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Non-Hodgkin and Hodgkin Lymphoma: an Individualized Treatment Approach

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Non-Hodgkin and Hodgkin Lymphoma: an Individualized Treatment Approach Non-Hodgkin and Hodgkin Lymphoma: An Individualized Treatment Approach Ann S. LaCasce, MD, MMSc 1 Presenter Disclosure Information The following relationships exist related to this presentation: Research to Practice: Speaker BMS: DSMB member Off Label/Investigational Discussion In accordance with Annenberg Center policy, faculty have been asked to disclose any discussion of unlabeled or unapproved use(s) of drugs or devices during the course of their presentations. 2 Diffuse Follicular large Mantle cell Hodgkin lymphoma B-cell lymphoma lymphoma lymphoma 3 Follicular lymphoma 4 Initial management of advanced stage follicular NHL What hasn’t changed: Newer options: Indications for therapy Obinutuzumab + chemo Rituximab plus lenalidomide Initial therapeutic options: Single agent rituximab Chemoimmunotherapy +/- maintenance 5 Bendamustine-R associated with improved PFS and toxicity compared to RCHOP without OS advantage in grade 1-2 FL n=279 Rummel et al. Lancet 2013 6 PRIMA Trial: maintenance R with improved PFS after R-chemo (95% R- CHOP/R-CVP), FL all grades Predated the use of bendamustine 7 Bachy et al. JCO 2019 Salles et al. Lancet 2011 Gallium: obinutuzumab associated with improved PFS but not OS Fatal AEs (infection, 2nd malignancies) more common with benda, during maintenance (R or O). Especially in patients > 70 y. Non-fatal AEs higher in the O arm (infections, cytopenias) Marcus et al. NEJM 2017 8 Relevance: R-chemo and R-lenalidomide plus maintenance with similar outcomes majority of patients received RCHOP Morschhauser et al. N Engl J Med 2018 9 Options for relapsed follicular lymphoma Older options: Newer options: Observation Lenalidomide + rituximab 200 cGY x 2 palliation PI3 kinase inhibitors Single agent rituximab Tazemetostat Chemoimmunotherapy Immunotherapies (CAR-T) 10 Augment: relapsed follicular lymphoma: lenalidomide + R with improved PFS compared with R alone Toxicity: R2 higher rates of neutropenia but infection rates similar. R2 higher incidence of low grade rash. No difference in rates of DVT/PE or 2nd malignancies. Leonard et al. JCO 2019 11 PI3K inhibitors in relapsed/refractory indolent lymphoma Agent isoform toxicity ORR Median PFS Idelalisib delta infection/ 57% 11.1 m colitis Copanlisib pan HTN/ 59% 11 m hyperglycemia Duvelisib gamma/delta infection/ 47% 9.5 m colitis Gopal et al. NEJM 2014 Dreyling et al. JCO 2017 Flinn et al. JCO 2019 12 Follicular Lymphoma and EZH2 • EZH2 an epigenetic regulator 1 Germinal Center Reaction EZH2 EZH2 EZH2 • EZH2 is required for normal B-cell biology and germinal center formation2 Dark Zone Light Zone – Oncogenic mutations in EZH2 “lock” B Plasma cell cells in the germinal center (makes antibodies) • EZH2 biology relevant in both mutant (MT) Apoptosis and wild-type (WT) FL Naive B- – ~20% of patients with FL also have EZH2 cell 3 gain of function mutations Memory B-cell Tazemetostat, an Oncogenic (remembers Mutations in EZH2 pathogens) investigational, first-in- class, selective, oral X inhibitor of EZH2 has shown antitumor activity Tazemetostat Germinal Center in non-Hodgkin’s Derived Neoplasms lymphoma patients with either MT or WT EZH24,5 The American Society of Hematology (ASH) 1. Gan L, et al. Biomark Res. 2018;6(1):10; 2. Béguelin W, et al. Cancer Cell. 2013;23(5)677-692. 3. Bödör C, et al. Blood13. 7-10 December 2019 2013;122:3165-3168. 4. Italiano A, et al. Lancet Oncol. 2018;19(5):649-59; 5. Morschhauser F, et al. Hematol Oncol. 2017 13 Orlando, FL Jun;35:24-5. Tazemetostat ORR in EZH2 Mutant and Wild Type Populations EZH2 Mutant cohort EZH2 WT cohort (n=45) (n=54) Parameter Investigator IRC Investigator IRC ORR, n (%) 35 (78) 31 (69) 18 (33) 19 (35) CR, n (%) 4 (9) 6 (13) 3 (6) 2 (4) PR, n (%) 31 (69) 25 (56) 15 (28) 17 (31) SD, n (%) 10 (22) 13 (29) 16 (30) 18 (33) PD, n (%) 0 1 (2)c 16 (30) 12 (22) DOR, months, ) 8.3 (5.5–13.8) 10.9 (7.2–NE) 14.7 (7.6–NE) 13.0 (5.6–NE) Morschhauser et al. ASH 2019 14 PFS in the ITT Population PFS – MT EZH2 PFS – WT EZH2 Median PFS 13.8 mos Median PFS 11.1 mos Endpoint by IRC Assessment MT EZH2 WT EZH2 (n=45) (n=54) PFS at 12 months, median (95% CI) 51.7 (34.4–66.6) 47.1 (31.6–61.1) PFS at 18 months, median (95% CI) 38.8 (22.7–54.7) 28.3 (14.8–43.4) 15 Morschhauser et al. ASH 2019 15 CD19 CAR-T with very high ORR in follicular lymphoma CR 100 93% ORR 95% ORR PR 81% ORR 80 SD ND 60 80% CR 81% CR (n = 77) (n = 65) 75% CR 40 (n = 12) 19% (n = 3) 20 5% 3% Best Objective Response,Best Objective % 2% 3% 13% PR (n = 5) 14% PR 6% PR (n = 2) (n = 2) (n = 2) 0 (n = 12) (n = 11) (n = 1) 0 ORR SD NDa ORR SD ND ORR SD ND All Patients (N = 96) FL (n = 80) MZL (n = 16) 16 The median time to first response was 1 month (range, 0.8 – 3.1) Of the 80 patients with FL, 10 (13%) had an initial response of PR at Week 4 and later converted to CR Jacobson et al. ASCO 2020 16 Progression-Free Survival and Overall Survival 17 With a median follow-up of 15.3 months, median PFS was 23.5 The 12-month OS rate was 94.3% for all patients Jacobson et al. ASCO 2020 17 Summary: new therapies for follicular lymphoma Obinutuzumab-chemo + O maintenance is superior to R-chemo + R maintenance with small PFS only. Lenalidomide plus rituximab is an alternative approach. Choice of therapy dependent on patient age, burden of disease and preference. 18 Summary: new therapies for relapsed follicular lymphoma Lenalidomide plus rituximab has superior PFS compared with rituximab monotherapy. PI3K inhibitors have similar efficacy with distinct side effect profiles. Tazemetostat is active in both mutated and WT EZH2 with higher ORR in mutated. Preliminary results of CAR-T are promising in FL (not FDA approved). 19 Aggressive B-cell lymphoma 20 Initial management of aggressive lymphoma What hasn’t changed: What’s new: RCHOP x 6 PET directed therapy in localized disease DA-REPOCH x 6 in double hit Many negative studies CNS prophylaxis in subset 21 PET directed therapy for stage I/II DLBCL Cycle 3 Cycle 3 Day 15-18 Day 21-35 Day 21-42 after IFRT Ibritumomab iPET+ 36-45 Gy IFRT tiuxetan Deauville 4-5 Stage I/II DLBCL Eligibility criteria R-CHOP x 3 by CT and PET • Newly diagnosed DLBCL • Non-bulky (< 10 cm) stage I/II Deauville 1-3 • Measurable or evaluable disease iPET- R-CHOP x 1 • Excluded – CNS, testicular, primary mediastinal, and Stage I/II DLBCL concurrent/preceding indolent by CT but III/IV R-CHOP x 6 lymphoma by PET Persky et al. JCO 2020 22 Favorable PFS for both PET- and PET+ patients Persky et al. JCO 2020 23 Gene expression profiling in DLBCL identifies prognostic subsets Dunleavy and Wilson. Oncology. 2014 Lenz et al. NEJM. 2008 24 US Intergroup phase 3 RCT: no difference in PFS/OS analysis according to molecular subtype underway Bartlett et al. JCO 2019 25 Novel targets in non-GCB DLBCL Nowakowski et al. ASCO 2015 26 RCHOP + novel drug vs RCHOP: three studies without benefit in PFS Bortezomib Ibrutinib Lenalidomide Leonard et al. JCO 2017 Younes et al. JCO 2019 Vittolo et al. ICML 2019 27 Phase 3 POLARIX study DLBCL Polatuzumab + RCHP: ORR 91% CR 78% n=45 28 Intensive regimens superior to R-CHOP in DHL Landsburg et al. JCO 2017 29 No benefit to ASCT in first remission Landsburg et al. JCO 2017 30 DA-REPOCH associated with favorable outcomes in MYC rearranged aggressive Dunleavy et al. Lancet Hem 2018 31 Options for relapsed aggressive lymphoma Older options: Newer options: Second line chemotherapy plus CAR-T ASCT in chemosensitive patients Polatuzumab + BR Tafasitamab + lenalidomide Palliative chemotherapy Selinexor 32 Prognosis of chemotherapy refractory aggressive lymphoma dismal using chemotherapy Crump et al. Blood 2017 33 CD19 CAR-T cell products Chow et al. Blood 2018 34 Depth of response and eligibility for ZUMA 1 associated with improved outcomes Jacobson et al. JCO 2020 35 Polatuzumab bendamustine rituximab approved in relapsed/refractory DLBCL ORR 62.5% CR rate 50% Sehn et al. JCO 2019 36 Selinexor in highly selected population of patients with DLBCL 60 mg D1,3 weekly Key eligibility: 60 days after CR/PR 98 days after refractory disease Kalakonda. Lancet Heme 2020 37 Activity modest and tolerability problematic Kalakonda. Lancet Heme 2020 38 PD-1 inhibition (nivo) disappointing in DLBCL Possible exceptions: PMBCL, EBV+ DLBCL, TCHRLBCL Ansell et al. JCO 2019 39 Tafasitamab plus lenalidomide active in relapsed/refractory DLBCL Tafasitamab: 12 mg/kg weekly for 3 cycles. Then q 14 days until progression. Lenalidomide: 25 mg for 12 cycles LDH 56% Prior ASCT 11% Salles et al. Lancet Onc 2020 40 Tafasitamab plus lenalidomide with durable responses in CR 60% of patients received one year of both agents. 46% required dose reduction of lenalidomide and 22% permanently discontinued. Salles et al. Lancet Onc 2020 41 Summary: initial therapy aggressive lymphoma RCHOP remains standard of care except in DHL (REPOCH). RCHOP x 4 an option in localized DLBCL with PET3 negative. No benefit for upfront ASCT including in DHL. 42 Summary: relapsed aggressive lymphoma Salvage followed by ASCT remains SOC in chemotherapy sensitive, transplant eligible patients. CAR-T cell is approved for patients with chemotherapy refectory disease. Polatuzumab/BR is active in relapsed/refractory setting. Tafasitmab/lenalidomide is an option for transplant ineligible patients, though long course of therapy.
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