Nuances in the Management of Aggressive Lymphomas Michelle Wisniewski, PA Paul A. Hamlin, MD Memorial Sloan Kettering Cancer Center Learning Objectives 1. Demonstrate increased understanding of the mechanisms of action of targeted and immunotherapy agents in the treatment of primary and relapsed/refractory lymphomas, and their emerging role(s) in treatment regimens 2. Identify potential adverse events that may be associated with newer targeted and immunotherapies and how such adverse events may be adequately addressed to optimize patient outcome 3. Demonstrate an understanding of relevant clinical practice guidelines for lymphomas 4. Evaluate emerging treatment data in primary and relapsed/refractory lymphomas and its potential impact in clinical practice Financial Disclosure • Dr. Hamlin: • Consulting/Advisory Board: Genentech, Celgene, Gilead • Research Support: Seattle Genetics, Novartis, Molecular Templates, Portola, Janssen • Ms. Wisniewski has nothing to disclose. NHL Epidemiology in the United States • Most common hematologic cancer • Prevalence ~300,000 patients • ~80,900 new cases/year (2015) • ~20,940 deaths/year (2015) • From 2007–2011 NHL incidence rates increased slightly in men • Lifetime probability of developing NHL: 1:42 male, 1:52 female • Demographic shift accounts for most of increase NHL = non-Hodgkin lymphoma. American Cancer Society. Cancer Facts & Figures 2015, http://www.cancer.org/acs/groups/content/@editorial/documents/document/acspc-044552.pdf. WHO Classification of Lymphoid Neoplasms (2008) Precursor Indolent B Aggressive B Mature T/NK HL and PTLD • B lymphoBlastic leukemia/lymphoma • Chronic lymphocytic leukemia/ small • Mantle cell lymphoma • T-cell prolymphocytic leukemia • Hodgkin Lymphoma (HL) lymphocytic lymphoma • Diffuse large B-cell lymphoma • T-cell large granular lymphocytic leukemia • Nodular lymphocyte predominant • B lymphoBlastic leukemia/lymphoma, • B-cell prolymphocytic leukemia (DLBCL), NOS Hodgkin lymphoma NOS • Chronic lymphoproliferative disorder of NK-cells • Splenic marginal zone lymphoma • T-cell/histiocyte rich large B-cell • Aggressive NK cell leukemia • Classical Hodgkin lymphoma • B lymphoBlastic leukemia/lymphoma with lymphoma • Hairy cell leukemia • Systemic EBV positive T-cell lymphoproliferative • Nodular sclerosis classical Hodgkin recurrent genetic aBnormalities • Primary DLBCL of the CNS • Splenic lymphoma/leukemia, • disease of childhood lymphoma unclassifiable* • Primary cutaneous DLBCL, leg type • B lymphoBlastic leukemia/lymphoma with • Hydroa vaccineforme-like lymphoma • Lymphocyte-rich classical Hodgkin t(9;22)(q34;q11.2); BCR-ABL1 • Splenic diffuse red pulp small B-cell • EBV positive DLBCL of the elderly lymphoma lymphoma • Adult T-cell leukemia/lymphoma • DLBCL associated with chronic • Mixed cellularity classical Hodgkin • B lymphoBlastic leukemia/lymphoma with • Extranodal NK/T cell lymphoma, nasal type • Hairy cell leukemia-variant inflammation lymphoma t(v;11q23); MLL rearranged • Enteropathy-associated T-cell lymphoma • Lymphoplasmacytic lymphoma • Lymphomatoid granulomatosis • Lymphocyte depleted classical Hodgkin • B lymphoBlastic leukemia/lymphoma with• Waldenström’s macrogloBulinemia • Primary mediastinal (thymic) large B- • Hepatosplenic T-cell lymphoma lymphoma t(12;21)(p13;q22); TEL-AML1 (ETV6- • Heavy chain diseases cell lymphoma • SuBcutaneous panniculitis-like T-cell lymphoma • Post-Transplant Lymphoproliferative RUNX1) • Intravascular large B-cell lymphoma • Alpha heavy chain disease • Mycosis fungoides Disorders (PTLD) • B lymphoBlastic leukemia/lymphoma with • Gamma heavy chain disease • ALK positive large B-cell lymphoma • Sézary syndrome • Early lesions hyperdiploidy • Mu heavy chain disease • Plasmablastic lymphoma • Primary cutaneous CD30 positive T-cell • Large B-cell lymphoma arising in lymphoproliferative disorders • Plasmacytic hyperplasia • B lymphoBlastic leukemia/lymphoma with• Plasma cell myeloma HHV8-associated multicentric • Infectious mononucleosis-like PTLD hypodiploidy (hypodiploid ALL) • Solitary plasmacytoma of Bone • Lymphomatoid papulosis Castleman disease • Extraosseous plasmacytoma • Primary cutaneous anaplastic large cell lymphoma • Polymorphic PTLD • B lymphoBlastic leukemia/lymphoma with • Primary effusion lymphoma • Extranodal marginal zone lymphoma of • Primary cutaneous gamma-delta T-cell lymphoma • Monomorphic PTLD (B- and T/NK-cell t(5;14)(q31;q32); IL3-IGH • Burkitt lymphoma mucosa-associated lymphoid tissue • Primary cutaneous CD8 positive aggressive types) • B-cell lymphoma, unclassifiable, with • B lymphoBlastic leukemia/lymphoma with (MALT lymphoma) epidermotropic cytotoxic T-cell lymphoma • Classical Hodgkin lymphoma type t(1;19)(q23;p13.3); E2A-PBX1; (TCF3- • Nodal marginal zone lymphoma features intermediate between diffuse • Primary cutaneous CD4 positive small/medium T-cell PTLD large B-cell lymphoma and Burkitt PBX1) • Paediatric nodal marginal zone lymphoma lymphoma lymphoma • Peripheral T-cell lymphoma, NOS • T lymphoBlastic leukemia/lymphoma • B-cell lymphoma, unclassifiable, with • AngioimmunoBlastic T-cell lymphoma • Follicular lymphoma features intermediate between diffuse • Paediatric follicular lymphoma large B-cell lymphoma and classical • Anaplastic large cell lymphoma, ALK positive • Primary cutaneous follicle centre Hodgkin lymphoma • Anaplastic large cell lymphoma, ALK negative lymphoma ALL = acute lymphoBlastic leukemia; CNS = central nervous system; EBV = Epstein-Barr virus; HHV = human herpesvirus; NK = natural killer; NOS = not otherwise specified; WHO = World Health Organization. 2016 WHO Classification of Lymphoma Mature B-cell Neoplasms • Chronic lymphocytic leukemia /small lymphocytic lymphoma • Mantle cell lymphoma • Monoclonal B-cell lymphocytosis* • In situ mantle cell neoplasia* • B-cell prolymphocytic leukemia • Diffuse large B-cell lymphoma (DLBCL), NOS • Splenic marginal zone lymphoma • Hairy cell leukemia • Germinal center B-cell type* • Splenic B-cell lymphoma/leukemia, unclassifiaBle • Activated B-cell type* • Splenic diffuse red pulp small B-cell lymphoma • T cell/histiocyte-rich large B-cell lymphoma • Hairy cell leukemia-variant • Lymphoplasmacytic lymphoma • Primary DLBCL of the CNS • Waldenström macrogloBulinemia • Primary cutaneous DLBCL, leg type • Monoclonal gammopathy of undetermined significance (MGUS), IgM* • EBV positive DLBCL, NOS* • Mu heavy chain disease • EBV+ Mucocutaneous ulcer* • Gamma heavy chain disease • Alpha heavy chain disease • DLBCL associated with chronic inflammation • Monoclonal gammopathy of undetermined significance (MGUS), IgG/A* • Lymphomatoid granulomatosis • Plasma cell myeloma • Primary mediastinal (thymic) large B-cell lymphoma • Solitary plasmacytoma of Bone • Extraosseous plasmacytoma • Intravascular large B-cell lymphoma • Monoclonal immunogloBulin deposition diseases* • ALK positive large B-cell lymphoma • Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) • Plasmablastic lymphoma • Nodal marginal zone lymphoma • Primary effusion lymphoma • Pediatric nodal marginal zone lymphoma • Follicular lymphoma • HHV8 positive DLBCL, NOS* • In situ follicular neoplasia* • Burkitt lymphoma • Duodenal-type follicular lymphoma* • Burkitt-like lymphoma with 11q aberration* • Pediatric-type follicular lymphoma* • High grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 • Large B-cell lymphoma with IRF4 rearrangement* rearrangements* • Primary cutaneous follicle center lymphoma • High grade B-cell lymphoma, NOS* • B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin lymphoma 2016 WHO Classification of Lymphoma Mature T and NK Neoplasms • Primary cutaneous CD4 positive small/medium T-cell lymphoproliferative disorder* • T-cell prolymphocytic leukemia • Peripheral T-cell lymphoma, NOS • AngioimmunoBlastic T-cell lymphoma • T-cell large granular lymphocytic leukemia • Follicular T-cell lymphoma* • Chronic lymphoproliferative disorder of NK cells • Nodal peripheral T-cell lymphoma with TFH phenotype* • Anaplastic large cell lymphoma, ALK positive • Aggressive NK cell leukemia • Anaplastic large cell lymphoma, ALK negative* • Systemic EBV+ T-cell Lymphoma of childhood* • Breast implant-associated anaplastic large cell lymphoma • Hydroa vacciniforme-like lymphoproliferative disorder* Hodgkin Lymphoma • Adult T-cell leukemia/lymphoma • Nodular lymphocyte predominant Hodgkin lymphoma • Extranodal NK/T-cell lymphoma, nasal type • Classical Hodgkin lymphoma • Nodular sclerosis classical Hodgkin lymphoma • Enteropathy-associated T-cell lymphoma • Lymphocyte-rich classical Hodgkin lymphoma • Monomorphic epitheliotropic intestinal T-cell lymphoma* • Mixed cellularity classical Hodgkin lymphoma • Lymphocyte-depleted classical Hodgkin lymphoma • Indolent T-cell lymphoproliferative disorder of the GI tract * • Hepatosplenic T-cell lymphoma Post-Transplant Lymphoproliferative Disorders (PTLD) • Plasmacytic hyperplasia PTLD • SuBcutaneous panniculitis-like T-cell lymphoma • Infectious mononucleosis PTLD • Mycosis fungoides • Florid follicular hyperplasia PTLD* • Sézary syndrome • Polymorphic PTLD • Monomorphic PTLD (B- and T/NK-cell types) • Primary cutaneous CD30 positive T-cell lymphoproliferative disorders • Classical Hodgkin lymphoma PTLD • Lymphomatoid papulosis Histiocytic and Dendritic Cell Neoplasms • Primary cutaneous anaplastic large cell lymphoma • Histiocytic sarcoma • Primary cutaneous gamma-delta T-cell lymphoma • Langerhans cell histiocytosis • Langerhans