ACCME/Disclosures. DLBCL, NOS from the clinician perspective. Diffuse large B cell lymphoma

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1 , NOS from the clinician perspective John P. Leonard, M.D. Weill Cornell Medicine New York Presbyterian Hospital ACCME/Disclosures The USCAP requires that anyone in a position to influence or control the content of CME disclose any relevant financial relationship WITH COMMERCIAL INTERESTS which they or their spouse/partner have, or have had, within the past 12 months, which relates to the content of this educational activity and creates a conflict of interest. Dr. Leonard declares that he has served as a consultant for Teva, ADC Therapeutics, Biotest, Medimmune, Hospira, Bayer, Juno Therapeutics, Oncotracker, Gilead Sciences Diffuse large B cell lymphoma Practical objective of treatment cure Reasonably good clinical prognostic tools Most patients treated same (R-CHOP) Unmet need roughly 1/3 not cured, reduce toxicity of treatments Who should we treat differently? If refractory to second-line therapy, prognosis is poor Treatment algorithm for Cure (6-7%) Relapsed/Refractory (3-4%) Transplant eligible (2-25%) ASCT + HDC (1%) 2 nd line therapy R-ICE, R-DICE, R-DHAP, etc Transplant ineligible (1-15%) Cure (5%) Relapse (15-2%) Relapse (1-15%) 3 rd line or later therapy (25-35%) 1

2 What does the clinician need or want to know when approaching a new patient? Clinical features International Prognostic Index Primary mediastinal, CNS, Testicular Pathological features BM involvement (none vs indolent vs ) Double hit (FISH) > Double protein Cell of origin International Prognostic Index (IPI) in aggressive NHL Prognostic factors (APLES) Age 6 years Performance status 1 OR LDH 1 normal Extranodal sites 1 Stage III or IV Risk Category Factors Low (L) or 1 Low intermediate (LI) 2 High intermediate (HI) 3 High (H) 4 or 5 Patients (%) OS LI HI Years L H International NHL Prognostic Factors Project. N Engl J Med. 1993;329:987. Armitage. CA Cancer J Clin. 25;55:368. What does the clinician need or want to know when approaching a new patient? Clinical features International Prognostic Index Little evidence to modify therapy Primary mediastinal R-EPOCH CNS Methotrexate, Ara-C,? XRT Testicular Add XRT, intrathecal therapy What does the clinician need or want to know when approaching a new patient? Pathological features BM involvement (none vs indolent vs ) Underlying transformation, CNS prophylaxis Double hit (FISH) > Double protein? R-EPOCH Cell of origin? Subset-directed therapy 2

3 Double hit vs Double protein Double-hit lymphoma High-grade B-cell lymphoma with translocations of MYC as well as BCL2, BCL6, or both ( triple-hit ) Histologically classified as or B-cell lymphoma unclassifiable with intermediate features between and Burkitt Lymphoma (BCLu) Virtually always GCB-like Outcome poor with standard therapies Double-expressing lymphomas with dual immunohistochemical expression of MYC ( 4%) and BCL2 ( 7%) in the absence of translocations ABC-like > GCB-like Outcome inferior to other s treated with R-CHOP, but not as poor as DHL Caveats in understanding clinical characteristics and outcomes in double hit lymphoma Clinical features of the subtype are less favorable Selection biases of series Variability in molecular testing Challenges and changes in morphologic/pathologic classification Non-uniform therapy Single vs multicenter Retrospective FISH DH and treatment with R-CHOP DA-EPOCH-R in double hit lymphoma EFS OS Green et al, JCO 212 Petrich et al Blood 214 Oki et al BJH 214 3

4 Planned Intergroup Trial in DH Phase I then Phase II-III BCL-2 inhibitor Venetoclax DA-EPOCH-R What about new approaches in? Strategies under investigation independent of cell of origin Untreated DHL/DPL R DA-EPOCH-R + Venetoclax (ABT199) Strategies targeting specific cell of origin subtype CALGB 533: R-CHOP vs R-EPOCH in Newly Diagnosed Outcome by GCB vs non-gcb gene signatures in N=233 patients treated with R-CHOP PFS OS Untreated patients with newly diagnosed (N = 478) R-CHOP every 3 wks for 6 cycles R-EPOCH Doxorubicin, etoposide, vincristine Days 1-4; cyclophosphamide Day 5; prednisone Days 1-5 Primary endpoints: EFS, molecular predictors of outcome for each regimen Secondary endpoints: RR, OS, toxicity, use of molecular profiling for pathological diagnosis Clinical Trials.gov. NCT Lenz G, et al, NEJM November 27, 28 4

5 Oncogenic mechanisms and potential therapeutic targets in GCB and ABC s Upfront Novel agent/regimen in specific clinical or molecular patient subsets Study design Subset 1 Other regimen Subset 2 Other regimen Other regimen Roschewski M. et al. Nat. Rev. Clin. 213;11: ABC -associated signaling Ibrutinib in relapsed patients with ABC versus GCB subtype ABC subtype (N=29) GCB subtype (N=2) Unclassifiable Unknown 2 1 (N=16) (N=5) Total (N=7) Not Evaluable for Response PP ORR 4 (CR + PR) 1 (4%) 1 (5.3%) 2 (66.7%) 13 (21.7%) Complete Response (CR) 2 (8%) 1 (33.3%) 3 (5%) Partial Response (PR) 8 (32%) 1 (5.3%) 1 (33.3%) 1 (16.7%) PFS (months) NR GEP performed, but not assignable to ABC or GCB subtypes. 2 GEP not yet performed or tissue not available. 3 Not reached. 4 PP = per protocol. N=7 Median age=63 Median prior treatments=3 (range 1-7) IPI high-intermediate/high risk 59% Roschewski M. et al. Nat. Rev. Clin. 213;11: Wilson WH et al. Blood. 212;12:686. 5

6 Phase I trial of R-CHOP+ibrutinib Total of 24 patients, 11 with available cell of origin data GCB: 5/7 CR, 2/7 PR Non GCB: 4/4 CR MTD (with R-CHOP) not reached, recommended dose of ibrutinib 56 mg/d 82% of patients had a grade 3+ event though were mainly cytopenias Growth factors were used Adverse events comparable to historical studies with R- CHOP alone One patient died during the study Upfront Novel agent/regimen in specific clinical or molecular patient subsets Study design GCB Non-GCB Other regimen Ibrutinib + Younes A et al. Lancet Oncology. 214;15: A5131 Study Schema Relapsed/Refractory -ABC Salvage PR, stem cells collected ABC -associated signaling Randomization Stratify by time to relapse, conditioning regimen Arm A ASCT: CBV or BEAM + Ibrutinib 56 mg Arm B ASCT: CBV or BEAM Ibrutinib x 12 months Placebo x 12 months Follow Up Follow Up Roschewski M. et al. Nat. Rev. Clin. 213;11:

7 Response to Lenalidomide in Relapsed and Refractory Based on Subtype RCHOP - inferior results in non-gcb Retrospective analysis of patients with relapsed treated with lenalidomide as a single agent or in combination with rituximab/steroids at several institutions (N=56) suggests activity in the non-gcb subset Mayo Phase 2 R2CHOP vs RCHOP Case-matched Controls Hernandez-Illizaliturri et al. Cancer 211 Nowakowski et al. JCO 215 PFS by GCB vs. non-gcb Subtype* in Case-matched RCHOP cohort vs R2CHOP E1412: R2CHOP vs. RCHOP RCHOP R2CHOP RCHOP N=1 evaluable pts p=.4 subtype (Hans) * GCB non-gcb unknown p=ns 12 (42%) 11 (4%) 5 (18%) R 1:1 Stratification Age IPI R2CHOP N=1 evaluable pts 1% path ineligibility rate total ~22 pts# Nowakowski et al. JCO 215 * As defined by Hans et al. Blood 24 up to 3 patients can be enrolled to meet a goal of 5 ABC patients per arm as defined by GEP 7

8 patients receiving frontline R-CHOP+bortezomib had similar PFS and OS in GCB and non-gcb subtypes N=4 2Y PFS 64% 2Y OS 7% Randomized phase 2 open-label study of R-CHOP ± bortezomib in patients with untreated non-germinal center B-cell-like subtype diffuse large cell lymphoma: Results from the PYRAMID trial (NCT931918) GCB 14 Non-GCB 18 JP Leonard, K Kolibaba, JA Reeves, A Tulpule, IW Flinn, T Kolevska, R Robles, C Flowers, R Collins, NJ DiBella, SW Papish, P Venugopal, A Horodner, A Tabatabai, J Hajdenberg, G Mulligan, R Neuwirth, K Suryanarayan, D-L Esseltine, S de Vos Suggests improvement over standard therapy for non-gcb Ruan J et al. J Clin Oncol. 211;29: Previously untreated Non-GCB Measurable Selection disease ECOG PS 2 IHC algorithm Assay/scoring in real time at central US lab* FPI: Oct 29 LPI: July 213 Hans method 1 (CD1, bcl-6, MUM-1) hour turnaround Retrospective molecular analyses of RNA patterns, DNA mutations STUDY DESIGN R A N D O M I Z E Arm A (n=95) Bortezomib 1.3 mg/m 2 IV, Days 1 and 4 R-CHOP 21 X 6 cycles Arm B (n=95) R-CHOP 21 X 6 cycles *Local IHC testing by certified local pathologists was also employed, confirmed by central review; R-CHOP standard dose (rituximab 375 mg/m 2, cyclophosphamide 75 mg/m 2, doxorubicin 5 mg/m 2, vincristine 1.4 mg/m 2 [max 2 mg], all IV on Day 1, and prednisone 1 mg PO on Days 1 5) ECOG PS, Eastern Cooperative Oncology Group performance status; IHC, immunohistochemistry; IV, intravenous; PO, oral administration 1. Hans CP, et al. Blood 24;13: Median age, years (range) DEMOGRAPHICS AND BASELINE CHARACTERISTICS R-CHOP N=91* IPI, International Prognostic Index; LDH, lactate dehydrogenase; ULN, upper limit of normal VR-CHOP N=92* Total N=183* 62 (24 85) 65 (2 83) 64 (2 85) Age >65 years, % Male, % IPI Risk Group, % Low Low/Intermediate High/Intermediate High LDH > ULN, % ECOG PS /1/2, % 44/44/12 59/4/1 52/42/7 *mitt population

9 BEST OVERALL RESPONSE RATE* % (R-CHOP) and 59% (VR-CHOP) of patients had a negative FDG-PET result at the end-of-treatment visit CR CR/PR CR CR/PR *Response-evaluable population (confirmed non-gcb, measureable disease and at least one post-baseline response assessment); response assessments based on the 27 Revised Response Criteria for Malignant Lymphoma 1; Investigator-assessed PR, partial response 1. Cheson BD, et al. J Clin Oncol. 27;25: PFS probability PROGRESSION-FREE SURVIVAL 2-year PFS: 78% R-CHOP vs 82% VR-CHOP HR (95% CI):.73 (.43, 1.24); p= Patients at risk: R-CHOP 91 VR-CHOP 92 R-CHOP (N=91) Events 25% VR-CHOP (N=92) 18% Treatment group: Censored observations: R-CHOP VR-CHOP R-CHOP VR-CHOP 5 51 Time to event (months) CI, confidence interval; HR, hazard ratio; PFS, progression-free survival (time from randomization to investigator-assessed progression or death) PFS BY IPI RISK GROUP Low/Low-Intermediate: 2-year PFS, 9% R-CHOP vs 89% VR-CHOP HR (95% CI):.85 (.35, 2.1) p=.958 High-Intermediate/High: 2-year PFS, 65% R-CHOP vs 72% VR-CHOP HR (95% CI):.67 (.34, 1.29) p=.66 PFS probability PFS probability R-CHOP (N=45) Events 16% Treatment group: Censored observations: R-CHOP VR-CHOP R-CHOP VR-CHOP Time to event (months) R-CHOP (N=46) Events 35% VR-CHOP (N=51) 14% VR-CHOP (N=41) 24% Treatment group: Censored observations: R-CHOP VR-CHOP R-CHOP VR-CHOP Time to event (months) OS probability OVERALL SURVIVAL 2-year OS: 88% R-CHOP vs 93% VR-CHOP HR (95% CI),.75 (.38, 1.45); p= Patients at risk: R-CHOP 91 VR-CHOP 92 R-CHOP (N=91) Events 15% VR-CHOP (N=92) 12% OS, overall survival (time from randomization to death) Treatment group: Time to event (months) Censored observations: R-CHOP VR-CHOP R-CHOP VR-CHOP

10 A Prospective Randomised Trial of Targeted Therapy for Diffuse Large B-Cell Lymphoma () Based upon Real-Time Gene Expression Profiling. Study design The REMoDL-B Study of the UK NCRI and SAKK Lymphoma Groups Andrew J Davies 1, Josh Caddy 2,TomMaishman 2, Sharon Barrans 3, Christoph Mamot 4,Matthew Care 5, Christopher Pocock 6, Louise Stanton, 2, Debbie Hamid 2,KeithPugh 2, Andrew McMillan, 7,Paul Fields 8,AntonKruger 9, Andrew Jack 1 and Peter W.M. Johnson 1 1 CancerResearchUKCentre,UniversityofSouthampton,Southampton,UnitedKingdom 2 Southampton Clinical Trials Unit, University of Southampton, Southampton, United Kingdom 3 St James Institute of Oncology, HMDS, Leeds, United Kingdom 4, Cantonal Hospital of Aarau, Aarau, Switzerland 5 University of Leeds, Leeds Institute of Cancer and Pathology, Leeds, United Kingdom 6 East Kent Hospitals, Canterbury, United Kingdom 7Nottingham City Hospital, Nottingham, United Kingdom 8 Department of Haematology, Guy's and St Thomas' Hospitals NHS Trust, London, United Kingdom 9 RoyalCornwallHospital, Truro, United Kingdom 1 HMDS, Leeds Cancer Centre, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom REMoDL-B 37 Powered to detect a 1% improvement in 3 month PFS (α=.5; power.9). n=688 ABC and GCB randomised. ABC 26 Amendment 2 nd May 214 Bortezomib 1.6 mg/m 2 day 1+8 sub cut Trial Registration R CHOP Cycle 1 Molecular phenotype result received from HMDS and randomised Response rate (%): Molecular profile and arm 87.7% 9.2% 88.% 87.5% 9.5% 96.3% 81.8% Technical Fail(n=29) Screen Fail (n=13) ABC (n=248) GCB (n=477) Unclassifiable (n=21) CR/ CR(u) Randomisation Randomisation R CHOP x5 (n=159) R CHOP x5 (n=364) RB CHOP x5 (n=361) R CHOP x5 (n=99) RB CHOP x5 (n=12) PR Target population 32 pts. treated at 1.3 mg/m2 IV 143 pts treat at 1.6 mg/m2 sub cut REMoDL-B Non random. ABC GCB Unclass. 1

11 Progression-free survival by molecular profile Overall survival by molecular profile FAIL ABC GCB Unc. Total Characteristic (n=159) (n=248) (n=477) (n=21) (n=185) PFS at 12 months % (95% CI) 79.3 (71.2, 85.4) 79. (73., 83.9) 79.5 (75.3, 83.1) 77.6 (7.2, 83.4) 79. (76.2, 81.5) PFS at 24 months % (95% CI) 7.5 (61., 78.1) 68.9 (61.5, 75.1) 75. (7.2, 79.1) 67.8 (58.1, 75.8) 71.7 (68.4, 74.8) No. of events observed Proportion of patients with an event 23.1% 26.6% 2.6% 23.2% 22.8% Median follow up, in months (95% CI) (14.3, 24.7) (15.8, 21.6) (15.7, 17.7) (12.9, 15.8) (15.7, 17.) Characteristic FAIL ABC GCB Unc. Total (n=159) (n=248) (n=477) (n=21) (n=185) OS at 12 months 79.3 (71.2, 85.4) 79. (73., 83.9) 79.5 (75.3, 83.1) 77.6 (7.2, 83.4) 79. (76.2, 81.5) % (95% CI) OS at 24 months % (95% CI) 7.5 (61., 78.1) 68.9 (61.5, 75.1) 75. (7.2, 79.1) 67.8 (58.1, 75.8) 71.7 (68.4, 74.8) No. of events observed Proportion of patients with an event 17.9% 14.7% 1.7% 11.6% 12.8% Median follow up, in months (95% CI) 16.9 (14.3, 24.7) 17.2 (15.8, 21.6) 16.5 (15.7, 17.7) 14.3 (12.9, 15.8) 16.3 (15.7, 17.) Comparison of R-CHOP in ABC/Non-GCB Retrospective vs Prospective studies Retrospective (Lenz, NEJM 28) 2-year PFS 4% ABC by GEP with R-CHOP Higher PFS rates for GCB vs ABC subtype (P<.1) Spectrum of ABC/Non-GCB patients Less Favorable More Favorable Prospective (Offner, Blood 215) and recent data 2-year PFS 8% non-gcb by IHC with R-CHOP Republished with permission of Blood, American Society of Hematology, HighWire Press, from Frontline rituximab, cyclophosphamide, doxorubicin, and prednisone with bortezomib (VR-CAP) or vincristine (R-CHOP) for non-gcb, Offner et al. 126(15), copyright 215; permission conveyed through Copyright Clearance Center, Inc. Randomized in an unselected patient population or Assessed retrospectively (as in Lenz) GEP, gene expression profiling 1. Lenz G, et al. N Engl J Med. 28;359: Offner F, et al. Blood. 215;126: Standard outcome 11

12 Spectrum of ABC/Non-GCB patients Conclusions on therapy Less Favorable More Favorable Clinical features may result in therapy modifications in some patients Double hit subtype is important subset and impacts treatment Excluded due to concerns about delays/risk Randomized in a selected patient population (patients who could wait for screening/enrollment) Modification of therapy based on cell of origin is attractive but may be challenging to validate studies ongoing Favorable outcome 12