Dr.Umberto VitoloSCDO Ematologia 2

Azienda Ospedaliera-UniversitariaSan Giovanni Battista Torino

I Linfomi non-Hodgkin:I Linfomi non-Hodgkin:Ruolo degli anticorpiRuolo degli anticorpi

radiomarcatiradiomarcati

Pre-dose + Zevalin®

Anti-CD20 anticorpo freddo*(Rituximab 250 mg/m2)

giorni 81 2 3 4 5 6 7

Seguito da 90Y-Zevalin®

(15 MBq/kg BW;dose max 1200 MBq)

*Dose of cold anti-CD20 monoclonal antibody to*Dose of cold anti-CD20 monoclonal antibody tooptimize biodistribution of Zevalinoptimize biodistribution of Zevalin® ® BW, bodyBW, bodyweightweight Zevalin® Summary of Product Characteristics (SmPC), EMEA 2004

Prima pre-dose

Anti-CD20 anticorpo freddo*(Rituximab 250 mg/m2)

Zevalin®: schema di trattamentoZevalin®: schema di trattamento

9

o o

Ruolo degli anticorpi radiomarcatiRuolo degli anticorpi radiomarcati

Linfomi Follicolari in recidivaLinfomi Follicolari in recidiva

Linfomi follicolari come consolidamento della rispostaLinfomi follicolari come consolidamento della risposta

In indicazione approvataIn indicazione approvata

In sperimentazione avanzataIn sperimentazione avanzata Linfomi Follicolari in prima linea single agentLinfomi Follicolari in prima linea single agent

Linfomi follicolari o aggressivi in recidiva comeLinfomi follicolari o aggressivi in recidiva come

potenziamento del condizionamento pre trapiantopotenziamento del condizionamento pre trapianto

9090Y-ibritumomab tiuxetan:Y-ibritumomab tiuxetan:indicazioni approvate nella EUindicazioni approvate nella EU

““Trattamento di pazienti adulti con LinfomaTrattamento di pazienti adulti con Linfomafollicolare a cellule B CD20+ resistenti ofollicolare a cellule B CD20+ resistenti o

ricaduti dopo Rituximabricaduti dopo Rituximab”” Gennaio 2004

““Consolidamento della risposta dopoConsolidamento della risposta dopochemioterapia di prima linea nei pazienti adultichemioterapia di prima linea nei pazienti adulti

con Linfoma follicolare a cellule B CD20+. Ilcon Linfoma follicolare a cellule B CD20+. Ilbeneficio nei pazienti pretrattati con Rituximabbeneficio nei pazienti pretrattati con Rituximab

non è dimostratonon è dimostrato”” Marzo 2008

Months

15.0

24.7

15.0

0 5 10 15 20 25

TTP in CR/CRu

10.6

13.4

13.2

10.2

10.1TTP in allpatients

TTP inresponders

TTP infollicularhistology

ZevalinZevalin®: ®: 73 patients73 patients

Rituximab: 70 patientsRituximab: 70 patients

Gordon et al. Clin Lymphoma 2004;5:98-101

Phase III Trial: Zevalin® Increases TTPPhase III Trial: Zevalin® Increases TTPMedian follow-up 44 monthsMedian follow-up 44 months

0%

10%

20%

30%

40%

50%

60%

70%

80%

OR CR

428 pz: R-CHOP x 6-8 vs CHOP x 6-8428 pz: R-CHOP x 6-8 vs CHOP x 6-8Hiddemann W et al: Blood 2005Hiddemann W et al: Blood 2005

R-CHOP

CHOP

State of the art as first line treatment in advancedState of the art as first line treatment in advancedstage FL: Rituximab + any chemotherapystage FL: Rituximab + any chemotherapy

0 20 40 5060

1.00

0.75

0.50

0.25

0

Prog

ress

ion-

free

surv

ival

201 pz FL: R-MCP x 8 vs MCP x 8201 pz FL: R-MCP x 8 vs MCP x 8Herold M et al: ASH 2004Herold M et al: ASH 2004

MCPMCPmedian 19.7 monthsmedian 19.7 months

R-MCP median not reachedR-MCP median not reached(88.5% at 19.7 months)(88.5% at 19.7 months)

R-CVP:mediana 32 mesi

CVP: mediana 15 mesi

321 pz: R-CVP x 8 vs CVP x 8321 pz: R-CVP x 8 vs CVP x 8Marcus R et al: Blood 2005Marcus R et al: Blood 2005

63%63%

78%78%100

75

50

25

0

Rituximab +Rituximab +CHVP/IFNCHVP/IFN

CHVP/IFNCHVP/IFN

Log-rankp=0.0031

358 pz: R-CHVP x 6 + IFN vs CHVP x 6 + IFN358 pz: R-CHVP x 6 + IFN vs CHVP x 6 + IFNSalles G et al: ASH 2005Salles G et al: ASH 2005

IIL-FOLL05: Linfoma Follicolare inIIL-FOLL05: Linfoma Follicolare instadio II-IVstadio II-IV

R-CVP x 3

R-FM x 3

RANDOM

CRPR

R-CHOP x 3 R-CHOP x 3 + 2 R

R-FM x 3 + 2 R

R-CVP x 5

RESTAGING

Quale è la miglior chemioterapia inQuale è la miglior chemioterapia inassociazione al Rituximab?associazione al Rituximab?

Persistance of high risk patients according to FLIPIin Rituximab-CHOP era (Buske et al, Blood 2006)

Good

Intermediate

Poor

MORTALITY ACCORDING TO FLIPP INDEX

Survival probability

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Months

0 12 24 36 48 60 72 84

COME è possibile migliorare lCOME è possibile migliorare l’’outcome deioutcome deilinfomi follicolari?linfomi follicolari?

Migliorare la qualità della risposta:Migliorare la qualità della risposta:Risposta MolecolareRisposta Molecolare

Migliorare le percentuali diMigliorare le percentuali diRemissione CompletaRemissione Completa

Aumentare lAumentare l’’efficacia terapeuticaefficacia terapeuticariducendo la tossicità eriducendo la tossicità e

aumentando la possibilità diaumentando la possibilità ditrattamento anche nelltrattamento anche nell’’anzianoanziano

Treatment of NHL: Consolidation options

Chemo + rituximab CRCRPRPR

90Y-ibritumomab tiuxetan

ASCT

No treatment

RituximabRituximab

Poor risk

Relapse, refractoryRelapse, refractoryUpfront lineUpfront lineB-cell lymphomaB-cell lymphoma

Radiommunotherapy: rationale asRadiommunotherapy: rationale asconsolidation after first line R-chemotherapyconsolidation after first line R-chemotherapy

Reduced toxicity and increased efficacyReduced toxicity and increased efficacy

RIT may overcome Rituximab resistanceRIT may overcome Rituximab resistance((131131I Tositumobab ORR 65% Horning JCO 2005; 90YI Tositumobab ORR 65% Horning JCO 2005; 90YIbritumobab ORR 74%-83% Witzig JCO 2002, OguraIbritumobab ORR 74%-83% Witzig JCO 2002, OguraASH 2006)ASH 2006)

Can radioimmunotherapy eliminate residual disease inpatients achieving a first-line response?

Shipley et al. Proc ASCO 2005.abst 6577

Settimane 1 3 4 5 8 11 16 -18

R Zevalin®R R R CHOP (or CVP)

R

2

CHOP (or CVP)

R CHOP (or CVP)

R

0

10

20

30

40

50

60

70CR%CR%

CHOP-R ZEVALIN

28%

67%

First-line treatment in FL: Consolidation radiolabelledimmunotherapy after R-chemotherapy

•• Patients: Patients: 42 Previously untreated follicular lymphoma (grades 142 Previously untreated follicular lymphoma (grades 1––3,3,stages IIstages II––IV), Stage IV 60%IV), Stage IV 60%

•• Treatment: Treatment: weekly rituximab x 4, followed by 3 weekly rituximab x 4, followed by 3 courses of R-CHOP*-21,courses of R-CHOP*-21,Responders with < 25% BM involvement received ZevalinResponders with < 25% BM involvement received Zevalin®® consolidation, consolidation,5 weeks after last dose of CHOP-R5 weeks after last dose of CHOP-R

Response; Response; final restaging performed 12 weeksafter Zevalin® administration

Shipley et al. JCO 23: 2005 (abst 6577)

Months

100%

80%

60%

40%

20%

0%

0 3 6 9 12 15 18 21 24 27 30 33 36

Results Total Fail 2yrEFS 40 5 85OS 40 2 95

OS

EFS

First line treatment in Follicular Lymphoma:consolidation RIT after R-chemotherapy

FIT Study Schema

ZevalinZevalin(n = 208)(n = 208)

Rituximab 250 mg/mRituximab 250 mg/m22

IV Day -7 and Day 0 +IV Day -7 and Day 0 +Zevalin 14.8 MBq/kgZevalin 14.8 MBq/kg

(maximum 1184(maximum 1184MBq/kg) Day 0MBq/kg) Day 0

First-line therapywith CVP, CHOP-like,

fludarabinecombinations,

chlorambucil, orrituximab combination

INDUCTION

CONSOLIDATION

No furtherNo furthertreatmenttreatment(n=206)(n=206)

NRPD

CR/CRCR/CRu or PRu or PR

No inclusion

RANDOMIZATION

CONTROLCONTROL

Start of study

FIT: 90Y-Ibritumomab as ConsolidationTherapy in FL (cont’d)

Hagenbeek A, et al. ASH 2007. Abstract 643.

PR to CR/CRu Conversion

Ibritumomab (n = 208)Ibritumomab (n = 208) Observation (n = 206)Observation (n = 206)

CHOP-Like

First-Line Regimen

Overall Chlorambucil CVP/COP CHOP FludarabineCombination

RituximabCombination

77.284.6

72.7 75.6 76.9

100

71.4

17.57.7 10.3

25

0 0

41.7

020406080

100

Perc

enta

ge o

f Pat

ient

s

P < .001 P < .001P < .001 P < .001 P < .005

P < .05

P < .34

FIT Primary Endpoint:Median PFS in All Patients*

0

20

40

60

80

100

0 6 12 18 24 30 36 42 48 54 60 66

PFS, Time From Randomization (months)

Pro

po

rtio

n R

em

ain

ing

Pro

gre

ssio

n F

ree (

%)

Log-rankP<0.0001HR 0.463

Zevalin: median 37 monthsn=208

Control: median 13.5 monthsn=206

*Median observation period was 3.5 years.

PFS in Patients With CR/CRuAfter First-line Therapy

0

20

40

60

80

100

0 6 12 18 24 30 36 42 48 54 60 66

PFS, Time From Randomization (months)

Pro

po

rtio

n R

em

ain

ing

Pro

gre

ssio

n F

ree (

%)

Log-rankP=0.01

HR 0.609Zevalin: median 54.6 mon=107

Control: median 29.9 mon=109

PFS in Patients With PRAfter First-line Therapy

0

20

40

60

80

100

0 6 12 18 24 30 36 42 48 54 60 66

PFS, Time From Randomization (months)

Pro

po

rtio

n R

em

ain

ing

Pro

gre

ssio

n F

ree (

%)

Control: median 6.3 mon=97

Log-rankP<0.0001HR 0.304

Zevalin: median 29.7 mon=101

90% of Patients Converted From PCR+Status to PCR- (in blood) After Zevalin

Consolidation

No. of patients converting from bcl-2 PCR+(after remission-induction treatment)to PCR- status post-randomization

Control, n/N*(%)

Zevalin, n/N*(%)

Blood 21/59 (36) 61/68 (90)

*Patients with PCR+ status at randomization and who have had at least 1 post-randomization PCR assessment; all other patients were either PCR- at

randomization or lacked a second assessment.

Ruolo degli anticorpi radiomarcatiRuolo degli anticorpi radiomarcati

Linfomi Follicolari in recidivaLinfomi Follicolari in recidiva

Linfomi follicolari come consolidamento della rispostaLinfomi follicolari come consolidamento della risposta

In indicazione approvataIn indicazione approvata

In sperimentazione avanzataIn sperimentazione avanzata Linfomi Follicolari in prima linea single agentLinfomi Follicolari in prima linea single agent

Linfomi follicolari o aggressivi in recidiva comeLinfomi follicolari o aggressivi in recidiva come

potenziamento del condizionamento pre trapiantopotenziamento del condizionamento pre trapianto

First-line radioimmunotherapy•• Single course of Single course of 131131I-tositumomabI-tositumomab

–– 76 patients, stage III/IV FL76 patients, stage III/IV FL

•• ORR 95%, CR rate 75%ORR 95%, CR rate 75%•• 8-year PFS is 50%8-year PFS is 50%

•• Among CRsAmong CRs–– molecular CRs in 80% of evaluable patientsmolecular CRs in 80% of evaluable patients–– patients with molecular CR had better PFS than patientspatients with molecular CR had better PFS than patients

remaining PCR+remaining PCR+

•• No cases of MDS or AMLNo cases of MDS or AML–– Median follow-up 8 yearsMedian follow-up 8 years

Kaminski, et al. ASCO 2007 Abstract 8033; Kaminski et al. N Engl J Med 2005;352:441-9

ORRCR/CRu

0%10%20%30%40%50%60%70%80%90%

100% 95%

75%

Kaminski MS, et al. N Engl J Med. 2005; 352: 441–449.

0

Surv

ival

(%)

Years after Dosimetric Dose

20

40

60

80

100

01 2 3 4 5 6 7 8

Overall SurvivalProgression-free Survival

0Prog

ress

ion-

free

Sur

viva

l (%

)Years after Dosimetric Dose

20

40

60

80

100

01 2 3 4 5 6 7 8

Complete Responders(57/76 = 75%)Partial Responders(15/76 = 20%)

PFS and OS (All 75 Patients) PFS for Responders

131I Tositumomab alone as first line treatment in131I Tositumomab alone as first line treatment infollicular lymphomafollicular lymphoma

Phase II study of 90Y Ibritumomab Tiuxetan (Zevalin®) inPhase II study of 90Y Ibritumomab Tiuxetan (Zevalin®) inpatients with untreated Follicular Non Hodgkinpatients with untreated Follicular Non Hodgkin‘‘s Lymphomas Lymphoma

Principal Investigator: AM Carella, GenovaParticipating centers: PL Zinzani, Bologna; E Morra, Milano; M Lazzarino,Pavia; M Petrini, Pisa; Cascavilla, San Giovanni Rotondo; U Vitolo, Torino

PLANNEDPLANNEDENROLLEMENT:ENROLLEMENT:

50 PATIENTS50 PATIENTS

Witzig et al. J Clin Oncol 2003;21:1263–1270

Platelets = 50 000ANC = 1000

Platelets (103/µl)

Study week

0

4

8

12

16

0 2 4 6 8 10 12 140

50

100

150

200

250

300

350

400

450Absolute neutrophil countHaemoglobin Platelets

Hb = 10

Haemoglobin (g/dl)

ANC(103/µl)

9090Y-ibritumomab tiuxetan safety:Y-ibritumomab tiuxetan safety:Kinetics of median blood countsKinetics of median blood counts

68%59%70%Thrombocytopenia grade III/IV

68%47%66%Neutropenia grade III/IV

Patients≥70 years

(n=40)

Patients60-69 years

(n=58)

Patients<60 years (n=113)

Pooled analysis of four registrational studies

(n=211)

Schilder RJ et al. J Clin Oncol 200; 23(16S):575s, abstr 6562

0

20

40

60

80

100

<60 years 60-69 years ≥70 years

Res

pons

e ra

te (%

)

PR

CR/CRu7871

80

35 3338

0

2

4

6

8

10

Median duration of response

Mon

ths

12

9.9

11

9.4<60 years

60-69 years

≥70 years

9090Y-ibritumomab tiuxetan:Y-ibritumomab tiuxetan:efficacy and safety in geriatric patientsefficacy and safety in geriatric patients

746 patients 746 patients from registration and compassionate use trials,from registration and compassionate use trials,19961996––20022002

Median 3 prior therapies (0Median 3 prior therapies (0––9+) with a m9+) with a median follow-up of 4.4 yearsedian follow-up of 4.4 years–– 19 cases of t-MDS or t-AML reported (crude rate 2.5%)19 cases of t-MDS or t-AML reported (crude rate 2.5%)

•• 11 cases in registration trials11 cases in registration trials•• 8 cases in compassionate-use trial8 cases in compassionate-use trial

Annualized rateAnnualized rate–– 0.3% after diagnosis of NHL0.3% after diagnosis of NHL–– 0.7% after 90Y-ibritumomab tiuxetan0.7% after 90Y-ibritumomab tiuxetan

Cytogenetic aberrationsCytogenetic aberrations–– Multiple, commonly on chromosomes 5 and 7Multiple, commonly on chromosomes 5 and 7

Cox regression analysisCox regression analysis–– Previous treatment with fludarabine significant risk factor forPrevious treatment with fludarabine significant risk factor for

MDS or AML (HR 3.5; 95% CI, 1.4 to 8.8; p= .006) along with boneMDS or AML (HR 3.5; 95% CI, 1.4 to 8.8; p= .006) along with bonemarrow involvementmarrow involvement

Czuczman et al, J Clin Oncol 2007; 25: 4285-92

9090Y-ibritumomab tiuxetan long term toxicity:Y-ibritumomab tiuxetan long term toxicity:treatment related myelodysplastic syndrometreatment related myelodysplastic syndrome

9090Y-ibritumomab tiuxetan long term toxicity:Y-ibritumomab tiuxetan long term toxicity:treatment related myelodysplastic syndrometreatment related myelodysplastic syndrome

Cumulative incidence of treatment related MDS and AML

Czuczman et al, J Clin Oncol 2007; 25: 4285-92

The finding of abnormalities of chromosome 5 and/or 7 in patientswith secondary MDS or AML after 90Y-ibritumomab tiuxetansuggests an association with previous exposure to chemotherapy.

Interestingly, no cases of MDS/AML have developed in a group of76 patients receiving 131I-tositumomab as single agent first-linetherapy with a median follow-up of almost 8 years.

According to these data, the incidence of MDS and AML isconsistent with that expected in NHL after conventionalchemotherapy and does not appear to be increased after 90Y-ibritumomab tiuxetan.

Panel discussion: response assessment, follow-up, long Panel discussion: response assessment, follow-up, longterm safetyterm safety

Italian Society of Hematology

Consensus Conference on the use of Consensus Conference on the use of9090YY-ibritumomab tiuxetan therapy in clinical practice-ibritumomab tiuxetan therapy in clinical practice

Refractory DLBCL: HDC + ASCT Refractory DLBCL: HDC + ASCT

100

80

60

40

20

01086420

31%

11%11%

P=0.02

REFRACTORYREFRACTORY

CHEMOSENSITIVE

Event-Free SurvivalEvent-Free Survival

Martelli M et al, EBMT 2001Martelli M et al, EBMT 2001

Progression-free survival CRProgression-free survival CRcompared to PRcompared to PR

Zelenetz et al, Ann Oncol 2003Zelenetz et al, Ann Oncol 2003

aa-IPI predicts Autologous Stem Cellaa-IPI predicts Autologous Stem CellTransplantation Outcome for patients withTransplantation Outcome for patients with

relapsed or primary refractory DLBCL.relapsed or primary refractory DLBCL.

Hamnlin P et al, Blood 2003Hamnlin P et al, Blood 2003

PFS

InpatientInpatientOutpatientOutpatient

-14 -7 -4 -2

9090Y-ibritumomabY-ibritumomabtiuxetantiuxetan therapytherapy

0.4 mCi/Kg0.4 mCi/Kg VP/AraCVP/AraC MelMelTRANSPLANTTRANSPLANT

Close observation,Close observation,discharge upondischarge upon

blood countblood countrecoveryrecoveryClose observationClose observation

BCNUBCNU

-5 -3-6 -1 0

n = 12n = 12 Age: median 61 yrs (20-78 yrs)Age: median 61 yrs (20-78 yrs) Histology: DLCBL, MCLHistology: DLCBL, MCL

Fung H, et al. ASH 2003Fung H, et al. ASH 2003

9090Y-ibritumomab tiuxetanY-ibritumomab tiuxetan32 mCi/BEAM32 mCi/BEAM

Time to recovery: WBC 11 days,Time to recovery: WBC 11 days,platelets 11 daysplatelets 11 days

Pilot study: Combining conventional dose Z-BEAMPilot study: Combining conventional dose Z-BEAMas a conditioning regimenas a conditioning regimen

-21

RituximabRituximab250 mg/sqm250 mg/sqm

Z-BEAM in poor risk NHL patients ineligible for total-bodyZ-BEAM in poor risk NHL patients ineligible for total-bodyirradiation:irradiation:

Overall and progression-free survivalOverall and progression-free survival

89%

70%

Krishnan et al, JCO 26:90-5, 2008

n = 41n = 41 Age: median 60 yrs (19-Age: median 60 yrs (19-

78 yrs)78 yrs) Histology: Histology: DLCBLDLCBL (20), (20),

MCLMCL (13), (13), FLFL (4), (4), Transf.Transf.LNHLNH (4) (4)

90Median time torecovery: WBC 11 d(range 9-26), platelets12 d (range: 3-107)

ITALIAN EXPERIENCE:ITALIAN EXPERIENCE:BASELINE CHARACTERISTICS 53 ptsBASELINE CHARACTERISTICS 53 pts

Median age, y (range) 54 yrs (20-75)

Histology, no. (%) Follicular 16 (30%) Aggressive 37 (70%)

III-IV stage at diagnosis, no. (%) 40 (75%)

Median number of prior chemotherapy 2 (2-5)

IPI, grade 0 8 (15%) > I 45 (85%)

Bone marrow involvement at diagnosis 19 (36%)

Prior rituximab, no. (%) 48 (91%)

high risk high risk patients !!! patients !!!

By courtesy of Enzo Pavone

Status at enrollment Relapse Progression PR CR

Status at transplant Progressive disease PR RC

Median time to ASCT, months (range)

11 (21%)13 (25%)24 (45%) 5 (9%)

11 (21%)27 (51%)15 (28%)

16 (5-108)

ITALIAN EXPERIENCE:ITALIAN EXPERIENCE:BASELINE CHARACTERISTICS 53 ptsBASELINE CHARACTERISTICS 53 pts

By courtesy of Enzo Pavone

Early Response post Z-BEAM (90 days)Early Response post Z-BEAM (90 days)

CR 32 (74 %) PR 5 (11 %) PD 6 (14 %)

ORR 85%ORR 85%

RESULTSRESULTS

2 - septic shock (day +6 and +39)

1 - pneumonitis (day +22)

1 – BK viral encephalites (day +61)

1 - MOF (day +14)

Early Death before 90 daysEarly Death before 90 daysTRM all 9.3%TRM all 9.3%

TRM <65 3.4%TRM <65 3.4%(multivariate analysis)(multivariate analysis)

By courtesy of Enzo Pavone

2-Years EFS2-Years EFS

64%64%

By courtesy of Enzo Pavone

44 G. BenevoloG. Benevolo44 C. BoccominiC. Boccomini44 B. BottoB. Botto44 A. ChiappellaA. Chiappella44 L. OrsucciL. Orsucci44 P. PregnoP. Pregno

HEMATOLOGY 2- Lymphoma sectionHEMATOLOGY 2- Lymphoma sectionASO S.Giovanni Battista TorinoASO S.Giovanni Battista Torino

PATHOLOGYPATHOLOGYUniversity of Torino Prof G. InghiramiUniversity of Torino Prof G. Inghirami

44 P. Francia di CelleP. Francia di Celle44 L. GodioL. Godio44 D. NoveroD. Novero44 A. StacchiniA. Stacchini

Aknowledgments

CANCER EPIDEMIOLOGYCANCER EPIDEMIOLOGYUniversity of Torino Prof F. MerlettiUniversity of Torino Prof F. Merletti

44 G. CicconeG. Ciccone44 M. CeccarelliM. Ceccarelli44 F. SacconaF. Saccona

All Physicians of IILAll Physicians of IILCentersCenters

NUCLEAR MEDICINENUCLEAR MEDICINEProf G. BisiProf G. Bisi

44 M. LadettoM. Ladetto44 B. MantoanB. Mantoan

NUCLEAR MEDICINENUCLEAR MEDICINEUniversity of Torino Prof G.BisiUniversity of Torino Prof G.Bisi

44 M. BellòM. Bellò44 P. ScapoliP. Scapoli

HEMATOLOGY 1HEMATOLOGY 1Prof M. BoccadoroProf M. Boccadoro