T-cell Lymphomas Biology and Management March-27-2017
Outline Epidemiology Initial Work-up International Prognostic Index Treatment of Diffuse Large B-cell Lymphoma: -Limited Stage -Advanced Stage Frontline: R-CHOP Relapse: PARMA, CORAL CNS prophylaxis PMBCL Testicular Lymphoma Paranasal Sinus Lymphoma
NHL Etiology Immune deficiency (Congenital or Acquired) Autoimmune disorders (e.g. Hashimoto s thyroiditis, Sjogren s syndrome, RA) Infectious agents HIV Helicobacter pylori (infection of stomach and MALT) EBV, Human T-cell leukemia virus, KS-associated Herpes virus Chemical and physical agents (e.g. pesticides) Dietary
Epidemiology
Non-Hodgkin Lymphoma PMLBCL 3% MZL-NT 1% ALCL 2% BL 2% PTCL 7% MALT 6% DLBCL 36% MCL 7% SLL 7% FL 26% ALCL = Anaplastic large cell lymphoma, BL= Burkitt s lymphoma, DLBCL = diffuse large B-cell lymphoma, FL = Follicular lymphoma, SLL = small lymphocytic lymphoma, MCL = Mantle cell lymphoma, MZL-NT = Nodal marginal zone lymphoma, PTCL = Peripheral T-cell lymphoma, MALT = Mucosa-associated lymphoid tissue, PMLBCL = Primary mediastinal large B-cell lymphoma. JCO 1998
WHO Classification (2016) of Lymphoid Neoplasms Swerdlow. Blood 2016 * Change from 2008
WHO Classification Peripheral T-cell Lymphoma Predominantly Nodal Peripheral TCL, NOS Angioimmunoblastic TCL Anaplastic large cell lymphoma, ALK+ Anaplastic large cell lymphoma, ALK- Predominantly Extranodal NK/T-cell lymphoma, nasal/ type Enteropathy-associated TCL Hepatosplenic TCL EBV+ T-cell LPD of childhood Predominantly Leukemic T-cell prolymphocytic leukemia T-cell LGL leukemia Chronic LPD of NK cells Aggressive NK-cell leukemia Adult T-cell leukemia/lymphoma Predominantly Cutaneous Mycosis Fungoides Primary cutaneous CD30+ T-cell LPD Primary cutaneous peripheral TCL Sezary syndrome Subcutneous Panniculitis-like TCL Primary cutaneous CD8+ cytotoxic TCL Primary cutaneous small/medium CD4+ TCL
PTCL
Initial Workup History and Physical: B symptoms LN Biopsy : excisional, core, FNA Laboratory: CBC, Chem, LDH HIV CT scans C/A/P with contrast PET scan Bone Marrow Biopsy: Flow, IHC, FISH, Cytogenetics MUGA, Echocardiogram MRI, LP if indicated B symptoms: Fever, drenching night sweats, > 10% unintentional weight loss in 6 months
Costwolds Modification of Ann Arbor Staging System PET PET/CT
Peripheral T-cell Lymphoma Heterogeneous group PTCL 10% of NHL Prognosis: - 5 year OS < 30% Untreated PTCL: CHOP, CHOEP ASCT in CR1 PTCL-NOS
Chromosomal translocations in NHL T(14;18)(q32;q21) T(11;18)(q21;q21) T(14;18)(q32;q21) T(1;14)(q22;q32) T(3;14)(p14.1;q32) T(11;14)(q13;q32) T(3;14)(q27;q32) T(14;18)(q32;q21) T(2;5)(p23;q35) Follicular Lymphoma MALT Lymphoma MALT Lymphoma MALT Lymphoma MALT Lymphoma Mantle cell Lymphoma DLBCL DLBCL ALCL, ALK+
Anaplastic Large cell Lymphoma t(2;5)(p23;q35) ALK Chromosome 2q23 Novel tyrosine kinase NPM Chromosome 5q35 Involved in ribosomal assembly Mechanism NPM-ALK fusion protein autophosphorylates the tyrosine kinase domain of ALK Incidence 40-60% of anaplastic large cell lymphomas
Anaplastic Large Cell Lymphoma
Anaplastic Large Cell Lymphoma
NPM/ALK Translocation
ALK Fusion Proteins in ALK+ ALCL Falini B. Br J Haematol. 2001 Sep;114(4):741-60.
T-cell subtypes Registry PTCL NOS AITL ALCL, ALK + ALCL, ALK NK/T ATL EATL IPTCL (NA) 34% 16% 16% 8% 5% 2% 6% BCCA 59% 5% 6% 9% 9% NA* 5% COMPLETE 34% 15% 11% 8% 6% 2% 3% Vose JM, et al. J Clin Oncol. 2008;26:4124-4130 Savage, K.J., et al.. Ann Oncol,2004.15(10): 1467-75. Foss, F.M., et al., Blood, 2012. 120(21).
International Prognostic Index IPI (APLES): -Age > 60 -Performance Status 2 -LDH > ULN -Extranodal sites > 1 -Stage III-IV Risk model No. of factors Distribution of cases (%) 5-year OS (%) CR rate (%) Low 0-1 49 73 87 Low-intermediate 2 31 51 67 High-intermediate 3 15 43 55 High 4-5 5 26 55 The International Non-Hodgkin s Lymphoma Prognostic Factors Project. N Engl J Med1993; 329:987-994.
PFS in PTCL: Swedish National Registry ALK+ ALCL TCL U ALK ALCL ALK U ALCL AITL PTCL NOS Fredrik Ellin et al. Blood 2014;124:1570-1577
Question 1 For a fit patient with newly diagnosed PTCL, in the absence of a clinical trial, what is your preferred initial treatment approach? 1. CHOP 2. CHOEP 3. EPOCH 4. CHOEP or EPOCH-HDT-ASCT 5. CHOEP or EPOCH-Allo SCT 6. Something else
CHOP Based Treatment for Mature T Cell and NK Cell Lymphomas Always Anaplastic Large Cell ALK 1 positive Never Mycosis fungoides Sezary syndrome Sometimes Peripheral T cell lymphoma NOS AngioimmunoblasticT cell lymphoma Anaplastic Large Cell ALK 1 positive Enteropathy type intestinal lymphoma Subcutaneous panniculitis like T cell Primary cutaneous CD30+ disorders Anaplastic large cell lymphoma Lymphomatoid papulosis T cell large granular lymphocytic Extranodal NK /T cell lymphoma nasal Hepatosplenic T cell lymphoma NK /T cell leukemia / lymphoma AdultT cell leukemia / lymphoma T cell prolymphocytic leukemia
Patients (%) Patients (%) Patients (%) Adding Etoposide to CHOP: German Prospective High-Grade NHL Studies 100 100 Etoposide (n = 34) 80 6 x CHOEP-14/21 (n = 42) 80 60 40 6 x CHOP-14/21 (n = 41) EFS, aged < 60 yrs 60 40 Non-etoposide (n = 12) EFS, ALCL, ALK+ 20 P =.003 0 0 10 20 30 40 50 60 70 80 90 100 110 Mos PTCL Subtype n ALCL, ALK+ 78 ALCL, ALK 113 PTCL NOS 70 AITL 28 Other 31 Total 320 100 80 60 40 20 0 20 0 0 10 20 30 40 50 60 70 80 90 100 110 P =.057 P =.012 Etoposide (n = 69) Non-etoposide (n = 29) 0 10 20 30 40 50 60 70 80 90 100 110 Mos Mos EFS, other subtypes Schmitz N, et al. Blood. 2010;116:3418 3425.
ALCL: OS based on genetic subtype Parrilla Castellar E R et al. Blood 2014;124:1473 1480
Prognosis by Interim PET PFS by Interim PET ASCT ITT; PFS by Interim PET/IPI N=61 % EFS CR IPI 0-2 CR IPI >2 No CR IPI 0-2 No CR - High IPI >2 2 yrs 3 yrs 5 yrs 78.9 66.2 66.2 52.7 52.7 52.7 32.3 21.5 21.5 26.7 10.0 10.0 Casulo et al., Leukemia & Lymphoma 2013; 54(10): 2163 2167 Mehta et al. Clin Leuk Lym 2013;13(6):664 70
Brentuximab vedotin (BV) Beyond Relapsed ALCL PTCL (Relapsed) 1 Best Clinical Response Overall Response CR n (%) PR n (%) SD n(%) PD n (%) CR + PR n (%) Mature T /NK cell (n=34) 8 (24) 6 (18) 6 (18) 14 (41) 14 (41) AITL (n=13) 5 (38) 2 (15) 3 (23) 3 (23) 7 (54) PTCL NOS (n=21) 3 (14) 4 (19) 3 (14) 11 (52) 7 (33) Front Line: BV + cyclophosphamide, doxorubicin and prednisone (CHP) 2 ALCL N (%) Other N (%) Total N (%) PFS N=26 Median F/U 21.4 mos Est 1 yr PFS 71% ORR 19 (100) 7 (100) 26 (100) CR 16 (84) 7 (100) 23 (88) PR 3 (16) -- 3 (12) 1. Horwitz S M et al. Blood 2014;123:3095 3100 2. Fanale et al JCO 2014:3137 3143;
Question 2 For a fit patient with relapsed PTCL, in the absence of a clinical trial, what is your preferred initial treatment approach? 1. ICE or DHAP-ASCT 2. Single agent until progression 3. ICE or DHAP-Allo SCT 4. Single agent followed by Allo
Autologous stem cell transplantation as first line therapy in PTCL 166 pts enrolled Histologies: PTCL NOS (39%) Alk- ALCL (19%) AITL (19%) EATL Outcomes, (13%) % 5-year PFS 44% Induction: CHOEP x 6 115 pts autohct Results: 5 yr PFS and OS = 51% Median Follow-up of 10 years Alk- ALCL has best survival All Patients, ITTP ALK-negative ALCL N= 160 N=31 PFS by histology OS 41 48 PFS 38 48 Gisselbrecht C et al. J Clin Oncol. 2010 Sep 20;28(27):4184-90
HSCT for PTCL Autologous HSCT more efficacious in early disease CR1 pts have better outcomes compared to >CR1 pts Moderately better PFS/OS than population based series with CHOP 30-50% pts do not reach transplant mainly due to PD Does autosct as consolidation improve results or just selecting for healthier people with chemosensitive disease? Myeloablative allogeneic SCT associated with high TRM Reduced intensity conditioning promising Histologies to consider for allosct in CR1/PR1 Hepatoplenic T cell Enteropathy associated T cell Gamma delta T cell
Relapsed/Refractory PTCL
Autologous Transplantation in Relapsed PTCL CIBMTR: PFS excluding pt in CR1 (Most patients ALCL) The Stanford Experience Auto MSKCC 1.0 Median PFS 6 months 0.8 0.6 % 0.4 0.2 0 12 24 36 48 60 72 84 96 108 120 132 PFS ICE months Response to ICE 70% (28/40) Received ASCT 68% (27/40) Benefits are unclear. Most single institution studies show low PFS rates while registry data suggests better outcomes Smith S, et al. JCO September 1, 2013 vol. 31 no. 25 3100 3109 Chen AI, et al. Biol Blood MarrowTransplant. 2008;14(7):741 747. Horwitz et al, ASHAnnual Meeting Abstracts 2005;106:2679. 0.0
Allogeneic Transplantation in T-cell lymphoma N=65 2Year OS: 59% 2Year PFS: 48% Median PFS 20.26 mo N. Mehta Shah et al ASH 2015
FDA approved Agents for TCL Overall Response Rate (%) Philip T, et al. N Engl J Med. 1995 Dec 7;333(23):1540-5
FDA approved Agents for TCL Subtype Pralatrexate Romidepsin Belinostat Brentuximab vedotin PTCL, NOS 31 29 23 33 AITL 8 30 46 54 ALCL 29 24 15 86 O Connor OA, et al. J Clin Oncol. 2011;29:1182-1189 Coiffier B, et al. J Clin Oncol. 2012;30:631-636 O Connor OA et al, ASCO 2013; Horwitz, S et al ICML 2013 Pro B, et al. J Clin Oncol. 2012;30:2190-2196 Horwitz S M et al. Blood 2014;123:3095-3100
Brentuximab vedotin (BV) Relapsed ALCL ORR= 86% CR= 57% Pro B et al. J Clin Oncol. 2012 Jun 20;30(18):2190-6
Anaplastic Large-Cell Lymphoma
Question #1 A 43-year-old man presents with cervical adenopathy. Evaluation of a biopsy specimen indicates anaplastic large cell lymphoma. Neoplastic cells are positive for CD30 and ALK but negative for CD20 and PAX5. Staging studies show stage IV disease with bone marrow involvement.
Question #1 (continued) Which of the following markers is the most likely to be associated with better outcome in this patient? Expression of ALK Expression of CD30 Lack of CD20 expression Lack of t(2;5) Lack of PAX5 expression
Explanation Anaplastic large-cell lymphoma is a distinct clinical entity and is composed of large anaplastic cells expressing CD30. B-cell markers such as CD20 and PAX5 are absent. CD30, although an important marker in the diagnosis and treatment of relapsed disease (with brentuximab vedotin), is not prognostic. However, ALK-positive anaplastic large-cell lymphoma is associated with excellent outcomes when treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), with the majority of patients cured from the disease, even patients with high-stage disease according to the international prognostic index. ALK expression is associated with a characteristic chromosomal translocation, t(2;5)(p23;q35), resulting in a fusion gene, NPM-ALK, encoding a chimeric protein with tyrosine kinase activity. Hence, the presence of t(2;5) is a marker of ALK positivity and is associated with a good prognosis. In contrast, the outcomes for patients with ALK-negative anaplastic large-cell lymphoma are poor and similar to those for patients with peripheral T-cell lymphoma.
Peripheral T Cell Lymphoma
Question #1 A 52-year-old man with a history of well-controlled hypertension presents with progressive sweats over the past 3 months associated with a 10-lb (4.5- kg) weight loss. Initial evaluation is notable for bilateral axillary and left inguinal adenopathy. Evaluation of the left inguinal lymph node, obtained with excisional biopsy, indicates diffuse proliferation of medium-to-large cells that are positive for CD2, CD3, and CD4 but negative for CD7 and ALK. The large cells stain brightly for CD30. Computed tomography images of the chest, abdomen, and pelvis show lymph nodes on both sides of the diaphragm, with the largest ones measuring 2 to 3 cm. Evaluation of a bone marrow biopsy sample indicates normal trilineage hematopoiesis without lymphoma. Results from laboratory studies, including a complete blood cell count and chemistry panel, are within normal parameters. A serum lactate dehydrogenase level is nearly twice the upper limit of normal
Question #1 (continued) Which of the following is the best treatment for this patient? Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) Brentuximab vedotin plus CHOP Cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone (CHOEP) Anthracycline-based chemotherapy plus a consolidative allogeneic stem cell transplant
Explanation The patient in this clinical scenario has a nodal peripheral T-cell lymphoma (PTCL). On the basis of the available histology and immunophenotypic markers, he most likely has ALK-negative anaplastic large-cell lymphoma (ALCL) or PTCL not otherwise specified (NOS) with associated CD30 + expression. ALCL is a type of PTCL that may or may not be associated with ALK expression due to t(2;5) rearrangement. ALK-negative ALCL is characterized by sheets of monomorphic CD30 + T cells without ALK expression but is histologically identical to ALK-positive ALCL. Patients with ALK-positive ALCL tend to be younger and have a more favorable outcome than patients with ALK-negative ALCL. PTCL-NOS is a provisional category in the 2008 World Health Organization classification that is likely to be further subdivided as advances in gene expression profiling and other molecular techniques refine our ability to identify subgroups. ALK-negative ALCL can often be difficult to distinguish from PTCL-NOS, which can have CD30 + overexpression in more than half of cases.
Explanation (continued) Given the lack of large prospective trials in the frontline setting, initial management of T-cell lymphomas is based on the aggregate experience with aggressive B-cell lymphomas, in which the standard backbone is cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). Unfortunately, CHOP is not nearly as effective in T-cell histologies, with only one-third of patients remaining progression-free 1 year after treatment. Because of these suboptimal outcomes with CHOP, two approaches include the incorporation of etoposide into frontline treatment (CHOEP) and the inclusion of consolidative autologous, not allogeneic, stem cell transplantation. The use of CHOEP as frontline management for young patients comes from an unplanned analysis of patients included in prospective trials of CHOP vs CHOEP by German cooperative groups. In these studies, the addition of etoposide was associated with a progression-free survival benefit for patients younger than 60 years of age. Prospective data also support the safety and feasibility of CHOEP followed by consolidative autologous hematopoietic cell transplant. Although there are no comparative data for autologous hematopoietic cell transplant vs chemotherapy alone, the findings of several phase 2 trials suggest an improved progression-free and overall survival. Consolidative allogeneic stem cell transplant remains investigational. Brentuximab vedotin is an antibody-drug conjugate approved for use in patients with relapsed ALCL, Hodgkin lymphoma, and other CD30 + T-cell lymphomas. It is being tested in frontline regimens. However, because the major toxicity is peripheral neuropathy, a large ongoing trial uses brentuximab vedotin to replace vincristine, which is being compared with CHOP.