UPDATE ON PERIPHERAL T-CELL LYMPHOMA by Patients- Against-Lymphoma

Peripheral T-cell Lymphoma: Current State of Knowledge Regarding Diagnosis, Staging, and Treatment EDITOR, JAMES O. ARMITAGE, MD AUTHOR, KIERON DUNLEAVY, MD PROGRAM OVERVIEW This chapter update focuses on the diagnosis, staging and treatment of rare lymphomas and includes updates on the World Health Organization classiﬁcation system, review of results from recently completed clinical trials, and discussion of contemporary knowledge regarding the role of diagnostic and prognostic factors in the treatment of patients with peripheral T-cell non-Hodgkin’s lymphomas.

Jointly sponsored by the Elsevier Ofﬁce of Continuing Medical Education and Carus Clinical Communications. This activity is supported by an educational grant from Allos Therapeutics, Inc.

ABELOFF PERIPHERAL T-CELL LYMPHOMA CHAPTER UPDATE

ACCREDITATION STATEMENT This educational activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Elsevier Office of Continuing Medical Education (EOCME) and Carus Clinical Communications. The EOCME is accredited by the ACCME to provide continuing medical education (CME) for physicians. CREDIT DESIGNATION STATEMENT The EOCME designates this educational activity for a maximum of 2.0 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity. All other health care professionals completing continuing education credit for this activity will be issued a certificate of participation. FACULTY PROFILES & DISCLOSURE INFORMATION As a sponsor accredited by the ACCME, it is the policy of the EOCME to require the disclosure of anyone who is in a position to control the content of an educational activity. All relevant financial relationships with any commercial interests and/or manufacturers must be disclosed to participants at the beginning of each activity. The faculty of this educational activity discloses the following: James O. Armitage, MD Joe Shapiro Professor, Section of Hematology/Oncology, Department of Internal Medicine University of Nebraska Medical Center, Omaha, Nebraska Disclosures: Advisory Board: Seattle Genetics; Ziopharm Independent Data Monitoring Committee: Biogen Idec Consultant: Allos Therapeutics, Inc. Kieron Dunleavy, MD Investigator and Attending Physician, Lymphoma Section, Metabolism Branch, National Cancer Institute, Bethesda, Maryland. Disclosures: Nothing to disclose Mary Ellen Shepard, PhD—Medical Writer Disclosures: Nothing to disclose Robert Reina, MS, MBA—Educational Reviewer Disclosures: Nothing to disclose EOCME Staff Disclosures: The following EOCME staff have nothing to disclose: Tania Dickson, PhD Jennifer DiBenedetto, EdM Sandy Breslow, B.Sc. RESOLUTION OF CONFLICT OF INTEREST The EOCME has implemented a process to resolve conflict of interest for each CME activity. In order to help ensure content objectivity, independence, and fair balance, and to ensure that the content is aligned with the interest of the public, the EOCME has resolved the conflict by external content review.

ABELOFF PERIPHERAL T-CELL LYMPHOMA CHAPTER UPDATE

UNAPPROVED/OFF-LABEL USE DISCLOSURE The EOCME requires CME faculty to disclose to the participants: 1. When products or procedures being discussed are off-label, unlabeled, experimental, and/or investigational (not US Food and Drug Administration [FDA] approved); and 2. Any limitations on the information presented, such as data that are preliminary or that represent ongoing research, interim analyses, and/or unsupported opinion. Faculty may discuss information about pharmaceutical agents that is outside of FDA-approved labeling. This information is intended solely for CME and is not intended to promote off-label use of these medications. If you have questions, contact the medical affairs department of the manufacturer for the most recent prescribing information. INTENDED AUDIENCE This program is intended for hematologists, oncologists, and health care providers responsible for the care of patients with peripheral T-cell non-Hodgkin’s lymphoma. EDUCATIONAL OBJECTIVES After reading this publication and taking the post-test, participants should be able to: 1. Cite the incidence and prevalence of peripheral T-cell non-Hodgkin’s lymphomas as well as differentiate between the subsets of cancers that comprise this designation 2. Describe the epidemiology and the underlying causes (where known) of the various peripheral T-cell lymphomas 3. Identify the appropriate diagnostic and prognostic criteria necessary for the diagnosis and staging of the various peripheral T-cell lymphomas 4. Formulate an appropriate treatment plan based on appraisal of the benefits and limitations of current and future treatment options for patients with peripheral T-cell lymphomas Release Date of Activity: May 2010 Expiration Date of Activity for AMA PRA Credit: May 31, 2011 Estimated Time to Complete is Activity: 2.0 hour CME INQUIRIES For all CME certificate inquiries, please contact Tristan Nelsen at t.nelsen@elsevier.com. FINANCIAL SUPPORT This activity has been supported by an educational grant from Allos Therapeutics, Inc. Allos Therapeutics, Inc. had no role in developing the content or in faculty selection for this program. OUTCOMES PARTICIPATION To better define and meet the CME needs of health care professionals and enhance future CME activities, the EOCME will conduct an outcomes-measurement survey following the conclusion of the program. This follow-up survey is designed to measure changes to attendees’ practice behaviors that are a result of their participation in this CME activity. You will be contacted by email 30 days following the conclusion of this activity with an outcomes-measurement survey. We would greatly appreciate your participation. © 2010 Elsevier

ABELOFF PERIPHERAL T-CELL LYMPHOMA CHAPTER UPDATE UNDERSTANDING THE REVISED WORLD HEALTH ORGANIZATION CLASSIFICATION SYSTEM

INTRODUCTION Peripheral T-cell lymphomas (PTCLs) represent approximately 12% of lymphomas.1 The incidence of PTCL increases with age, has a higher incidence in men with a male-to-female ratio of about 1.8:1, and is dependent upon geographic location.2 Worldwide, the incidence of PTCL varies geographically from 4% in Vancouver to 21% in Hong Kong. Based on data from the US Surveillance, Epidemiology, and End Results program, among 13 geographically distinct registries in the United States, the incidence of PTCL is highest among American Indians and Alaska natives and lowest in Utah. For some subtypes of PTCL, the incidence is higher in blacks, Asians, or Pacific Islanders than in whites. The incidence of PTCL has increased significantly in the past 2 decades.2 In the United States, during the period between 1992 and 2005, the incidence of PTCL increased 7.9% annually.2 Of note, more than 50% of PTCL cases present with stage III or IV disease.2-4 In the United States, 5-year relative survival rates for PTCL remain poor, ranging from 29% to 48%.2 PTCL includes a heterogeneous group of at least 14 distinct T-cell lymphomas that differ significantly in pathobiology and response to treatment. Due to the rarity and heterogeneity of this entity, PTCL remains poorly understood and for many subtypes optimal therapies are lacking and there is no consensus on treatment. With the exception of patients with anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma, who have an excellent outcome with anthracycline-based chemotherapy, most other PTCL patients have poor outcomes with current treatment strategies and should be considered for enrollment into clinical trials. In 2001, the World Health Organization (WHO) published the third edition of the Classification of Tumours of Haematopoietic and Lymphoid Tissues, which was the first worldwide consensus on the classification of these tumors, including PTCL.5 Recently, in 2008, an updated fourth edition of this WHO Classification was published. However, since the publication of the fourth edition in 2008, several studies have shed new light on the understanding and treatment of PTCL. Here we provide an updated review that highlights the recent findings which contribute to the current understanding of the epidemiology, pathophysiology, role of diagnostic and prognostic markers, and novel therapies for the treatment of PTCL by subtype.

PTCL constitutes a heterogeneous group of diseases with distinct clinical characteristics, presentation, and outcomes. Agreement between experts is poor for many lymphoma subtypes and misdiagnosis is common.4,6,7 In a retrospective study, the rate of misdiagnosis of PTCL was approximately 10%.6 In this analysis, experienced pathologists misdiagnosed at a rate of 11.2% compared with a non-hematologist group, who misdiagnosed 24.4% of cases. Pathology findings from the International T-Cell Lymphoma Project revealed a similar rate of misdiagnosis of 10.4%.4 However, misdiagnosis varied significantly depending on PTCL subtype. The most frequently misdiagnosed subtypes were hepatosplenic, ALK-negative anaplastic large cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, and anaplastic large cell lymphoma. In the revised fourth edition of the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, PTCL nodal and extranodal disease included: PTCL-not otherwise specified (NOS); angioimmunoblastic T-cell lymphoma; adult T-cell leukemia/lymphoma; anaplastic large cell lymphoma; extranodal natural killer (NK)/T-cell lymphoma, nasal type; enteropathy-associated T-cell lymphoma; and subcutaneous panniculitis-like T-cell lymphoma.5 Hepatosplenic T-cell lymphoma is classified as an extranodal and systemic disorder.5 Subtypes of PTCL were further defined based on new clinical, pathological, immunophenotypic, or genetic findings (Table 1).8 In the 2008 edition, classification of angioimmunoblastic T-cell lymphoma includes information on its association with follicular helper T cells of the germinal center.5 The follicular variant of PTCL-NOS shares a similar phenotype to angioimmunoblastic T-cell lymphoma, but not genetic or clinical characteristics.8 The WHO 2008 classification recognizes that further clarification is needed between angioimmunoblastic T-cell lymphoma with limited paracortical involvement and the follicular variant of PTCL-NOS.5 Enteropathy-associated T-cell lymphoma has been redefined using more restrictive criteria and was renamed from enteropathy-type T-cell lymphoma. The disease often presents with intestinal perforation, an aggressive clinical course, and has a poor prognosis. It has a broad morphological spectrum and adjacent mucosa often 4

ABELOFF PERIPHERAL T-CELL LYMPHOMA CHAPTER UPDATE

TABLE 1. SUMMARY OF KEY UPDATES TO THE 2008 WHO CLASSIFICATION OF PTCL5 PTCL Subtype Update AITL

Follicular helper T-cell involvement now recognized; follicular variant of PTCL-NOS has similar phenotype

EATL

Renamed from enteropathy-type T-cell lymphoma; a variant is classiﬁed as type II EATL with distinct immunophenotype with CD56+, CD8+, and CD4- and MYC ampliﬁcations

ALCL

Classiﬁed as ALK+ and ALK-; ALK- is new provisional entity that lacks the ALCL kinase protein and has a poor prognosis; ALK- is PAX5 and CD15 negative

SPTCL

Disease is restricted to ab subtype only

PTCL, peripheral T-cell lymphoma; AITL, angioimmunoblastic T-cell lymphoma; NOS, not otherwise speciﬁed; EATL, enteropathy-associated T-cell lymphoma; ALCL, anaplastic large cell lymphoma; ALK, anaplastic lymphoma kinase; SPTCL, subcutaneous panniculitis-like T-cell lymphoma.

an ab T-cell phenotype are distinct from those with a ɣδ phenotype differing in their clinicopathologic ﬁndings and prognosis.10 Patients with ab subcutaneous panniculitislike T-cell lymphoma had a signiﬁcantly better prognosis than those with ɣδ subcutaneous panniculitis-like T-cell lymphoma with 5-year overall survival rates of 82% versus 11%, respectively. The ɣδ subcutaneous panniculitis-like T-cell lymphoma is now referred to as a cutaneous ɣδ T-cell lymphoma.

shows villous atrophy. Diagnosis relies on evidence of celiac disease either genetically by determination of a human leukoctye antigen phenotype or by histology in the adjacent uninvolved small bowel mucosa.8 In cases where monomorphic medium-sized cells are present, the disease is subclassified as type II enteropathy-associated T-cell lymphoma.5 Type II enteropathy-associated T-cell lymphoma has a distinct immunophenotype that is now recognized as also being CD56+, CD8+, and CD4-. The classical enteropathy-associated T-cell lymphoma often has gains in 1q and 5q, whereas type II enteropathyassociated T-cell lymphoma is characterized by MYC amplifications. Anaplastic large cell lymphoma is now classified into ALK-positive and ALK-negative disease. ALKnegative disease is now a provisional entity that is similar to ALK-positive disease in terms of morphology, phenotype, and genotype, but lacks the anaplastic large cell lymphoma kinase protein.5 ALK-negative disease generally has a poorer prognosis than ALK-positive disease. However, unlike Hodgkin lymphoma, ALK-negative anaplastic large cell lymphoma is negative for both PAX5 and CD15. The diagnostic criteria for subcutaneous panniculitislike T-cell lymphoma were redefined because of significant differences in the clinical course of the disease based on T-cell receptor phenotype and immunophenotye (Table 2). The WHO classification now restricts the disease to include only cases that express the T-cell receptor ab phenotype.9 The European Organization for Research and Treatment of Cancer Cutaneous Lymphoma Group reported on a study of 83 cases of subcutaneous panniculitislike T-cell lymphoma. The study demonstrated that subcutaneous panniculitis-like T-cell lymphomas with

NOVEL TARGETS FOR THE TREATMENT OF PTCL UNDER INVESTIGATION IN CLINICAL TRIALS A signiﬁcant effort has been made to identify novel targets for the treatment of PTCL and a number of targeted therapies are currently under investigation in clinical trials for the treatment of PTCL (Table 3). These agents include targeted humanized antibodies, folate antagonists, immunomodulatory agents, histone deacetylase inhibitors, and proteasome inhibitors, which target a variety of novel pathways for the treatment of PTCL (Figure 1). For example, pralatrexate, a folate antagonist, which will be discussed in detail in the following section, has promising activity in PTCL and is FDA-indicated for relapse and refractory PTCL. Histone deacetylase inhibitors including romidepsin and belinostat also have promising activity in refractory or recurrent PTCL.11,12 Preliminary studies show efﬁcacy of zanolimumab, an anti-CD4R antibody, in 21 patients with relapsed or refractory PTCL including enteropathy-associated T-cell lymphoma, anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma, and PTCL-NOS.13 An objective tumor response was achieved in 23.8% of 5

ABELOFF PERIPHERAL T-CELL LYMPHOMA CHAPTER UPDATE

TABLE 2. SUMMARY OF DISTINGUISHING FEATURES OF SPTCL-ab AND SPTCL-ɣδ. Adapted from Willemze et al.10

Immunophenotype T-cell receptor T-cell phenotype Coexpression CD56 Histological features Clinical features

HPS 5-year overall survival Without HPS With HPS Preferred terminology

SPTCL-ab

SPTCL-ɣδ

bF1+, TCRδ1CD3+, CD4-, CD8+ Absent Subcutaneous Nodules and plaques, rarely ulceration, association with autoimmune disorders (20%)

bF1-, TCRδ1+ CD3+, CD4-, CD8Common (60%) Subcutaneous and epidermal/dermal Nodules and plaques, ulceration common

Uncommon (17%) 82% 91% 46% SPTCL

Common (50%) 11% — — CGD-TCL

CGD-TCL, cutaneous gamma/delta T-cell lymphoma; HPS, hemophagocytic syndrome; SPTCL, subcutaneous panniculitis-like T-cell lymphoma.

patients with 2 complete responses and 3 partial responses. Another monoclonal antibody, SGN-35, against CD30, was evaluated in 45 patients with relapsed or refractory CD30-positive lymphomas.14 The objective response rate was 46% with a complete remission rate of 25%. Median duration of response was 22 weeks, although the study was ongoing at time of publication. A number of phase 2 clinical trials are under way investigating denileukin diftitox, an anti-CD25R target, in patients with PTCL. In the CONCEPT trial, patients (n = 41) receiving denileukin diftitox plus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) achieved an overall response rate of 90% with 71% complete responses.15 The initial report of an ongoing phase 2 trial evaluating oral lenalidomide in patients with previously untreated or relapsed PTCL suggests clinical activity of this agent.16 Of 10 patients treated, 4 partial responses were achieved in patients with PTCL-NOS and angioimmunoblastic T-cell lymphoma and stable disease in 1 patient with PTCL-NOS. The proteasome inhibitor bortezomib has also shown activity in a study that included 2 patients with PTCL-NOS with 1 patient who had isolated skin involvement responding.17 Other studies demonstrate efﬁcacy of the anti-CC chemokine receptor 4 (CCR4) antibody, KW-0761, in patients with relapsed or refractory CCR4-positive adult T-cell leukemia/ lymphoma and PTCL. As optimal treatment regimens

TABLE 3. NOVEL TARGETED THERAPIES IN CLINICAL DEVELOPMENT FOR THE TREATMENT OF PTCL Phase of Therapy Target Development Daclizumab Anti-CD25R Denileukin diftitox Anti-CD25R Yttrium-CD25 Anti-CD25R SGN-30 Anti-CD30 MDX-060 AntiCD30 SGN-35 Anti-CD30 Zanolimumab Anti-CD4R KW-0761 Anti-CCR4 Pralatrexate Folate inhibitor Bortezomib Proteasome inhibitor Belinostat HDAC inhibitor Vorinostat HDAC inhibitor Romidepsin HDAC inhibitor Panobinostat HDAC inhibitor Lenalidomide Immunomodulator

1/2 2 1/2 1/2 1/2 1/2 2 1 2 2 2 2 2 2 2

CCR4, CC chemokine receptor 4; HDAC, histone deacetylase.

ABELOFF PERIPHERAL T-CELL LYMPHOMA CHAPTER UPDATE Anti-CD25R mAbs

CD3 complex

Anti-CD4R

TCR

Anti-CD30 mAbs

LC K 70 ZA P-

LA T

C CD D4 4R R

x 2R I L-

Zanolimumab *Inhibits amplification of TCR via lck

Daclizumab Y90-anti-CD25R Denileukin diftitox *Target IL-2 effects

MDX-060 SGN-30 SGN-35 *Target TNF-α effects (NK-β signaling)

Proteosome Inhibitors Bortezomib

CD-30 Immunomodulators Lenalidomide

Anitbody Dependent Cellular Cytotoxicity Histone Deacetylases

anti-CCR4 KW-0761

Vorinostat Belinostat Pabinostat Romidepsin

Figure 1. Schematic representation of the pathways targeted in the treatment of PTCL currently under clinical investigation. only detected bone marrow involvement in 20% of patients with bone marrow involvement conﬁrmed by biopsy. Thus, additional studies into the feasibility of 18 ﬂuoro-2-deoxyglucose PET in staging PTCL are needed.

and single-agent clinical activity of these targeted therapies are being elucidated, new agents with signiﬁcant clinical activity are being investigated in combination therapy. PTCL (STUDIES NOT SUBDIVIDED BY TYPE)

Therapy As demonstrated by large studies such as the International T-cell Lymphoma Project,4 with the exception of ALK-positive anaplastic large cell lymphoma, outcomes with conventional chemotherapy have been very disappointing in most PTCLs and indeed the only subtype that has been shown to beneﬁt from anthracyclinebased therapy is anaplastic large cell lymphoma. Therefore, novel approaches and the development of new agents are needed and, over the past few years, several new drugs have been tested in PTCL, many demonstrating good activity. Recently, data from one of the largest prospective phase 2 studies on PTCL to date, the Pralatrexate in Patients with Relapsed or Refractory Peripheral T-cell Lymphoma (PROPEL) study, demonstrated signiﬁcant clinical activity using pralatrexate (Table 4, Table 5).19 In PROPEL, pralatrexate was administered to 111 heavily pretreated patients with

Diagnosis The role of 18fluoro-2-deoxyglucose positron emission tomography (PET) in the diagnosis of PTCL has not been well established at this time and is currently under investigation in clinical trials. However, findings of high positive pretreatment 18fluoro-2-deoxyglucose PET rates suggest a possible role for 18fluoro-2-deoxyglucose PET in the management of patients with PTCL. Based on the utility of 18fluoro-2-deoxyglucose PET in the staging, response, and prognosis of malignant lymphoma, a study of 41 patients with PTCL evaluated the role of 18 fluoro-2-deoxyglucose PET in NK/T-cell lymphomas.18 18 Fluoro-2-deoxyglucose PET detected a lymphoma lesion in 100% of patients with extranodal NK/T-cell lymphoma, nasal type, anaplastic large cell lymphoma, and angioimmunoblastic T-cell lymphoma and in 91% of patients with PTCL-NOS. However, 18fluoro-2-deoxyglucose PET 7

ABELOFF PERIPHERAL T-CELL LYMPHOMA CHAPTER UPDATE disorders including PTCL.22,23 This study established the maximum tolerated dose and schedule of the combination of pralatrexate and gemcitabine in 33 evaluable heavily pretreated patients with non-Hodgkin’s lymphoma and Hodgkin’s lymphoma, 12 of whom had PTCL. The study determined that treatment with pralatrexate plus gemcitabine was feasible when given every 2 weeks. Weekly dosing resulted in unacceptable toxicity. When given on sequential days every 2 weeks, the maximum tolerated dose was pralatrexate/gemcitabine 10/400 mg/m2, but when administered every 2 weeks on the same day it was 15/600 mg/m2. The most frequent grade 3/4 adverse events were anemia, neutropenia, thrombocytopenia, leukopenia, and abnormal liver function. Of the 33 evaluable patients, 8 (24%) achieved a partial response. Of 11 evaluable patients with PTCL, 2 patients achieved a partial response, 2 had stable disease, and 7 had progressive disease. Based on these preliminary findings a phase 2 expansion study is under way to evaluate both sequential and same-day combination therapy given every 2 weeks in patients with PTCL, Hodgkin lymphoma, and B-cell lymphoma. In newly diagnosed patients with PTCL, 2 studies have evaluated the role of high-dose chemotherapy and autologous stem cell transplantation consolidation.24,25 In one study of 18 patients primarily with stage III or IV disease, patients were treated with sequential chemotherapy of 3 cycles of a CHOEP-21-like regimen (CHOP plus etoposide), 1 cycle of an ifosfamide and methotrexate-based regimen, and a priming regimen with high-dose cytosine arabinoside followed by consolidation with myeloablative conditioning and autologous stem cell support.25 Patients had a complete response rate of 61%, partial response rate of 17%, and 22% had stable disease. Two-year progression-free survival was 52%. In another study, 39 patients with PTCL were treated with ranimustine, carboplatin, etoposide, and cyclophosphamide or a total body irradiation-based regimen prior to autologous stem cell transplantation. Five-year overall survival was 62.2% with a median follow-up of 78 months and was significantly higher in patients who were in complete or partial remission during transplantation than in those with other disease status (73.1% vs 45.8%; P = .033). Furthermore, a recent study suggests that intensive primary chemotherapy and autologous stem cell transplantation may significantly improve outcomes in patients with PTCL compared with CHOP-like regimens.26 This study evaluated a regimen of CHOP followed by

TABLE 4. SUMMARY OF RESPONSE RATES IN PATIENTS RECEIVING PRALATREXATE ENROLLED IN THE PROPEL STUDY (N = 109) EVALUABLE PATIENTS Response n Response Rate (%) CR + CRu + PR CR CRu PR SD PD

29 10 1 18 23 40

27 9 <1 17 21 37

CR, complete response; CRu, unconﬁrmed complete response; PD, progressive disease; PR, partial response; SD, stable disease.

relapsed or refractory PTCL. The majority of patients (53%) had PTCL-NOS. The overall response rate was 27% with 10% of patients achieving a complete response, 17% achieving a partial response, and 21% having stable disease. Sixty-nine percent of responders did so after cycle 1. The mean duration of response was 306 days (range 1–673) and median overall survival was 14.5 months with 55% of patients surviving longer than 12 months. The most frequent grade 3 or 4 adverse events were mucosal inﬂammation and thrombocytopenia. Based on data from the PROPEL study, pralatrexate received accelerated US Food and Drug Administration approval and is currently the only drug indicated for the treatment of relapsed or refractory PTCL. As a result of this trial, National Comprehensive Cancer Network guidelines now suggest the use of pralatrexate as second-line therapy for the treatment of PTCL.20 Subgroup analyses from PROPEL assessed response to pralatrexate in patients who were considered refractory to their prior therapy, deﬁned as: (1) no evidence of response to their most recent treatment (n = 69); or (2) no evidence of response to any prior therapies (n = 26).21 Among patients with no evidence of response to their most recent therapy, 17/69 responded to pralatrexate (overall response rate 25%) and the overall duration of response ranged from 41 to 673 days. Among the patients with no evidence of response to any prior therapy, 5/26 (19%) responded to pralatrexate and the duration of response ranged from 52 to 306 days.21 Recently, a phase 1 study investigated the combination of pralatrexate and gemcitabine with B12 and folic acid in patients with relapsed or refractory lymphoproliferative 8

ABELOFF PERIPHERAL T-CELL LYMPHOMA CHAPTER UPDATE

TABLE 5. SUMMARY OF KEY FINDINGS FROM RECENT CLINICAL TRIALS OF NOVEL TREATMENT STRATEGIES IN PTCL PTCL Subtype erapy/Study N Key Findings Reference PTCL/PTCL-NOS Pralatrexate/PROPEL

111

ORR: 27% CR: 10% PR: 17% SD: 21%

CHOEP-21 x 3 cycles, ifosfamide x 1 cycle, methotrexatebased regimen, priming regimen with cytosine arabinoside followed by consolidation with myeloablative conditioning and autologous stem cell support

CR: 61% PR: 17% SD: 22% 2-year PFS: 52%

Ranimustine, carboplatin, etoposide, and cyclophosphamide or a total body irradiation-based regimen prior to autologous SCT

5-year OS: 62.2% 5-year PFS: 60.6% CR: n = 23 CR1/PR1: n = 17

Alemtuzumab + CHOP/GITIL

CR: 50% PR: 7% MR: 7% Duration: 11 months

Alemtuzumab + ﬂudarabine

↑ susceptibility to EBV

CR: 100%

142 evaluable

CR: 70% 2-year OS: 59%

Allogeneic SCT

3-year OS: 64%

First-line R-CHOP

CR: 100%

Cyclosporine

RR: 67% CR: n = 3 PR: n = 5

CR: 100%

AITL Alemtuzumab + CHOP/GITIL High-dose chemotherapy + autologous SCT

ALCL Alemtuzumab + CHOP

3 ALK–

Daclizumab

CR: >45 months

SGN-30/phase 1

CR: 26 months

SGN-30/phase 2

RR: 32% CR: n = 2 PR: n = 5

MDX-060/phase 1/2

CR: n = 2

Alemtuzumab + allogeneic SCT

CR: >39 months

Alemtuzumab

No response

HSTCL

ABELOFF PERIPHERAL T-CELL LYMPHOMA CHAPTER UPDATE

TABLE 5. (CONT) SUMMARY OF KEY FINDINGS FROM RECENT CLINICAL TRIALS OF NOVEL TREATMENT STRATEGIES IN PTCL PTCL Subtype erapy/Study N Key Findings Reference Alemtuzumab + cladribine

CR: clinical + molecular over 2 years

Alemtuzumab + ﬂudarabine

CR: 3 months' duration

High-dose chemotherapy + autologous SCT

CR: 25% No improvement in survival

Alemtuzumab + CHOP/GITIL

CR: 100%

First-line radiotherapy vs radiochemotherapy

5-year survival: 57% vs 62%; P = .47 PFS: 52%; P = .13 CR: 69.6% vs 87.8%

Concurrent radiation + cisplatin followed by VIPD

CR: 80% PR: 20% 3-year OS: 86% 3-year PFS: 85%

First-line concurrent radiotherapy + DeVIC vs radiotherapy 26 alone/JCOG0211

ORR: 81% CR: 77%

EATL

Extranodal NK/T-cell lymphoma, nasal type

SPTCL Denileukin diftitox

CR: 100% Duration: >6 months After bexarotene: 1 patient returned to remission

Fludarabine, mitoxantrone, dexamethasone

CR: 100% Duration: >40 months

Pirarubicin, cyclophosphamide, dexamethasone, vincristine, 1 L-asparaginase followed by CHASE + autologous SCT

CR: 100% Duration: >3 years

ATLL Arsenic trioxide, IFN-a, zidovudine

RR: 100% CR: 80% Duration: >8 months

Autologous SCT

Ineﬀective as salvage therapy

AITL, angioimmunoblastic T-cell lymphoma; ALCL, anaplastic large cell lymphoma; ALK, anaplastic lymphoma kinase; ATLL, adult T-cell leukemia/ lymphoma; CHASE, cyclophosphamide, cytarabine, etoposide, and dexamethasone; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; CHOEP, CHOP + etoposide; CR, complete response; DeVIC, dexamethasone, etoposide, ifosfamide, and carboplatin; EATL, enteropathy-associated T-cell lymphoma; EBV, Epstein-Barr virus; GITIL, Gruppo Italiano Terapie Innovative nei Linfomi; HSTCL, hepatosplenic T-cell lymphoma; IFN, interferon; JCOG, Japan Clinical Oncology Group; MR, minor response; NOS, not otherwise speciﬁed; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PR, partial response; PROPEL, Pralatrexate in Patients with Relapsed or Refractory Peripheral T-cell Lymphoma; PTCL, peripheral T-cell lymphoma; R-CHOP, rituximab + CHOP; RR, response rate; SCT, stem cell transplantation; SD, stable disease; SPTCL, subcutaneous panniculitis-like T-cell lymphoma; VIPD, etoposide, ifosfamide, cisplatin, dexamethasone.

ABELOFF PERIPHERAL T-CELL LYMPHOMA CHAPTER UPDATE subgroup of PTCL-NOS with features of cytotoxic cells, a distinct set of cytokines and receptors, and a complex immunosuppressive gene signature.29 Patients in this subgroup had a poorer overall survival (P = .05) and event-free survival (P = .06) compared with other PTCL-NOS cases. Bone marrow involvement is present in 30% to 50% of all PTCL patients.30 The incidence of bone marrow inﬁltration is higher (57%) in patients with PTCL and T-cell lymphoma-associated hemophagocytic syndrome than in those without the syndrome (32%; P <.05). These results suggest that early bone marrow inﬁltration may characterize T-cell lymphomas with T-cell lymphoma-associated hemophagocytic syndrome.

3 courses of ifosfamide, etoposide, and epirubicin alternating with intermediate-dose methotrexate followed by consolidation with myeloablative autologous stem cell transplantation. The majority of patients had enteropathyassociated T-cell lymphoma or PTCL-NOS. Of 55 patients evaluated, 71% achieved complete remission, 5% achieved partial remission, and 24% failed treatment. Three-year progression-free survival was 59% and overall survival was 67%. The most common severe toxicities were pancytopenia, infection, nausea and vomiting, and obstruction or perforation. PTCL-NOT OTHERWISE SPECIFIED Epidemiology and Pathophysiology PTCL-NOS is the most common (40% to 50%) and heterogeneous subtype of PTCL due to its diagnosis of exclusion.2 Due to its heterogeneous nature, the tumor cell morphology is variable.2,27 Most patients present in the fifth to seventh decade of life with the majority having stage III to IV disease.2,27 PTCL-NOS is generally an aggressive disease with poor overall survival with 5-year survival rates between 20% and 30%.2,27 The pathophysiology of PTCL-NOS is poorly understood. However, distinct transforming genetic alterations have been identified for PTCL-NOS.28 While the precise role in disease manifestation is not known, these findings provide insight into the complexity of the disease. Recurrent copy number gain on chromosomes 8q, 9p, and 19q and a loss of copy number was recently detected at chromosomes 3q and 9p.28 Specific genes were found to map to these locations including those for cyclin-dependent kinases often silenced or deleted in cancer cells, CDKN2A and CDKN2B, which correlated with poor clinical outcome. Poor prognosis has been linked to overexpression of the caspase recruitment domain membrane-associated guanylate kinase protein 1 (CARMA1) at 7p22, which is overexpressed in B-cell and adult T-cell leukemia/ lymphoma, and the MYC-binding protein 2 gene (MYCBP2) at 13q22, a large protein that binds to the oncogene MYC. A loss of heterozygosity was detected at chromosome 2, which correlated with expression of a novel isoform of IKZF2, an IKAROS-family related transcriptional factor for regulation of lymphocyte development. The variant isoform of IKZF2 was found to correlate with several patients with PTCL-NOS but not other patients or healthy subjects. Most recently, gene expression profiling identified a distinct molecular

The Current Role of Diagnostic and Prognostic Markers in PTCL-NOS The availability of prognostic and diagnostic data is increasing with preliminary analyses identifying prognostic genetic factors occurring in specific PTCL subtypes. Larger registries and comparative analyses are revealing differences among PTCL subtypes in clinical characteristics and prognostic markers. A new clinical-pathologic prognostic score was proposed for PTCL-NOS based on the evaluation of 19 markers in 93 patients with PTCL-NOS. The prognostic index was composed of a mixed patient- and tumor-specific prognostic score that included proliferationassociated protein Ki-67 ≥80%, age >60 years, high lactate dehydrogenase, and poor performance status.31 This scoring system differentiated between 3 groups of patients with differing responses to therapy and survival based upon the presence and number of factors. Patients in group 1 had none or one of the factors, group 2 had 2 factors present, and group 3 had 3 or 4 factors present. This prognostic index was highly correlated with clinical outcome (P < .0001). Several additional factors have been identified as predictive of clinical outcome in patients with PTCL-NOS. In a study of 63 patients with PTCL-NOS from the Czech Lymphoma Study Group registry, the 3-year survival probability was 36%.3 Multivariate analyses revealed clinical stage IV and achievement of complete response as independent predictors of survival. Another retrospective study of 84 patients with PTCL-NOS revealed a 5-year survival rate of 41%.32 In this study, multivariate analyses demonstrated that the presence of B symptoms, International Prognostic Index scores ≥3, a Prognostic Index for PTCL-NOS ≥2, and poor Eastern Cooperative Oncology 11

ABELOFF PERIPHERAL T-CELL LYMPHOMA CHAPTER UPDATE Group performance status were poor prognostic factors. In a study evaluating the clinical outcomes and prognostic factors for high-dose chemotherapy followed by autologous stem cell transplantation in 64 Korean patients with PTCLNOS, 3-year overall survival was 53%.33 Multivariate analysis revealed that a failure to achieve a complete response at transplantation and high Prognostic Index scores of 2 to 3 were both independent prognostic factors for survival. Data from 123 patients with relapsed/refractory PTCL registered in the GEL/TAMO registry was evaluated to identify pretransplant prognostic information.34 Five-year overall survival was 45% while progressionfree survival was 34%. Multivariate analysis showed that adjusted International Prognostic Index score and b2-microglobulin levels predicted overall survival after autologous stem cell transplantation.34 The b2-microglobulin level also independently predicted progression-free survival. Using these factors allowed for stratification of patients into 3 prognostic groups. Patients with no pretransplant adverse factors had an overall survival of 60%, those with 1 adverse factor had an overall survival of 28%, and those with both factors all died from their disease. Another study evaluating 31 patients with angioimmunoblastic T-cell lymphoma and 37 patients with PTCL-NOS for prognostic factors determined that a low serum albumin and mediastinal lymphadenopathy were predictive of worse overall survival in patients with PTCL-NOS.35 Independent predictors for a shorter progression-free survival were performance status ≥2 and mediastinal lymphadenopathy. Comparative analysis of extranodal NK/T-cell lymphoma and PTCL, including PTCL-NOS, angioimmunoblastic T-cell lymphoma, anaplastic large cell lymphoma, and other subtypes, revealed significant differences in clinical characteristics and prognosis.36 Patients with extranodal NK/T-cell lymphoma typically presented with early stage (I or II) and had more than 2 sites of extranodal involvement compared with patients with PTCL. However, 5-year survival rates for patients with PTCL, regardless of subtype, were significantly better than for those with NK/T-cell lymphoma (48% vs 20%; P < .003). Patients with extranodal NK/T-cell lymphoma were 4 times more likely to die from their disease compared with PTCL patients. Prognosis-related chromosome copy number alterations have been identified in patients with PTCL-NOS.28 A poor prognosis was linked to copy number gains at

13q22.3 locus, which correlated with increased MYCBP2 expression in patients with PTCL-NOS. A loss of heterozygosity at chromosome 8 was also correlated with poor clinical outcome. Therapy The outcome for patients with PTCL-NOS is poor with current treatments, and novel strategies are needed. The International Peripheral T-Cell Lymphoma Study demonstrated that patients with PTCL-NOS as well as NK/T-cell lymphoma did not benefit from the use of an anthracycline-containing regimen.4 Currently, even the best available therapies do not appear to significantly improve outcomes in these patients evidenced by dismal long-term survival rates of 10% to 30%. Several recent findings suggest targeted therapy with the anti-CD52 agent, alemtuzumab, in combination with chemotherapy may be effective in patients with PTCL-NOS. A recent study demonstrated that PTCL-NOS is positive for CD52 with 92% of cases expressing CD52 in neoplastic cells (Figure 2).37 It is still unknown whether the expression of CD52 correlates with a response to therapy. However, a prospective multicenter study from the Gruppo Italiano Terapie Innovative nei Linfomi (GITIL) evaluated the efficacy of the combination of alemtuzumab and CHOP as first-line treatment of 24 patients with PTCL, angioimmunoblastic T-cell lymphoma, or anaplastic large cell lymphoma.38 Of 14 patients with PTCL-NOS, 50% achieved a complete response and 1 patient each had a partial and minor response. The median complete response duration was 11 months in 14 of 17 patients. The combination of alemtuzumab with dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin has also demonstrated good efficacy in PTCL.39 While the clinical impact is unclear, Weisel et al recently suggested that combination therapy with alemtuzumab and fludarabine may increase susceptibility to Epstein-Barr virus-associated B-cell lymphoma in patients with PTCL-NOS or angioimmunoblastic T-cell lymphoma.40 Two cases were identified in which patients who were severely immunocompromised developed Epstein Barr virus-associated B-cell lymphoma after treatment with this regimen. The authors suggested that the addition of immunosuppressive therapy with cytotoxic drugs may significantly exacerbate patients’ immunodeficiency. 12

ABELOFF PERIPHERAL T-CELL LYMPHOMA CHAPTER UPDATE ANGIOIMMUNOBLASTIC T-CELL LYMPHOMA Epidemiology and Pathophysiology The molecular mechanisms for the development of angioimmunoblastic T-cell lymphoma are not well understood. In order to help characterize the relationships between angioimmunoblastic T-cell lymphoma, PTCL-NOS, anaplastic large cell lymphoma, and normal T cells, gene expression profiling studies were undertaken.41 Angioimmunoblastic T-cell lymphoma is closely related to activated T cells, specifically CD4 cells with a gene expression profile typical of T follicular helper lymphocytes.41 Compared with normal CD4 and CD8 cells, angioimmunoblastic T-cell lymphoma tumors overexpressed genes related to tissue invasiveness, angiogenesis, resistance to chemotherapy, neoplastic transformation, and cell adhesion. A review of the presence of PTCL in the bone marrow of 173 patients, showed that 54% of these patients have bone marrow involvement, including 7 of 11 (64%) of the patients with angioimmunoblastic T-cell lymphoma.30 Among all patients with PTCL, bone marrow involvement was associated with a worse prognosis. The median overall survival was 120 days and 356 days for patients with or without bone marrow involvement, respectively. Immunohistochemical expression of the signaling lymphocyte activation molecule associated protein and programmed death-1 (PD-1), both markers of germinal center T cells, by 95% of the cases of angioimmunoblastic T-cell lymphoma studied suggests that this malignancy arises from these cells.42 In another study, 95% of the 59 cases of angioimmunoblastic T-cell lymphoma were positive for the follicular helper T-cell markers CXCL13 and PD-1.43

PTCL Subtype N=3

CD52 Expression (%)

100

N=4 N = 13

N = 34

60 N=2

40 N=4

AITL

HSTCL PTCL-NOS ATLL

ALCL Extranodal NK/T-Cell

7000

Mean CD52 ABC (SD)

6000 5000 N=3

4000 3000

N = 32

N=3 N = 12

2000

N=1

1000 N=1

AITL

HSTCL PTCL-NOS ATLL

ALCL Extranodal NK/T-Cell

The Current Role of Diagnostic and Prognostic Markers in Angioimmunoblastic T-cell Lymphoma Single nucleotide polymorphism–typing microarrays have been used to determine chromosomal changes that affect prognosis in 40 patients with angioimmunoblastic T-cell lymphoma. The presence of alterations in copy number affected survival in these patients with loss or gain most common in chromosomes 3, 8, 9, and 19.28 Reduced expression of CDRN2A and increased expression of MYCBP2 and CARMA1 were associated with worse prognosis. Gain at chromosomes 2, 5, loss

Figure 2. Expression of CD52 in PTCL by subtype and the CD52 cell surface antibody-binding capacity by tumor cells in CD52-positive patients with PTCL. Data adapted from Jiang et al.37 AITL, angioimmunoblastic T-cell lymphoma; ALCL, anaplastic large cell lymphoma; ATLL, adult T-cell leukemia/lymphoma; HSTCL, hepatosplenic T-cell lymphoma; NK, natural killer; NOS, not otherwise speciﬁed; PTCL, peripheral T-cell lymphoma.

ABELOFF PERIPHERAL T-CELL LYMPHOMA CHAPTER UPDATE of heterozygosity at chromosomes 8 or 9, and gain at 13q22.3 were all associated with poorer prognosis. Iqbal et al identiﬁed a molecular prognosticator in 36 patients with angioimmunoblastic T-cell lymphoma, which was an independent predictor of outcomes. This molecular prognosticator consisted of a small subset of 15 transcripts that predicted overall survival and event-free survival (P<.001).29 Genes associated with a poor outcome included VSIG4, an inhibitor of T-cell activation, and receptors or cell adhesion molecules including plateletderived growth factor receptor (PDGFR) a and PDGFRb. The records of 31 consecutive patients with angioimmunoblastic T-cell lymphoma were reviewed to determine prognostic factors for overall survival and progression-free survival. Diverse factors for this analysis included staging information, previous treatments, laboratory parameters, International Prognostic Index risk groups, and performance status.35 In the multivariate analysis, male sex, hemoglobin <10 g/dL, and performance status ≥2 were associated with a shorter median overall survival. In a separate multivariate analysis, there was no association with any of these factors and progression-free survival.35

70% achieved a complete response with 65% of patients alive at a median follow-up of 31 months and an estimated overall survival at 48 months of 59%. The role of allogeneic stem cell transplant was shown in an analysis of 45 patients who underwent allogeneic stem cell transplant with either myeloablative or reducedintensity regimens.45 The rate of disease relapse was 13% and 20% at 1 and 3 years, respectively, with an estimated overall survival at 3 years of 64%. As B cells are thought to be an important component of the pathogenesis of angioimmunoblastic T-cell lymphoma, some studies have looked at anti-CD20 therapy in this disease. For example, 4 patients with untreated disease were treated with rituximab plus CHOP (R-CHOP) with complete remission in all of the patients.46 This response has not been studied in a larger trial. The immune dysregulation associated with angioimmunoblastic T-cell lymphoma led to a retrospective analysis of 12 patients who were treated with cyclosporine 3 to 5 mg/kg daily for 6 to 8 weeks with a taper over 1 to 3 weeks and maintenance therapy in patients who responded.47 The response rate was 67% with a complete response in 3 patients and partial response in 5 patients, suggesting that this is potentially a very effective strategy in this disease.

Therapy As with PTCL-NOS, current therapies for angioimmunoblastic T-cell lymphoma have limited efﬁcacy. Interestingly, angioimmunoblastic T-cell lymphoma is frequently associated with immunodeﬁciency and immune dysregulation and many patients succumb to infectious complications rather than to the disease itself. Alemtuzumab is a monoclonal antibody that binds to CD52 on the cell surface leading to cell death by both complement and antibody-dependent cytotoxicity and apoptosis.37 In an analysis of the expression of CD52 on T-cell lymphomas, CD52 was expressed on all 3 of the cases of angioimmunoblastic T-cell lymphoma.37 Additional evidence for the importance of CD52 expression comes from the GITIL trial, which enrolled 6 patients with angioimmunoblastic T-cell lymphoma. Patients received a combination of CHOP and alemtuzumab.38 All 6 patients had a complete response to therapy. The role of high-dose therapy followed by autologous stem cell transplantation for patients with angioimmunoblastic T-cell lymphoma was shown in a retrospective trial that analyzed data from 146 patients.44 The high-dose therapy used as the conditioning regimen varied by center, but 74% of patients received bleomycin and carmustine, etoposide, ara-C, and melphalan. Of 142 assessable patients,

ANAPLASTIC LARGE CELL LYMPHOMA Epidemiology and Pathophysiology The 2008 WHO classiﬁcation distinguishes between ALK-positive and ALK-negative anaplastic large cell lymphoma. ALK-positive anaplastic large cell lymphoma has rearrangement of the ALK gene, which encodes a tyrosine kinase located on chromosome 2 with t(2;5) and t(1;2) representing the 2 most common translocations.27 Pathogenesis of ALK-positive anaplastic large cell lymphoma is dependent upon activation of the ERK, JAK3-STAT3, and PI3K-Akt pathways. Gene expression studies have shown BCL6, CEBPB, and SERPINA1 are differentially expressed in ALK-positive and ALK-negative anaplastic large cell lymphoma.27 The clinical and immunophenotypic features of anaplastic large cell lymphoma were determined in a retrospective review that incorporated data from 1314 patients, including 181 patients with ALCL. Patients with ALK-positive anaplastic large cell lymphoma had a median age of 34 years compared with a median age of 14

ABELOFF PERIPHERAL T-CELL LYMPHOMA CHAPTER UPDATE 58 years for patients with ALK-negative anaplastic large cell lymphoma with no gender differences or differences in stage at presentation.48 Review of bone marrow involvement in 173 patients with PTCL, including 17 with anaplastic large cell lymphoma, showed bone marrow involvement in 29% of patients.30 This is less than the average marrow involvement of 54% of all patients with PTCL.

and 1460 days with a median duration of response for patients with a partial response of 100 days. Another anti-CD30 monoclonal antibody is MDX060, which was tested in a phase1/2 trial enrolling 72 patients including 3 patients with anaplastic large cell lymphoma in the phase 1 portion and 4 patients in the phase 2 portion.53 Two patients in the phase 2 portion of the study had a complete response. There were no patients with anaplastic large cell lymphoma who had a partial response.

Therapy While the outcome for patients with ALK-positive anaplastic large cell lymphoma is excellent with anthracycline-based therapy, though better than for PTCL-NOS, the outcome for ALK-negative anaplastic large cell lymphoma remains relatively poor and improvements are needed. The GITIL study, in which patients with PTCL received first-line therapy with alemtuzumab and CHOP, enrolled 3 patients with ALK-negative anaplastic large cell lymphoma.38 All 3 patients with anaplastic large cell lymphoma had a complete response. The anti-CD25 monoclonal antibody, daclizumab, targets the interleukin-2 receptor, which is overexpressed on T-cell lymphoma cells. Daclizumab was given to an 8-year-old girl with anaplastic large cell lymphoma that recurred after treatment with 2 combination chemotherapy regimens and an autologous transplant.49 Despite a remission of only 8 weeks after salvage chemotherapy and 3 weeks following transplant, she had a complete response with 2 weeks of therapy and was in remission after 45 months. The benefit of this therapy for adult patients and as front-line therapy has not been well tested and sipilizumab, a monoclonal antibody that targets the CD2 antigen present on most T and NK cells, is also under investigation but has been associated with the development of EBV-positive lymphoproliferative disorders.50 SGN-30 is a chimeric monoclonal antibody to CD30 that showed a complete remission in a patient with recurrent, cutaneous anaplastic large cell lymphoma enrolled in a phase 1 trial with a 26-month remission after 6 weeks of therapy.51 A phase 2 trial of SGN-30 enrolled 38 patients with Hodgkin’s lymphoma and 41 patients with anaplastic large cell lymphoma who received either 6 mg/kg or 12 mg/kg weekly.52 Two patients with anaplastic large cell lymphoma had a complete response with a partial response in 5 patients for a clinical benefit in 32% of these patients. The duration of the complete response was over 172 days

HEPATOSPLENIC T-CELL LYMPHOMA Therapy The outcome for this rare and very aggressive type of PTCL is extremely poor and novel approaches need to be investigated. Due to its rarity, studies in hepatosplenic T-cell lymphoma are very limited but the treatment approach has conventionally included anthracyclinebased chemotherapy. Hepatosplenic T-cell lymphoma is a disease where strategies such as allogeneic stem cell transplantation should be considered in the up-front setting. Regarding novel approaches in this disease, in a recent study, Jiang et al reported that in 4 cases of hepatosplenic T-cell lymphoma, all patients were CD52positive suggesting a potential for targeted therapy with the monoclonal antibody, alemtuzumab.37 Chanan-Khan et al first reported the use of alemtuzumab in a case study of a patient with stage IV disease.54 The patient responded to alemtuzumab followed by allogeneic stem cell transplantation and donor lymphocyte infusions with induction of complete remission for over 39 months. Other studies have reported efficacy with combinations of alemtuzumab and cladribine and a transient response with fludarabine and alemtuzumab in patients with hepatosplenic T-cell lymphoma.55,56 Collectively, these case reports suggest a possible role for alemtuzumab in patients with hepatosplenic T-cell lymphoma and warrant further investigation. ENTEROPATHY-ASSOCIATED T-CELL LYMPHOMA Epidemiology and Pathophysiology In 2008, the first publication of the incidence of enteropathy-associated T-cell lymphoma in a general population reported an incidence of 0.10/100,000.57 15

ABELOFF PERIPHERAL T-CELL LYMPHOMA CHAPTER UPDATE The peak incidence occurred in the seventh decade of life. Enteropathy-associated T-cell lymphoma is correlated with celiac disease and occurs more frequently in men than women. Another study determined that bone marrow involvement is present in about 13% of patients with enteropathy-associated T-cell lymphoma, which is typically associated with a poorer prognosis.30

very little is known about the etiology of the disease, an analysis of 74 cases of extranodal NK/T-cell lymphoma, nasal type, in China suggests that along with the Epstein Barr virus, external stimuli may play a role in the pathogenesis of this disease.59 In this study, the occurrence of epithelial lesions, including minute squamous carcinomas, were hypothesized to be due to the presence of oncogenic external stimuli. The identity of the causal stimuli is unknown. A recent analysis of 136 cases of extranodal NK/T-cell lymphoma with 68% of the nasal type and 26% extranasal type identified clinical differences in the characteristics of the 2 subtypes of the disease.60 Most patients with nasal-type extranodal disease had fewer adverse clinical characteristics compared with extranasal disease. Median overall survival was significantly longer for patients with nasal-type versus extranasal disease at 1.6 years compared with 0.36 years (P< .001). A survival benefit was observed for patients with nasal-type disease receiving radiotherapy (P = .045).

Therapy The outcome for patients with this disease who receive anthracycline-based chemotherapy has traditionally been very poor with most patients relapsing and dying from their disease. Again, this is a disease where approaches like allogeneic stem cell transplantation should be considered in the up-front setting. While autologous stem cell transplantation can induce a durable complete remission in some patients with PTCL, in a study of 4 patients with stage IV enteropathy-associated T-cell lymphoma, high-dose chemotherapy followed by autologous stem cell transplantation failed to improve survival.58 One patient achieved complete remission, but 3 of the 4 patients died following autologous stem cell transplantation. In the prospective GITIL study, which evaluated the efficacy of alemtuzumab and CHOP chemotherapy as firstline treatment in a variety of PTCL subtypes, 1 patient with enteropathy-associated T-cell lymphoma was treated. This patient achieved a complete remission.38 In the study reported by Sieniawski et al, intensive primary chemotherapy and autologous stem cell transplantation significantly improved outcomes in patients with enteropathy-associated PTCL compared with CHOP-like regimens.26 Although this study included patients with various subtypes of PTCL, almost 50% of patients had enteropathy-associated PTCL. Of the 26 patients evaluated with enteropathy-associated PTCL, 65% achieved complete remission and 4% achieved partial remission. Three-year progression-free survival was 52% and overall survival was 60%.

The Current Role of Diagnostic and Prognostic Markers in Extranodal NK/T-cell Lymphoma, Nasal Type Flow cytometry is proving useful in the differential diagnosis of extranodal NK/T-cell lymphoma. A study evaluated the utility of flow cytometry to determine the phenotypic characteristics of 490 patients with extranodal NK/T-cell lymphoma. The expression of CD56 was present in all samples of nasal NK/T-cell lymphoma (P<.001) while CD10 was expressed in angioimmunoblastic T-cell lymphoma, CD30 in anaplastic large cell lymphoma, and CD34 in lymphoblastic lymphoma.61 Along with CD56 and the Epstein Barr virus-encoded small nuclear early region 1, serum Epstein Barr virusDNA copy number is useful as a specific tumor marker and a predictive prognostic tool.62 High levels of serum Epstein Barr virus-DNA copy numbers were predictive of an aggressive disease course and poor prognosis. The DNA levels were shown to decrease in response to treatment and increased upon relapse. A new staging system has been proposed for nasal extranodal NK/T-cell disease based on treatment outcomes.63 Using this system, extranodal NK/T-cell disease is classified as limited disease, defined as stage I/II nasal NK/T-cell lymphoma without tumor invasiveness; or as extensive disease, defined as either stage I/II nasal NK/T-cell lymphoma with local invasiveness, stage III/IV disease, or extranodal

EXTRANODAL NK/T-CELL LYMPHOMA, NASAL TYPE Epidemiology and Pathophysiology Extranodal NK/T-cell lymphoma is a rare, heterogeneous disease in Western populations, but common among Asians, Mexicans, and American Indians. Although 16

ABELOFF PERIPHERAL T-CELL LYMPHOMA CHAPTER UPDATE 26 evaluable patients with nasal NK/T-cell lymphoma.68 The overall response rate was 81% with 77% of patients achieving a complete remission. Historical controls treated with radiotherapy alone had a 2-year overall survival rate of 45%, which was inferior to the new regimen.

NK/T-cell lymphoma. Patients with limited disease were shown to beneﬁt from chemotherapy followed by radiotherapy with prolonged survival, but patients with extensive disease had a poor prognosis and treatment remains generally unsuccessful. A retrospective analysis of 172 patients including 123 with nasal NK/T-cell lymphoma and 27 with extranasal lymphoma was conducted to develop a prognostic model for NKcell lymphomas.64 Complete response rates were 73% for patients with stage I disease and 15% with stage IV disease. Multivariate analysis demonstrated that non-nasal type, stage, performance status, and numbers of extranodal involvement were poor prognostic factors. The authors constructed an NK prognostic index that stratiﬁed patients by number of factors present.

SUBCUTANEOUS PANNICULITIS-LIKE T-CELL LYMPHOMA Epidemiology and Pathophysiology Subcutaneous panniculitis-like T-cell lymphoma-ab is a distinct subtype of PTCL. Molecular cytogenetic analyses have revealed that subcutaneous panniculitis-like T-cell lymphoma is characterized by the neuron navigator 3 deletion, a gene previously associated with mycosis fungoides and Sezary syndrome, and 5q and 13q gains speciﬁc to subcutaneous panniculitis-like T-cell lymphoma, providing further evidence that subcutaneous panniculitislike T-cell lymphoma is distinct from other subtypes.69 Another molecular study in 22 Asian patients revealed the majority of cases of subcutaneous panniculitis-like T-cell lymphoma are of a CD4-/CD8+ phenotype and Epstein Barr virus negative.70

Therapy Because nasal NK/T-cell lymphoma is a poorly understood, heterogeneous disease, treatment is not standardized and large studies are lacking.65 Radiotherapy remains an effective treatment for patients with limited disease.66 A study compared the treatment outcome of 64 patients with early-stage nasal NK/T-cell lymphoma who received radiotherapy alone or radiochemotherapy as first-line therapy.66 No significant difference in 5-year overall survival rates between patients receiving radiotherapy (57%) versus radiochemotherapy (62%; P = .47) was observed. Progression-free survival was also similar between groups (52%; P = .13). Importantly, the majority of patients receiving radiotherapy (69.6%) or radiochemotherapy (87.8%) achieved complete remission and their 5-year overall survival rate was 72.1%. A phase 2 study, the Consortium for Improving Survival of Lymphoma Study, reported significant clinical activity of concurrent radiation and weekly cisplatin followed by etoposide, ifosfamide, cisplatin, and dexamethasone (VIPD) chemotherapy in 30 patients with stage IE to IIE nasal lymphoma.67 All patients received concurrent chemoradiotherapy and achieved a response with 22 complete remissions and 8 partial remissions. After the completion of VIPD therapy, a total of 24 patients were in complete remission. The 3-year overall survival and progression-free survival rates were 86% and 85%, respectively. The JCOG0211 phase 1/2 study demonstrated significant clinical activity using concurrent radiotherapy with dexamethasone, etoposide, ifosfamide, and carboplatin compared with radiotherapy alone as first-line therapy in

The Current Role of Diagnostic and Prognostic Markers in Subcutaneous Panniculitis-like T-cell Lymphoma Few studies have examined diagnostic and prognostic markers in subcutaneous panniculitis-like T-cell lymphoma. PET may be clinically useful in subcutaneous panniculitislike T-cell lymphoma staging and for monitoring of response to treatment.71 A case study demonstrated that pretreatment and posttreatment PET using 18 fluoro-2-deoxyglucose was useful in monitoring resolution of disease. Kong et al reported that in 22 Asian patients with subcutaneous panniculitis-like T-cell lymphoma, angioinvasion was a poor prognostic factor.70 Mortality was significantly higher in patients with subcutaneous panniculitis-like T-cell lymphoma with angioinvasion than in those without. Therapy Optimal therapy for subcutaneous panniculitis-like T-cell lymphoma remains undefined at this point in time with only a few studies evaluating or reporting treatment options for these patients. In terms of novel approaches, 2 case studies suggest efficacy of denileukin diftitox in patients 17

ABELOFF PERIPHERAL T-CELL LYMPHOMA CHAPTER UPDATE with subcutaneous panniculitis-like T-cell lymphoma.72 Two patients who were treated with denileukin diftitox experienced a complete remission of disease with a median response duration of more than 6 months. Furthermore, one patient, who progressed after 6 cycles of denileukin diftitox therapy, received bexarotene in combination with denileukin diftitox and subsequently returned to remission. Another case report suggests efficacy using the combination of fludarabine, mitoxantrone, and dexamethasone.73 In addition, one case report suggests that autologous stem cell transplantation may have efficacy in patients with subcutaneous panniculitis-like T-cell lymphoma.74

The Current Role of Diagnostic and Prognostic Markers in Adult T-cell Leukemia/Lymphoma For patients with the lymphoma type of adult T-cell leukemia/lymphoma, analysis of data from the International Peripheral T-cell Lymphoma Project showed that the International Prognostic Index, originally developed for use in patients with B-cell lymphoma, was the only independent predictor of overall survival in patients with this aggressive form of adult T-cell leukemia/lymphoma.76 In the 116 patients with adult T-cell leukemia/lymphoma in the study, the median overall survival was 0.8 years with a freedom from progression of 0.6 years. A consensus statement on the prognostic factors, classification, and treatment options was published in conjunction with the 13th International Conference on Human Retrovirology.75 Multivariate analysis identified prognostic factors including performance status, high lactic dehydrogenase, age ≥40 years, more than 3 lesions, and hypercalcemia, which are similar to those in the International Prognostic Index.75,76 Additional poor prognostic factors include thrombocytopenia, eosinophilia, bone marrow involvement, elevated interleukin-5, CCR4 expression, lung resistance-related protein, p53 mutation, and a p16 deletion.75 Recently, a study of gene expression profiling in a small group of adult T-cell leukemia/lymphoma patients demonstrated an important role for the gene BIRC5 in adult T-cell leukemia/lymphoma cell viability.79

ADULT T-CELL LEUKEMIA/LYMPHOMA Epidemiology and Pathophysiology Adult T-cell leukemia/lymphoma is a PTCL subtype associated with the retrovirus, human T-cell leukemia virus type 1 or human T-cell lymphotropic virus type 1.75 Adult T-cell leukemia/lymphoma is linked to regulatory T cells that express forkhead box P3 (FoxP3), a gene involved in immune system responses.76 The disease is more common in Asia than in North America and Europe. Subclassiﬁcation of adult T-cell leukemia/ lymphoma using Shimoyama criteria published in 1991 is recommended, which includes 4 subtypes: smoldering, chronic, acute, and lymphoma.75-77 Bone marrow involvement varies signiﬁcantly by subtype.76 Genetic alterations such as overexpression of enhancer of polycomb 1 have been shown to contribute to the development of adult T-cell leukemia/lymphoma.78 Generation of an enhancer of polycomb 1 gene (EPC1)/ additional sex combs-like 2 gene (ASXL2) fusion gene and a truncated EPC1 gene were shown to enhance cellular growth and proliferation leading to adult T-cell leukemia/lymphoma leukemogenesis. EPC1 is involved in chromatin formation and gene regulation and has been linked to malignant transformation of many cancers and ASXL2 is also a member of the polycomb group of genes. Recently, expression of the gene BIRC5 has been shown to be increased in adult T-cell leukemia/lymphoma cells and this likely plays a role in adult T-cell leukemia/ lymphoma cell viability and could potentially be a therapeutic target.79

Therapy Treatment decisions for patients with adult T-cell leukemia/lymphoma vary based on the subclassiﬁcation of adult T-cell leukemia/lymphoma but include vincristine, cyclophosphamide, doxorubicin, and prednisone; doxorubicin, ranimustine, and prednisone; and vindesine, etoposide, carboplatin, and prednisone (VCAP-AMP-VECP), interferon-a plus zidovudine, interferon-a plus arsenic trioxide, allogeneic stem cell transplantation, and targeted therapies such as vorinostat, romidepsin, panobinostat, daclizumab, and pralatrexate (Table 6).75,80 Responses to therapy vary signiﬁcantly by subtype of adult T-cell leukemia/lymphoma. A report from an International Consensus Meeting determined that VCAP-AMP-VECP is effective in patients with acute lymphoma or chronic subtypes of adult T-cell leukemia/lymphoma, interferon-a plus zidovudine appears particularly useful for the treatment of acute, 18

ABELOFF PERIPHERAL T-CELL LYMPHOMA CHAPTER UPDATE chronic, and smoldering adult T-cell leukemia/lymphoma, and allogeneic stem cell transplantation is particularly useful in younger adult T-cell leukemia/lymphoma patients.75 A recent phase 2 study showed promising clinical activity of the combination of arsenic trioxide, interferon-a, and zidovudine in newly diagnosed patients with chronic adult T-cell leukemia/lymphoma subtype.80 Of 10 patients treated, the response rate was 100% without disease progression or relapse at a follow-up of 8 months. Of these patients, 70% achieved complete remission. Autologous stem cell transplantation is of limited value in patients with adult T-cell leukemia/lymphoma based upon data from a handful of reported cases in Japan and one most recently in North America.81 The North American study evaluated the activity of autologous stem cell transplantation in 4 Caribbean and Latin American patients who had relapsed disease of the acute or lymphoma subtype.81 Stage IV disease was present in 3 patients and stage I in the fourth patient. This study demonstrated that autologous stem cell transplantation was ineffective as salvage therapy in relapsed adult T-cell leukemia/lymphoma patients similar to previous ﬁndings. Jiang et al recently reported that of 34 patients with adult T-cell leukemia/lymphoma, CD52 expression was positive in 94.1% of patients.37 These data may suggest a response to treatment with anti-CD52 antibody, alemtuzumab, but studies are lacking.37

TABLE 6. RECOMMENDED STRATEGIES FOR THE TREATMENT OF ATLL. Adapted from Tsukasaki et al.75 Smoldering or favorable chronic-type ATLL • Consider inclusion in prospective clinical trials • Symptomatic patients (skin lesions, opportunistic infections, and so on): consider AZT/IFN-a or watch and wait • Asymptomatic patients: consider watch and wait Unfavorable chronic or acute-type ATLL • Recommend: inclusion in prospective clinical trials • If outside clinical trial, check prognostic factors including clinical and molecular factors if possible – Good prognostic factors: consider chemotherapy with VCAP-AMP-VECP or AZT/IFN-a – Poor prognostic factors: consider chemotherapy followed by conventional or reduced-intensity allogeneic HSCT Lymphoma-type ATLL • Recommend: inclusion in prospective clinical trials • If outside clinical trials, consider chemotherapy with VCAP-AMP-VECP • Check prognostic factors and response to chemotherapy including clinical and molecular factors if possible – Favorable prognostic proﬁles and good response to initial therapy: consider chemotherapy – Unfavorable prognostic proﬁles or poor response to initial therapy with chemotherapy: consider conventional or reduced-intensity allogeneic HSCT

FUTURE DIRECTIONS

Options for clinical trials (ﬁrst-line) • Test the effect of up-front allogeneic HSCT • Test promising targeted therapies such as arsenic trioxide + IFN-a, bortezomib + chemotherapy, or antiangiogenic therapy • Consider a phase 2 global study testing pegylated IFN and AZT

Apart from ALK-positive anaplastic large cell lymphoma, which has a good prognosis with anthracyclinebased chemotherapy, the outcome for most patients with PTCL is very poor and novel treatment approaches are needed. Recently, there have been a spate of interesting drugs that have shown promising activity in these diseases and there has been a leap in our understanding of the molecular biology of these diseases thanks to gene expression proﬁling studies. Preliminary results from targeted agents are promising and suggest usefulness in these diseases. The recent signiﬁcant gains and insights into the epidemiology, pathophysiology, prognosis, and treatment of PTCL will likely contribute to identifying optimal treatment strategies and additional targeted therapies for the treatment of each distinct subtype of PTCL.

Options for clinical trials (relapse or progressive disease) • Test promising targeted therapies such as arsenic trioxide + IFN-a, bortezomib, a purine nucleotide phosphorylase inhibitor, histone deacetylase inhibitors, monoclonal antibodies, antiangiogenic therapy, and surviving, a-catenin, syk, and lyn inhibitors, etc • Consider conventional or reduced-intensity allogeneic HSCT when possible ATLL, adult T-cell leukemia/lymphoma; AZT, zidovudine; HSCT, hematopoietic stem cell transplantation; IFN-a, interferon alpha; VCAP-AMP-VECP, vincristine, cyclophosphamide, doxorubicin, and prednisone; doxorubicin, ranimustine, and prednisone; and vindesine, etoposide, carboplatin, and prednisone.

ABELOFF PERIPHERAL T-CELL LYMPHOMA CHAPTER UPDATE REFERENCES

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ABELOFF PERIPHERAL T-CELL LYMPHOMA CHAPTER UPDATE 57. Verbeek W, Van de Water M, Al-Toma A, Oudejans J, Mulder C, Coupe V. Incidence of enteropathy-associated T-cell lymphoma: a nation-wide study of a population-based registry in The Netherlands. Scand J Gastroenterol. 2008;43:1322-1328.

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62. Harabuchi Y, Takahara M, Kishibe K, Moriai S, Nagato T, Ishii H. Nasal natural killer (NK)/T-cell lymphoma: clinical, histological, virological, and genetic features. Int J Clin Oncol. 2009;14(3):181-190. 63. Kim TM, Heo DS. Extranodal NK / T-cell lymphoma, nasal type: new staging system and treatment strategies. Cancer Sci. 2009; 100(12):2242-2248.

76. Suzumiya J, Ohshima K, Tamura K, et al. The International Prognostic Index predicts outcome in aggressive adult T-cell leukemia/lymphoma: analysis of 126 patients from the International Peripheral T-cell Lymphoma Project. Ann Oncol. 2009; 20:715-721.

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ABELOFF PERIPHERAL T-CELL LYMPHOMA CHAPTER UPDATE

CME TEST QUESTIONS 1. Which of the following is NOT included in the WHO classiﬁcation system as a subtype of PTCL? A. Adult T-cell leukemia/lymphoma B. Anaplastic large cell lymphoma C. Angioimmunoblastic T-cell lymphoma D. Diffuse large B-cell lymphoma E. Enteropathy-associated T-cell lymphoma

6. Which treatment regimens have produced signiﬁcant responses in patients with angioimmunoblastic T-cell lymphoma? A. Alemtuzumab in combination with CHOP, radiotherapy, radiation plus cisplatin and VIPD B. Alemtuzumab in combination with CHOP, zidovudine C. Alemtuzumab in combination with CHOP, high dose therapy plus autologous stem cell transplantation, cyclosporine, and allogeneic stem cell transplantation D. Alemtuzumab in combination with CHOP

2. Changes to the WHO classification of PTCL include all of the following except: A. Enteropathy-type T-cell lymphoma was redefined to enteropathy-associated T-cell lymphoma B. Anaplastic large cell lymphoma is now classified as ALK-positive and ALK-negative C. Angioimmunoblastic T-cell lymphoma with limited paracortical involvement and the follicular variant of PTCL-NOS are now separate entities D. Subcutaneous panniculitis-like T-cell lymphoma is now restricted to only cases that express the TCRab phenotype E. Classification of angioimmunoblastic T-cell lymphoma now includes information on its association with follicular helper T cells of the germinal center

7. Alemtuzumab alone or in combination with CHOP has demonstrated clinical activity in which of the following PTCL subtypes? A. PTCL-NOS, angioimmunoblastic T-cell lymphoma, anaplastic large cell lymphoma, hepatosplenic T-cell lymphoma, enteropathy-associated T-cell lymphoma B. Angioimmunoblastic T-cell lymphoma, hepatosplenic T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma C. Anaplastic large cell lymphoma, PTCL-NOS D. Adult T-cell leukemia/lymphoma, subcutaneous panniculitis-like T-cell lymphoma, extranodal NK/T-cell lymphoma, nasal type

3. Which of the following is a targeted therapy under investigation for the treatment of PTCL? A. Anti-CD25R B. HDAC inhibitor C. Proteasome inhibitor D. All of the above

8. Of the recommended treatment strategies for adult T-cell leukemia/ lymphoma, which remains the primary recommendation? A. Inclusion in clinical trials B. Zidovudine with IFN-a C. Bortezomib plus chemotherapy or arsenic trioxide with IFN-a D. Allogeneic stem cell transplantation

4. Based on data from the PROPEL study which demonstrated a signiﬁcant clinical response in relapsed and refractory patients with PTCL, pralatrexate became the only drug indicated for the treatment of relapsed/refractory PTCL. A. True B. False

9. Expression of CD52 has been found in >90% of patients with which of the following PTCL subtypes? A. Angioimmunoblastic T-cell lymphoma and hepatosplenic T-cell lymphoma B. PTCL-NOS C. Extranodal NK/T-cell lymphoma and anaplastic large cell lymphoma D. Angioimmunoblastic T-cell lymphoma, hepatosplenic T-cell lymphoma, PTCL-NOS, and adult T-cell leukemia/lymphoma

5. Which of the following best describes the role of CD52 positivity in the response to therapy for patients with PTCL? A. Correlation of CD52 positivity with response to therapy has not been established B. CD52 positivity correlates with response to therapy in patients with PTCL-NOS C. Patients who are CD52 positive achieve signiﬁcant responses to alemtuzumab D. CD52 positivity correlates with response to therapy in patients with angioimmunoblastic T-cell lymphoma and anaplastic large cell lymphoma

ABELOFF PERIPHERAL T-CELL LYMPHOMA CHAPTER UPDATE 10. Which of the following statements is TRUE about the distinction between subcutaneous panniculitis-like T-cell lymphoma-ab and SPTCL-ɣδ? A. Prognosis is signiﬁcantly greater in patients with subcutaneous panniculitis-like T-cell lymphoma-ab with 5-year overall survival of 82% versus only 11% in patients with subcutaneous panniculitis-like T-cell lymphoma-ɣδ B. The presence of the hemophagocytic syndrome is uncommon in both variants of the disease C. Subcutaneous panniculitis-like T-cell lymphoma-ab is frequently characterized by ulceration D. CD56 expression is high is both variants of the disease with about 60% of patients expressing the gene

14. Which of the following is TRUE of enteropathyassociated T-cell lymphoma? A. Autologous stem cell transplantation was ineffective in the treatment of enteropathy-associated T-cell lymphoma B. Enteropathy-associated T-cell lymphoma is more prevalent in women than in men C. Most patients have bone marrow involvement D. The peak incidence of enteropathy-associated T-cell lymphoma occurs in the fourth decade of life 15. The 2008 WHO classiﬁcation distinguishes between ALK+ and ALK-anaplastic large cell lymphoma. Patients with ALK+ disease typically have a lower median age of 34 years compared with ALK- disease with a median of 58 years with no differences in gender or stage at presentation. A. True B. False

11. Which of the following is NOT TRUE of adult T-cell leukemia/ lymphoma? A. Adult T-cell leukemia/lymphoma is associated with the retrovirus, human T-cell leukemia virus type 1 or human T-cell lymphotrophic virus type 1 B. Subtypes of adult T-cell leukemia/lymphoma include smoldering, chronic, acute, and lymphoma C. Genetic alterations that contribute to the development of adult T-cell leukemia/lymphoma include overexpression of EPC1 and the generation of EPC1/ASXL2 fusion gene D. Some of the identiﬁed prognostic factors of adult T-cell leukemia/lymphoma include performance status, high lactic dehydrogenase, age ≥40 years, more than 3 lesions and hypercalcemia E. Bone marrow involvement is high in all subtypes of adult T-cell leukemia/lymphoma

16. Recent data suggests a possible role for which targeted therapy for the treatment of anaplastic large cell lymphoma? A. Anti-CD22 B. Proteasome inhibitor C. Anti-CD30 D. HDAC inhibitor 17. Which of the following is FALSE with regard to PTCL-NOS? A. Numerous prognostic genetic factors have been identiﬁed but clinical relevance is still unknown B. PTCL-NOS is the most common PTCL subtype C. Most patients present in the 5th to 7th decade of life D. Preliminary studies failed to demonstrate a clinical beneﬁt of alemtuzumab in patients with PTCL-NOS

12. Which of the following is FALSE regarding the proposed new staging system for extranodal NK/T-cell lymphoma? A. Extranodal nasal NK/T-cell disease is classiﬁed as limited if stage I/II without tumor invasiveness or as extensive disease if either stage I/II with local invasiveness, stage III/IV, or extranodal disease B. The new staging system is based upon prognostic factors C. Patients with limited disease beneﬁt from chemotherapy followed by radiation but patients with extensive disease have a poor prognosis with limited treatment options D. The new staging system is based upon treatment outcomes

18. Which of the following is TRUE of pralatrexate in patients with PTCL? A. Pralatrexate produced a overall response rate of 67% with a median overall survival of 6 months B. The most common stage 3 or 4 adverse events are thrombocytopenia and leukopenia C. Phase I data demonstrated that pralatrexate in combination with gemcitabine resulted in unacceptable toxicity D. NCCN guidelines suggest the use of pralatrexate as second-line therapy for the treatment of PTCL

13. Several case reports suggest a possible role of which agent for the treatment of hepatosplenic T-cell lymphoma? A. Bortezomib B. Zanolimumab C. Denileukin diftitox D. Alemtuzumab

ABELOFF PERIPHERAL T-CELL LYMPHOMA CHAPTER UPDATE

CME TEST ANSWER SHEET AND EVALUATION FORM Release Date of Activity: May 2010 | Expiration Date of Activity for AMA PRA Credit: May 31, 2011 Estimated Time to Complete this Activity: 2.0 hour Get instant CME credits. Complete your test online and download your certiﬁcate now! Log on to www.elseviercme.com/getcme/930006 Please add eocme@elseviercme.com to your e-mail “safe” list. Please Print Name:

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Degree: ❒ MD ❒ DO ❒ PharmD ❒ RPh ❒ NP ❒ RN ❒ BS ❒ PA ❒ Other: Afﬁliation: Street: City:

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(All information is conﬁdential.) CME Credit Veriﬁcation I verify that I have spent ____ hour(s)/______ minutes of actual time working on this CME activity. No more than 2.0 CME credit(s) will be issued for this activity. PRETEST ASSESSMENT: Please rate your current knowledge regarding the diagnosis, staging, and treatment of peripheral T-cell lymphoma, with 1 being the lowest and 5 the highest. 1 2 3 4 5 CME TEST (Please circle correct answers.) 1. A B C D E

5. A B C D

9. A B C D

13. A B C D

17. A B C D

2. A B C D E

6. A B C D

10. A B C D

14. A B C D

18. A B C D

3. A B C D

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11. A B C D E

15. A B

4. A B

8. A B C D

12. A B C D

16. A B C D

ABELOFF PERIPHERAL T-CELL LYMPHOMA CHAPTER UPDATE COURSE EVALUATION:

Please evaluate the effectiveness of this activity in increasing your knowledge regarding the following by circling your choice on a scale of 1 to 5, with 1 being the lowest and 5 the highest. Lowest

Highest

Cite the incidence and prevalence of peripheral T-cell non-Hodgkin’s lymphomas as well as differentiate between the subsets of cancers that comprise this designation

Describe the epidemiology and the underlying causes (where known) of the various peripheral T-cell lymphomas

Identify the appropriate diagnostic and prognostic criteria necessary for the diagnosis and staging of the various peripheral T-cell lymphomas

Formulate an appropriate treatment plan based on appraisal of the beneﬁts and limitations of current and future treatment options for patients with peripheral T-cell lymphomas

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Was the presented information fair, objective, balanced, and free of bias in the discussion of any commercial product or service?

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Please indicate if this activity has improved your: 1. ❒ Medical knowledge 2. ❒ Practice-based learning and improvement 3. ❒ Communication & interpersonal skills 4. ❒ Professionalism 5. ❒ Systems-based practice 6. ❒ Patient care Approximate percentage of patients you manage for the disease addressed by this activity?

❒ 0–20% ❒ 21–40% ❒ 41–60% ❒ 61–80% ❒ >80% ❒ Yes ❒ No After participation in this activity, have you decided to change one or more aspects of the treatment of your patients? If yes, what changes will you make?: If no, please indicate what barriers you might have encountered: ❒ Already treating this way ❒ Time ❒ Patient non-adherence ❒ Not on formulary ❒ Not reimbursable by insurance ❒ Other: Please specify

Please indicate How you heard about this activity? Would you be willing to participate in post-activity follow-up surveys?

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The EOCME thanks you for your participation in this CME activity. All information provided improves the scope and purpose of our programs and your patients’ care. CME INSTRUCTIONS This activity provides up to 2.0 free AMA PRA Category 1 Credit(s)™. Log on to above URL to print your certiﬁcate now, or forward the Test Answer Sheet and Evaluation Form to the address shown below. Elsevier Ofﬁce of Continuing Medical Education Department 930006 1600 John F Kennedy Blvd. #1800 Phila., PA 19103-2398

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NOTES

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