CARE at ASH 2014 Lymphoma Dr. Diego Villa Medical Oncologist British Columbia Cancer Agency Vancouver Cancer Centre
High-yield lymphoma sessions Sat, Dec 6 th Sun, Dec 7 th Mon, Dec 8 th EDUCATIONAL SESSIONS 7:30AM-9:00AM Survivorship, Viruses 9:30AM-11:00AM Double hit, HL ORAL SESSION 12:00PM-1:30PM CLL EDUCATIONAL SESSIONS 2:00PM-3:30PM Genomics (CLL, DLBCL) 4:00PM-5:30PM Double hit, Viruses POSTER SESSION 5:30PM-7:30PM EDUCATIONAL SESSIONS 7:30AM-9:00AM Genomics, HL, Survivorship 9:30AM-11AM Microenvironment, Genomics ORAL SESSION 2:00PM-4:00PM Plenary Session ORAL SESSION 4:30PM-6:00PM Novel agents indolent NHL POSTER SESSION 6:00-8:00PM ORAL SESSIONS 7:00AM-8:30AM Novel agents CLL 10:30AM-12:00PM DLBCL 2:45 PM-4:15PM HL 4:30PM-6:00PM MCL and other novel agents 6:00PM-8:00PM POSTER SESSION Tues, Dec 9 th 7:30AM-9:00AM ORAL SESSION FL
Lymphoma Themes at ASH 2014 Chronic Lymphocytic Leukemia Upfront therapy Maintenance CD20 antibody therapy Relapsed/refractory therapy Indolent NHL Immune Modulatory Drugs (R 2 ) Relapsed/refractory therapy Hodgkin Lymphoma
Lymphoma Themes at ASH 2014 Chronic Lymphocytic Leukemia Upfront therapy Maintenance CD20 antibody therapy Relapsed/refractory therapy Indolent NHL Immune Modulatory Drugs (R 2 ) Relapsed/refractory therapy Hodgkin Lymphoma
Abstract 19 CLL-10 Final Analysis - 564 patients across 158 hospitals, Oct 2008 June 2011-17p- excluded -CIRS <6 - Median age 62 (range 33 82)
CLL-10 Major Results FCR (n=274) BR (n=273) p Age >70 14% 22% 0.020 Unmutated IVGH 55% 68% 0.003 ORR 98% 98% 1.0 CR 41% 32% 0.026 MRD negative 74% 63% 0.001 Median PFS 54 months 43 months 0.001 PFS significant for <65 years and low CIRS subgroups treated with FCR 3-year OS 91% 92% 0.910 Neutropenia 88% 68% <0.001 Severe infection 40% 25% 0.001 TRM 4% 2%
CLL-10 Author Conclusions FCR remains the standard of care for young, fit patients with CLL Improved CR, MRD negativity, PFS BR is an alternative for elderly patients Similar efficacy as FCR in subset >65 years Less toxicity than FCR Are there other strategies to improve outcomes, especially in those who respond?
PRIMA Trial N=1217 Salles, Lancet 2011
ASH 2013 (Abstract 507) 6-year follow-up of PRIMA 6-year R No R PFS 60% 43% OS 87% 89% TRFL 3% 4% ORR 2 nd Rx 76% (51%) 79% (61%) Salles, Lancet 2011 72 months
Abstract 20: AGMT-CLL8 Rituximab Maintenance in CLL 263 patients in CR/PR after 1 st or 2 nd line rituximab-chemo for CLL Maintenance R x2 years vs. observation Baseline characteristics well balanced Median age 63 29% female FCR 74%, BR 20%. 81% post 1 st line chemo Unmutated IVGH 67% 17p- 3%, 11q- 28%, tri12 11%, 13q- 36%, normal 21% CR 58%, PR 42%
Abstract 20: AGMT-CLL8 Rituximab Maintenance in CLL 85% mr (n=134) 76% obs (n=129) SAE well-balanced but more infections in the maintenance arm (32 vs. 22 cases). End of maintenance This is an interim analysis. Study will continue. Median follow-up 17 months
Abstract 21: PROLONG Study Ofatumumab maintenance in CLL 474 patients with relapsed CLL in CR/PR post 2 nd or 3 rd line chemotherapy 1:1 randomization OFA 300mg, then 1000 mg q8wk (up to 2 years) Balanced characteristics Median age 64 Male 67% 2 nd line 70%, 3 rd line 30% Prior R-chemo 84% Cheson, JCO 2010
Abstract 21: PROLONG Study Ofatumumab maintenance in CLL OFA OBS P PFS N 238 236 Therapy Duration 12.5 mo N/A Median PFS 29 mo 15 mo <0.001 End of ofatumumab COMPARISON STUDY Phase II study of OFA in 138 patients with fludarabine-refractory CLL Median PFS 6 mo, OS 15 mo. Wierda, JCO 2010 Median TTNT Median OS 38 mo 27 mo 0.008 similar 0.74 More infections, neutropenia, and pneumonia in the OFA arm
Idelalisib B-cell receptor Y CD79 CD20 Ibrutinib CD10 CD21 CD22
RESONATE Study Ibrutinib vs. Ofatumumab in CLL Phase III RCT of 391 patients with REL/REF CLL Med age 67 (30-86) 127 (32%) with 17p- Median 3 (range 1-13) prior therapies 90% prior rituximab 90% prior alkylator 90% prior purine analog Byrd, NEJM 2014
Outcomes in RESONATE Activity across poor prognostic subgroups, including 17p- RESONATE led to the HC & FDA approval of ibrutinib Byrd, NEJM 2014
Role of cytogenetics in CLL Dohner, NEJM 2000
CLL8: OS in patients receiving FCR by cytogenetic abnormalities 17p deletion ORR 68% CR 5% 3-yr PFS 18% 3-yr OS 38% Hallek, Lancet 2010
Abstract 327: RESONATE-17 Ibrutinib R/R CLL with 17p- Design Phase II study (n=144) R/R CLL/SLL 17p- failing >1 prior therapy Ibrutinib 420 mg daily until toxicity/progression Baseline characteristics Median age 64 63% Rai stage 3 or 4, 10% bulky masses Median 2 (range 1-7) prior therapies
Abstract 327: RESONATE-17 Ibrutinib R/R CLL with 17p- Median f/u 13 months 12 month PFS 80% 88% responders are progression-free ORR 83%, including 17% PR-L. CR in three patients. Toxicity as previously reported.
Idelalisib B-cell receptor Y CD79 CD20 Ibrutinib CD10 CD21 CD22
Idelalisib-R for REL/REF CLL Phase III study Median age: 71 Median prior therapies: 3 (range 1-12) Del 17p: 43% IGVH unmutated: 83% Study stopped after 1 st interim analysis Furman NEJM 2014 Led to FDA approval N=220 Current report on 2 nd interim analysis and subgroup data Idelalisib 150 mg po bid continuously + Rituximab x8 doses Placebo po bid continuously + Rituximab x8 doses
Idelalisib-R for REL/REF CLL HR 0.15 (95% CI 0.08, 0.28), p<0.001 HR 0.28 (95% CI 0.09, 0.86), p=0.02 TOXICITY IDELA-R (any/>gr3) Fever (35%/3%), Fatigue (28%/3%), Nausea (26%/0), Diarrhea/colitis (21%/5%), Transaminitis (40%/8%), Anemia (25%/5%), Neutropenia 55%/34%), Thrombocytopenia (17%/10%) Furman, NEJM 2014
Abstract 330 Idelalisib+rituximab in R/R CLL
Lymphoma Themes at ASH 2014 Chronic Lymphocytic Leukemia Upfront therapy Maintenance CD20 antibody therapy Relapsed/refractory therapy Indolent NHL Immune Modulatory Drugs (R 2 ) Relapsed/refractory therapy Hodgkin Lymphoma
Lenalidomide + Rituximab = R 2 Months 1 2 3 4 5 6 Lenalidomide 20mg Days 1-21 Cycles 1-6* 7 8 9 10 11 12 Lenalidomide 20mg Days 1-21 Cycles 7-12* Rituximab 375mg/M 2 Day 1 of Cycles 1-6 Rituximab 375mg/M 2 Day 1 of Cycles 7-12 If clinical benefit, can proceed to 12 cycles Single institution (MD Anderson Cancer Center) Planned Enrollment N= 50 Follicular lymphoma (grade I/II) N=30 Small lymphocytic lymphoma N=30 Marginal zone lymphoma R R Fowler, ASH 2012
Lenalidomide + Rituximab = R 2 103 patients with advanced, untreated NHL Histological Subtype Small lymphocytic lymphoma (n=30) Marginal zone lymphoma (n=27) ORR (CR) 80% (27%) 89% (67%) Comparisons IELSG-19 trial (N=114 Chl-R) 94% (78%) Follicular lymphoma (n=46) 98% (87%) Total (n=103) 90% (64%) Marcus trial (N=162 CVP-R) 81% (41%) BRIGHT trial (N=148 B-R) 99% (30%) STIL trial (N=261 B-R) 93% (40%)
NCIC CTG LY.16 RELEVANCE trial Morschhauser, Lugano 2013 New Evidence in Oncology, Sept 2013
Abstract 625 1 st line R 2 in mantle cell lymphoma Phase II study of 38 patients new dx MCL Median age 65 (range 42-86) All stage III/IV, 89% BM, even MIPI distribution Len 20mg days 1-21 (of 28) x12 cycles Rituximab every other cycle x9 doses Maintenance R 2 until progression ORR 84% (CR 53%) median time to response 3 months, time to CR 11 months 79% remain on study without PD. 2y PFS 84%. Toxicity consistent with prior data.
Abstract 799: SAKK 35/10 1 st line R 2 in follicular lymphoma RCT of R vs. R 2 in FL requiring therapy Median age 61 (range 26-80) Stage IV 48%, Poor FLIPI 47% R weekly x4 starting weeks 1 and 12 Len 15mg continuously until week 17 No maintenance ORR 81% (CR 36%) 19 (25%) discontinued therapy (13 toxicity, 3 progresssion)
Objective StiL NHL 1 To assess the efficacy and safety of BR versus R-CHOP as first-line treatment for patients with indolent non-hodgkin lymphoma and mantlecell lymphoma Methodology Phase III, open-label, randomized, noninferiority trial No maintenance or consolidation was allowed Rummel, Lancet 2013
StiL-1 Primary Endpoint PFS Median follow up: 45 months Rummel, Lancet 2013
StiL-1 PFS by Histology Follicular Mantle cell Marginal zone Waldenström s Rummel, Lancet 2013
Objectives Abstract 145 STiL NHL-2 2003 Study Compare the efficacy and safety profile of BR with that of FR in patients with relapsed follicular, indolent, or mantle cell lymphoma Methodology Phase III, open-label, randomized, parallel group, multicenter study N=114 N=105 FR dose at BCCA: 20 mg/m 2 x3 days or 25 mg/m 2 x5 days
Abstract 145 8-year follow-up of STiL-2 Baseline characteristics balanced Median age 68 (range 38-87) Stage III/IV 90% Median 1 prior therapy (range 1-7) FL 46%, WM 11%, MCL 21%, Other 21% Protocol amended in 2006 to allow maintenance rituximab 23 BR + 17 FR = 40 patients Unplanned analysis showed PFS and OS
Progression-Free Survival 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Abstract 145 8-year follow-up of STiL-2 BR (n=114) FR (n=105) p 6 cycles 75% 53% ORR(CR) 84% (39%) 53%(16%) <0.001 Med OS 110 months 49 months 0.013 SAE rate 17% 22% NS BR FR 0 12 24 36 48 60 72 84 months Median PFS 11 versus 34 months HR 0.54 (95% CI 0.38, 0.72), p<0.0001
Lymphoma Themes at ASH 2014 Chronic Lymphocytic Leukemia Upfront therapy Maintenance CD20 antibody therapy Relapsed/refractory therapy Indolent NHL Immune Modulatory Drugs (R 2 ) Relapsed/refractory therapy Hodgkin Lymphoma
GHSG HD9: BEACOPP in adv HL BEACOPP esc BEACOPP bas COPP/ABVD Engert, JCO 2009
Italian HD2000 Study ABVD vs. BEACOPP vs. CEC for six cycles for advanced HL Protocol included radiotherapy to initial bulky or partially responding sites. BEACOPP = 4 esc and 2 baseline. CEC = MOPP/EBV/CAP Federico, JCO 2009
Abstract 499 10-year follow-up of HD2000 ABVD BEA CEC p PFS 69% 74% 74% 0.64 OS 84% 84% 86% 0.88 2 nd malig Type 0.9% 6.7% 4.4%? 1solid 1MDS 1NHL 4solid 1MDS 1NHL 2solid Federico, JCO 2009
Abstract 500: HD18 study Addition of R to BEACOPP esc 1100 patients with advanced HL receiving BEACOPPesc x2 between 2008-2011 440 (40%) PET(+) 660 (60%) PET(-) 220 BEACOPPesc x6 220 BEACOPPesc +Rituximab x6 3-yr PFS 91.4% vs. 93.0% (p=0.99) 3-yr OS 96.5% vs. 94.4% (p=0.31) BEACOPPesc x6 BEACOPPesc x2 Suggests PET2 does not identify a high-risk subgroup. Excellent outcomes in PET2(+) difficult to see R effect.
Abstract 501 Brentuximab Vedotin as salvage therapy prior to ASCT Phase II study of 36 patients with REL/REF HL after ABVD, BEACOPP, or other +/- RT BV 1.8 mg/kg IV every 3 weeks up to 4 doses prior to ASCT. ORR 69% (CR 33%). SD 28% & PD 3% and these required additional chemo prior to ASCT. 90% patients proceeded with ASCT. Median CD34 5.6x10 6 (range 2.6-22.4); 8 required plerixafor. COMPARISON STUDY 131 patients with R/R HL receiving salvage GDP x2-3 ORR 76% (CR 15%). ASCT 86%. Villa, Haematologica 2012
Thank you! Enjoy San Francisco and ASH 2014