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.

Selinexor has modest activity and significant toxicity.

43 Mantle cell lymphoma

44 Initial management of mantle cell lymphoma

Initial therapeutic options: What’s new:

Induction therapy followed by Ongoing US Intergroup study ASCT and maintenance in younger patients without TP53 mutation

BR in older patients

45 R-bendamustine superior PFS c/w RCHOP for initial treatment of MCL

n=94

Rummel et al. Lancet. 2013 46 Auto SCT for MCL in 1st remission

Only 1 randomized trial in CR1 following CHOP induction (no rituximab) associated with PFS but no OS benefit.

Many phase II studies showing excellent PFS/OS, especially for low risk patients.

Inclusion of cytarabine in induction and with conditioning improves PFS, but not overall survival.

Maintenance R, improves EFS and OS.

47 US Intergroup MCL study in transplant eligible patients

48 Management of relapsed mantle cell lymphoma

What’s new: Older options:

Acalabrutinib Lenalidomide +/- rituximab Zanabrutinib Bortezomib Venetoclax Ibrutinib Brexucabtagene autoleucel

49 BTK inhibitors/venetoclax in relapsed/refractory MCL

Agent toxicity ORR/CR Median PFS Ibrutinib Afib, bleeding, fatigue, 67%/23% 13 m myalgias, hypertension Acalabrutinib ? Less afib, fatigue, 81%/40% 20 m myalgias but with HA Zanabrutinib neutropenia 84%/69% 19.5 m

Venetoclax Leukopenia/TLS risk 50%/21% 8 m

Wang et al. Blood 2015 Wang et al. Lancet 2018 Song et al. CCR 2020 Zhao et al. Am J Hem 2020 50 Brexucabtagene autoleucel in relapsed/refractory MCL after BTKi

Median of 3 prior therapies

Grade >3 CRS = 15% Grade >3 NT = 31%

Wang et al. NEJM. 2020 51 Hodgkin lymphoma

52 What hasn’t changed: Management of Hodgkin lymphoma

Initial therapeutic options: What’s new:

Early stage: ABVD +/-RT BV-AVD for initial therapy

Advanced stage: Options in relapsed/refractory disease: ABVD for most PD-1 inhibitor BV/nivolumab CAR-T

53 Balancing cumulative risks: early stage Hodgkin Lymphoma

Armitage. NEJM 2010 54 Initial treatment of early stage Hodgkin lymphoma

ABVD x 2 + 20 Gy in GSHG favorable patients.

ABVD alone with slightly lower PFS than combined modality therapy without difference in OS.

PET adapted therapies have favorable outcomes.

Balancing risk of recurrence with late toxicities, depending on individual factors is key.

55 Discontinuation of bleomycin in PET2 negative patients without significant decrease in PFS

Johnson et al. NEJM 2016 56 BV-AVD associated with modest improvement in modified PFS compared with ABVD

Connors et al. NEJM 2017 57 Initial treatment of advanced stage Hodgkin lymphoma

BEACOPP has PFS advantage compared with ABVD but no survival benefit and more toxicity.

PET driven de-escalation with BEACOPP with very favorable outcomes but not used routinely in the US.

Discontinuation of bleomycin in PET2 negative patients with similar outcomes to ABVD.

BV-AVD with modest improvement in PFS. Consider in high risk younger patients.

58 On-going trials in advanced stage HL

BEACOPP BV-AVD

Advanced stage HL

BrECADD Nivo-AVD

59 Management of relapsed Hodgkin lymphoma

What’s new: What hasn’t changed:

BV Maintenance

Standard option: BV containing salvage

Second line chemotherapy/ASCT PD-1 inhibitors

CAR-T

60 Aethera: maintenance brentuximab vedotin after ASCT improves PFS in patients with high risk disease

61 Moskowitz et al. Lancet. 2015 RS cells characterized by copy gain of 9p24.1

9p24.1 encodes PD-L1, PD-L2

Vast majority of cases with copy gain or amplification

In chemotherapy treated patients, amplification associated with inferior PFS

Roemer et al J Clin Oncol 2016 62 PD-1 inhibitors approved in relapsed/refractory HL

Grade 3-4 immune Pembrolizumab mediated AEs rare. ORR 67-78% CR 26-32% 4-6% of patients 2017: approved after 3 prior discontinued therapy therapies for toxicity.

Chen et al. Blood 2019

Nivolumab ORR 65-73% CR 12-29% 2016: approved after ASCT and BV

Armand et al JCO 2018

63 Younes et al. Lancet Onc 2016 BV plus nivolumab in first relapse

Refractory: 42% Remission < 1 yr: 30% Remission > 1 yr: 29%

2 patients discontinued therapy for AEs

64 Moskowitz et al. ASH 2019 BV plus nivolumab with favorable PFS

65 Moskowitz et al. ASH 2019 Preliminary data on CD30 CAR-T

Median prior therapies = 7

Ramos et al. JCO 2020 66 Relapsed Hodgkin lymphoma

ASCT remains standard for chemo-sensitive relapse.

For early relapse/primary refractory disease, BV/nivo may be effective strategy.

Maintenance brentuximab after ASCT has PFS but no survival benefit.

Nivolumab/pembrolizumab are highly active in relapsed/refractory disease.

67 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.

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