable HL patients We included patients ge60 years of age in the German Hodgkin Study Group HD10 and HD13 trials randomized to either 2 cycles of ABVD (2XABVD n = 137) or AVD (2xAVD n = 82) each followed by involved-field radiotherapy (IF-RT) with patients randomized to 4xABVD+IFRT (n =68) Patientsrsquo median age was 65 years (range 60-75) with comparable patient and disease characteristics Grade III-IV adverse event rates were similar in patients receiving 2xAVD and 2xABVD (40 and 39 respectively) but considerably higher in patients receiving 4xABVD (65) Similarly BLT was rare in patients receiving 2xABVDAVD but occurred in 769 (10) of patients randomized to 4xABVD with 3 lethal events In conclusion no effects of bleomycin on toxicity rates were detectable in older patients receiving 2 cycles of chemotherapy However we found a high risk of severe toxicity of bleomycin in older HL patients receiving more than 2 cycles of ABVD (Blood 2016 127(18)2189-2192)

Forty-four advanced-stage older HL patients (aged ge60 years) were treated on the randomized study E2496 Toxicities were mostly similar between chemotherapy regimens although 24 of older patients developed bleomycin lung toxicity (BLT) which occurred mainly with ABVD (91) Further the BLT-related mortality rate was 18 The overall treatment-related mortality for older HL patients was 9 versus 03 for patients aged lt60 years (plt0001) Among older patients there were no survival differences between ABVD and SV According to age outcomes were significantly inferior for older versus younger patients (5-year FFS 48 vs 74 respectively p=0002 5-year OS 58 and 90 respectively plt00001)Among the 45 older HL patients enrolled 11 (24) developed BLT of whom 211 (18) died due to acute pulmonary fibrosisrespiratory failure) Furthermore 1011 (91) BLT cases occurred withduring ABVD (BLT incidence 43 with ABVD vs 5 Stanford V p=004) This toxicity appeared to occur later in the chemotherapy course however the two BLT-related deaths occurred during cycle 3 of ABVD We did not identify any factors that predicted the development of BLT or death due to BLT Granulocyte growth factor was given the vast majority of patients thus it was not analyzed as a risk factor

The Efficacy and Tolerability of ABVD and Stanford V in Older Hodgkin Lymphoma Patients A Comprehensive Analysis from the North American Intergroup Trial E2496 Andrew M Evens et al BJH 2013

Conclusions

bull Both baseline PETCT and PET-2 are recommendedbull Deauville scores 1-3 should be considered a negative PET resultbull Positive PET-2 (DS 4-5) is a poor prognostic sign when treatment is initiated

with ABVD or even with EB (Gallamini Johnson Casasnovas)bull Escalation of therapy in PET-2 positive patients improves the outcomebull Escalation of therapy to EB in early-stage HL Pts with positive PET-2 (DS 4-5)

improves PFS (Andrersquo M Straus D)bull Pts with high IPS or bulky mediastinal mass have a worse outcome if

therapy is initiated with ABVD and a higher probability of a positive PET-2 (Johnson)

bull If therapy is initiated with escalated BEACOPP de-escalation of therapy to ABVD does not impair the outcome (Casasnovas)

bull The same percentage of PET-2 negativity was found in patients with IPS 0-2 who initiated therapy with ABVD (5-y PFS 079) and in patients with IPS 3-7 whose initial therapy was escalated BEACOPP (5-y PFS 081) (Dann)

bull Salvage therapy should be considered in PET-2 (DS-5) or PET-4 (DS 4-5) positive patients (Johnson Casasnovas )

Thank You e_dannrambamhealthgovil

Should BLEOMYCIN be omitted at age ge 65

RAPID trial toxicity

Bleomycin in older early-stage favorable Hodgkin lymphoma patients analysis of the German Hodgkin Study Group (GHSG) HD10 and HD13 trialsBoris Bumloll et al German Hodgkin Study Group

Two cycles of ABVD or AVD were equally tolerable in older early-stage favorable HL patients Excessive toxicity including severe bleomycin-induced lung toxicity occurred in older HL patients receiving 4 cycles of ABVD Doxorubicin bleomycin vinblastine sulfate and dacarbazine (ABVD) is associated with severe toxicity in older patients particularly from bleomycin-induced lung toxicity (BLT) Therefore using bleomycin has been questioned in older Hodgkin lymphoma (HL) patients especially in early-stage HL We therefore analyzed feasibility toxicity and efficacy of ABVD or AVD in 287 older early-stage favorable HL patients We included patients ge60 years of age in the German Hodgkin Study Group HD10 and HD13 trials randomized to either 2 cycles of ABVD (2XABVD n = 137) or AVD (2xAVD n = 82) each followed by involved-field radiotherapy (IF-RT) with patients randomized to 4xABVD+IFRT (n =68) Patientsrsquo median age was 65 years (range 60-75) with comparable patient and disease characteristics Grade III-IV adverse event rates were similar in patients receiving 2xAVD and 2xABVD (40 and 39 respectively) but considerably higher in patients receiving 4xABVD (65) Similarly BLT was rare in patients receiving 2xABVDAVD but occurred in 769 (10) of patients randomized to 4xABVD with 3 lethal events In conclusion no effects of bleomycin on toxicity rates were detectable in older patients receiving 2 cycles of chemotherapy However we found a high risk of severe toxicity of bleomycin in older HL patients receiving more than 2 cycles of ABVD (Blood 2016 127(18)2189-2192)

Forty-four advanced-stage older HL patients (aged ge60 years) were treated on the randomized study E2496 Toxicities were mostly similar between chemotherapy regimens although 24 of older patients developed bleomycin lung toxicity (BLT) which occurred mainly with ABVD (91) Further the BLT-related mortality rate was 18 The overall treatment-related mortality for older HL patients was 9 versus 03 for patients aged lt60 years (plt0001) Among older patients there were no survival differences between ABVD and SV According to age outcomes were significantly inferior for older versus younger patients (5-year FFS 48 vs 74 respectively p=0002 5-year OS 58 and 90 respectively plt00001)Among the 45 older HL patients enrolled 11 (24) developed BLT of whom 211 (18) died due to acute pulmonary fibrosisrespiratory failure) Furthermore 1011 (91) BLT cases occurred withduring ABVD (BLT incidence 43 with ABVD vs 5 Stanford V p=004) This toxicity appeared to occur later in the chemotherapy course however the two BLT-related deaths occurred during cycle 3 of ABVD We did not identify any factors that predicted the development of BLT or death due to BLT Granulocyte growth factor was given the vast majority of patients thus it was not analyzed as a risk factor

The Efficacy and Tolerability of ABVD and Stanford V in Older Hodgkin Lymphoma Patients A Comprehensive Analysis from the North American Intergroup Trial E2496 Andrew M Evens et al BJH 2013

Should BLEOMYCIN be omitted at age ge 65

RAPID trial toxicity

Bleomycin in older early-stage favorable Hodgkin lymphoma patients analysis of the German Hodgkin Study Group (GHSG) HD10 and HD13 trialsBoris Bumloll et al German Hodgkin Study Group

Two cycles of ABVD or AVD were equally tolerable in older early-stage favorable HL patients Excessive toxicity including severe bleomycin-induced lung toxicity occurred in older HL patients receiving 4 cycles of ABVD Doxorubicin bleomycin vinblastine sulfate and dacarbazine (ABVD) is associated with severe toxicity in older patients particularly from bleomycin-induced lung toxicity (BLT) Therefore using bleomycin has been questioned in older Hodgkin lymphoma (HL) patients especially in early-stage HL We therefore analyzed feasibility toxicity and efficacy of ABVD or AVD in 287 older early-stage favorable HL patients We included patients ge60 years of age in the German Hodgkin Study Group HD10 and HD13 trials randomized to either 2 cycles of ABVD (2XABVD n = 137) or AVD (2xAVD n = 82) each followed by involved-field radiotherapy (IF-RT) with patients randomized to 4xABVD+IFRT (n =68) Patientsrsquo median age was 65 years (range 60-75) with comparable patient and disease characteristics Grade III-IV adverse event rates were similar in patients receiving 2xAVD and 2xABVD (40 and 39 respectively) but considerably higher in patients receiving 4xABVD (65) Similarly BLT was rare in patients receiving 2xABVDAVD but occurred in 769 (10) of patients randomized to 4xABVD with 3 lethal events In conclusion no effects of bleomycin on toxicity rates were detectable in older patients receiving 2 cycles of chemotherapy However we found a high risk of severe toxicity of bleomycin in older HL patients receiving more than 2 cycles of ABVD (Blood 2016 127(18)2189-2192)

Forty-four advanced-stage older HL patients (aged ge60 years) were treated on the randomized study E2496 Toxicities were mostly similar between chemotherapy regimens although 24 of older patients developed bleomycin lung toxicity (BLT) which occurred mainly with ABVD (91) Further the BLT-related mortality rate was 18 The overall treatment-related mortality for older HL patients was 9 versus 03 for patients aged lt60 years (plt0001) Among older patients there were no survival differences between ABVD and SV According to age outcomes were significantly inferior for older versus younger patients (5-year FFS 48 vs 74 respectively p=0002 5-year OS 58 and 90 respectively plt00001)Among the 45 older HL patients enrolled 11 (24) developed BLT of whom 211 (18) died due to acute pulmonary fibrosisrespiratory failure) Furthermore 1011 (91) BLT cases occurred withduring ABVD (BLT incidence 43 with ABVD vs 5 Stanford V p=004) This toxicity appeared to occur later in the chemotherapy course however the two BLT-related deaths occurred during cycle 3 of ABVD We did not identify any factors that predicted the development of BLT or death due to BLT Granulocyte growth factor was given the vast majority of patients thus it was not analyzed as a risk factor

The Efficacy and Tolerability of ABVD and Stanford V in Older Hodgkin Lymphoma Patients A Comprehensive Analysis from the North American Intergroup Trial E2496 Andrew M Evens et al BJH 2013

Bleomycin in older early-stage favorable Hodgkin lymphoma patients analysis of the German Hodgkin Study Group (GHSG) HD10 and HD13 trialsBoris Bumloll et al German Hodgkin Study Group

Two cycles of ABVD or AVD were equally tolerable in older early-stage favorable HL patients Excessive toxicity including severe bleomycin-induced lung toxicity occurred in older HL patients receiving 4 cycles of ABVD Doxorubicin bleomycin vinblastine sulfate and dacarbazine (ABVD) is associated with severe toxicity in older patients particularly from bleomycin-induced lung toxicity (BLT) Therefore using bleomycin has been questioned in older Hodgkin lymphoma (HL) patients especially in early-stage HL We therefore analyzed feasibility toxicity and efficacy of ABVD or AVD in 287 older early-stage favorable HL patients We included patients ge60 years of age in the German Hodgkin Study Group HD10 and HD13 trials randomized to either 2 cycles of ABVD (2XABVD n = 137) or AVD (2xAVD n = 82) each followed by involved-field radiotherapy (IF-RT) with patients randomized to 4xABVD+IFRT (n =68) Patientsrsquo median age was 65 years (range 60-75) with comparable patient and disease characteristics Grade III-IV adverse event rates were similar in patients receiving 2xAVD and 2xABVD (40 and 39 respectively) but considerably higher in patients receiving 4xABVD (65) Similarly BLT was rare in patients receiving 2xABVDAVD but occurred in 769 (10) of patients randomized to 4xABVD with 3 lethal events In conclusion no effects of bleomycin on toxicity rates were detectable in older patients receiving 2 cycles of chemotherapy However we found a high risk of severe toxicity of bleomycin in older HL patients receiving more than 2 cycles of ABVD (Blood 2016 127(18)2189-2192)

Forty-four advanced-stage older HL patients (aged ge60 years) were treated on the randomized study E2496 Toxicities were mostly similar between chemotherapy regimens although 24 of older patients developed bleomycin lung toxicity (BLT) which occurred mainly with ABVD (91) Further the BLT-related mortality rate was 18 The overall treatment-related mortality for older HL patients was 9 versus 03 for patients aged lt60 years (plt0001) Among older patients there were no survival differences between ABVD and SV According to age outcomes were significantly inferior for older versus younger patients (5-year FFS 48 vs 74 respectively p=0002 5-year OS 58 and 90 respectively plt00001)Among the 45 older HL patients enrolled 11 (24) developed BLT of whom 211 (18) died due to acute pulmonary fibrosisrespiratory failure) Furthermore 1011 (91) BLT cases occurred withduring ABVD (BLT incidence 43 with ABVD vs 5 Stanford V p=004) This toxicity appeared to occur later in the chemotherapy course however the two BLT-related deaths occurred during cycle 3 of ABVD We did not identify any factors that predicted the development of BLT or death due to BLT Granulocyte growth factor was given the vast majority of patients thus it was not analyzed as a risk factor

The Efficacy and Tolerability of ABVD and Stanford V in Older Hodgkin Lymphoma Patients A Comprehensive Analysis from the North American Intergroup Trial E2496 Andrew M Evens et al BJH 2013

Forty-four advanced-stage older HL patients (aged ge60 years) were treated on the randomized study E2496 Toxicities were mostly similar between chemotherapy regimens although 24 of older patients developed bleomycin lung toxicity (BLT) which occurred mainly with ABVD (91) Further the BLT-related mortality rate was 18 The overall treatment-related mortality for older HL patients was 9 versus 03 for patients aged lt60 years (plt0001) Among older patients there were no survival differences between ABVD and SV According to age outcomes were significantly inferior for older versus younger patients (5-year FFS 48 vs 74 respectively p=0002 5-year OS 58 and 90 respectively plt00001)Among the 45 older HL patients enrolled 11 (24) developed BLT of whom 211 (18) died due to acute pulmonary fibrosisrespiratory failure) Furthermore 1011 (91) BLT cases occurred withduring ABVD (BLT incidence 43 with ABVD vs 5 Stanford V p=004) This toxicity appeared to occur later in the chemotherapy course however the two BLT-related deaths occurred during cycle 3 of ABVD We did not identify any factors that predicted the development of BLT or death due to BLT Granulocyte growth factor was given the vast majority of patients thus it was not analyzed as a risk factor

The Efficacy and Tolerability of ABVD and Stanford V in Older Hodgkin Lymphoma Patients A Comprehensive Analysis from the North American Intergroup Trial E2496 Andrew M Evens et al BJH 2013

JCO 2016

Neg interim PET No RT vs RT p=0288 Neg interim PET with No RT vs Pos interim PET p= 002Neg interim PET with RT vs Pos interim PET p= 0063

H2 study early disease results according to PET-2 at a median follow-up of 44 months

At a median follow-up of 47months (4-114) the 5-year PFS for ED patients was 091 for negative PET-2 and 068 for positive PET-2 (p=009)

Neg interim PET No RT vs RT p=0288 Neg interim PET with No RT vs Pos interim PET p= 002Neg interim PET with RT vs Pos interim PET p= 0063

H2 study early disease results according to PET-2 at a median follow-up of 44 months

At a median follow-up of 47months (4-114) the 5-year PFS for ED patients was 091 for negative PET-2 and 068 for positive PET-2 (p=009)