update on peripheral t-cell lymphoma

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.

Peripheral T-cell Lymphoma: Current State of Knowledge RegardingDiagnosis, Staging, and TreatmentEDITOR, JAMES O. ARMITAGE, MDAUTHOR, KIERON DUNLEAVY, MD

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

ACCREDITATION STATEMENTThis educational activity has been planned and implemented in accordance with the Essential Areas and policiesof 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 STATEMENTThe 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 INFORMATIONAs a sponsor accredited by the ACCME, it is the policy of the EOCME to require the disclosure of anyonewho is in a position to control the content of an educational activity. All relevant financial relationships withany 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, MDJoe Shapiro Professor, Section of Hematology/Oncology, Department of Internal MedicineUniversity of Nebraska Medical Center, Omaha, NebraskaDisclosures: Advisory Board: Seattle Genetics; Ziopharm Independent Data Monitoring Committee: Biogen Idec Consultant: Allos Therapeutics, Inc.

Kieron Dunleavy, MDInvestigator and Attending Physician, Lymphoma Section, Metabolism Branch, National Cancer Institute,Bethesda, Maryland. Disclosures: Nothing to disclose

Mary Ellen Shepard, PhD—Medical WriterDisclosures: Nothing to disclose

Robert Reina, MS, MBA—Educational ReviewerDisclosures: Nothing to disclose

EOCME StaffDisclosures: The following EOCME staff have nothing to disclose:Tania Dickson, PhDJennifer DiBenedetto, EdMSandy Breslow, B.Sc.

RESOLUTION OF CONFLICT OF INTERESTThe EOCME has implemented a process to resolve conflict of interest for each CME activity. In order to helpensure content objectivity, independence, and fair balance, and to ensure that the content is aligned with theinterest of the public, the EOCME has resolved the conflict by external content review.

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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 ongoingresearch, interim analyses, and/or unsupported opinion.

Faculty may discuss information about pharmaceutical agents that is outside of FDA-approved labeling. Thisinformation is intended solely for CME and is not intended to promote off-label use of these medications. Ifyou have questions, contact the medical affairs department of the manufacturer for the most recent prescribinginformation.

INTENDED AUDIENCEThis program is intended for hematologists, oncologists, and health care providers responsible for the care ofpatients with peripheral T-cell non-Hodgkin’s lymphoma.

EDUCATIONAL OBJECTIVESAfter 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 thevarious peripheral T-cell lymphomas

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

Release Date of Activity: May 2010Expiration Date of Activity for AMA PRA Credit: May 31, 2011Estimated Time to Complete is Activity: 2.0 hour

CME INQUIRIESFor all CME certificate inquiries, please contact Tristan Nelsen at [email protected].

FINANCIAL SUPPORTThis 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 PARTICIPATIONTo 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

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INTRODUCTION

Peripheral T-cell lymphomas (PTCLs) represent approximately 12% of lymphomas.1 The incidence ofPTCL increases with age, has a higher incidence in menwith a male-to-female ratio of about 1.8:1, and is dependentupon geographic location.2 Worldwide, the incidence ofPTCL 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 somesubtypes of PTCL, the incidence is higher in blacks,Asians, or Pacific Islanders than in whites.

The incidence of PTCL has increased significantly inthe past 2 decades.2 In the United States, during the periodbetween 1992 and 2005, the incidence of PTCL increased7.9% annually.2 Of note, more than 50% of PTCL casespresent with stage III or IV disease.2-4 In the UnitedStates, 5-year relative survival rates for PTCL remainpoor, ranging from 29% to 48%.2

PTCL includes a heterogeneous group of at least 14 distinct T-cell lymphomas that differ significantly inpathobiology and response to treatment. Due to the rarityand heterogeneity of this entity, PTCL remains poorlyunderstood and for many subtypes optimal therapies arelacking and there is no consensus on treatment. With theexception of patients with anaplastic lymphoma kinase(ALK)-positive anaplastic large cell lymphoma, whohave an excellent outcome with anthracycline-basedchemotherapy, most other PTCL patients have pooroutcomes with current treatment strategies and shouldbe considered for enrollment into clinical trials. In 2001,the World Health Organization (WHO) published thethird edition of the Classification of Tumours ofHaematopoietic and Lymphoid Tissues, which was thefirst worldwide consensus on the classification of thesetumors, including PTCL.5 Recently, in 2008, an updatedfourth edition of this WHO Classification was published.However, since the publication of the fourth edition in2008, several studies have shed new light on the under-standing and treatment of PTCL. Here we provide anupdated review that highlights the recent findings whichcontribute to the current understanding of the epidemiology,pathophysiology, role of diagnostic and prognostic markers, and novel therapies for the treatment of PTCL by subtype.

UNDERSTANDING THE REVISED WORLD HEALTH ORGANIZATION CLASSIFICATION SYSTEM

PTCL constitutes a heterogeneous group of diseases with distinct clinical characteristics, presentation, andoutcomes. Agreement between experts is poor for manylymphoma subtypes and misdiagnosis is common.4,6,7

In a retrospective study, the rate of misdiagnosis ofPTCL was approximately 10%.6 In this analysis, experienced pathologists misdiagnosed at a rate of11.2% compared with a non-hematologist group, whomisdiagnosed 24.4% of cases. Pathology findings fromthe International T-Cell Lymphoma Project revealed a similar rate of misdiagnosis of 10.4%.4 However, misdiagnosis varied significantly depending on PTCLsubtype. The most frequently misdiagnosed subtypeswere hepatosplenic, ALK-negative anaplastic large celllymphoma, subcutaneous panniculitis-like T-cell lymphoma,and anaplastic large cell lymphoma.

In the revised fourth edition of the WHO Classificationof Tumours of Haematopoietic and Lymphoid Tissues, PTCLnodal and extranodal disease included: PTCL-not otherwisespecified (NOS); angioimmunoblastic T-cell lymphoma;adult T-cell leukemia/lymphoma; anaplastic large celllymphoma; 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 extranodaland systemic disorder.5 Subtypes of PTCL were furtherdefined based on new clinical, pathological, immunophenotypic,or genetic findings (Table 1).8

In the 2008 edition, classification of angioimmunoblasticT-cell lymphoma includes information on its associationwith follicular helper T cells of the germinal center.5

The follicular variant of PTCL-NOS shares a similarphenotype to angioimmunoblastic T-cell lymphoma,but not genetic or clinical characteristics.8 The WHO2008 classification recognizes that further clarification isneeded between angioimmunoblastic T-cell lymphomawith limited paracortical involvement and the follicularvariant of PTCL-NOS.5

Enteropathy-associated T-cell lymphoma has beenredefined using more restrictive criteria and was renamedfrom enteropathy-type T-cell lymphoma. The diseaseoften presents with intestinal perforation, an aggressiveclinical course, and has a poor prognosis. It has a broadmorphological spectrum and adjacent mucosa often

4


5


shows villous atrophy. Diagnosis relies on evidence ofceliac disease either genetically by determination of ahuman leukoctye antigen phenotype or by histology inthe adjacent uninvolved small bowel mucosa.8 In caseswhere monomorphic medium-sized cells are present, thedisease is subclassified as type II enteropathy-associatedT-cell lymphoma.5 Type II enteropathy-associated T-celllymphoma has a distinct immunophenotype that is nowrecognized as also being CD56+, CD8+, and CD4-. Theclassical enteropathy-associated T-cell lymphoma oftenhas gains in 1q and 5q, whereas type II enteropathy-associated T-cell lymphoma is characterized by MYCamplifications.

Anaplastic large cell lymphoma is now classifiedinto ALK-positive and ALK-negative disease. ALK-negative disease is now a provisional entity that is similarto ALK-positive disease in terms of morphology, phenotype,and genotype, but lacks the anaplastic large cell lymphomakinase protein.5 ALK-negative disease generally has apoorer prognosis than ALK-positive disease. However,unlike Hodgkin lymphoma, ALK-negative anaplasticlarge cell lymphoma is negative for both PAX5 and CD15.

The diagnostic criteria for subcutaneous panniculitis-like T-cell lymphoma were redefined because of significantdifferences in the clinical course of the disease based onT-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 Researchand Treatment of Cancer Cutaneous Lymphoma Groupreported on a study of 83 cases of subcutaneous panniculitis-like T-cell lymphoma. The study demonstrated thatsubcutaneous panniculitis-like T-cell lymphomas with

an ab T-cell phenotype are distinct from those with a ɣδphenotype differing in their clinicopathologic findingsand prognosis.10 Patients with ab subcutaneous panniculitis-like T-cell lymphoma had a significantly better prognosisthan those with ɣδ subcutaneous panniculitis-like T-celllymphoma with 5-year overall survival rates of 82% versus11%, respectively. The ɣδ subcutaneous panniculitis-likeT-cell lymphoma is now referred to as a cutaneous ɣδ T-celllymphoma.

NOVEL TARGETS FOR THE TREATMENT OF PTCL UNDER INVESTIGATION INCLINICAL TRIALS

A significant effort has been made to identify noveltargets 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, histonedeacetylase inhibitors, and proteasome inhibitors, whichtarget a variety of novel pathways for the treatment ofPTCL (Figure 1). For example, pralatrexate, a folate antagonist, which will be discussed in detail in the following section, has promising activity in PTCL and isFDA-indicated for relapse and refractory PTCL. Histonedeacetylase inhibitors including romidepsin and belinostatalso have promising activity in refractory or recurrentPTCL.11,12 Preliminary studies show efficacy of zanolimumab,an anti-CD4R antibody, in 21 patients with relapsed orrefractory PTCL including enteropathy-associated T-celllymphoma, anaplastic large cell lymphoma, angio -immunoblastic T-cell lymphoma, and PTCL-NOS.13

An objective tumor response was achieved in 23.8% of

AITL Follicular helper T-cell involvement now recognized; follicular variant of PTCL-NOS hassimilar phenotype

EATL Renamed from enteropathy-type T-cell lymphoma; a variant is classified as type II EATLwith 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 kinaseprotein 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-celllymphoma; ALCL, anaplastic large cell lymphoma; ALK, anaplastic lymphoma kinase; SPTCL, subcutaneous panniculitis-like T-cell lymphoma.

TABLE 1. SUMMARY OF KEY UPDATES TOTHE 2008 WHO CLASSIFICATION OF PTCL5

PTCL Subtype Update

patients with 2 complete responses and 3 partial responses.Another monoclonal antibody, SGN-35, against CD30,was evaluated in 45 patients with relapsed or refractoryCD30-positive lymphomas.14 The objective responserate was 46% with a complete remission rate of 25%.Median duration of response was 22 weeks, although thestudy was ongoing at time of publication. A number ofphase 2 clinical trials are under way investigating denileukindiftitox, an anti-CD25R target, in patients with PTCL. Inthe CONCEPT trial, patients (n = 41) receiving denileukindiftitox plus cyclophosphamide, doxorubicin, vincristine,and prednisone (CHOP) achieved an overall response rateof 90% with 71% complete responses.15 The initial reportof an ongoing phase 2 trial evaluating oral lenalidomidein patients with previously untreated or relapsed PTCLsuggests clinical activity of this agent.16 Of 10 patientstreated, 4 partial responses were achieved in patients withPTCL-NOS and angioimmunoblastic T-cell lymphomaand stable disease in 1 patient with PTCL-NOS. Theproteasome inhibitor bortezomib has also shown activityin a study that included 2 patients with PTCL-NOS with1 patient who had isolated skin involvement responding.17

Other studies demonstrate efficacy of the anti-CC chemokinereceptor 4 (CCR4) antibody, KW-0761, in patients withrelapsed or refractory CCR4-positive adult T-cell leukemia/lymphoma and PTCL. As optimal treatment regimens

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ImmunophenotypeT-cell receptor bF1+, TCRδ1- bF1-, TCRδ1+T-cell phenotype CD3+, CD4-, CD8+ CD3+, CD4-, CD8-Coexpression CD56 Absent Common (60%)

Histological features Subcutaneous Subcutaneous and epidermal/dermal

Clinical features Nodules and plaques, rarely Nodules and plaques, ulceration, association with ulceration commonautoimmune disorders (20%)

HPS Uncommon (17%) Common (50%)

5-year overall survival 82% 11%Without HPS 91% —With HPS 46% —

Preferred terminology SPTCL CGD-TCL

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

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

SPTCL-ab SPTCL-ɣδ

Daclizumab Anti-CD25R 1/2Denileukin diftitox Anti-CD25R 2Yttrium-CD25 Anti-CD25R 1/2SGN-30 Anti-CD30 1/2MDX-060 AntiCD30 1/2SGN-35 Anti-CD30 1/2Zanolimumab Anti-CD4R 2KW-0761 Anti-CCR4 1Pralatrexate Folate inhibitor 2Bortezomib Proteasome inhibitor 2Belinostat HDAC inhibitor 2Vorinostat HDAC inhibitor 2Romidepsin HDAC inhibitor 2Panobinostat HDAC inhibitor 2Lenalidomide Immunomodulator 2

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

TABLE 3. NOVEL TARGETED THERAPIESIN CLINICAL DEVELOPMENT FOR THETREATMENT OF PTCL

Phase of Therapy Target Development

and single-agent clinical activity of these targeted therapiesare being elucidated, new agents with significant clinicalactivity are being investigated in combination therapy.

PTCL (STUDIES NOT SUBDIVIDED BY TYPE)

DiagnosisThe role of 18fluoro-2-deoxyglucose positron emission

tomography (PET) in the diagnosis of PTCL has notbeen well established at this time and is currently underinvestigation in clinical trials. However, findings of highpositive pretreatment 18fluoro-2-deoxyglucose PET ratessuggest a possible role for 18fluoro-2-deoxyglucose PET inthe management of patients with PTCL. Based on theutility of 18fluoro-2-deoxyglucose PET in the staging,response, and prognosis of malignant lymphoma, a study of 41 patients with PTCL evaluated the role of18fluoro-2-deoxyglucose PET in NK/T-cell lymphomas.18

18Fluoro-2-deoxyglucose PET detected a lymphoma lesionin 100% of patients with extranodal NK/T-cell lymphoma,nasal type, anaplastic large cell lymphoma, and angio -immunoblastic T-cell lymphoma and in 91% of patientswith PTCL-NOS. However, 18fluoro-2-deoxyglucose PET

only detected bone marrow involvement in 20% of patients with bone marrow involvement confirmed bybiopsy. Thus, additional studies into the feasibility of 18fluoro-2-deoxyglucose PET in staging PTCL are needed.

TherapyAs demonstrated by large studies such as the Inter-

national T-cell Lymphoma Project,4 with the exception ofALK-positive anaplastic large cell lymphoma, outcomeswith conventional chemotherapy have been very disappointing in most PTCLs and indeed the only subtype that has been shown to benefit from anthracycline-based 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, manydemonstrating good activity. Recently, data from one ofthe largest prospective phase 2 studies on PTCL to date,the Pralatrexate in Patients with Relapsed or RefractoryPeripheral T-cell Lymphoma (PROPEL) study, demon-strated significant clinical activity using pralatrexate (Table 4, Table 5).19 In PROPEL, pralatrexate was administered to 111 heavily pretreated patients with

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CD4R

LAT

LCK

ZAP-7

0

CD4R

IL-2Rx

CD-30

TCR

CD3complex

Anti-CD25R mAbs

DaclizumabY90-anti-CD25R

Denileukin diftitox*Target IL-2 effects

Anti-CD4R

Zanolimumab*Inhibits amplification

of TCR via lck

Anti-CD30 mAbs

MDX-060SGN-30SGN-35

*Target TNF-α effects(NK-β signaling)

Histone Deacetylases

VorinostatBelinostatPabinostatRomidepsin

Proteosome Inhibitors

Bortezomib

Immunomodulators

Lenalidomide

Anitbody DependentCellular Cytotoxicity

anti-CCR4 KW-0761

Figure 1. Schematic representation of the pathways targeted in the treatment of PTCL currently under clinical investigation.

relapsed or refractory PTCL. The majority of patients(53%) had PTCL-NOS. The overall response rate was27% with 10% of patients achieving a complete response,17% achieving a partial response, and 21% having stabledisease. Sixty-nine percent of responders did so aftercycle 1. The mean duration of response was 306 days (range1–673) and median overall survival was 14.5 months with55% of patients surviving longer than 12 months. Themost frequent grade 3 or 4 adverse events were mucosal inflammation and thrombocytopenia. Based on data fromthe PROPEL study, pralatrexate received accelerated USFood and Drug Administration approval and is currentlythe only drug indicated for the treatment of relapsed orrefractory PTCL. As a result of this trial, National Comprehensive Cancer Network guidelines now suggestthe use of pralatrexate as second-line therapy for thetreatment of PTCL.20

Subgroup analyses from PROPEL assessed responseto pralatrexate in patients who were considered refractoryto their prior therapy, defined as: (1) no evidence of responseto 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 theirmost recent therapy, 17/69 responded to pralatrexate(overall response rate 25%) and the overall duration ofresponse ranged from 41 to 673 days. Among the patientswith no evidence of response to any prior therapy, 5/26(19%) responded to pralatrexate and the duration of responseranged from 52 to 306 days.21

Recently, a phase 1 study investigated the combinationof pralatrexate and gemcitabine with B12 and folic acidin patients with relapsed or refractory lymphoproliferative

disorders including PTCL.22,23 This study established themaximum tolerated dose and schedule of the combinationof pralatrexate and gemcitabine in 33 evaluable heavilypretreated patients with non-Hodgkin’s lymphoma andHodgkin’s lymphoma, 12 of whom had PTCL. Thestudy determined that treatment with pralatrexate plusgemcitabine was feasible when given every 2 weeks.Weekly dosing resulted in unacceptable toxicity. Whengiven on sequential days every 2 weeks, the maximumtolerated dose was pralatrexate/gemcitabine 10/400mg/m2, but when administered every 2 weeks on thesame day it was 15/600 mg/m2. The most frequentgrade 3/4 adverse events were anemia, neutropenia,thrombocytopenia, leukopenia, and abnormal liver function.Of the 33 evaluable patients, 8 (24%) achieved a partialresponse. Of 11 evaluable patients with PTCL, 2 patientsachieved a partial response, 2 had stable disease, and 7had progressive disease. Based on these preliminary findingsa phase 2 expansion study is under way to evaluate bothsequential and same-day combination therapy given every2 weeks in patients with PTCL, Hodgkin lymphoma, andB-cell lymphoma.

In newly diagnosed patients with PTCL, 2 studieshave evaluated the role of high-dose chemotherapy andautologous stem cell transplantation consolidation.24,25 Inone study of 18 patients primarily with stage III or IV disease,patients were treated with sequential chemotherapy of 3cycles 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 arabinosidefollowed by consolidation with myeloablative conditioningand autologous stem cell support.25 Patients had a completeresponse rate of 61%, partial response rate of 17%, and22% had stable disease. Two-year progression-free survivalwas 52%. In another study, 39 patients with PTCL weretreated with ranimustine, carboplatin, etoposide, and cyclophosphamide or a total body irradiation-based regimenprior to autologous stem cell transplantation. Five-yearoverall survival was 62.2% with a median follow-up of78 months and was significantly higher in patients whowere in complete or partial remission during transplan-tation than in those with other disease status (73.1% vs45.8%; P = .033).

Furthermore, a recent study suggests that intensiveprimary chemotherapy and autologous stem cell trans-plantation may significantly improve outcomes in patientswith PTCL compared with CHOP-like regimens.26

This study evaluated a regimen of CHOP followed by

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CR + CRu + PR 29 27CR 10 9CRu 1 <1PR 18 17SD 23 21PD 40 37

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

TABLE 4. SUMMARY OF RESPONSE RATESIN PATIENTS RECEIVING PRALATREXATEENROLLED IN THE PROPEL STUDY (N = 109) EVALUABLE PATIENTS

Response n Response Rate (%)

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PTCL/PTCL-NOS

Pralatrexate/PROPEL 111 ORR: 27% 17CR: 10%PR: 17%SD: 21%

CHOEP-21 x 3 cycles, ifosfamide x 1 cycle, methotrexate- 18 CR: 61% 23based regimen, priming regimen with cytosine arabinoside PR: 17%followed by consolidation with myeloablative conditioning SD: 22%and autologous stem cell support 2-year PFS: 52%

Ranimustine, carboplatin, etoposide, and cyclophosphamide 39 5-year OS: 62.2% 22or a total body irradiation-based regimen prior to autologous 5-year PFS: 60.6%SCT CR: n = 23

CR1/PR1: n = 17

Alemtuzumab + CHOP/GITIL 14 CR: 50% 36PR: 7%

MR: 7%Duration: 11 months

Alemtuzumab + fludarabine 2 ↑ susceptibility to EBV 38

AITL

Alemtuzumab + CHOP/GITIL 6 CR: 100% 36

High-dose chemotherapy + autologous 142 CR: 70% 42SCT evaluable 2-year OS: 59%

Allogeneic SCT 45 3-year OS: 64% 43

First-line R-CHOP 4 CR: 100% 44

Cyclosporine 12 RR: 67%CR: n = 3PR: n = 5 45

ALCL

Alemtuzumab + CHOP 3 ALK– CR: 100% 36

Daclizumab 1 CR: >45 months 47

SGN-30/phase 1 1 CR: 26 months 49

SGN-30/phase 2 41 RR: 32% 50CR: n = 2 PR: n = 5

MDX-060/phase 1/2 7 CR: n = 2 51

HSTCL

Alemtuzumab + allogeneic SCT 1 CR: >39 months 52

Alemtuzumab 1 No response 53

TABLE 5. SUMMARY OF KEY FINDINGS FROM RECENT CLINICAL TRIALS OF NOVEL TREATMENTSTRATEGIES IN PTCL

PTCL Subtype erapy/Study N Key Findings Reference

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Alemtuzumab + cladribine 1 CR: clinical + 55molecular over 2 years

Alemtuzumab + fludarabine 1 CR: 3 months' duration 54

EATL

High-dose chemotherapy + autologous SCT 4 CR: 25% 57No improvement

in survival

Alemtuzumab + CHOP/GITIL 1 CR: 100% 36

Extranodal NK/T-cell lymphoma, nasal type

First-line radiotherapy vs radiochemotherapy 64 5-year survival: 6557% vs 62%; P = .47

PFS: 52%; P = .13CR: 69.6% vs 87.8%

Concurrent radiation + cisplatin followed by VIPD 30 CR: 80% 66PR: 20%

3-year OS: 86%3-year PFS: 85%

First-line concurrent radiotherapy + DeVIC vs radiotherapy 26 ORR: 81% 67alone/JCOG0211 CR: 77%

SPTCL

Denileukin diftitox 2 CR: 100% 71Duration: >6 months

After bexarotene: 1 patient returned to remission

Fludarabine, mitoxantrone, dexamethasone 1 CR: 100% 72Duration: >40 months

Pirarubicin, cyclophosphamide, dexamethasone, vincristine, 1 CR: 100% 73L-asparaginase followed by CHASE + autologous SCT Duration: >3 years

ATLL

Arsenic trioxide, IFN-a, zidovudine 10 RR: 100% 79CR: 80%

Duration: >8 months

Autologous SCT 4 Ineffective as salvage 80therapy

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-associatedT-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.

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

3 courses of ifosfamide, etoposide, and epirubicin alternatingwith intermediate-dose methotrexate followed by consolidation with myeloablative autologous stem celltransplantation. The majority of patients had enteropathy-associated T-cell lymphoma or PTCL-NOS. Of 55 patientsevaluated, 71% achieved complete remission, 5% achievedpartial remission, and 24% failed treatment. Three-yearprogression-free survival was 59% and overall survivalwas 67%. The most common severe toxicities were pancytopenia, infection, nausea and vomiting, and obstruction or perforation.

PTCL-NOT OTHERWISE SPECIFIED

Epidemiology and PathophysiologyPTCL-NOS is the most common (40% to 50%) and

heterogeneous subtype of PTCL due to its diagnosis ofexclusion.2 Due to its heterogeneous nature, the tumorcell morphology is variable.2,27 Most patients present inthe fifth to seventh decade of life with the majority havingstage III to IV disease.2,27 PTCL-NOS is generally an aggressive disease with poor overall survival with 5-yearsurvival rates between 20% and 30%.2,27

The pathophysiology of PTCL-NOS is poorly under-stood. However, distinct transforming genetic alterationshave been identified for PTCL-NOS.28 While the preciserole in disease manifestation is not known, these findingsprovide insight into the complexity of the disease. Recurrentcopy number gain on chromosomes 8q, 9p, and 19q anda loss of copy number was recently detected at chromosomes3q and 9p.28 Specific genes were found to map to theselocations including those for cyclin-dependent kinasesoften silenced or deleted in cancer cells, CDKN2A andCDKN2B, which correlated with poor clinical outcome.Poor prognosis has been linked to overexpression of thecaspase recruitment domain membrane-associatedguanylate kinase protein 1 (CARMA1) at 7p22, whichis 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 theoncogene MYC. A loss of heterozygosity was detected at chromosome 2, which correlated with expression of a novel isoform of IKZF2, an IKAROS-family relatedtranscriptional factor for regulation of lymphocyte development. The variant isoform of IKZF2 was foundto correlate with several patients with PTCL-NOS butnot other patients or healthy subjects. Most recently,gene expression profiling identified a distinct molecular

subgroup of PTCL-NOS with features of cytotoxic cells,a distinct set of cytokines and receptors, and a compleximmunosuppressive gene signature.29 Patients in thissubgroup had a poorer overall survival (P = .05) andevent-free survival (P = .06) compared with otherPTCL-NOS cases.

Bone marrow involvement is present in 30% to50% of all PTCL patients.30 The incidence of bone marrow infiltration is higher (57%) in patients withPTCL and T-cell lymphoma-associated hemophagocyticsyndrome than in those without the syndrome (32%; P <.05). These results suggest that early bone marrowinfiltration may characterize T-cell lymphomas with T-cell lymphoma-associated hemophagocytic syndrome.

The Current Role of Diagnostic and PrognosticMarkers in PTCL-NOS

The availability of prognostic and diagnostic data isincreasing with preliminary analyses identifying prognosticgenetic factors occurring in specific PTCL subtypes. Largerregistries and comparative analyses are revealing differencesamong PTCL subtypes in clinical characteristics andprognostic markers. A new clinical-pathologic prognosticscore was proposed for PTCL-NOS based on the evaluationof 19 markers in 93 patients with PTCL-NOS. Theprognostic index was composed of a mixed patient- andtumor-specific prognostic score that included proliferation-associated protein Ki-67 ≥80%, age >60 years, high lactatedehydrogenase, and poor performance status.31 This scoringsystem differentiated between 3 groups of patients withdiffering responses to therapy and survival based uponthe presence and number of factors. Patients in group 1had none or one of the factors, group 2 had 2 factorspresent, and group 3 had 3 or 4 factors present. Thisprognostic 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 CzechLymphoma Study Group registry, the 3-year survivalprobability was 36%.3 Multivariate analyses revealedclinical stage IV and achievement of complete response asindependent predictors of survival. Another retrospectivestudy of 84 patients with PTCL-NOS revealed a 5-yearsurvival rate of 41%.32 In this study, multivariate analysesdemonstrated that the presence of B symptoms, Inter -national Prognostic Index scores ≥3, a Prognostic Index forPTCL-NOS ≥2, and poor Eastern Cooperative Oncology

11


Group performance status were poor prognostic factors.In a study evaluating the clinical outcomes and prognosticfactors for high-dose chemotherapy followed by autologousstem cell transplantation in 64 Korean patients with PTCL-NOS, 3-year overall survival was 53%.33 Multivariateanalysis revealed that a failure to achieve a complete response at transplantation and high Prognostic Indexscores of 2 to 3 were both independent prognostic factorsfor survival.

Data from 123 patients with relapsed/refractory PTCL registered in the GEL/TAMO registry was evaluatedto identify pretransplant prognostic information.34

Five-year overall survival was 45% while progression-free 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 predictedprogression-free survival. Using these factors allowed for stratification of patients into 3 prognostic groups.Patients with no pretransplant adverse factors had anoverall survival of 60%, those with 1 adverse factor hadan overall survival of 28%, and those with both factorsall died from their disease.

Another study evaluating 31 patients with angio -immunoblastic T-cell lymphoma and 37 patients withPTCL-NOS for prognostic factors determined that a low serum albumin and mediastinal lymphadenopathywere predictive of worse overall survival in patients with PTCL-NOS.35 Independent predictors for a shorterprogression-free survival were performance status ≥2 andmediastinal lymphadenopathy.

Comparative analysis of extranodal NK/T-cell lymphoma and PTCL, including PTCL-NOS, angioimmunoblastic T-cell lymphoma, anaplastic largecell lymphoma, and other subtypes, revealed significantdifferences in clinical characteristics and prognosis.36

Patients with extranodal NK/T-cell lymphoma typicallypresented with early stage (I or II) and had more than 2 sites of extranodal involvement compared with patientswith PTCL. However, 5-year survival rates for patientswith PTCL, regardless of subtype, were significantlybetter than for those with NK/T-cell lymphoma (48%vs 20%; P < .003). Patients with extranodal NK/T-celllymphoma were 4 times more likely to die from theirdisease compared with PTCL patients.

Prognosis-related chromosome copy number alterationshave been identified in patients with PTCL-NOS.28

A poor prognosis was linked to copy number gains at

13q22.3 locus, which correlated with increasedMYCBP2 expression in patients with PTCL-NOS. A loss of heterozygosity at chromosome 8 was also correlated with poor clinical outcome.

TherapyThe outcome for patients with PTCL-NOS is poor

with current treatments, and novel strategies are needed.The International Peripheral T-Cell Lymphoma Studydemonstrated that patients with PTCL-NOS as well asNK/T-cell lymphoma did not benefit from the use of ananthracycline-containing regimen.4 Currently, even thebest available therapies do not appear to significantlyimprove outcomes in these patients evidenced by dismallong-term survival rates of 10% to 30%.

Several recent findings suggest targeted therapywith the anti-CD52 agent, alemtuzumab, in combinationwith chemotherapy may be effective in patients withPTCL-NOS. A recent study demonstrated that PTCL-NOSis positive for CD52 with 92% of cases expressing CD52in neoplastic cells (Figure 2).37 It is still unknown whetherthe expression of CD52 correlates with a response totherapy. However, a prospective multicenter study fromthe Gruppo Italiano Terapie Innovative nei Linfomi(GITIL) evaluated the efficacy of the combination ofalemtuzumab and CHOP as first-line treatment of 24patients with PTCL, angioimmunoblastic T-cell lymphoma,or anaplastic large cell lymphoma.38 Of 14 patients with PTCL-NOS, 50% achieved a complete responseand 1 patient each had a partial and minor response. The median complete response duration was 11 monthsin 14 of 17 patients. The combination of alemtuzumabwith dose-adjusted etoposide, prednisone, vincristine,cyclophosphamide, and doxorubicin has also demon-strated 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 susceptibilityto Epstein-Barr virus-associated B-cell lymphoma in patients with PTCL-NOS or angioimmunoblastic T-celllymphoma.40 Two cases were identified in which patientswho were severely immunocompromised developed Epstein Barr virus-associated B-cell lymphoma aftertreatment with this regimen. The authors suggestedthat the addition of immunosuppressive therapy withcytotoxic drugs may significantly exacerbate patients’immunodeficiency.

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ANGIOIMMUNOBLASTIC T-CELL LYMPHOMA

Epidemiology and PathophysiologyThe molecular mechanisms for the development

of angioimmunoblastic T-cell lymphoma are not well understood. In order to help characterize the relation-ships between angioimmunoblastic T-cell lymphoma,PTCL-NOS, anaplastic large cell lymphoma, and normal T cells, gene expression profiling studies wereundertaken.41 Angioimmunoblastic T-cell lymphoma is closely related to activated T cells, specifically CD4cells with a gene expression profile typical of T follicularhelper lymphocytes.41 Compared with normal CD4 andCD8 cells, angioimmunoblastic T-cell lymphoma tumorsoverexpressed genes related to tissue invasiveness, angiogenesis, resistance to chemotherapy, neoplastictransformation, and cell adhesion.

A review of the presence of PTCL in the bone marrowof 173 patients, showed that 54% of these patients havebone marrow involvement, including 7 of 11 (64%) of thepatients with angioimmunoblastic T-cell lymphoma.30

Among all patients with PTCL, bone marrow involvementwas associated with a worse prognosis. The median overall survival was 120 days and 356 days for patientswith or without bone marrow involvement, respectively.

Immunohistochemical expression of the signalinglymphocyte activation molecule associated protein andprogrammed death-1 (PD-1), both markers of germinalcenter T cells, by 95% of the cases of angioimmunoblasticT-cell lymphoma studied suggests that this malignancyarises from these cells.42 In another study, 95% of the 59 cases of angioimmunoblastic T-cell lymphoma werepositive for the follicular helper T-cell markers CXCL13and PD-1.43

The Current Role of Diagnostic and Prognostic Markers in Angioimmunoblastic T-cell Lymphoma

Single nucleotide polymorphism–typing microarrayshave been used to determine chromosomal changes thataffect prognosis in 40 patients with angioimmunoblasticT-cell lymphoma. The presence of alterations in copynumber affected survival in these patients with loss orgain most common in chromosomes 3, 8, 9, and 19.28

Reduced expression of CDRN2A and increased expression of MYCBP2 and CARMA1 were associatedwith worse prognosis. Gain at chromosomes 2, 5, loss

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0

20

40

60

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Extranodal NK/T-Cell

ALCLATLLPTCL-NOSHSTCLAITL

Extranodal NK/T-Cell

ALCLATLLPTCL-NOSHSTCLAITL0

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6000

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52 E

xpre

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N = 3 N = 4

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N = 2

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N = 12

N = 32

N = 1

N = 1

PTCL Subtype

Figure 2. Expression of CD52 in PTCL by subtypeand the CD52 cell surface antibody-binding capacityby 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 otherwisespecified; PTCL, peripheral T-cell lymphoma.

of heterozygosity at chromosomes 8 or 9, and gain at13q22.3 were all associated with poorer prognosis.

Iqbal et al identified a molecular prognosticator in36 patients with angioimmunoblastic T-cell lymphoma,which was an independent predictor of outcomes. Thismolecular prognosticator consisted of a small subset of 15transcripts that predicted overall survival and event-freesurvival (P<.001).29 Genes associated with a poor outcomeincluded VSIG4, an inhibitor of T-cell activation, andreceptors or cell adhesion molecules including platelet-derived growth factor receptor (PDGFR) a and PDGFRb.

The records of 31 consecutive patients with angio -immunoblastic T-cell lymphoma were reviewed to determineprognostic factors for overall survival and progression-freesurvival. Diverse factors for this analysis included staginginformation, previous treatments, laboratory parameters,International Prognostic Index risk groups, and performancestatus.35 In the multivariate analysis, male sex, hemoglobin<10 g/dL, and performance status ≥2 were associatedwith a shorter median overall survival. In a separatemultivariate analysis, there was no association with anyof these factors and progression-free survival.35

TherapyAs with PTCL-NOS, current therapies for angio -

immunoblastic T-cell lymphoma have limited efficacy. Interestingly, angioimmunoblastic T-cell lymphoma is frequently associated with immunodeficiency and immune dysregulation and many patients succumb toinfectious complications rather than to the disease itself.Alemtuzumab is a monoclonal antibody that binds toCD52 on the cell surface leading to cell death by bothcomplement and antibody-dependent cytotoxicity andapoptosis.37 In an analysis of the expression of CD52 on T-cell lymphomas, CD52 was expressed on all 3 ofthe 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 autologousstem cell transplantation for patients with angio -immunoblastic T-cell lymphoma was shown in a retrospectivetrial that analyzed data from 146 patients.44 The high-dosetherapy 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,

70% achieved a complete response with 65% of patientsalive at a median follow-up of 31 months and an estimatedoverall survival at 48 months of 59%.

The role of allogeneic stem cell transplant was shownin an analysis of 45 patients who underwent allogeneicstem cell transplant with either myeloablative or reduced-intensity regimens.45 The rate of disease relapse was13% 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 componentof the pathogenesis of angioimmunoblastic T-cell lymphoma,some studies have looked at anti-CD20 therapy in thisdisease. For example, 4 patients with untreated diseasewere 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 angio -immunoblastic T-cell lymphoma led to a retrospectiveanalysis of 12 patients who were treated with cyclosporine3 to 5 mg/kg daily for 6 to 8 weeks with a taper over 1 to 3 weeks and maintenance therapy in patients whoresponded.47 The response rate was 67% with a completeresponse in 3 patients and partial response in 5 patients,suggesting that this is potentially a very effective strategyin this disease.

ANAPLASTIC LARGE CELL LYMPHOMA

Epidemiology and PathophysiologyThe 2008 WHO classification distinguishes between

ALK-positive and ALK-negative anaplastic large celllymphoma. ALK-positive anaplastic large cell lymphomahas 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 trans -locations.27 Pathogenesis of ALK-positive anaplastic largecell lymphoma is dependent upon activation of the ERK,JAK3-STAT3, and PI3K-Akt pathways. Gene expressionstudies 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 ofanaplastic large cell lymphoma were determined in aretrospective review that incorporated data from 1314patients, including 181 patients with ALCL. Patientswith ALK-positive anaplastic large cell lymphoma had a median age of 34 years compared with a median age of

14


58 years for patients with ALK-negative anaplastic largecell lymphoma with no gender differences or differencesin stage at presentation.48

Review of bone marrow involvement in 173 patientswith 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.

TherapyWhile the outcome for patients with ALK-positive

anaplastic large cell lymphoma is excellent with anthracycline-based therapy, though better than forPTCL-NOS, the outcome for ALK-negative anaplasticlarge cell lymphoma remains relatively poor and improvements are needed. The GITIL study, in whichpatients with PTCL received first-line therapy withalemtuzumab and CHOP, enrolled 3 patients withALK-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 overexpressedon T-cell lymphoma cells. Daclizumab was given to an8-year-old girl with anaplastic large cell lymphoma thatrecurred after treatment with 2 combination chemotherapyregimens and an autologous transplant.49 Despite a remission of only 8 weeks after salvage chemotherapyand 3 weeks following transplant, she had a completeresponse with 2 weeks of therapy and was in remissionafter 45 months. The benefit of this therapy for adultpatients and as front-line therapy has not been welltested 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 withthe development of EBV-positive lymphoproliferativedisorders.50

SGN-30 is a chimeric monoclonal antibody toCD30 that showed a complete remission in a patientwith recurrent, cutaneous anaplastic large cell lymphomaenrolled in a phase 1 trial with a 26-month remissionafter 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 patientsfor a clinical benefit in 32% of these patients. The duration of the complete response was over 172 days

and 1460 days with a median duration of response forpatients with a partial response of 100 days.

Another anti-CD30 monoclonal antibody is MDX-060, which was tested in a phase1/2 trial enrolling 72patients including 3 patients with anaplastic large celllymphoma in the phase 1 portion and 4 patients in thephase 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.

HEPATOSPLENIC T-CELL LYMPHOMA

TherapyThe 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 hepatosplenicT-cell lymphoma are very limited but the treatment approach has conventionally included anthracycline-based chemotherapy. Hepatosplenic T-cell lymphoma is a disease where strategies such as allogeneic stem celltransplantation 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 ofhepatosplenic T-cell lymphoma, all patients were CD52-positive suggesting a potential for targeted therapy withthe monoclonal antibody, alemtuzumab.37 Chanan-Khanet al first reported the use of alemtuzumab in a casestudy of a patient with stage IV disease.54 The patient responded to alemtuzumab followed by allogeneic stemcell transplantation and donor lymphocyte infusionswith induction of complete remission for over 39 months.Other studies have reported efficacy with combinationsof alemtuzumab and cladribine and a transient responsewith fludarabine and alemtuzumab in patients with hepatosplenic T-cell lymphoma.55,56 Collectively, thesecase reports suggest a possible role for alemtuzumab in patients with hepatosplenic T-cell lymphoma andwarrant further investigation.

ENTEROPATHY-ASSOCIATED T-CELL LYMPHOMA

Epidemiology and PathophysiologyIn 2008, the first publication of the incidence of

enteropathy-associated T-cell lymphoma in a generalpopulation reported an incidence of 0.10/100,000.57

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The peak incidence occurred in the seventh decade of life.Enteropathy-associated T-cell lymphoma is correlatedwith celiac disease and occurs more frequently in menthan women. Another study determined that bone marrow involvement is present in about 13% of patientswith enteropathy-associated T-cell lymphoma, which istypically associated with a poorer prognosis.30

TherapyThe outcome for patients with this disease who receive

anthracycline-based chemotherapy has traditionally beenvery poor with most patients relapsing and dying fromtheir disease. Again, this is a disease where approacheslike allogeneic stem cell transplantation should be considered in the up-front setting. While autologousstem cell transplantation can induce a durable completeremission in some patients with PTCL, in a study of 4 patients with stage IV enteropathy-associated T-celllymphoma, high-dose chemotherapy followed by autologous stem cell transplantation failed to improvesurvival.58 One patient achieved complete remission, but3 of the 4 patients died following autologous stem celltransplantation.

In the prospective GITIL study, which evaluated theefficacy of alemtuzumab and CHOP chemotherapy as first-line treatment in a variety of PTCL subtypes, 1 patient withenteropathy-associated T-cell lymphoma was treated.This patient achieved a complete remission.38

In the study reported by Sieniawski et al, intensiveprimary chemotherapy and autologous stem cell trans-plantation significantly improved outcomes in patientswith enteropathy-associated PTCL compared withCHOP-like regimens.26 Although this study includedpatients with various subtypes of PTCL, almost 50% ofpatients had enteropathy-associated PTCL. Of the 26patients evaluated with enteropathy-associated PTCL,65% achieved complete remission and 4% achieved partial remission. Three-year progression-free survivalwas 52% and overall survival was 60%.

EXTRANODAL NK/T-CELL LYMPHOMA, NASAL TYPE

Epidemiology and PathophysiologyExtranodal NK/T-cell lymphoma is a rare, hetero -

geneous disease in Western populations, but commonamong Asians, Mexicans, and American Indians. Although

very little is known about the etiology of the disease, ananalysis of 74 cases of extranodal NK/T-cell lymphoma,nasal type, in China suggests that along with the Epstein Barrvirus, external stimuli may play a role in the pathogene-sis 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 oncogenicexternal stimuli. The identity of the causal stimuli isunknown.

A recent analysis of 136 cases of extranodal NK/T-celllymphoma with 68% of the nasal type and 26% extranasaltype identified clinical differences in the characteristics ofthe 2 subtypes of the disease.60 Most patients with nasal-typeextranodal disease had fewer adverse clinical characteristicscompared with extranasal disease. Median overall survivalwas significantly longer for patients with nasal-type versusextranasal disease at 1.6 years compared with 0.36 years (P< .001). A survival benefit was observed for patients withnasal-type disease receiving radiotherapy (P = .045).

The Current Role of Diagnostic and PrognosticMarkers in Extranodal NK/T-cell Lymphoma,Nasal Type

Flow cytometry is proving useful in the differential diagnosis of extranodal NK/T-cell lymphoma. A studyevaluated the utility of flow cytometry to determine thephenotypic characteristics of 490 patients with extranodalNK/T-cell lymphoma. The expression of CD56 waspresent in all samples of nasal NK/T-cell lymphoma(P<.001) while CD10 was expressed in angioimmunoblasticT-cell lymphoma, CD30 in anaplastic large cell lymphoma,and CD34 in lymphoblastic lymphoma.61

Along with CD56 and the Epstein Barr virus-encodedsmall nuclear early region 1, serum Epstein Barr virus-DNA copy number is useful as a specific tumor markerand a predictive prognostic tool.62 High levels of serumEpstein Barr virus-DNA copy numbers were predictive ofan aggressive disease course and poor prognosis. The DNAlevels were shown to decrease in response to treatment andincreased upon relapse.

A new staging system has been proposed for nasalextranodal NK/T-cell disease based on treatment outcomes.63

Using this system, extranodal NK/T-cell disease is classifiedas limited disease, defined as stage I/II nasal NK/T-celllymphoma without tumor invasiveness; or as extensivedisease, defined as either stage I/II nasal NK/T-cell lymphomawith local invasiveness, stage III/IV disease, or extranodal

16


NK/T-cell lymphoma. Patients with limited diseasewere shown to benefit from chemotherapy followed byradiotherapy with prolonged survival, but patients withextensive disease had a poor prognosis and treatment remains generally unsuccessful.

A retrospective analysis of 172 patients including 123with nasal NK/T-cell lymphoma and 27 with extranasallymphoma was conducted to develop a prognostic modelfor NKcell lymphomas.64 Complete response rates were73% for patients with stage I disease and 15% withstage IV disease. Multivariate analysis demonstratedthat non-nasal type, stage, performance status, andnumbers of extranodal involvement were poor prognosticfactors. The authors constructed an NK prognostic indexthat stratified patients by number of factors present.

TherapyBecause nasal NK/T-cell lymphoma is a poorly under-

stood, heterogeneous disease, treatment is not standardizedand large studies are lacking.65 Radiotherapy remains an effective treatment for patients with limited disease.66

A study compared the treatment outcome of 64 patientswith early-stage nasal NK/T-cell lymphoma who receivedradiotherapy alone or radiochemotherapy as first-linetherapy.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 betweengroups (52%; P = .13). Importantly, the majority of patients receiving radiotherapy (69.6%) or radiochemo -therapy (87.8%) achieved complete remission and their5-year overall survival rate was 72.1%.

A phase 2 study, the Consortium for Improving Survivalof Lymphoma Study, reported significant clinical activityof concurrent radiation and weekly cisplatin followed by etoposide, ifosfamide, cisplatin, and dexamethasone(VIPD) chemotherapy in 30 patients with stage IE toIIE nasal lymphoma.67 All patients received concurrentchemoradiotherapy and achieved a response with 22complete remissions and 8 partial remissions. After thecompletion of VIPD therapy, a total of 24 patients werein 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 radiotherapywith dexamethasone, etoposide, ifosfamide, and carboplatincompared with radiotherapy alone as first-line therapy in

26 evaluable patients with nasal NK/T-cell lymphoma.68

The overall response rate was 81% with 77% of patientsachieving a complete remission. Historical controlstreated with radiotherapy alone had a 2-year overall survivalrate of 45%, which was inferior to the new regimen.

SUBCUTANEOUS PANNICULITIS-LIKE T-CELL LYMPHOMA

Epidemiology and PathophysiologySubcutaneous panniculitis-like T-cell lymphoma-ab

is a distinct subtype of PTCL. Molecular cytogeneticanalyses have revealed that subcutaneous panniculitis-likeT-cell lymphoma is characterized by the neuron navigator3 deletion, a gene previously associated with mycosisfungoides and Sezary syndrome, and 5q and 13q gainsspecific to subcutaneous panniculitis-like T-cell lymphoma,providing further evidence that subcutaneous panniculitis-like 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 andEpstein Barr virus negative.70

The Current Role of Diagnostic and PrognosticMarkers in Subcutaneous Panniculitis-like T-cellLymphoma

Few studies have examined diagnostic and prognosticmarkers in subcutaneous panniculitis-like T-cell lymphoma.PET may be clinically useful in subcutaneous panniculitis-like T-cell lymphoma staging and for monitoring of response to treatment.71 A case study demonstrated that pretreatment and posttreatment PET using 18fluoro-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 Mortalitywas significantly higher in patients with subcutaneouspanniculitis-like T-cell lymphoma with angioinvasionthan in those without.

TherapyOptimal therapy for subcutaneous panniculitis-like

T-cell lymphoma remains undefined at this point in timewith only a few studies evaluating or reporting treatmentoptions for these patients. In terms of novel approaches, 2case studies suggest efficacy of denileukin diftitox in patients

17


with subcutaneous panniculitis-like T-cell lymphoma.72

Two patients who were treated with denileukin diftitox experienced a complete remission of disease with a medianresponse duration of more than 6 months. Furthermore,one patient, who progressed after 6 cycles of denileukindiftitox therapy, received bexarotene in combinationwith denileukin diftitox and subsequently returned toremission. Another case report suggests efficacy usingthe combination of fludarabine, mitoxantrone, and dexamethasone.73

In addition, one case report suggests that autologousstem cell transplantation may have efficacy in patientswith subcutaneous panniculitis-like T-cell lymphoma.74

ADULT T-CELL LEUKEMIA/LYMPHOMA

Epidemiology and PathophysiologyAdult T-cell leukemia/lymphoma is a PTCL subtype

associated with the retrovirus, human T-cell leukemiavirus type 1 or human T-cell lymphotropic virus type 1.75

Adult T-cell leukemia/lymphoma is linked to regulatoryT 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 Bonemarrow involvement varies significantly by subtype.76

Genetic alterations such as overexpression of enhancerof 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 geneand a truncated EPC1 gene were shown to enhance cellular growth and proliferation leading to adult T-cellleukemia/lymphoma leukemogenesis. EPC1 is involvedin chromatin formation and gene regulation and hasbeen linked to malignant transformation of many cancersand ASXL2 is also a member of the polycomb group ofgenes. Recently, expression of the gene BIRC5 has beenshown to be increased in adult T-cell leukemia/lymphomacells and this likely plays a role in adult T-cell leukemia/lymphoma cell viability and could potentially be a therapeutic target.79

The Current Role of Diagnostic and PrognosticMarkers 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 Projectshowed 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 patientswith adult T-cell leukemia/lymphoma in the study, themedian overall survival was 0.8 years with a freedomfrom progression of 0.6 years.

A consensus statement on the prognostic factors,classification, and treatment options was published inconjunction with the 13th International Conference onHuman Retrovirology.75 Multivariate analysis identifiedprognostic factors including performance status, highlactic 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, p53mutation, and a p16 deletion.75 Recently, a study of geneexpression profiling in a small group of adult T-cellleukemia/lymphoma patients demonstrated an importantrole for the gene BIRC5 in adult T-cell leukemia/lymphomacell viability.79

TherapyTreatment decisions for patients with adult T-cell

leukemia/lymphoma vary based on the subclassificationof 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 celltransplantation, and targeted therapies such as vorinostat,romidepsin, panobinostat, daclizumab, and pralatrexate(Table 6).75,80 Responses to therapy vary significantly bysubtype of adult T-cell leukemia/lymphoma. A reportfrom an International Consensus Meeting determinedthat VCAP-AMP-VECP is effective in patients withacute lymphoma or chronic subtypes of adult T-cellleukemia/lymphoma, interferon-a plus zidovudine appears particularly useful for the treatment of acute,

18


chronic, and smoldering adult T-cell leukemia/lymphoma,and allogeneic stem cell transplantation is particularlyuseful in younger adult T-cell leukemia/lymphoma patients.75

A recent phase 2 study showed promising clinicalactivity of the combination of arsenic trioxide, interferon-a,and zidovudine in newly diagnosed patients with chronicadult T-cell leukemia/lymphoma subtype.80 Of 10 patientstreated, the response rate was 100% without diseaseprogression or relapse at a follow-up of 8 months. Ofthese patients, 70% achieved complete remission.

Autologous stem cell transplantation is of limitedvalue in patients with adult T-cell leukemia/lymphomabased upon data from a handful of reported cases inJapan and one most recently in North America.81 TheNorth American study evaluated the activity of autologousstem cell transplantation in 4 Caribbean and LatinAmerican patients who had relapsed disease of the acuteor lymphoma subtype.81 Stage IV disease was present in3 patients and stage I in the fourth patient. This studydemonstrated that autologous stem cell transplantationwas ineffective as salvage therapy in relapsed adult T-cellleukemia/lymphoma patients similar to previous findings.

Jiang et al recently reported that of 34 patients with adult T-cell leukemia/lymphoma, CD52 expressionwas 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

FUTURE DIRECTIONS

Apart from ALK-positive anaplastic large cell lymphoma, which has a good prognosis with anthracycline-based chemotherapy, the outcome for most patients withPTCL is very poor and novel treatment approaches areneeded. Recently, there have been a spate of interestingdrugs that have shown promising activity in these diseasesand there has been a leap in our understanding of themolecular biology of these diseases thanks to gene expressionprofiling studies. Preliminary results from targetedagents are promising and suggest usefulness in thesediseases. The recent significant gains and insights intothe epidemiology, pathophysiology, prognosis, andtreatment of PTCL will likely contribute to identifyingoptimal treatment strategies and additional targetedtherapies for the treatment of each distinct subtype ofPTCL.

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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

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

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 allogeneicHSCT when possible

ATLL, adult T-cell leukemia/lymphoma; AZT, zidovudine; HSCT, hematopoieticstem cell transplantation; IFN-a, interferon alpha; VCAP-AMP-VECP, vincristine,cyclophosphamide, doxorubicin, and prednisone; doxorubicin, ranimustine, andprednisone; and vindesine, etoposide, carboplatin, and prednisone.

TABLE 6. RECOMMENDED STRATEGIESFOR THE TREATMENT OF ATLL. Adaptedfrom Tsukasaki et al.75

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43. Rodriguez-Pinilla S, Atienza L, Murillo C, et al. Peripheral T-celllymphoma with follicular T-cell markers. Am J Surg Pathol. 2008;32:1787-1799.

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48. Savage KJ, Harris NL, Vose JM, et al. ALK- anaplastic large-celllymphoma is clinically and immunophenotypically different fromboth ALK+ ALCL and peripheral T-cell lymphoma, not otherwisespecified: report from the International Peripheral T-Cell LymphomaProject. Blood. 2008;111(12):5496-5504.

49. Costa V, Oliva T, Norton L. Successful treatment with daclizumabof refractory anaplastic lymphoma. Pediatr Blood Cancer. 2009;53(6):1130-1131.

50. O’Mahony D, Morris JC, Stetler-Stevenson M, et al. EBV-relatedlymphoproliferative disease complicating therapy with the anti-CD2monoclonal antibody, siplizumab, in patients with T-cell malignancies.Clin Cancer Res. 2009;15(7):2514-2522.

51. Bartlett NL, Younes A, Carabasi MH, et al. A phase 1 multidosestudy of SGN-30 immunotherapy in patients with refractory or recurrent CD30+ hematologic malignancies. Blood. 2008;111(4):1848-1854.

52. Forero-Torres A, Leonard JP, Younes A, et al. A phase II study of SGN-30 (anti-CD30 mAb) in Hodgkin lymphoma or systemicanaplastic large cell lymphoma. Br J Haematol. 2009;146(2):171-179.

53. Ansell SM, Horwitz SM, Engert A, et al. Phase I/II study of an anti-CD30 monoclonal antibody (MDX-060) in Hodgkin’s lymphomaand anaplastic large-cell lymphoma. J Clin Oncol. 2007;25(19):2764-2769.

54. Chanan-Khan A, Islam T, Alam A, et al. Long-term survival withallogeneic stem cell transplant and donor lymphocyte infusion following salvage therapy with anti-CD52 monoclonal antibody(Campath) in a patient with alpha/beta hepatosplenic T-cell non-Hodgkin’s lymphoma. Leuk Lymphoma. 2004;45(8):1673-1675.

55. Mittal S, Milner BJ, Johnston PW, Culligan DJ. A case of hepatosplenic gamma-delta T-cell lymphoma with a transient response to fludarabine and alemtuzumab. Eur J Haematol.2006;76(6):531-534.

56. Jaeger G, Bauer F, Brezinschek R, Beham-Schmid C, Mannhalter C,Neumeister P. Hepatosplenic gammadelta T-cell lymphoma successfullytreated with a combination of alemtuzumab and cladribine. AnnOncol. 2008;19(5):1025-1026.

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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.

58. Al-Toma A, Verbeek W, Visser O, et al. Disappointing outcome of autologous stem cell transplantation for enteropathy-associatedT-cell lymphoma. Dig Liver Dis. 2007;39:634-641.

59. Wang J, Hasui K, Jia X, Matsuyama T, Eizuru Y. Possible role for external environmental stimuli in nasopharyngeal NK/T-celllymphomas in the northeast of China with EBV infection-relatedautophagic cell death: a pathoepidemiological analysis. J Clin ExpHematop. 2009;49(2):97-108.

60. Au WY, Weisenburger DD, Intragumtornchai T, et al. Clinical differences between nasal and extranasal natural killer/T-cell lymphoma: a study of 136 cases from the International PeripheralT-Cell Lymphoma Project. Blood. 2009;113(17):3931-3937.

61. Karube K, Aoki R, Nomura Y, et al. Usefulness of flow cytometryfor differential diagnosis of precursor and peripheral T-cell and NK-cell lymphomas: analysis of 490 cases. Pathol Int. 2008;58(2):89-97.

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.

64. Suzuki R, Suzumiya J, Yamaguchi M, et al. Prognostic factors for mature natural killer (NK) cell neoplasms: aggressive NK cellleukemia and extranodal NK cell lymphoma, nasal type. Ann Oncol.Oct 22, 2009:Epub ahead of print.

65. Kohrt H, Advani R. Extranodal natural killer/T-cell lymphoma:current concepts in biology and treatment. Leuk Lymphoma.2009;50(11):1773-1784.

66. Ma HH, Qian LT, Pan HF, et al. Treatment outcome of radiotherapyalone versus radiochemotherapy in early stage nasal natural killer/T-cell lymphoma. Med Oncol. Aug 15, 2009.

67. Kim SJ, Kim K, Kim BS, et al. Phase II trial of concurrent radiationand weekly cisplatin followed by VIPD chemotherapy in newly diagnosed, stage IE to IIE, nasal, extranodal NK/T-cell lymphoma:Consortium for Improving Survival of Lymphoma Study. J ClinOncol. 2009;27(35):6027-6032.

68. Yamaguchi M, Tobinai K, Oguchi M, et al. Phase I/II study of concurrent chemoradiotherapy for localized nasal natural killer/T-cell lymphoma: Japan Clinical Oncology Group StudyJCOG0211. J Clin Oncol. 2009;27(33):5594-5600.

69. Hahtola S, Burghart E, Jeskanen L, et al. Clinicopathological characterization and genomic aberrations in subcutaneous panniculitis-like T-cell lymphoma. J Invest Dermatol.2008;128(9):2304-2309.

70. Kong YY, Dai B, Kong JC, et al. Subcutaneous panniculitis-like T-cell lymphoma: a clinicopathologic, immunophenotypic, and molecular study of 22 Asian cases according to WHO-EORTC classification. Am J Surg Pathol. 2008;32(10):1495-1502.

71. Rodriguez VR, Joshi A, Peng F, Rabah RM, Stockmann PT,Savasan S. Positron emission tomography in subcutaneous panniculitis-like T-cell lymphoma. Pediatr Blood Cancer.2009;52(3):406-408.

72. Hathaway T, Subtil A, Kuo P, Foss F. Efficacy of denileukin diftitox in subcutaneous panniculitis-like T-cell lymphoma. Clin Lymphoma Myeloma. 2007;7(8):541-545.

73. Chim C-S, Loong F, Ng W-K, Kwong Y-L. Use of fludarabine-containing chemotherapeutic regimen results in durable completeremission of subcutaneous panniculitis-like T-cell lymphoma. Am J Clin Dermatol. 2008;9(6):396-398.

74. Nakahashi H, Tsukamoto N, Yamane A, et al. Autologous peripheralblood stem cell transplantation to treat CHOP-refractory aggressivesubcutaneous panniculitis-like T-cell lymphoma. Acta Haematol.2009;121:239-242.

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22


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

2. Changes to the WHO classification of PTCL include all ofthe 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 ofPTCL-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 follicularhelper T cells of the germinal center

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

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

5. Which of the following best describes the role of CD52 positivity in the response to therapy for patients withPTCL?

A. Correlation of CD52 positivity with response to therapyhas 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 andanaplastic large cell lymphoma

6. Which treatment regimens have produced significant responses in patients with angioimmunoblastic T-celllymphoma?

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

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

8. Of the recommended treatment strategies for adult T-cell leukemia/ lymphoma, which remains the primaryrecommendation?

A. Inclusion in clinical trials

B. Zidovudine with IFN-a

C. Bortezomib plus chemotherapy or arsenic trioxide withIFN-a

D. Allogeneic stem cell transplantation

9. Expression of CD52 has been found in >90% of patientswith 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-cellleukemia/lymphoma

23


CME TEST QUESTIONS

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-abwith 5-year overall survival of 82% versus only 11% in patients with subcutaneous panniculitis-like T-celllymphoma-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 diseasewith about 60% of patients expressing the gene

11. Which of the following is NOT TRUE of adult T-cellleukemia/ lymphoma?

A. Adult T-cell leukemia/lymphoma is associated with theretrovirus, 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 ofadult 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

12. Which of the following is FALSE regarding the proposed new staging system for extranodal NK/T-celllymphoma?

A. Extranodal nasal NK/T-cell disease is classified as limitedif stage I/II without tumor invasiveness or as extensive disease if either stage I/II with local invasiveness, stageIII/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 diseasehave a poor prognosis with limited treatment options

D. The new staging system is based upon treatment outcomes

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

14. Which of the following is TRUE of enteropathy-associated T-cell lymphoma?

A. Autologous stem cell transplantation was ineffective inthe 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 betweenALK+ and ALK-anaplastic large cell lymphoma. Patients with ALK+ disease typically have a lower median age of 34 years compared with ALK- diseasewith a median of 58 years with no differences in genderor stage at presentation.

A. True

B. False

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

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

24


Release Date of Activity: May 2010 | Expiration Date of Activity for AMA PRA Credit: May 31, 2011Estimated Time to Complete this Activity: 2.0 hour

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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

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25


CME TEST ANSWER SHEET AND EVALUATION FORM

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 HighestCite 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 1 2 3 4 5

Describe the epidemiology and the underlying causes (where known) of the various peripheral T-cell lymphomas 1 2 3 4 5

Identify the appropriate diagnostic and prognostic criteria necessary for the diagnosis and staging of the various peripheral T-cell lymphomas 1 2 3 4 5

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 1 2 3 4 5

How do you rate the overall quality of the activity? 1 2 3 4 5

How do you rate the educational content of the activity? 1 2 3 4 5

Compared to activities that you have participated-in during the past 6 months, how do you rate the overall quality of this activity? 1 2 3 4 5

Was the presented information fair, objective, balanced, and free of bias in the discussion of any commercial product or service? � Yes � No

If no, please comment:

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IMPROVEMENT IN KNOWLEDgE, COMPETENCy, OR PRACTICE

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%

After participation in this activity, have you decided to change one or more aspects of the treatment of your patients? � Yes � No

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 indicateHow you heard about this activity? � Mail/Print � Internet/Email � Live Activity

Would you be willing to participate in post-activity follow-up surveys? � Yes � No

Would you be willing to participate in a focus group or teleconference aimed at identifying/creating future educational activities that would improve performance in practice or patient outcomes? � Yes � No

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 INSTRUCTIONSThis 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.

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Elsevier Office of Continuing Medical EducationDepartment 9300061600 John F Kennedy Blvd. #1800Phila., PA 19103-2398

Please allow 6 to 8 weeks for processing. A photocopy of this form is acceptable. (Refer to pages 2-3 for CME Information.)Responses for AMA PRA credit must be submitted by May 31, 2011.

Elsevier Office of Continuing Medical Education1600 John F Kennedy Blvd. #1800Phila., PA 19103-2398

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