Pr. Christian Gisselbrecht, Hôpital Saint Louis, Paris, France Relapsed & Refractory Non-Hodgkin’s Lymphoma: Summary of GELA Trials Tel Aviv, February 12, 2009 Groupe d’Etude des Lymphomes de l’Adulte

Management of aggressive NHL Primary refractory Relapse Second-line therapy Investigational or BSC HDT/ASCT Investigational or BSC CR/PR NR (R)-CHOP or (R)-CHOP-like CR Cure

EVENT FREE SURVIVAL ACCORDING TO TREATMENT PARMA STUDY - MEDIAN FOLLOW-UP : 8.3 yrs Conventional treatment (N = 54) Transplantation (N = 55) Months after randomization % Event-free survival p = % 13% Philip T, et al. N Engl J Med 1995;333:1540–5

Improving salvage regimen with the use of immunotherapy Improving post transplant outcome with the use of immunotherapy Improving conditioning regimen before ASCT with RIT

RegimenDisease statusnORR/CRASCT performed Survival in ASCT patients R-ICEDLBCL3678%/53%70%67% OS at 2 years R-ICEAggressive B NHL875%/ 50%100% R-various (mostly ICE) DLBCL59Not given100%81% OS at 2 years R-ICEAggressive B NHL1189%/67%27% R-DHAPAggressive B NHL5362%/32%38%Median 20.4 months OS DHAP/VIM/DHAP ± R Aggressive B NHL22575%/46% versus 54%/35% ± R, respectively 63% versus 46% ± R, respectively At 2 years FFS 50%versus 24% in favour of R (p<.001) R-ESHAPDLBCL/MCL/HD24 (15 = DLBCL) Not given79%DFS = 53% R-ESHAPDLBCL/MCL6100%/67%Not done R-ESHAPAggressive B NHL26 92 %/46%88% R-ESHAPAggressive B NHL1856%/28%38% R-ICE or R-DHAPDLBCL1060%/10%Not done R-ASHAPAggressive B NHL2075%/45%25% R-DHAOXNHL33 (10 were HIV+) 70%/27%Not stated R-ICE or R-DHAP followed by HDT (BEAM) and ASCT ± R maintenance Relapsed DLBCL39663%/38%52% (n= 204)49% OS at 3 years Gisselbrecht C. B J H: , 607–621

Vellenga E et al (Blood. 2008;111: )

RITUXIMAB IMPROVES DHAP-VIM-DHAP, ASCT IN CD20+ NHL Response rate 75% vs 54% Failure free survival Patients with CR/PR and BEAM.SCT Vellenga E et al (Blood. 2008;111: )

The standard of care in relapsing diffuse large B cell lymphoma is salvage chemotherapy followed in responding patients with autologous stem cell transplantation. Questions in 2002 for relapsed/refractory diffuse large B cell lymphoma CD 20+ ?: Does rituximab improve salvage treatment?: patients naïve of rituximab exposure patients prior exposure to rituximab Which salvage regimen is the best? Place of immunotherapy post transplantation? CORAL : COllaborative trial in Relapsed Aggressive Lymphoma

CORAL Trial of RICE v DHAP CD20+ DLBCL Relapsed/Refractory R-ICE x 3 R-DHAP x 3 RANDOMIZERANDOMIZE RANDOMIZERANDOMIZE SD/POD → Off PR/CR → → ASCTASCT R x 6 Obs N=400 Which salvage regimen is the best? Place of immunotherapy post transplantation?

CORAL Study Patient distribution Australasia 60 Germany 113 Cesz Republic 36 France 128 Belgium 31 Israel 13 US 9 Sweden 13 Switzerland patients 30/6/2008 Ireland 4 UK 50 Thank you to all investigators and pathologists C. Gisselbrecht, 2008

CORAL Study: Diffuse large B Cell Lymphoma, CD 20+ in 1st relapse, less than PR or partial response to first line treatment First randomization:R-ICE vs R-DHAP Stratification a) Center, group: upfront treatment intensive or not b) Treatment with Rituximab during first line: evaluation of response according to prior treatment c) Refractory : non achieving CR after first line of treatment ( PR, Stable, PD) and relapse < 12months ( Parma study)  Second randomization : Rituximab vs no further therapy San Francisco December, 2008 / Coral study

Arm of treatment All ARM A / R- ICE ARM B / R- DHAP N%N%N% Response after first line COMPLETE RESPONSE UNCONFIRMED COMPLETE RESPONSE PARTIAL RESPONSE STABLE DISEASE PROGRESSIVE DISEASE NOT EVALUATED TOTAL WHAT TYPE OF PATIENTS HAVE BEEN INCLUDED IN CORAL RESPONSE AT 1ST LINE San Francisco December, 2008 / Coral study C. Gisselbrecht

Coral patients main characteristics at inclusion R-ICE (202) R-DHAP (194) Median age 54y 55y Sex Stage I-II Stage III-IV ENS > LDH > Nl S-AaIPI S-AaIPI P=0.09 San Francisco December, 2008 / Coral study C. Gisselbrecht

R-ICE R-DHAP N% N% Response including deaths COMPLETE RESPONSE UNCONFIRMED COMPLETE RESPONSE PARTIAL RESPONSE STABLE DISEASE PROGRESSIVE DISEASE DEATH PREMATURE WITHDRAWAL / NOT EVALUATED 4242 Total RESPONSE AFTER INDUCTION TREATMENT INCLUDING DEATHS FOR ALL PATIENTS (INDUCTION ITT) 63.5 % 62.8 % Arm of treatmentNb patients Nb responders with successful mobilizationMARR (%)95% CI lower95% CI upper ARM A / R-ICE ARM B / R-DHAP San Francisco December, 2008 / Coral study C. Gisselbrecht

CORAL TOXICITY (Median + range) R-ICE R-DHAP HB(g/dl) day (15-6) 11.1(16-7) day (15-5) 10.1 (15-7) WBC(/µl) day (30-0) 6 (86-0) day (71-0) 6 (68-0) Platelets(/µl)day (1088-9) 101(2940-2) day (616-2) 47 (2360-1) Transfusions % pts 35% 57% Nb pts with 3 cycles 169 (86%) 161(84%) San Francisco December, 2008 / Coral study C. Gisselbrecht

CORAL TOXICITY R-ICE R-DHAP Infection with neutropenia Grade 3-4 Yes 33 (17%) 31 (16%) Infection without neutropenia Grade 3-4 Yes 11 (6%) 15 (8%) Renal Grade 3-4 Yes 2(1%) 11 (6%) Toxic deaths 1 3 San Francisco December, 2008 / Coral study C. Gisselbrecht On induction safety population, a total of 90 SAEs in R-ICE arm and 120 in the R-DHAP arm were reported during the whole study, concerning respectively 58 patients (29%) and 69 patients (36%).

Response p Patients CR/Cru/PR All patients % CR/CRu % Prior RituximabNo12283% < Yes12451% Relapse > 12 months14088% < refractory < 12 months10646% s IPI< % < > 17652% CORAL STUDY RESPONSE RATE ACCORDING TO PROGNOSTIC FACTORS *No difference between GELA DSHNHL ALLG ** More early relapse in prior Rituximab Group San Francisco December, 2008 / Coral study C. Gisselbrecht

RESPONSE RATE PROGNOSTIC FACTORS CR/CRu/PR and for CR Logistic Model p value ORR CR  Prior Rituximab  Relapse < 12 months  sIPI >  Treatment Arm Prior rituximab exposure will be the rule in future study !! Relapses after rituximab exposure are more severe.!! Early relapses and failure are the main adverse prognostic factors. San Francisco December, 2008 / Coral study C. Gisselbrecht

Arm of treatment ARM A / R-ICE ARM B / R- DHAP N%N% Consolidation treatment (BEAM) Yes No Total Transplantation CONSOLIDATION – PATIENTS WITH BEAM AND ASCT (INDUCTION ITT) Main Reasons for premature withdrawals: Progressive lymphoma 53% Toxicity 7% Collection failure 10% Deaths 4% San Francisco December, 2008 / Coral study C. Gisselbrecht

Figure 4.5 ‑ 6 Secondary criteria – Overall Survival (induction ITT) FIGURE 4.5 ‑ 6 SECONDARY CRITERIA – OVERALL SURVIVAL (INDUCTION ITT) San Francisco December, 2008 / Coral study C. Gisselbrecht FIGURE 4.5 ‑ 4 SECONDARY CRITERIA – PROGRESSION-FREE SURVIVAL (INDUCTION ITT)

Progression-Free Survival according to Response after Induction including deaths for all patients (CR/CRu Vs PR) - induction ITT San Francisco December, 2008 / Coral study C. Gisselbrecht

FIGURE 4.5 ‑ 7 OVERALL SURVIVAL ACCORDING TO TREATMENT ARM (INDUCTION ITT) San Francisco December, 2008 / Coral study C. Gisselbrecht FIGURE 4.5 ‑ 5 PROGRESSION-FREE SURVIVAL ACCORDING TO TREATMENT ARM (INDUCTION ITT)

FIGURE 4.5 ‑ 23 EXPLORATORY ANALYSES – PROGRESSION-FREE SURVIVAL ACCORDING TO AGE ADJUSTED IPI (INDUCTION ITT) San Francisco December, 2008 / Coral study C. Gisselbrecht

PROGRESSION-FREE SURVIVAL ACCORDING TO PRIOR RITUXIMAB (INDUCTION ITT) San Francisco December, 2008 / Coral study C. Gisselbrecht PROGRESSION-FREE SURVIVAL ACCORDING TO FAILURE FROM DIAGNOSIS (INDUCTION ITT)

Failure from diagnosis =>= 12 months Event-Free Survival by Prior Rituximab - induction ITT Failure from diagnosis =< 12 months

MULTIVARIATE ANALYSIS FOR SURVIVAL p value PFS EFS OS  Prior Rituximab  Relapse < 12 months < < <  sIPI > 1 < < <  Treatment Arm Prior rituximab exposure will be the rule in future study Relapses after rituximab exposure are more severe. Early relapses and failure are the main adverse prognostic factors. San Francisco December, 2008 / Coral study C. Gisselbrecht

Improving salvage regimen with the use of immunotherapy Improving post transplant outcome with the use of immunotherapy Improving conditioning regimen before ASCT with RIT

PROGRESSION-FREE SURVIVAL OF PATIENTS SUBMITTED TO ASCT from date of 1st randomization (INDUCTION ITT) San Francisco December, 2008 / Coral study C. Gisselbrecht Progression-Free Survival of maintenance ITT population measured from date of 2nd randomization to date of progression/relapse or death from any cause. RANDOMIZERANDOMIZE PR/CR → R x 6 Obs

140 events will be required to conclude. According to the definition of events nowadays: 85 patients (43%) presented with an event: 2 (1%) with a new treatment out of progression, 77 (39%) with progression/relapse and 6 (3%) with death without progression. PART II MAINTENANCE: EVENT-FREE SURVIVAL San Francisco December, 2008 / Coral study C. Gisselbrecht RANDOMIZERANDOMIZE PR/CR → R x 6 Obs

Main Conclusions from the CORAL study In relapsing patients > 12 months, not previously treated with rituximab, rituximab associated salvage chemotherapy provides a high response rate: 82% and 2 yr EFS 66% In refractory patients ( <12months) to upfront rituximab associated chemotherapy, results of salvage with R Chemo remain poor: response rate: 54% and 2 yr EFS 34%. After transplantation the number of events to analyse the post transplant immunotherapy is not reached until now, and preclude subgroups analysis. No safety concerns. However we will have to wait two more years for the second part. Last patient will finish treatment next fall. A new profile of relapses and refractory patients will come out from the study. (« Genomic » profile to be studied, GELA P) From CORAL to Bio CORAL first meeting with pathologists in February.

What is the standard for second-line therapy in NHL in older patients?

LNH98-5 patients in the CHOP arm : overall survival after progression p= Salvage with rituximab (n=22) Salvage without rituximab (n=87) Feugier et al, JCO 2005 n= Years Cumulative Proportion Surviving A

p= LNH98-5 patients in the R-CHOP arm : overall survival after progression Salvage with rituximab (n=9) Salvage without rituximab (n=64) Feugier et al, JCO 2005 n= Years Cumulative Proportion Surviving

RegimenDisease statusnORR/CRSurvivalReference R-GEMHigh grade B-NHL (64–78 years) 771%/29%median PFS and OS, 10 and 11 months, (Wenger et al, 2005) R- GEMOX Aggressive NHL4674%/72%2-year EFS 43%, 2-year OS 66% (El Gnaoui et al, 2007) R-GIFOXAggressive NHL1377%/54%median FFS 80%(Corazzelli et al, 2006) GaRDAggressive NHL1979%/42%(Cabanillas et al, 2006) GaRDAggressive B-NHL2255%/27% (CR/CRu) (Smith et al, 2006) R + EDLBCL667%/50%(Leonard et al, 2005) R + EDLBCL1547%/33% (CR/CRu) median PFS 6 months (Strauss et al, 2006) R-CMDDLBCL (65–79 years) 3074%/57% (CR/CRu) 2-year OS 45%, PFS 37% (Niitsu et al, 2006) R-TTPAggressive NHL71 (32 primary refractory) 70% 25%primary refractory median DR 21 months (Younes et al, 2005) R-TTPB-cell lymphoma1060%/30%(Canales et al, 2005) R-ADOXDLBCL (heavily pre-treated) 2070%/25%Median OS 11 mos(Woehrer et al, 2005) Rituximab and other salvage regimens CMD: irinotecan, mitoxantrone, dexamethasoneTTP: paclitaxel, topotecan E: epratuzumab Gisselbrecht C. B J H: , 607–621

Rituximab: 375 mg/m² d1 Gemcitabine: 1000 mg/m² d2 followed by Oxaliplatin: 100 mg/m² d2 Toxicity: d1 = d15 Rituximab, Gemcitabine and Oxaliplatin (R-GEMOX) grade 3-4 % of cycles neutropenia 42 thrombocytopenia 22 infection 3 neurologic, renal 0 46 PTS ORR 83% CR 50% Median TTP 20 m El Gnaoui et al ann oncol :1363-8

R-GEMOX pilot study: progression-free survival Median follow-up: 27 months (n=46) Survival distribution function DELPFS Product-limit estimate curve Censored observations 43% + 8 at 2 years El Gnaoui et al ann oncol :1363-8

Improving conditioning regimen before ASCT

HIGH DOSE CONDITIONING REGIMEN  Conditioning regimens are designed to overcome drug resistance and stem cell autologous transplant to overcome toxicity  Combination of drugs without TBI: BEAM and others…… BEAM and others……  Combination of drugs with TBI: Cyc + Etoposide, Cytarabine+melphalan. Cyc + Etoposide, Cytarabine+melphalan.  Combination of drugs with involved field radiotherapy:  Pre transplant Parma study, MSKCC  Pre transplant Parma study, MSKCC  Post transplant residual mass, routine  Post transplant residual mass, routinepractice

HIGH DOSE CONDITIONING REGIMEN Conditioning regimens are designed to overcome drug resistance and stem cell autologous transplant to overcome toxicity Conditioning regimens are designed to overcome drug resistance and stem cell autologous transplant to overcome toxicity Combination of drugs without TBI: Combination of drugs without TBI: BEAM and others…… BEAM and others…… Combination of drugs with TBI: Combination of drugs with TBI: Cyc + Etoposide, Cytarabine+melphalan. Cyc + Etoposide, Cytarabine+melphalan. Combination of drugs with involved field radiotherapy: Combination of drugs with involved field radiotherapy:  Incorporation of Radioimmunotherapy in may improve conditioning regimen by targeting the residual disease. Is it Safe?  Incorporation of Radioimmunotherapy by targeting the residual disease. may improve conditioning regimen

Comparable biological effect? IFRTTBI (transplant procedure) RIT 20–40 Gy12 Gy 15–30 Gy 90 Y-ibritumomab tiuxetan (0.4 mCi/kg) 131 I-tositumomab (0.75 Gy TBD) 20–30 fractions 4–6 weeks 6 fractions 3 days Continuous exposure T 1/2 – 64 h  Incorporation of radioimmunotherapy by targeting the residual disease may improve conditioning regimen

Use of radiolabeled immunotherapy in myeloablative concepts + ASCT Principles: 90 Y-ibritumomab tiuxetan dose escalation (escalation Z) 90 Y-ibritumomab tiuxetan + high-dose chemotherapy (eg Z-BEAM) 90 Y-ibritumomab tiuxetan dose escalation instead of TBI (eg escalation Z-Etoposide/Cy) 90 Y-ibritumomab tiuxetan dose escalation + high-dose chemotherapy (eg escalation Z-BEAM) ZBEAM Etoposide/Cy BEAM Z Z Z

Inpatient Outpatient Day Indium- In2B8 Imaging Zevalin therapy 0.4 mCi/Kg VP/AraC Mel TRANSPLANT Close observation, discharge upon blood count recovery Close observation Biodistribution study BCNU (Z-BEAM) Patients: 12 age: Median 61yr yr. Histology:DLCL, MCL 90 Y Zevalin 32 mCi ( )BEAM Time to recovery: WBC 11 days, platelets 11 jours Fung H et al ASH 2003 TRIALS COMBINING CONVENTIONAL-DOSE RIT AND BEAM AS A CONDITIONING REGIMEN

IBRITUMOMAB TIUTEXAN WITH HIGH-DOSE BEAM Progression Free Survival by histology Time after transplantation (months ) Diffuse large B-cell lymphoma (n = 20) Mantle cell lymphoma (n = 13) P =.54 Proportion of patients ( A. krishnan et al., JCO, 2008)

IBRITUMOMAB TIUXETAN ( 90 Y-Ibritumomab Tiuxetan) COMBINED BEAM AND ASCT IN 23 AGGRESSIVE NON-HODGKIN’S LYMPHOMAS PET + BEFORE ASCT (A. Shimoni et al., Experimental hematology 2007 OVERALL SURVIVAL Median FU 17 m Months after Transplantation Overall Survival OS : 67% PFS: 52% Months after Transplantation relapse Relapse rate : 31% RELAPSE Induction failure : 12pts Refractory relapse: 11 pts CR post transplant 70%

Ibritumomab Tiuxetan BEAM CONSOLIDATION IN 1st LINE DIFFUSE LARGE B CELL LYMPHOMA WITH POOR PROGNOSIS : Z BEAM 2 Diffuse Large B cell Lymphoma IPI >1 Upfront treatment No more than 1 initial chemotherapy CHOP like Treatment with Rituximab – Mobilization PBPC CR or PR / PET + or - Z-BEAM - Autograft Day 100 evaluation Follow up Inclusion – Informed consent Completed With 75 patients

Is there a place for allotransplantation in diffuse large B cell lymphoma

Zevalin RIC allo in refractory NHL Z fluda/bu =6 Z fluda/mel= 6 SLL transf: 4 DLBCL:3 FL: 3 MCL:2 Refractory relapse : 11 PET + pre transplant: Months after transplantation Relapse rate Months after transplantation Overall survival 0.0 (A. Shimoni, et al., Bone Marrow Transplantation 2008, 41: )

Conclusions The use of rituximab in DLBCL patients in relapsing patients improves the outcome –in younger patients –in older patients These combinations are well tolerated and do not hamper the ability to harvest stem cells Evaluation of treatment requires PET scan Questions –when rituximab is used in first-line therapy, what is the optimal salvage combination? New drugs mandatory –What is the place of rituximab post transplant? –can we improve consolidation with radioimmunotherapy conditioning regimen or high dose RIT with stem cell support? –RIC allo can be proposed in selected patients

Pr. Christian Gisselbrecht Hôpital Saint Louis Paris, France VII U728 VII