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Updates in the Treatment of Relapsed Or Refractory B-Cell Non-Hodgkin Lymphoma Kirollos S

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Updates in the Treatment of Relapsed Or Refractory B-Cell Non-Hodgkin Lymphoma Kirollos S Updates in the Treatment of Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma Kirollos S. Hanna, PharmD, BCPS, BCOP Assistant Professor of Pharmacy Mayo Clinic College of Medicine Hematology/Oncology Clinical Pharmacist University of Minnesota Medical Center Minneapolis, Minnesota © 2019. All rights reserved. No part of this report may be reproduced or distributed without the expressed written permission of PTCE. Educational Objectives At the completion of this activity, participants will be able to: • Describe the pathophysiology of follicular lymphoma (FL) and mantle cell lymphoma (MCL) and risk factors for disease progression that guide treatment decisions • Distinguish new and emerging agents for treating FL and MCL based on mechanisms of action and clinical efficacy and safety data • Explain appropriate prevention and management of therapy- induced adverse effects • Identify the multifaceted roles of the pharmacist in improving adherence and disease outcomes in patients receiving therapy for B-cell NHL Non-Hodgkin Lymphoma Overview Follicular Lymphoma (FL) and Mantle Cell Lymphoma (MCL) Non-Hodgkin Lymphoma (NHL) Overview • Lymphoproliferative disorders originating in B-lymphocytes, T- lymphocytes, or natural killer cells • 74,200 new cases and 19,970 deaths in 2019 • Seventh most common; 4%-5% of new cases and 3%-4% of deaths • Diagnosis median age 67 years • Death median age 76 years • >60 specific NHL subtypes have been identified by the World Health Death rates have been falling on average Organization • Aggressive lymphomas: 60% of cases 2.2% each year over 2007-2016. • Indolent lymphomas: 40% of cases 5-year OS = 72% SEER Cancer Stat Facts: non-Hodgkin Lymphoma. National Cancer Institute. Bethesda, MD. seer.cancer.gov/statfacts/html/nhl.html; National Comprehensive Cancer Network (NCCN) clinical practice guidelines in oncology. B-Cell Lymphomas v4.2019. Clinical Presentation “B” Symptoms Signs Unintentional weight loss ≥10% of body weight Lymphadenopathy within the previous 6 months Splenomegaly Fevers of >100.5°F (>38°C) for ≥2 weeks without evidence of infection Hepatomegaly Drenching night sweats for ≥1 month without evidence of infection Skin and other organ involvement Extreme fatigue Cytopenias and autoimmune diseases Some patients are asymptomatic and are diagnosed on routine exams. Hallek M, et al. Blood. 2018;131(25):2745-2760; NCCN clinical practice guidelines in oncology. B-Cell Lymphomas v4.2019. NHL Major Subtypes DLBCL CLL/SLL FL MZL MCL PTCL-NOS “Indolent” form of NHL, yet aggressive behavior that arises 4% 2% from cells originating in the mantle zone. 8% 32% Accounts for 3%-6% of all NHL. Median overall survival (OS), 17% 5-7 years. Indolent form of NHL that arises 19% from B-lymphocytes. Approximately 20% of all NHL. 5-year OS rates all stages: ≈88%. CLL/SLL, chronic lymphocytic leukemia/small lymphocytic lymphoma; DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; MZL, marginal zone lymphoma; MCL, mantle cell lymphoma; PTCL-NOS, peripheral T-cell lymphoma not otherwise specified. Al-hamadani M, et al. Am J Hematol. 2015;90(9):790-795; Cheah CY, et al. J Clin Oncol. 2016;34(11):1256-1269; Herrmann A, et al. J Clin Oncol. 2009;27(4):511-518; Martin P, et al. Ann Oncol. 2008;19(7):1327-1330. FL and MCL Overview FL MCL • t(14;18) translocation (90%) • t(11;14) translocation • Deregulated expression of • Overexpression of cyclin D1 BCL2 • More aggressive disease • Indolent forms may not course compared with require treatment for years indolent lymphomas • Predictors of outcomes: • Predictors of outcomes: number of centroblasts • Age, performance status, • Activated B cell in the serum LDH, white blood germinal center cell (WBC) count, Ki-67 • WHO classification score • FL1 and FL2 → FL1-2 • WHO classification • FL3A → centrocytes present • MCL “in situ” Picture adapted from: Koues OI, et al. Trends Genet. 2015;31(12):720-731. • FL3B → sheets of • Stage I-II centroblasts • Stage II (bulky) and Stage III-IV NCCN clinical practice guidelines in oncology. B-Cell Lymphomas v4.2019; Hoster E, et al. Blood. 2008;111(2):558-565. FL Treatment Decision Making GELF Criteria FLIPI-1 Criteria Involvement of ≥3 nodal sites, each with a diameter of ≥3 cm Age ≥60 y Ann Arbor Stage III-IV Any nodal or extranodal tumor mass with a diameter of ≥7 cm Hemoglobin level <12 g/dL B symptoms Serum LDH level >ULN Splenomegaly Number of nodal sites ≥5 Pleural effusions or peritoneal ascites Risk Group According to FLIPI Chart Low 0-1 Cytopenias (leukocytes <1.0 x 109/L and/or platelets <100 x 109/L) Moderate 2 9 Leukemia (>5.0 x 10 /L malignant cells) High ≥3 • Therapy with rituximab in patients not meeting the modified • FLIPI-1 developed in pre-rituximab era but still retains its GELF criteria does not improve OS and outside a clinical trial prognostic significance • Observation is still standard practice for patients with • FLIPI-2 (not mentioned) was developed for newly diagnosed advanced stage low-tumor-burden FL patients treated with rituximab ULN, upper limit of normal. NCCN clinical practice guidelines in oncology. B-Cell Lymphomas v4.2019; Solal-Celigny P, et al. Blood. 2004;104(5):1258-1265. MCL Treatment Decision Making Incurable with conventional chemotherapy Disease/Patient Factors • SOX11 expression—more aggressive phenotype • Age, Ki-67, ECOG PS, LDH, WBC define risk groups Observation plays a limited role and in select patients (ie, MCL in situ, smoldering MCL)* Treatment Pathway • Induction → consolidation → maintenance Chemotherapy Stage I-II: radiation ± chemoimmunotherapy • No accepted standard of care across practice • Aggressive induction reserved for patients able to tolerate therapy Stage II (bulky) and Stage III-IV: chemotherapy ± • Less aggressive induction for patients with autologous hematopoietic cell transplantation (HCT) comorbidities precluding aggressive treatment High-Dose Chemotherapy With Stem Cell Rescue • Best chance for long-term survival is to consolidate *Observation may be appropriate in select patients with Ki-67 remission with autologous HCT <30%, maximum tumor diameter <3 cm, normal serum LDH and β2- • Earlier application of HCT results in better outcomes microglobulin levels, lack of B symptoms, and nonblastoid/pleomorphic histology. NCCN clinical practice guidelines in oncology. B-Cell Lymphomas v4.2019; Cheah CY, et al. J Clin Oncol. 2016;34(11):1256-69; Mcculloch R, Rule S. Best Pract Res Clin Haematol. 2018;31(1):90-98. Simplified MIPI Calculations for MCL • 4 prognostic factors for survival (age, PS, LDH, OS According to MIPI leukocyte counts) • Risk groups are well separated • Low: 0-3 points; Intermediate: 4-5 points; High: 6-11 points Hoster E, et al. Blood. 2008;111(2):558-565; Republished with permission of American Society of Hematology from "A new prognostic index (MIPI) for patients with advanced-stage mantle cell lymphoma," Blood, Hoster E, et al; 111 © 2008; permission conveyed through Copyright Clearance Center, Inc. ” Management Relapsed or Refractory FL Follicular Lymphoma NCCN Suggested Treatment Regimens First-Line Therapy Elderly or Infirm Second-line and Subsequent Therapy Elderly or Infirm Preferred Regimens • Rituximab (preferred) Preferred Regimens • Rituximab (preferred) (375 • Bendamustine + obinutuzumab (375 mg/m2 weekly • Bendamustine + obinutuzumab or rituximab mg/m2 weekly for 4 doses) or rituximab for 4 doses) • CHOP + obinutuzumab or rituximab • Chlorambucil + rituximab • CHOP + obinutuzumab or • Chlorambucil + • CVP + obinutuzumab or rituximab • Cyclophosphamide + rituximab rituximab • Rituximab rituximab • CVP + obinutuzumab or • Cyclophosphamide + • Lenalidomide ± rituximab • Chlorambucil rituximab rituximab Other recommended regimens • Cyclophosphamide • Lenalidomide + dexamethasone • Chlorambucil • Ibritumomab tiuxetan • Ibritumomab tiuxetan Other Recommended Regimens • Cyclophosphamide • PI3K inhibitors (relapsed/refractory after 2 (category 2B) • Rituximab (375 mg/m2 weekly • Ibritumomab tiuxetan therapies) for 4 doses) (consider for low • Idelalisib tumor burden) • Copanlisib • Duvelisib Consolidation or Extended Dosing • DLBCL therapies • Rituximab maintenance 375 mg/m2 one dose every 8 weeks for Consolidation or Extended Dosing 12 doses for patients initially presenting with high tumor burden (category 1) • Rituximab maintenance 375 mg/m2 one dose every 12 weeks for 2 years (category 1) • Obinutuzumab maintenance (1000 mg every 8 weeks for 12 • Obinutuzumab maintenance for rituximab-refractory (1 g every 8 weeks for total of 12 doses) doses) • If initially treated with single-agent rituximab, consolidation with • High-dose therapy with autologous stem cell rescue rituximab 375 mg/m2 one dose every 8 weeks for 4 doses • Allogeneic hematopoietic cell transplant for highly selected patients • Ibritumomab tiuxetan (category 2B) NCCN clinical practice guidelines in oncology. B-Cell Lymphomas v4.2019. Unmet Needs in Relapsed/Refractory FL Class FDA-Approved Pipeline • At least 20% of PI3K Inhibitors Idelalisib, copanlisib, duvelisib patients experience IMiDs Lenalidomide early relapse (within BCL2 Inhibitors Venetoclax 2 years of initiating Monoclonal Ocaratuzumab (CD20), epratuzumab and frontline treatment) Antibodies galiximab (CD22), otlertuzumab (CD37) • Drug resistance ADCs Polatuzumab vedotin* Inotuzumab ozogamicin BiTE antibody Blinatumomab • Cumulative toxicities BTK inhibitors Ibrutinib, acalabrutinib Immune checkpoint Nivolumab, pembrolizumab, inhibitors atezolizumab HDACs Vorinostat, panobinostat, mocetinostat Chimeric
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