Non-Hodgkin Lymphoma Luciano J. Costa MD, PhD
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1 Non-Hodgkin Lymphoma Luciano J. Costa MD, PhD Assistant Professor Department of Medicine Division of Hematology and Oncology Medical University of South Carolina
2 Objectives Discuss the molecular basis of the current classification of non-hodgkin lymphomas (NHL). Review the principal types of NHL and their prognosis Review therapeutic principles and current questions in the management of the common types of NHL Discuss key epidemiological, prognostic and therapeutic features of the less common types of NHL
3 2008 WHO classification of NHL B small lymphocytic lymphoma Splenic marginal zone lymphoma Lymphoplasmacytic lymphoma / Waldenstrom macroglobulinemia Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type Nodal marginal zone lymphoma Follicular lymphoma Primary cutaneous follicular lymphoma Mantle cell lymphoma Diffuse large B-cell lymphoma, NOS (T-cell / histiocyte-rich type; primary CNS type ; primary leg skin type & EBV+ elderly type) Diffuse large B-cell lymphoma with chronic inflammation Primary mediastinal large B-cell lymphoma Intravascular large B-cell lymphoma ALK+ large B-cell lymphoma Plasmablastic lymphoma Large B-cell lymphoma associated with HHV8+ Castleman disease Primary effusion lymphoma Burkitt lymphoma B cell lymphoma, unclassifiable, Burkitt-like B cell lymphoma, unclassifiable, Hodgkin lymphomalike T Adult T-cell lymphoma/leukemia Extranodal T-cell/NK-cell lymphoma, nasal type Enteropathy-associated T-cell lymphoma Hepato-splenic T-cell lymphoma Subcutaneous panniculitis-like T-cell lymphoma Mycosis fungoides Sézary syndrome Primary cutaneous CD30+ T-cell lymphoproliferative disorder Primary cutaneous gamma-delta T-cell lymphoma Peripheral T-cell lymphoma, NOS Angioimmunoblastic T-cell lymphoma Anaplastic large cell lymphoma, ALK+ type Anaplastic large cell lymphoma, ALK- type Infectious mononucleosis like PTLD Polymorphic PTLD Monomorphic PTLD (B & T/NK cell types)
4 Modern Diagnosis and Classification of NHL Morphology Flow-cytometry Metaphase Cytogenetics Immunohistochemistry FISH Lichtman MA et al. Lichtman s Atlas of Hematology
5 Lymphoma incidence in the US B-cell 92.0% CLL/SLL 25.3% Lymphoplasmacytic 3.1% Mantle 2.5% Burkitt 1.6% T-cell 8.0% Follicular 16.0% DLBCL 36.2% B- NOS 7.3% MF/SS 2.6% T/NK 2.2% PTCL-NOS 1.5% Angioimmunoblastic 0.3% Anaplastic 1.3% Most NHL are B-Cell derived DLBCL is the most common Blood 107:265, 2006
6 Ann Arbor staging
7 5 years survival 85.6% 85.6% 71.4% 63.8% 52.6% 47.9% 44.7% Follicular Marginal zone CLL/SLL lymphoplasmacytic Mantle cell DLBCL Burkitt There was recent increase in incidence of NHL Survival in DLBCL remains low
8 Diffuse Large B Cell Lymphoma CD 45 H&E 20x Courtesy of Dr. Carl Buckner Hem Path CD 20
9 PET-CT is desirable at diagnosis and essential at restaging
10 No combination chemotherapy has been proven superior to CHOP (cyclophosphamide, doxorubicin, vincristin and prednisone) N Engl J Med 328:1002, 1993
11 Gene microarray profiling defines subtypes of DLBCL N Engl J Med 346:1937, 2002
12 Blood 103:275, 2004
13
14 Probability Rituximab adds to CHOP and increases the chance of cure in DLBCL CHOP RCHOP N Engl J Med 346:235, 2002 J Clin Oncol 24:3121, 2006 Lancet Oncol 7:379, 2006
15 The Revised International Prognostic Index Blood 109:1857, 2007
16 Autologous HSC is superior to standard chemotherapy in relapsed and refractory DLBCL N Engl J Med 333:154, 1995
17 SALVAGE THERAPY IN THE RITUXIMAB ERA
18 Probability of Survival, % Probability of Survival after Autologous Transplants for Diffuse Large B-Cell Lymphoma, By Disease Status P < Sensitive (N=6,337) Resistant (N=453) Years Slide 37 SUM-WW11_36.ppt
19 Graft-versus lymphoma effect can overcome chemotherapy resistance in DLBCL J Clin Oncol 27:426, 2009
20 Probability of Survival, % Probability of Survival after Allogeneic Transplants for Diffuse Large B-Cell Lymphoma, By Disease Status P < Sensitive (N=383) Resistant (N=124) Years Slide 38 SUM-WW11_37.ppt
21 FOLLICULAR LYMPHOMA Normal reactive lymph node Follicular Lymphoma
22 Follicular Lymphomas Express Bcl-2 t(14;18) Follicular Lymphoma Normal Reactive Follicle Warnke et al
23 Warnke et al Follicular Lymphoma Grading Grade I 0-5 centroblasts/hpf Grade II 6-15 centroblasts/hpf Grade III >15 centroblasts/hpf Centrocytes Mixed Centroblasts Small cleaved follicle cells large blastic follicle cells
24 FLIPI- Follicular Lymphoma International Prognostic Index Score Prognosis % Patients OS (10 yr) 0-1 good moderate poor Solal-Céligny et al.
25
26 Age > 60 LoDLi >6 cm Anemia (<12g/dL) B2microglobulin (> ULN) Bone Marrow involvement FLIPI 2 (A) Progression-free survival (PFS) and (B) overall survival (OS) of the training sample (832 patients) according to the Follicular Lymphoma International Prognostic Index 2 (FLIPI2); (C) PFS and (D) OS of the validation sample (231 patients) Federico M et al. JCO 2009;27:
27 THERAPEUTIC PRINCIPLES Indolent, Incurable (?) Stage I, selected stage II (uncomon) Radiation with curative intent Advanced stage (majority of patients) Watch and wait Immunotherapy (Rituximab) Combined Chemoimmunotherapy R-CHOP R-Bendamustine R-CVP R-FCM Radioimmunotherapy Zevalin Bexxar
28 LymphoCare JCO 27:1202, 2009
29 FL- MAINTENANCE THERAPY
30 RELAPSED DISEASE Immunotherapy (Rituximab) Chemotherapy Chemoimmunotherapy Radioimmunotherapy Autologous stem cell transplantation Allogeneic stem cell transplantation Scarceness of comparative data
31 AUTOLOGOUS TRANSPLANTATION IN FL Median FU 13.5 years JCO 25:2554, 2007
32 Probability of Survival, % Probability of Survival after Autologous Transplants for Follicular Lymphoma, By Disease Status P < Sensitive (N=2,030) Resistant (N=172) Years Slide 35 SUM-WW11_34.ppt
33 Probability of Survival, % 100 Probability of Survival after HLA-identical Sibling Donor Transplants for Follicular Lymphoma, By Disease Status P < Sensitive (N=698) Resistant (N=144) Years Slide 36 SUM-WW11_35.ppt
34 MANTLE CELL LYMPHOMA Recently recognized entity Typically advanced stage Frequent extra-nodal involvement (GI) Male predominance (3:1)
35 MIPI score = age (y) (if ECOG > 1) log10(ldh/uln) log10(wbcs per 10 6 L). MCL PROGNOSIS
36 MCL TREATMENT Watch and wait in selected cases Conventional chemoimmunotherapy inferior R-CHOP R-FCM Intense chemoimmunotherapy HyperCVAD/MTX-AraC R-CHOP->R-DHAP Conventional chemoimmunotherapy + Autologous
37 MCL RELAPSED Bortezomib Lenalidomide mtor inhibitors Bendamustine Autologous transplantation Allogeneic transplantaion
38 Probability of Survival, % Probability of Survival after Transplants for Mantle Cell Lymphoma, By Donor Type P < Autologous (N=2,574) Sibling donor (N=498) Unrelated donor (N=325) Years Slide 39 SUM-WW11_38.ppt
39 CUTANEOUS T CELL LYMPHOMA Variable presentation and clinical course Incurable Initial management with skin directed therapies Systemic therapy for visceral or widespread disease Late participation of Hematologist/Medical Oncologist in care
40 PERIPHERAL T CELL LYMPHOMA Foss F M et al. Blood 2011;117:6756
41 PTCL TREATMENT Combination chemotherapy CHOP Combination chemotherapy + autologous transplantation Danileukin diftitoxin Praletrexate ALK inhibitors Brentuximab-vedotin
42 THE BEST OF THE REST B small lymphocytic lymphoma Splenic marginal zone lymphoma Lymphoplasmacytic lymphoma / Waldenstrom macroglobulinemia Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type Nodal marginal zone lymphoma Follicular lymphoma Primary cutaneous follicular lymphoma Mantle cell lymphoma Diffuse large B-cell lymphoma, NOS (T-cell / histiocyte-rich type; primary CNS type ; primary leg skin type & EBV+ elderly type) Diffuse large B-cell lymphoma with chronic inflammation Primary mediastinal large B-cell lymphoma Intravascular large B-cell lymphoma ALK+ large B-cell lymphoma Plasmablastic lymphoma Large B-cell lymphoma associated with HHV8+ Castleman disease Primary effusion lymphoma Burkitt lymphoma B cell lymphoma, unclassifiable, Burkitt-like B cell lymphoma, unclassifiable, Hodgkin lymphomalike T Adult T-cell lymphoma/leukemia Extranodal T-cell/NK-cell lymphoma, nasal type Enteropathy-associated T-cell lymphoma Hepato-splenic T-cell lymphoma Subcutaneous panniculitis-like T-cell lymphoma Mycosis fungoides Sézary syndrome Primary cutaneous CD30+ T-cell lymphoproliferative disorder Primary cutaneous gamma-delta T-cell lymphoma Peripheral T-cell lymphoma, NOS Angioimmunoblastic T-cell lymphoma Anaplastic large cell lymphoma, ALK+ type Anaplastic large cell lymphoma, ALK- type Infectious mononucleosis like PTLD Polymorphic PTLD Monomorphic PTLD (B & T/NK cell types)
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