Therapy for Lymphomas: An Update from ASCO 2009 F B Hagemeister, MD Professor of Medicine Department of Lymphoma/Myeloma M D Anderson Cancer Center
Aggressive Lymphomas 1. # 8506: R-CHOP-21 vs R-CHOP-14 for Untreated DLBCL (Cunningham) 2. # 8508: ER-CHOP Phase II Trial of ER-CHOP for Untreated DLBCL (Micallef) 3. # 8509: R-ICE vs R-DHAP followed by SCT for Relapsed/Refractory DLBCL (Gisselbrecht)
How Might We Further Improve Initial Therapy of DLBCL • Dose Density Therapy - CHOP (R) - 14 • Dose Intensity - AuSCT in First Remission • Other Regimens (+/- rituximab) – CHOEP, EPOCH, ACVBP • Addition of new agents to CHOP (R) – BCL-2 antisense, anti-CD22, anti-VEGF, bortezomib, idiotype vaccination, RIT • Improved “risk - adapted therapy” – Gene expression profiling, PET
CHOP -14 vs CHOP-21 vs CHOEP-14 vs CHOEP-21 for Patients > 60 with DLBCL: Event-Free Survival 1.0 .9 .8 CHOP-14 .7 56% .6 48 % .5 .4 CHOEP-14 (n=169) 42% .3 CHOEP-21 (n=170) 34 % .2 CHOP-21 (n=178) .1 CHOP-21 CHOP-14 (n=172) 0.0 0 10 20 30 40 50 60 70 80 90 Months Pfreundschuh et al. Blood 104: 634-642, 2004
CHOP -14 vs CHOP-21 vs CHOEP-14 vs CHOEP-21 for Patients <60 with DLBCL: Event-Free Survival 1.0 .9 .8 72 % .7 .6 .5 58 % CHOP-21 .4 CHOEP-14 (n=177) CHOP-14 .3 CHOEP-21 (n=185) .2 CHOP-21 (n=176) .1 CHOP-14 (n=172) 0.0 0 10 20 30 40 50 60 70 80 90 Months Pfreundschuh et al. Blood 104: 626-633, 2004.
RICOVER-60 Study 6x R-CHOP14 Does 6 or 8 cycles of 6x R-CHOP14 improve CHOP14 Randomised outcomes compared to Stage I-IV 8x CHOP14 in patients n=1222 R-CHOP14 aged 61-80? 8x CHOP14 Findings • Only R-CHOP14 superior to CHOP14 in terms of EFS, PFS and OS (3 yr OS 78.1% vs 67.7%) • R-CHOP14 x 8 no better than R-CHOP14 x 6 Pfreundschuh M; Lancet Oncol 2008
R-CHOP-14 vs R-CHOP-21 for DLBCL (# 8506) • 1080 Pts stratified by Age (> 60), PS (0-1), LDH • Median age 61 • TX: R-CHOP21 x 8 vs R-CHOP14 x 6, plus 2 Rituximab Features R-CHOP 21 (%) R-CHOP 14 (%) IPI 4-5 17 15 Stage III-IV 63 62 B SX 44 48 Bulky > 10 cm 51 48 Cunningham et al JCO 27: 435s, 2009 (abst 8506).
R-CHOP 21 vs R-CHOP-14 for DLBCL: Tolerability Gr 3-4 Events R-CHOP 21 (%) R CHOP 14 (%) ANC 57* 31 PLT 5 9* Infection 22* 17 Cardiac 1 2 Nausea/Vomit 8 8 Mucositis 2 3 Resp: CR,CRu/OR 63/87 58/90 All patients received G-CSF with R-CHOP 14 *P<0.01 Cunningham et al. JCO 27: 435s, 2009 (abst 8506).
2 Year FFS and OS by Prognostic Factors FFS OS % p % p Age: ≤60 76 0.48 83 0.047 >60 73 79 WHO: 0 80 <0.0001 87 <0.0001 1 73 79 2 56 63 Stage: I/II 81 0.0017 85 0.012 III 70 81 IV 68 75 IPI score: 0-1 85 <0.0001 90 <0.0001 2-3 72 80 4-5 60 64
GLSG Study for Pts < 60 with AA IPI 0-1 DLBCL Based on Risk Factors All have Low Risk according to IPI, excluding Stage I, Non-Bulky Bulky is defined as > 5 cm mass IPI 0 with Non-Bulky Disease: R-CHOP 21 x 6 vs R-CHOP 21 X 4 IPI 1 or Bulky Disease: R-CHOP 21 x 6 vs R-CHOP 14 x 6 All receive 36 GyRT to bulky sites Pfreundschuh et al. JCO 23: 567s, 2005 (abst 6529).
Ongoing Trials from the GELA for Aggressive Lymphomas Phase III, < 60 Years, 1 AAIPI Feature: R-ACVBP-14 vs R-CHOP-21, No RT Phase III, > 60 Years, Any Feature: R-CHOP-14 vs R-CHOP-21 Phase II, < 60 Years, 2-3 AAIPI Features: R-ACVBP 14 x 4 and BEAM-SCT Reyes, Personal Communcation
Selected Anti-Lymphoma Antibodies in Clinical Trials Antibody Company Target US Status Rituximab Genentech, Biogen-IDEC CD20 Approved Alemtuzumab Bayer Healthcare CD52 Approved Human(ized) anti-CD20 Various CD20 Phase 1-2 Lumaliximab Biogen-IDEC CD23 Phase 3 Bevacizumab Genentech VEGF Phase 3 Galiximab Biogen-IDEC CD80 Phase 2-3 Epratuzumab Immunomedics CD22 Phase 2 SGN-40 Seattle Genetics CD40 Phase 2-3 SGN-30, SGN-35 Seattle Genetics CD30 Phase 2
Phase II Trials: Epratuzumab Plus Rituximab in Recurrent NHL Regimen – Epratuzumab 360 mg/m 2 – Rituximab 375 mg/m 2 – Weekly for 4 weeks Most AEs were grade 1/2, self limited, or infusion related Leonard, 2005 Strauss, 2005 Response FL DLBCL FL DLBCL N 15 6 34 15 ORR 10 (67%) 4 (67%) 21 (64%) 7 (47%) CR/CRu 9 (60%) 3 (50%) 8 (24%) 5 (33%) TTP 17.8 months NR NR DOR 16 months 6 months NR PFS 11 months 6 months Leonard. J Clin Oncol. 2005;23:5044; Strauss. J Clin Oncol. 2006;24:3880.
Phase II ER-CHOP for DLBCL: Patient Features (#8508) • 107 pts, 29 (26%) ineligible (no follicular allowed) • Therapy: E-360 mg/m2 d 1/cycle, R-CHOP d 1 x 6 • 78 eligible patients: Med age 61 (21-92); PS 0-1: 88% Features Number % IPI: 0-1 17 22 2 22 28 3 29 37 4-5 10 13 R-IPI: 3-5 39 50 LDH: High 55 71 Micallef et al. JCO 27: 426s, 2009 (abst 8508).
Phase II ER-CHOP for DLBCL: Results at One Year by IPI Risk (%) IPI Patients OR CR EFS PFS OS 0-2 39 95 74 82 88 92 3-5 39 95 72 77 77 85 ALL 78 95 73 80 82 88 • ER-CHOP might be better than R-CHOP for higher risk disease? Micallef et al. JCO 27: 436s, 2009 (abst 8508).
ER-CHOP for DLBCL: Comparisons to Results with R-CHOP Group 1 YR 2 YR 1 YR 2 YR EFS EFS OS OS GELA 58 57 82 72 ECOG 72 64 80 71 Canada - - 85 77 Current 79 62 89 79 • A randomized study is needed to demonstrate for whom ER-CHOP might be better than R-CHOP Micallef et al. JCO 27: 436s, 2009 (abst 8508).
Auto SCT vs Chemotherapy Alone for Relapsed Chemotherapy-Sensitive Aggressive NHL (PARMA Trial) 100 P = 0.038 80 Percent Alive 60 Transplantation Conventional treatment 40 20 0 0 15 30 45 60 75 90 Months after Randomization Philip et al. N Engl J Med 1995;333:1540-1545
R-ICE vs R-DHAP for Rel/Ref DLBCL Followed by ASCT: The CORAL Study (COllaborative Trial in Relapsed Aggressive Lymphoma) • AutoSCT is standard second-line therapy for relapsed DLCL – Original study required CR to CHOP, no marrow disease, and pts <60 years • Best induction therapy for relapsed DLBCL prior to ASCT unknown – DHAP invented at MDACC in 1980’s – R-ICE from MSK popular for mobilization – No randomized comparisons of various combinations • In era of rituximab , value of R in relapse is unclear • CORAL trial: R-DHAP vs R-ICE, SCT, Maint R vs Obs
CORAL Trial of R-ICE vs R-DHAP (#8509) Which salvage regimen is the best? R R R-ICE R x 6 A A x 3 CD20+ DLBCL N A B N D D Relapsed/Refractory S E N=202 O PR/CR O Age < 65 C A M M T M I I R-DHAP Obs Z Z N=396, x 3 E E 11 Countries N=194 SD/PD → Off Place of immunotherapy post transplantation?
R-ICE vs R-DHAP for Rel/Ref DLBCL: Patients in the CORAL Trial (#8509) • 90 (45%) SAEs with R-ICE, 120 (62%) with R-DHAP • 206 underwent SCT Category Feature Patients % LDH High 149 38 Prior Rituximab Yes 224 57 Relapse Stage III-IV 240 61 Relapse Status < 12 mo 166 42 > 12 mo 225 57 Relapse IPI 0-1 226 57 2-3 149 38 Gisselbrecht et al. JCO 27: 436s, 2009 (abst 8509).
R-ICE vs R-DHAP for Relapsed DLBCL: 3 Year Results (ITT Group, #8509) Feature OR P EFS P OS TX: R-DHAP 63 NSig 35 0.3 51 R-ICE 64 26 47 Rit: Yes 51 <.001 21 <.001 NRep No 83 47 Ref: Yes 46 <.001 20 <.001 NRep No 88 45 AA-IPI:0-1 52 <.001 18 <.001 NRep 2-3 71 40 • By MVA, all 3 features important: If no factors, ORR > 80% • Longer F/U needed for R vs Obs (second randomization) Gisselbrecht et al. JCO 27: 436s, 2009 (abst 8509).
The CORAL Trial 56% OVERALL SURVIVAL 56% ACCORDING TO TREATMENT ARM (INDUCTION ITT) PROGRESSION-FREE SURVIVAL ACCORDING TO TREATMENT ARM 45% (INDUCTION ITT) 42% Gisselbrecht et al. JCO 27: 436s, 2009 (abst 8509).
The CORAL Trial 64% N=160 PROGRESSION-FREE SURVIVAL ACCORDING TO FAILURE N=228 FROM DIAGNOSIS 31% (INDUCTION ITT) 62% N=147 PROGRESSION-FREE SURVIVAL ACCORDING TO PRIOR RITUXIMAB (INDUCTION ITT) N=241 30% Gisselbrecht et al. JCO 27: 436s, 1009 (abst 8509).
The CORAL Trial: Failure-Free Survival by Prior Rituximab and Time to Relapse Failure from Diagnosis > 12 mo Prior Rituximab may N= 106 delay relapse, but at 3 yearsm results are the same N= 54 N= 41 Failure from Diagnosis < 12 mo N= 187 Standard salvage regimen does not overcome poor prognosis of early relapse Gisselbrecht JCO 27: 436s, 2009 (8509)
Follicular Lymphoma 1. # 2: Intensive Chemotherapy followed by Anti- Idiotype Vaccine for Advanced Untreated Follicular Lymphoma (Schuster) 2. # 8550: Bortezomib, Bendamustine, and Rituximab for Relapsed or Refractory Follicular Lymphoma (Matous)
Id+KLH Protein • The idiotype of the SmIg of antigen binding site / idiotype a B-cell lymphoma can be used as a tumor-specific immunogen that induces immunity against Id- bearing tumor cells • Keyhole lympet hemocyanin (KLH) carrier serves as an immune stimulant KLH • GM-CSF administered concurrently at site of injection as an adjuvant (with GM-CSF)
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