Lymphoma. Anas Younes, MD Professor of Medicine The University of Texas M. D. Anderson Cancer Center Houston, TX

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1 Best of ASCO 2011 Lymphoma Anas Younes, MD Professor of Medicine The University of Texas M. D. Anderson Cancer Center Houston, TX RCHOP21 in DLBCL (GELA LNH-98.5 Study) Survival Probability OS (N = 399) 1 CHOP R-CHOP P = Yrs Coiffier B, et al. NEJM 2002, updated ASCO Abstract

2 Current Regimens in Lymphoma: Recycling Old Drugs Disease Frontline Regimen Salvage Regimen DLBCL RCHOP R-ICE R-ESHAP R-DHAP T-Cell NHL CHOP ICE ESHAP DHAP MCL RCHOP R-Hyper-CVAD chl ABVD ICE ESHAP DHAP GND, IGEV CHOP RCHOP RCHOP ABVD ABVD ABVD Early 1970s ABVD=doxorubicin, bleomycin, vinblastine, and dacarbazine; chl=classical Hodgkin lymphoma; DLBCL=diffuse large B-cell lymphoma; GND= gemcitabine, vinorelbine, and liposomal doxorubicin; IGEV=ifosfamide, gemcitabine, and vinorelbine; MCL=mantle cell lymphoma; NHL=non-Hodgkin lymphoma; R-CHOP=rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; R- DHAP=rituximab, dexamethasone, ara-c, and cisplatin; R-ESHAP=rituximab, etoposide, cytarabine, cisplatin, and prednisone; R- Hyper-CVAD=rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone; R-ICE=rituximab, ifosfamide, carboplatin, and etoposide. How To Improve The Cure of Diffuse Large Cell Lymphoma? Improve the efficacy of front line regimens Should we intensify RCHOP21-based therapy? is R-CHOP14 better than R- CHOP21? Is RCHOP + ASCT better than RCHOP Should we add new agents to RCHOP21 Small molecules : Enzastaurin, Bortezomib, Lenalidomide Antibodies: Epratuzomab Emerging new agents Improve the efficacy of salvage therapy What is the best salvage regimen in the rituximab era Should we add new agents to salvage regimens 2

3 A phase III trial comparing R-CHOP 14 and R-CHOP 21 for the treatment of newly diagnosed diffuse large B cell lymphoma Results from a trial by the UK NCRI Lymphoma Clinical Study Group (CRUKE/03/019) D. Cunningham, P. Smith, P. Mouncey, W. Qian, C. Pocock, K. M. Ardeshna, J. Radford, J. Davies, A. McMillan, D. Linch on behalf of the NCRI trial collaborators Trial design: R-CHOP14 vs. 21 Newly diagnosed CD20+ve DLBCL Stratified by IPI (0-1, 2, 3, 4-5) Age 60 vs. >60 Treatment centre R n=540 n=540 R-CHOP21 CHOP21 8 cycles Rituximab 8cycles R-CHOP14 CHOP14 6 cycles Rituximab 8 cycles Lenograstim Day patients; 119 sites Recruitment March Nov

4 Overall response rates Based on end of treatment scan R-CHOP21 % R-CHOP14 % CR CRu PR SD 6 5 PD/relapse 6 4 CR/CRu, p= CR/CRu/PR, p= RCHOP21 vs RCHOP14 PFS OS R- R CHOP21 CHOP Events R- 123 (23) 117 (22) 0.5 R-CHOP21 CHOP14 0.5, n 2-yr (%) 81% 83% Logrank OS p=0.70 Events, n (29) 153 (28) 0. (%) 4 HR test yr FFS 75% 75% 0.3 (95% 0.95 ( ) Log-rank p=0.94 CI) 0.2 HR test 0.2 (95% R-CHOP ( ) CI) R-CHOP21 R-CHOP21 R-CHOP Patients at Risk Years from randomisation Patients at Risk Years from randomisation R-CHOP R-CHOP R-CHOP R-CHOP Probability Probability 4

5 Conclusions In patients receiving Rituximab, CHOP14 for 6 cycles is not superior to CHOP21 for 8 cycles No obvious sub group appears to derive a greater benefit from R-CHOP14, including age > 60, high IPI, high MIB1 or non-gc phenotype As expected a higher frequency of neutropenia was observed in R-CHOP21 which h reflects the primary prophylaxis with G-CSF in R-CHOP14 Randomized phase III US / Canadian Intergroup trial (SWOG S9704) comparing CHOP±R x 8 vs CHOP±R x 6 followed by high dose therapy and auto transplant for patients with diffuse aggressive non-hodgkin s lymphoma (NHL) in high- intermediate (H-Int) or high IPI risk groups. P.J. Stiff 1, J.M. Unger 2 J.R. Cook 3, L.S. Constine 4, S. Couban 5, T.C. Shea 6, J.N. Winter 7, T.P. Miller 8, R.R. Tubbs 3, D.C. Marcellus 9, J. Friedberg 4, K. Barton 1, G. Mills 10, M. LeBlanc 2, L. Rimsza 8, S.J. Forman 11, R.I. Fisher 4 1 Loyola University Medical Center, Maywood, IL; 2 SWOG Statistical Center, Seattle, WA; 3 Cleveland Clinic Foundation, Cleveland, OH; 4 University of Rochester, Rochester, NY; 5 Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia, CAN; 6 University of North Carolina at Chapel Hill, Chapel Hill, NC; 7 Northwestern University, Chicago, IL; 8 University of Arizona, Tucson, AZ; 9 Margaret and Charles Juravinski Cancer Centre, Hamilton, Ontario, CAN; 10 Louisiana State University Medical Center, Shreveport, LA; 11 City of Hope Medical Center, Duarte, CA 5

6 Schema CHOP or CHOP-R x 5 PR or CR <PR CHOP/CHOP-R x 1 CHOP/CHOP-R x 3 + Auto transplant Randomized phase III US / Canadian Intergroup trial (SWOG S9704) comparing CHOP±R x 8 vs CHOP±R x 6 followed by high dose therapy and auto transplant for patients with diffuse aggressive non-hodgkin s lymphoma (NHL) in high-intermediate (H-Int) or high IPI risk groups. 6

7 Targeted Therapy for Lymphoma Treatment Younes A. (2010) Beyond chemotherapy: new agents for targeted treatment of lymphoma. Nat Rev Clin Oncol. doi: /nrclinonc Single-Agent Activity in Relapsed DLBCL Overall Response Rate Everolimus SAR3419 Temsirolimus Lenalidomide MGCD0103 Fostambinib PCI32765 CMC544 Epratuzumab SGN40 Vorinostat YM155 ABT236 Mapatumumab 35% 33% 32% 28% 24% 22% 17% 15% 10% 10% 5% 3% 0% 0% 0% 20% 40% 60% 80% 100% Younes A. (2010) Beyond chemotherapy: new agents for targeted treatment of lymphoma. Nat Rev Clin Oncol. doi: /nrclinonc

8 Lenalidomide An international phase II trial of single-agent lenalidomide for relapsed or refractory aggressive B-cell non-hodgkin lymphoma % Response Rate in Different Histologies DLBCL FL MCL SLL/CLL T-Cell HL Relapsed NHL Rituximab 30% 50% 30% 15% - - Lenalidomide 28% 27% 42% 22% 45% 18% Witzig T E et al. Ann Oncol. 2011;annonc.mdq62.6 CLL=chronic lymphocytic leukemia; HL=Hodgkin lymphoma; SLL=small lymphocytic leukemia. A Phase II/III Multicenter, Randomized, Open-Label Study to Compare the Efficacy and Safety of Lenalidomide vs Investigator's Choice in Patients With Relapsed or Refractory DLBCL Experimental Drug: lenalidomide Lenalidomide 25 mg p.o. for 21/28 days until progressive disease. For pts with creatinine clearance 30 ml/min but <60 ml/min, lenalidomide 10 mg (max escalation is 15 mg). Investigator's Choice: active comparator with one of the following Lenalidomide de Gemcitabine 1250 mg/m2 IV days 1, 8, and 15/28 d for 6 cycles Oxaliplatin 100 mg/m2 IV day 1/21 d for 6 cycles Rituximab 375 mg/m2 IV days 1, 8, 15, and 22 cycle 1, and if SD at wk 12, also on day 1 of cycles 4, 6, 8, and 10 (CD20+ pts only) Etoposide 100 mg/m2 IV days 1-5/28 d for 6 cycles OR 50 mg/m2 oral days 1-21/28 d for 6 cycles 8

9 Combination Strategies With Conventional Regimens Randomized Phase III Trials in DLBCL Frontline - RCHOP ± enzastaurin - RCHOP ± everolimus - RCHOP ± lenalidomide RCHOP ± epratuzumab RCHOP ± bortezomib Pretransplant RICE ± X Posttransplant & not eligible for SCT CORAL: COllaborative trial in Relapsed Aggressive Lymphoma Maintenance with rituximab after autologous stem cell transplantation (ASCT) in relapsed patients with CD20 diffuse large B-cell lymphoma (DLBCL): CORAL final analysis C. Gisselbrecht, B. Glass, G. Laurent, D. S. Gill, M. D. Linch, M. Trneny, D. Bron, O. Shpilberg, H. Hagberg, M. Bargetzi, D. Ma, J. Briere, C. Moskowitz, N. Schmitz 9

10 CORAL trial: Study design Relapsed/ refractory DLBCL n = 396 R A N D O M I S E R-ICE x 3 R-DHAP x 3 Which salvage regimen is the best? PR, CR SD, PD R-DHAP = rituximab, dexamethasone, off study high-dose cytarabine, cisplatin ASCT BEAM R-ICE = rituximab, ifosfamide, carboplatin, etoposide R A N D O M I S E Rituximab 375 mg/m 2 q2mo x 6 Observation only Place of immunotherapy Post-transplantation? Gisselbrecht C, et al. J Clin Oncol 2010; 28: CORAL by induction treatment robability Survival p EFS (induction ITT) 1.0 R-ICE R-DHAP Survival p robability OS (induction ITT) R-ICE R-DHAP 0.0 p = p = EFS (months) OS (months) 10

11 CORAL by maintenance Survival probability PFS OS Observation Rituximab p = p = Survival probability 1.0 Observation 0.8 Rituximab PFS (months) Overall survival (months) Combination Strategies With Conventional Regimens Randomized Phase III Trials in DLBCL Frontline - RCHOP ± enzastaurin - RCHOP ± everolimus - RCHOP ± lenalidomide RCHOP ± epratuzumab RCHOP ± bortezomib Pretransplant RICE ± X Posttransplant & not eligible for SCT 11

12 The Challenge of Hodgkin Lymphoma Hodgkin Lymphoma by Era (N = 2167) Disease-Specific Survival Overall Survival Courtesy of Joe Connors, personal communication Relapse After ASCT: OS by Era of Transplant Overall Survival <1990 median 1.9 yrs median 2.6 yrs >2000* median 1.9 yrs >2000 vs : P (Gehan) =.02, P (logrank) =.03 Horning S et al, 2008 Lugano Hodgkin s Lymphoma Presentation 12

13 Current Regimens in HL Lymphoma Disease Front-Line Regimen Salvage Regimen chl ABVD ICE ESHAP DHAP GND, IGEV CHOP ABVD RCHOP ABVD RCHOP ABVD Early 1970s Single-Agent Activity in Relapsed chl Agent Target Route Phase N PR CR PR + CR 1 st Author SGN30 CD30 IV I/II (0%) Bartlett MDX060 CD30 IV II (8%) Ansell SGN35 CD30 IV I ( 3 wks) (37%) Younes SGN35 CD30 IV I (weekly) (46%) Fanale SGN35 CD30 IV II (3 wks) (74) 75% Chen MGCD0103 HDACs Oral II (38%) Younes Panobinostat HDACs Oral I (40%) DeAngelo Panobinostat HDACs Oral II (27%) Sureda Vorinostat HDACs Oral II (4%) Kirshbaum Lenalidomide? Oral II (17%) Fehniger Lenalidomide? Oral II (13%) Kuruvilla Everolimus mtor Oral II (53%) Johnston Younes A. Hematology Am Soc Hematol Educ Program. 2009: Younes A, et al. N Engl J Med 2010; 363: Sureda A, et al. ASH Chen R, et al. ASH

14 Single agent activity of new agents in post SCT relapsed chl Comparison to multiagent chemotherapy GVD GVD SGN35 Everolimus SGN35 Panobinostat SGN35 MGCD0103 Panobinostat Lenalidomide Lenalidomide MDX060 Vorinostat SGN30 PR CR % Response rate Event-free survival for transplant-naive patients receiving gemcitabine, vinorelbine, and pegylated liposomal doxorubicin (GVD), plus autologous stem-cell transplant in 39 of 49 (solid line), and patients receiving GVD after failing a prior transplant (dashed line). Bartlett N et al. Ann Oncol 2007;18: European Society for Medical Oncology 14

15 Event-free and overall survival of patients with chemosensitive disease.kaplan-meier estimates of the proportion of patients with chemosensitive disease to 2 cycles of ICE cytoreduction who are alive (+) and event free ( ) at a median follow-up of 43 months. Moskowitz C H et al. Blood 2001;97: by American Society of Hematology Results of salvage pre-transplant regimens in chl IGEV mini-beam ASHAP MINE Dexa-BEAM ICE CR PR DHAP GVD GDP ESHAP % response rate 15

16 Brentuximab Vedotin Mechanism of Action Brentuximab vedotin (SGN-35) ADC monomethyl auristatin E (MMAE), potent antimicrotubule agent protease-cleavable linker anti-cd30 monoclonal antibody ADC binds to CD30 ADC-CD30 complex traffics to lysosome MMAE is released MMAE disrupts microtubule network G2/M cell cycle arrest Apoptosis Phase I Brentuximab Vedotin in Relapsed HL Treatment Follow-up Cycle 1 21 days Cycle 2 21 days Restage* Stable disease or better may receive additional cycles D1 dosing D1 dosing SGN-35 administered IV every 21 days Dose cohorts: 0.1, 0.2, 0.4, 0.6, 0.8, 1.2, 1.8, 2.7, 3.6 mg/kg * CT and PET scans were retrospectively reviewed by an independent review facility (IRF) Younes A, et al. N Engl J Med 2010; 363:

17 Phase-I Brentuximab Vedotin in Relapsed HL Treatment Response Investigator Assessment IRF Assessment 86% of patients achieved tumor reductions 83% of patients achieved tumor reductions * Significant correlation observed between investigator and IRF assessment (Pearson correlation coefficient = 0.674; P<.001) Younes A, et al. N Engl J Med 2010; 363: Phase I Brentuximab Vedotin in Relapsed HL 21-year-old female HL diagnosed 2003 ABVD + XRT to mediastinum ICE BEAM ASCT HDAC-inhibitor SGN mg/kg x 8 cycles Best clinical response: CR CT 93% reduction, PET- PET negative Younes A, et al. N Engl J Med 2010; 363:

18 Durable Complete Remissions in a Pivotal Phase 2 Study of SGN-35 (Brentuximab Vedotin) in Patients with Relapsed or Refractory Hodgkin Lymphoma (HL) A Younes, AK Gopal, SE Smith, SM Ansell, JD Rosenblatt, KJ Savage, JM Connors, A Engert, EK Larsen, DA Kennedy, EL Sievers, R Chen International Conference on Malignant Lymphoma June, 2011 Lugano, Switzerland Pivotal, Multicenter, Open-Label Study of Brentuximab Vedotin in Relapsed/Refractory HL Eligibility Treatment (N=102) Follow-up Relapsed or refractory CD30+ HL Age 12 years Measurable disease 1.5 cm ECOG 0 1 Prior ASCT Brentuximab vedotin 1.8 mg/kg IV every 21 days Administered outpatient over 30 min Max 16 cycles for SD or better Restage* at Cycles 2, 4, 7, 10, 13, 16 Every 12 weeks * Revised Response Criteria for Malignant Lymphoma (Cheson, 2007) 18

19 Demographics and Baseline Characteristics N=102 Age* (years) 31 (15 77) Gender (M / F) 48 / 54 ECOG status (0 / 1) 42 / 60 Refractory to frontline therapy 72 (71%) Refractory to most recent treatment 43 (42%) Prior chemotherapy regimens* 3.5 (1 13) Relapse 1 year post ASCT 72 (71%) Time from ASCT to first post transplant relapse* 6.7 mo (0 131) * Median (range) Response Results Summary N=102 Objective response (OR) rate 75% 95% CI 65, 83 Median duration of OR 6.7 mo 95% CI 3.6, 14.8 Median (range) cycles of treatment = 9 (1 16) Estimated 12-month overall survival = 89% 19

20 Tumo or Size (% Change from Baseline) Maximum Tumor Reduction Complete remission 94% (96 of 102) of patients achieved tumor reduction Individual Patients PFS by Best Response or Death % Patients Free of PD o Time (months) 20

21 HL: Opportumities to improve treatment outcome Front-line ABVD vs ABVD + SGN-35 Pretransplant (Salvage) vs (salvage) + X SGN-35 naive SGN-35 vs SGN-35 + X Post transplant Post SGN-35 New single agent vs control 21