meeting educazionale: linfomi non-hodgkin aggressivivitolo.pdf · standard and novel...

Meeting Educazionale:Linfomi non-Hodgkin aggressivi

I linfomi aggressivi a prognosi sfavorevole: possibilità dimiglioramento della prognosi ottimizzando la

chemioimmunoterapia.

Dr. Umberto VitoloSC Ematologia 2 AOU San Giovanni Battista

Torino

• Topics:

– Prognostic factors Clinical Factors Role of PET New histological subtypes

– Treatment Young Elderly

– Novel approaches

Standard and novel chemoimmunotherapyStandard and novel chemoimmunotherapyapproaches as first line treatment to improve theapproaches as first line treatment to improve the

outcome in aggressive lymphoma at high riskoutcome in aggressive lymphoma at high risk



• Topics:


– Treatment Young Elderly


International Prognostic Index (IPI)International Prognostic Index (IPI)

Risk Factors - Age > 60 years - Stages III or IV - ≥2 extranodal sites - Performance Status ≥2 - LDH> normal

Prognostic Group No. of Factors

Low 0, 1Low/intermediate 2High intermediate 3High 4, 5

Aggressive Non-Hodgkin Lymphomas:Aggressive Non-Hodgkin Lymphomas:Survival of IPI Risk GroupsSurvival of IPI Risk Groups

Group Factors 5y PFS 5y-OS IPI ( Shipp 1993)Low 0-1 70% 73%

Low-int 2 50% 51%

High-int 3 49% 43%

High 4-5 40% 26%

R-IPI (Sehn 2006) Factors 4y-PFS 4y-OS

Very-good 0 94% 94%Good 1-2 80% 79%Poor 3-5 53% 55%

Revised International Prognostic FactorsRevised International Prognostic Factors (R-IPI) vs Standard IPI in patients treated (R-IPI) vs Standard IPI in patients treated

with R-CHOPwith R-CHOP

Sehn LH et al. Blood 2007; 109: 1857-61 Sehn LH et al. Blood 2007; 109: 1857-61

R-IPI: Risk groups remain in DLBCL in theR-IPI: Risk groups remain in DLBCL in therituximab erarituximab era

Sehn et al. Blood. 2007;109:1857

Analisi retrospettiva di unapopolazione non selezionata dipazienti con DLBCL (N= 365)

Tutti i pazienti trattati conR-CHOP: 45% erano alto rischio (IPI

3-5) >50% dei pz ad alto rischio

ha presentato una recidivaentro 4 anni

IPI score rimane unimportante indice

prognostico anche inera del rituximab

Role of PET to monitor response to therapy inRole of PET to monitor response to therapy inaggressive lymphomas?aggressive lymphomas?

• PET at the end of treatment

• Interim PET response

Juweid et al. J Clin Oncol 2005

53 pz con NHL aggressivo53 pz con NHL aggressivoValutazione finale con TAC e FDG-PET dopo CHOPValutazione finale con TAC e FDG-PET dopo CHOP

PFS PFS –– IWC / IWC + PET IWC / IWC + PET

Response Assessment of Aggressive Non-HodgkinResponse Assessment of Aggressive Non-Hodgkin’’ssLymphoma by Integrated International Workshop CriteriaLymphoma by Integrated International Workshop Criteriaand Fluorine-18-Fluorodeoxyglucose Positron Emissionand Fluorine-18-Fluorodeoxyglucose Positron Emission

TomographyTomography

Cheson B et al. J Clin Oncol 2007

Revised Response Criteria for MalignantRevised Response Criteria for MalignantLymphomaLymphoma

Early clinical trials of interim PET in lymphomaEarly clinical trials of interim PET in lymphoma

Kostakoglu et al, Cancer 107: 2678, 2006

Haioun et al, Blood 106: 1376, 2005Mikhaeel et al, Ann Oncol 16: 1514, 2005

Spaepen et al, Ann Oncol 13: 1356, 2002

PET after 4th cycle

PET after 3rd cycle PET after 2nd cyclePPV 50 %NPV 74 %Accuracy 68.5%

PET after 1st cycle

Interim-PET +

DLBCL: PET-adapted TherapyDLBCL: PET-adapted Therapy MSKCC 01-142 MSKCC 01-142

Positive Negative NPV 89%

55 pts (59 pts)49 EF

R-CHOP-14 x 4 (87 enrolled)

Interim PET86 pts (97 pts)

31 pts (38 pts)Bx. Pos. Bx. Neg

27 Pts23 EF

4 pts (5 pts)2 EF

A. Zelenetz, personal communication 2008

POD-1

PPV 26%PPV 26%

PET NEG vs. Bx NEG vs. BX POS

Outcome based upon Interim PET ScanOutcome based upon Interim PET Scan

EFSInterim PET(+) vs. PET(-)

60544842363024181260

Cum

ulat

ive

Surv

ival

1.0

.9

.8

.7

.6

.5

.4

.3

.2

.1

0.0

P=0.2

PET NEG (N=55, 49 cen)

PET POS (N=31, 25 cen)

Months

60544842363024181260

Cum

ulat

ive

Surv

ival

1.0

.9

.8

.7

.6

.5

.4

.3

.2

.1

0.0

PET NEG (n=55, 49 cen)

BX NEG (n=27, 23 cen)

BX POS (n=4, 2 cen)

P=NS

EFS

A. Zelenetz, personal communication 2008

Early evaluation of 18-FDG-PET in DLBCLEarly evaluation of 18-FDG-PET in DLBCL

Cashen A et al, ASH 2008Cashen A et al, ASH 2008

FDG-PET/TC after cycle 2FDG-PET/TC after cycle 2 FDG-PET/TC end of therapyFDG-PET/TC end of therapy

These results demonstrate that in DLCBL patients treated with R-CHOP whoThese results demonstrate that in DLCBL patients treated with R-CHOP whoare assessed prospectively, interim FDG-PET/CT does not predict PFS.are assessed prospectively, interim FDG-PET/CT does not predict PFS.

NPVNPV 85%85%PPV 25%PPV 25%

81 DLBCL at diagnosis treated with R-CHOP21/14; median age 56 (22-82)81 DLBCL at diagnosis treated with R-CHOP21/14; median age 56 (22-82)

Pregno P et al.Pregno P et al.Interim 18-FDG-PET Failed to Predict DifferentInterim 18-FDG-PET Failed to Predict DifferentOutcome in DLBCL Patients Treated withOutcome in DLBCL Patients Treated withRituximab-CHOP.Rituximab-CHOP.Oral Presentation ASH 2009.Oral Presentation ASH 2009.

18-months PFS by PET-2 evaluation 18-months PFS by PET-3 evaluation

Final PET pos 61%

Final PET neg 84%

Interim PET pos 74%

Interim-PET neg 84%

Interim PETInterim PET Final PETFinal PET

Early evaluation of 18-FDG-PET in DLBCLEarly evaluation of 18-FDG-PET in DLBCL

Pregno P et al, SIE 2009Pregno P et al, SIE 2009

Early PET evaluation: unsolved issueEarly PET evaluation: unsolved issue

42 year-old gentleman, DLBCL IPI 1 R-CHOP1442 year-old gentleman, DLBCL IPI 1 R-CHOP14

DiagnosisDiagnosis Early PET after 2Early PET after 2coursescourses Final PETFinal PET

Recommended timing of PET (PET/CT) scans inRecommended timing of PET (PET/CT) scans inlymphoma clinical trialslymphoma clinical trials

Cheson B et al, J Clin Oncol 2007Cheson B et al, J Clin Oncol 2007

Ancillary trial 18-FDG-PET in IIL-DLCL04Ancillary trial 18-FDG-PET in IIL-DLCL04

StagingCT scan and 18-FDG-PET

R-CHOP14/R-MegaCHOP14 X 2

R-CHOP14/R-MegaCHOP14 X 2

R-MADx 2

Final restagingCT scan and 18-FDG-PET

Early response evaluation18-FDG-PET

Interim response evaluation by CT scan

R-CHOP14/RMegaCHOP14

18-FDG-PET pre ASCT

BEAM-ASCT

RESPONSEEVALUATION

NO CHANGE OFTREATMENTBASED ONEARLY 18-FDG-PET RESULTS

DLBCL AND EBVDLBCL AND EBV

Park et al, Blood 2007Park et al, Blood 2007

BB--CCell ell LLymphoma, ymphoma, UUnclassifiable, nclassifiable, wwith ith FFeatureseaturesIIntermediate ntermediate BBetween etween DLBCLDLBCL aand nd BLBL

BCLUWFIBDLBCLABLBCLUWFIBDLBCLABL



• Topics:


• Treatment Young Elderly


Management of DLBCL: first line treatmentManagement of DLBCL: first line treatment

Efficacy of R-CHOP14/21 in DLBCL patients withEfficacy of R-CHOP14/21 in DLBCL patients withpoor prognosis?poor prognosis?

Brusamolino E et al, Haematologica 2006Sehn LH et al, Blood 2007

164 pts poor-RIPI R-CHOP21:4-yr OS 55%

31 pts poor IPI R-CHOP14:4-yr OS 45%

How to improve survival in DLBCLHow to improve survival in DLBCLwith poor-prognosis?with poor-prognosis?

Add more drugs and/or intensify the administration ofAdd more drugs and/or intensify the administration ofchemotherapy and/or Rituximabchemotherapy and/or RituximabRituximab-Dose dense therapyRituximab-Dose dense therapy

Rituximab-HDC+ASCT as first-line therapyRituximab-HDC+ASCT as first-line therapy

Add more and new drugs with different mechanismAdd more and new drugs with different mechanismof action beyond Rituximabof action beyond Rituximab

HDC and ASCT as first line treatment in aggressiveHDC and ASCT as first line treatment in aggressivelymphomas in pre-Rituximab era: contradictory resultslymphomas in pre-Rituximab era: contradictory results

Event-free survivalEvent-free survivalDLCL IPI 1-2DLCL IPI 1-2


GOELAMS GOELAMSstudystudy

Milpied et alMilpied et alNEJM 2004NEJM 2004

Intergruppo IntergruppoItaliano LinfomiItaliano Linfomi

studystudyVitolo et alVitolo et al

HaematologicaHaematologica20052005

Martelli etal. J Clin

Oncol 2003


P = 0.2P = 0.2

EFS LNH93-3 study. 370EFS LNH93-3 study. 370pts; age < 60yrs; AAIPI 2-3pts; age < 60yrs; AAIPI 2-3

Gisselbrechtet al: JCO

2002

Induction chemotherapy

Months 1 and 2

Intensified chemotherapy MAD(HD-ARAC + Mitoxantrone x 3

days)Months 3 and 4

High dosechemotherapyBEAM + ASCT

Month 5

R

MegaCEOP14 x 4

R R

MAD MAD BEAM

R RPBSC

ASCT

months

RR--HHDDCC

R = Rituximab

R

0 1 2 3 4 5

R-MEGACEOP14

R 375 mg/m2 d 1Epi 110 mg/m2 d 3Ctx 1200 mg/m2 d 3Vcr 1.4 mg/m2 d 3Pdn 40 mg/m2 dd 1 5G-CSF 5 mcg/kg dd 5 12

R-MAD

Mito 8 mg/m2 dd 1 3ARA-C 2 g/m2/12h dd 1 3Dex 4 mg/m2/12h dd 1 3R 375 mg/m2 d 4 and d -1PBSCG-CSF 5 µg/Kg d 4

+/- RT-IF to bulkydisease or residual

mass

R-Dose Dense + HDC supplemented with Rituximab + ASCTR-Dose Dense + HDC supplemented with Rituximab + ASCT

Vitolo U, et al. Haematologica 2009; 94: 1250-58Vitolo U, et al. Haematologica 2009; 94: 1250-58

R-HDC: June 2002 – December 2005 94 patients

4-yr OS 80%(95%CI: 71.6%-88.4%)

4-yr FFS 73%(95%CI: 63.5%-82.5%)

73% R-HDC73% R-HDC

44% HDC44% HDC

p = .0008p = .0008

R-HDC 94 patients CR 82%R-HDC 94 patients CR 82% HDC 41 patients CR 68%HDC 41 patients CR 68%

Retrospective Comparison:Retrospective Comparison:Rituximab-HDC+ASCT vs HDC+ASCTRituximab-HDC+ASCT vs HDC+ASCT

54% HDC54% HDC

80% R-HDC80% R-HDC

p = .0017p = .0017

4-yrs Failure-Free Survival4-yrs Failure-Free Survival 4-yrs Overall Survival4-yrs Overall Survival

FFS R-HDC R-HDC vs HDCHDC = 0.44 (95% CI=0.24-0.81, p=.01)= 0.44 (95% CI=0.24-0.81, p=.01)

OS R-HDC R-HDC vs HDCHDC = 0.45 (95% CI=0.22-0.90, p=.03)= 0.45 (95% CI=0.22-0.90, p=.03)

CoxCox’’s model:s model:adjusted Hazardadjusted Hazard

RatioRatio

ASCT upfront with Rituximab pretransplantASCT upfront with Rituximab pretransplant LNH 03 B. DLBCL: 18-60 yr, IPI 2-3 factors LNH 03 B. DLBCL: 18-60 yr, IPI 2-3 factors

Rituximab

R R R R

ACVBP

ACVBP

ACVBP

ACVBP

Wk 0 2 4 6 PBPCcollection

10 12 14 16 18 21 23

MTX3g/sqm BEAM+ASCT

Gisselbrecht C et al, ASH 2008Gisselbrecht C et al, ASH 2008

Median Follow-up 27 m %3-year PFS 763-year OS 813-year OS 60

GITIL trial: R-HDS maps in first line DLBCLGITIL trial: R-HDS maps in first line DLBCL112 patients age < 65, aa-IPI 2-3112 patients age < 65, aa-IPI 2-3

Tarella C et al, Leukemia 2007Tarella C et al, Leukemia 2007

OS by IPIOS by IPI EFS by IPIEFS by IPI

Most recent studies in poor-prognosis DLBCL treated with (Rituximab)dose-dense chemotherapy with R-HDC and ASCT

AUTHOR TREATMENT INCLUSION FFS/OS CR% TD%

CosoBMT 2006

RISC<61yr, aa-IPI 2-3,

stage II-IV5yr FFS 63% OS 65% 72 3

IntragumtornchaiLeuk Lymphoma

2006

CHOP<66yr, aaIPI2-3,

stage III-IV

5yr FFS 16% OS 24% 36 8CHOP-ESHAP-HDT 5yr FFS 34% OS 43% 44 17

RCHOP-ESHAP 5yr FFS 61% OS 61% 67 11Stewart

Blood 2006CHOP+DICEP+BEAM <65yr, aa-IPI 2-3 4yr EFS 72% OS 79% n.a. 1.8

TarellaLeukemia 2007

RHDS-maps<66yr, aa-IPI 2-3,

stage II-IV4yr FFS 73% OS 76% 80 5

ArranzEur J Haematol

2008

MegaCHOP (+/- IFE) +BEAM

18-65yr, low IPIwith

beta2microglobulinor

Intermediate/highrisk

5yr PFS 56% OS 64% n.a. 3.5

HaiounAnn Oncol 2009

ACE + HDT+ASCT +/- R18-60yr, aa-IPI 2-3 4yr EFS 71-80% OS 48-53% 72 4ACVBP + HDT+ASCT +/-

RVitolo

Haematologica 2009RMegaCEOP-RMAD-

BEAM<61yr, aa-IPI 2-3,

stage III-IV4yr FFS 73% OS 80% 82 5

Who are the patients at poor-risk for whom isWho are the patients at poor-risk for whom isworthwhile to intensify treatment?worthwhile to intensify treatment?

We need randomized controlled trials in youngWe need randomized controlled trials in youngpoor-prognosis DLBCLpoor-prognosis DLBCL

DLBCL age <60/65, aaIPI 2-3DLBCL age <60/65, aaIPI 2-3Ongoing Randomized TrialsOngoing Randomized Trials

Groups Risk categories OutlineDSHNHLDSHNHL Age < 60, aaIPI 2-3 R-megaCHOEP x 4 vs R-CHOEP14 x 8

IIL (DLCL04)IIL (DLCL04) Age < 60, aaIPI 2-3

R-CHOP14 x 8vs R-megaCHOP14 x 6

vs R-CHOP14 x 4 + R-HDCT + ASCTvs R-megaCHOP14 x 4 + R-HDCT + ASCT

(early FDG-PET evaluation)

HOVON (63 NHL)HOVON (63 NHL) Age < 65 aa IPI 2-3R-iCHOP x 6

vs R-iCHOP x 3 + R-HDCT x 2 +ASCT

US IntergroupUS IntergroupS9704S9704 Age < 60, aaIPI 2-3

R-CHOP21 x 8 vs R-CHOP21 x 5 + ASCT(early FDG-PET evaluation)

GOELAMGOELAM Age < 60, aaIPI 2-3R-CHOP14 x 8

vs R-CEEP x 2 + HDMTX/Ara-C + ASCT

NORDICNORDIC Age < 60, aaIPI 2-3R-CHOEP14 x 6 + HDMTX + HDAra-C x 6

(early FDG-PET evaluation)

GITILGITIL Age < 60, aaIPI 2-3 R-CHOP14 x 8 vs R-HDS

CALGBCALGB All patient groups R-CHOP21 x 8 vs DA-EPOCH x 6-8

NCRINCRIAll patient groups

Stratification according toIPI and age: < 60 vs ≥ 60

R-CHOP21 x 8 vs R-CHOP14 x 6 (R x 8)

mCHOEP IV

CYC 6000ADR 70VCR 2ETO 1480PRD 500

PBSC

R64

PBSCPBSC

mCHOEP III


43

mCHOEP II


mCHOEP I


221 77 98 days

CH

OEP

-14

CH

OE

P-14

CH

OEP

-14

CH

OEP

-14

CH

OEP

-14

CH

OEP

-14

CH

OEP

-14

CH

OEP

-14

CHOEP-14: CYC 750 VCR 2ADR 50 PRED 500ETO 300 G-CSF

DSHNHL 2002-1 (DSHNHL 2002-1 („„Mega-CHOEPMega-CHOEP““):):TRIAL DESIGN (TRIAL DESIGN (≤≤60 YRS60 YRS, AGE-ADJUSTED IPI , AGE-ADJUSTED IPI ≥≥2)2)

n=230

n=230rituximab

CR/PRCR/PR

CR/PRCR/PR

Off studyOff study

R-MegaCHOP14 x 4R-MegaCHOP14 x 4

R-CHOP14 x 4R-CHOP14 x 4R-MAD x 2 +R-MAD x 2 +BEAM + ASCTBEAM + ASCT

NRNR

RRAANNDDOOMMIIZZAATTIIOONN


R-CHOP14 x 4R-CHOP14 x 4

RR

EE

SS

TT

AA

GG

II

NN

GG

188188PtsPts

188188PtsPts


R-CHOP14 x 4R-CHOP14 x 4

Off studyOff studyNRNR

Phase III randomized, multicenter study in poor-prognosisPhase III randomized, multicenter study in poor-prognosis(aaIPI2-3) DLBCL young patients. Dose-dense(aaIPI2-3) DLBCL young patients. Dose-dense

chemotherapy + Rituximab +/- intensified and HDC withchemotherapy + Rituximab +/- intensified and HDC withASCT. ASCT. Study ID: IIL-DLCL04.Study ID: IIL-DLCL04.

*Patients at risk of CNS recurrence*Patients at risk of CNS recurrence(SIE guidelines 2006): IT Mtx 4 or 6 doses(SIE guidelines 2006): IT Mtx 4 or 6 doses

Accrual Target 376 patientsAccrual October 2009:

310 patients

Haematologica 2006

Prophylaxis of CNS relapse should be performed in patientswith involvement of specific extranodal sites such as the:testis, paranasal sinuses, hard palate, orbit, paravertebralmasses and bone marrow. (Grade B)

Prophylaxis of CNS relapse should be considered inpatients with involvement of more than one extranodal siteand increased LDH. (Grade B)

DLCL04 Enrollement: october 2009DLCL04 Enrollement: october 2009

Aggiornato al 6 ottobre 2009

TARGET TOTALEARRUOLATI

RandomSCHEMA

1SCHEMA

1 BIS SCHEMA 2 SCHEMA 2BIS IPI 2 IPI 3

376 310 75 78 80 77 224 86

0

50

100

150

200

250

300

mar

-06

apr-

06m

ag-0

6

giu-

06

lug-

06ag

o-06

set-0

6

ott-0

6no

v-06

dec-

06

gen-

07fe

b-07

mar

-07

apr-

07m

ag-0

7

giu-

07

lug-

07ag

o-07

set-0

7

ott-0

7

nov-

07di

c-07

gen-

08

feb-

08m

ar-0

8

apr-

08

mag

-08

giu-

08

lug-

08

ago-

08se

t-08

ott-0

8

nov-

08di

c-08

gen-

09

feb-

09m

ar-0

9

apr-

09

mag

-09

giu-

09

lug-

09

ago-

09

set-0

9ot

t-09

Arruolamento Pazienti

Arruolamento ideale

Response and safetyResponse and safety

Patients enrolled 317Evaluable for response andtoxicity

226

CR + CRu 167 (73.8%)2-year FFS 63%Toxic deaths 9/241 (3.7%)SAE + SUSAR 114 + 23

DLCL04: 2-year FFSDLCL04: 2-year FFS

At risk:

226 177 122 63 43 17 0

0.00

0.25

0.50

0.75

1.00

0 6 12 18 24 30 36Months

FAILURE-FREE SURVIVAL

63%



• Topics:




GELA-LNH 98.5:GELA-LNH 98.5:5-year OS5-year OS

Feugier P, et al. J Clin Oncol 2005 Pfreundschuh et al. Lancet Oncology 2008

RICOVER-60: 1222 Elderly.RICOVER-60: 1222 Elderly.OS by TrOS by Treatment Armeatment Arm

p<0.007

R-CHOP 58%

CHOP 45%

6x R-CHOP 14

8x R-CHOP 14

8x CHOP 14

6x CHOP 14

PFS - According to mid-therapy restagingPFS - According to mid-therapy restagingResponse adapted addition of chemotherapy is notResponse adapted addition of chemotherapy is not

justifiedjustified

0 10 20 30 40 50 60 70 80

CRu

Months

PR

0 10 20 30 40 50 60 70 80

Months6 x CHOP-14 (n=59)8 x CHOP-14(n=76)6 x R-CHOP-14(n=65)8 x R-CHOP-14(n=76)

6 x CHOP-14(n=112)8 x CHOP-14(n=118)6 x R-CHOP-14(n=122)8 x R-CHOP-14(n=107)

6 x CHOP-14 (n=59)8 x CHOP-14 (n=63)6 x R-CHOP-14(n=74)8 x R-CHOP-14(n=65)

100 90 80 70 60 50 40 30 20 10 0

%

CR

Months0 10 20 30 40 50 60 70 80

6xR- CHOP 14

8x R-CHOP 14

6x R-CHOP 14

8x R-CHOP 14

6x R-CHOP 14

8x R-CHOP 14

Pfreundschuh et al. Lancet Oncol. 2008

4 IT MTXR

R-CHOP 21x 8

0 3 6 9 Wks12 15 18 21

0 2 4 6 10 14 Wks8 12

R-CHOP 14 x 8

Primary endpoint: EFSExpected improvement: 10% at 3 years with R-CHOP 14 (55 to 65%)600 patients required (over 4 years)

GELA study LNH 03-6BGELA study LNH 03-6B61-80 years, aaIPI = 1,2,361-80 years, aaIPI = 1,2,3

Chair: R. Delarue, A. BoslyChair: R. Delarue, A. Bosly

0

10

20

30

40

50

60

70

Neutopenia

Thrombocytopenia

InfectionCardiac

% p

atie

nts

51%

37%

5%9%

22%17%

1% 2%

NCRI: R-CHOP-21 vs. R-CHOP-14: Grade 3&4NCRI: R-CHOP-21 vs. R-CHOP-14: Grade 3&4ToxicityToxicity

R-CHOP-14

R-CHOP-21

Cunningham et al. ASCO 2009; Abstract # 8506

RICOVER-60: Poor outcome for elderly DLBCLRICOVER-60: Poor outcome for elderly DLBCLpts with higher risk disease (IPI 3-5)pts with higher risk disease (IPI 3-5)

Pfreundschuh et al., Lancet Oncol. 2008; 9: 105. Personal communication: N. Schmitz.

DENSE-R-CHOP-14

CD20+ DLBCLStages I-IV

61 to 80 years

CHOP

CHOP

CHOP

CHOP

CHOP

CHOP

12 1410 8 6 4 2 0

W e e k s

Dose-dense Rituximab Improves Outcome of Elderly Patients withDose-dense Rituximab Improves Outcome of Elderly Patients withPoor-Prognosis Diffuse Large B-Cell Lymphoma (DLBCL):Poor-Prognosis Diffuse Large B-Cell Lymphoma (DLBCL):

Results of the DENSE-R-CHOP-14 Trial of the German High-Grade Non-Results of the DENSE-R-CHOP-14 Trial of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL)Hodgkin Lymphoma Study Group (DSHNHL)

By Courtesy of Pfreundschuh M et al; Blood 2007; 110, abs 789.By Courtesy of Pfreundschuh M et al; Blood 2007; 110, abs 789.

Rituximab 4 + 8

020406080100120140160180200

1 9 17 25 33 41 49 57 65 73 81 89 97 105 113day of treatment

n g

/ m

l • ••R-CHOP-14

RITUXIMAB PHARMACOKINETICS:RITUXIMAB PHARMACOKINETICS:Trough Serum LevelsTrough Serum Levels

Reiser et al., ASH 2006, Abs # 778

020406080100120140160180200

1 9 17 25 33 41 49 57 65 73 81 89 97 105 113day of treatment

n g

/ m

l

••• • • • • • • • •

• ••

•

•R-CHOP-14

DENSE-R-CHOP-14

RITUXIMAB PHARMACOKINETICS:RITUXIMAB PHARMACOKINETICS:Trough Serum LevelsTrough Serum Levels

Reiser et al., ASH 2006, Abs # 778

* with censoring at 12 months

RICOVER-60(n=183)CHOP-R-ESC(n=44)

0 2 4 6 8 10 120

0.10.20.30.40.50.60.70.80.91

Months

%

IPI 1, 2 IPI 3 - 5

0 2 4 6 8 10 120

0.10.20.30.40.50.60.70.80.9

1

Months

%

RICOVER-60(n=123)CHOP-R-ESC(n=53)

Event-free Event-freeSurvivalSurvivalDENSE-R-CHOP-14

RICOVER: 65%

DENSER: 74%

0%

10%

20%

# <=20 # >200%

20%

40%

# <=20 # >20

p=0.023 p=0.136

12.7%

6.4%

36%

19%

P a t i e n t s P a t i e n t s

Grade 3&4 Infectionsper Cycle

Grade 3&4 Infectionsper Patient

Effect of Prophylaxis on Effect of Prophylaxis on Grade 3&4 Infections Grade 3&4 InfectionsDENSE-R-CHOP-14

R-CHOP 14 + pegfilgrastim in DBLCLR-CHOP 14 + pegfilgrastim in DBLCLSevere adverse events*Severe adverse events*

Type Number

Total cycles 269Interstital pneumonitis (3 PC)Interstital pneumonitis (3 PC) 88Septic shock 2Pneumonia 2GI hemorrhage 1SAE/Cycles 13/269 (5%)Dead from SAE 1 (septic shock)1 (septic shock)

*By Courtesy of Brusamolino E et al;*By Courtesy of Brusamolino E et al;Haematologica 2006.Haematologica 2006.

**R-dose dense chemotherapy **R-dose dense chemotherapy carefull carefullprophylaxis and surveillance in elderly patientsprophylaxis and surveillance in elderly patients

**Habermann TM; educational session**Habermann TM; educational sessionASH 2007ASH 2007



• Topics:




Elderly R-CHOP14

EFS according to IPI

Months

0 10 20 30 40 50 60 70

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

IPI IH risk elderly R-CHOP14

IPI H risk elderly R-CHOP14

aa-IPI H risk young R-HDC+ASCT

aa-IPI IH risk young R-HDC+ASCT

Pfreundschuh et al. Lancet Oncology 2008Vitolo U et al. Haematologica 2009

Historical perspective: high-risk patientsR-HDC+ASCT and RICOVER-60

New drugs to improvethe induction

treatment?

Young R-HDC+ASCT25-40% of patients failed

to achieve CompleteRemission

LR-CHOP21 IIL-REAL07: study designLR-CHOP21 IIL-REAL07: study design

Course I

Course II

Course III

Course IV

Course V

Course VI

Day –28 to 0Pretreatment screening

Day +14 cohorts5, 10, 15, 20 mgLenalidomide

days 1-14 plus R-CHOP

Patients accrued:3 per cohort

Continual reassessment

CR, Cru, PRPD, SD, toxicity

Off study

Day +21

Day +42

Day +63

Day +84

Day +105

R-CHOP TherapyRituximab 375 mg/m2 D0 or D1

Cyclophosphamide 750 mg/m2 D1Doxorubicin 50 mg/m2 D1 Vincristine 1.4 mg/m2 D1

Prednisone 40 mg/m2 D1-D5PEG-filgrastim or G-CSF

Bortezomib + CHOP-Rituximab in DLBCLBortezomib + CHOP-Rituximab in DLBCL

Design Phase I/II trial Eligibility DLBCL ( 40 patients treatment naïve IPI= 2,3-5) Therapy Arm : Bortezomib (0.7, 1.0, 1.3 mg/m2) days 1 and 4 of a

21-day cycle with R-CHOP 21, G-CSF

Leonard et al. ASCO Proceedings vol. 25:8031,2007

Safety- Most common AE:3 pts did not complete therapy (1=withdrawal by patient,1= pulmonarytoxicity,1=concurrent meningitis

Grade 4 hematologic toxicity thrombocytopenia (15%) and leukopenia(15%)

Peripheral neuropathy: 22(55%), grade 4 hematologic toxicity: 7 (35%)

Response to TherapyEvaluable forResponse (n) CR/CRu PR OR

DLBCL 40 75% 25% 100%

2-yrs PFS= 72%

UntreatedN=13100 %

DLBCL

Ganjoo et al. Leuk Lymphoma 2006

Bevacizumab Efficacy in aggressive lymphoma:Bevacizumab Efficacy in aggressive lymphoma:Phase II experience plus R-CHOP (RA-CHOP)Phase II experience plus R-CHOP (RA-CHOP)

Day 1

Bevacizumab15 mg/kg

Cycle 1

Day 2

CHOP +Rituximab

3 weeks (RA-CHOP-21)

Day 1

Bevacizumab +CHOP + Rituximab

Cycles 2 - 8

EfficacyOverall response rate Complete remission Partial remission

85 % (n=11)38 % (n=5)46 % (n=6)

Responders in remission (median follow-up)

9/11 (16.9 months)

1-year PFS 77 %[51 %; 93 %]

Main Study: R-CHOP14/21 ± Bevacizumab in untreatedMain Study: R-CHOP14/21 ± Bevacizumab in untreatedDLBCL age 18-80, IPI DLBCL age 18-80, IPI ≥≥ 1 1

R-CHOP21 and/or R-CHOP14 are the standard of careR-CHOP21 and/or R-CHOP14 are the standard of carein DLBCLin DLBCL

The identification of poor-prognosis patients is aThe identification of poor-prognosis patients is apriority because they have no more than 50% chancespriority because they have no more than 50% chancesof cureof cure

Outside clinical trial a modification of treatment basedOutside clinical trial a modification of treatment basedon early-PET results is not supported by clinicalon early-PET results is not supported by clinicalevidenceevidence

Take-Home messages (1)Take-Home messages (1)

HDC supplemented with Rituximab + ASCT is anHDC supplemented with Rituximab + ASCT is aneffective treatment in high risk young patients thateffective treatment in high risk young patients thatshould be compared to Rituximab-dose-denseshould be compared to Rituximab-dose-densechemotherapy in large randomized trialschemotherapy in large randomized trials

Early PET scan and molecular biomarkers need to beEarly PET scan and molecular biomarkers need to beincorporated and tested into the ongoing trials toincorporated and tested into the ongoing trials tovalidate their predictive valuevalidate their predictive value

Novel drugs should be associated to R-CHOP regimenNovel drugs should be associated to R-CHOP regimeninto clinical trials to evaluate their efficacy and safetyinto clinical trials to evaluate their efficacy and safety

Take-Home messages (2)Take-Home messages (2)

4 G. Benevolo4 C. Boccomini4 B. Botto4 A. Chiappella4 C. Frairia4 L. Orsucci4 P. Pregno

Hematology 2 AOU S.Giovanni BattistaHematology 2 AOU S.Giovanni BattistaTorinoTorino

4 M. Ceccarelli4 A. Evangelista4 F. Saccona4 G. Ciccone

STATISTICAL ANALYSISSTATISTICAL ANALYSISCancer EpidemiologyCancer Epidemiology

University TorinoUniversity Torino

ACKNOWLEDGMENTSACKNOWLEDGMENTS

IIL CENTERSIIL CENTERS

meeting educazionale: linfomi non-hodgkin aggressivivitolo.pdf · standard and novel...

Documents