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Peripheral t-cell lymphomas: progress and challengesby Kerry J. Savage, MD, MSc; Tony Reiman, MD, MSc

Kerry J. Savage, MD, MSc and Tony Reiman, MD, MSc are Medical Oncologists; Dr savage is at the BC Cancer Agency in Vancouver, BC, and Dr Reiman is at the saint John Regional Hospital in saint John, NB. Corresponding author: Dr. Kerry J. savage, 600 West 10th Ave, Vancouver, BC V5Z 4E6; Email: ksavage@bccancer.bc.ca.

AbSTRAcT

Peripheral T-cell lymphomas (PTCLs) represent a com-plex group of diseases that remain a management challenge today. Although CHOP (cyclophosphamide,

doxorubicin, vincristine and prednisone) is considered the standard therapy, outcomes are disappointing and relapses are frequent. Therapeutic progress has lagged behind that for the more common and aggressive B-cell

lymphomas. With disease rarity, studies are small and often retrospective in nature. A number of novel agents are now being tested exclusively in PTCLs, some with promising activity that are moving into the clinical care setting.

Key words: peripheral T-cell lymphoma, CHOP therapy, B-cell lymphoma

PAThology of PTclSPeripheral T-cell lymphomas (PTCLs) are derived from post-thymic mature T-cells and represent approximately 10–15% of all non-Hodgkin lymphoma (NHL) in North America. This broad category encompasses a heterogeneous group of diseases, of which the most commonly encountered subtypes are PTCL not otherwise specified (PTCL-NOS), systemic anaplastic large cell lymphoma (ALCL) and angioimmunoblastic T-cell lymphoma (AITL); these subtypes collectively represent 66% of all cases of PTCL in North America (Table 1).1

Advances in immunophenotypic and molecular analysis over time have led to the recognition of PTCLs as a distinct and heterogeneous group of lymphomas. Given the disease complexity, expert review by an experienced hematopathologist is essential. Immunophenotyping for standard pan-T-cell antigens is typically performed and loss of T-cell antigens is considered abnormal.

The morphology of PTCL can be quite diverse, particularly for PTCL-NOS, and variation occurs even within a single tumour. In some cases, an inflammatory cell background can be seen, with sparse malignant cells. Gene rearrangement studies are used to document a monoclonal T-cell population.2 Further biologic characterization of PTCL-NOS is antici-pated, leading to the recognition of as yet undefined, distinct PTCL subtypes within this heterogeneous disease category.3,4

AILT has a characteristic appearance, with increased vascu-larity and expanded CD21+ follicular dendritic cell networks. Epstein-Barr virus-positive (EBV+) B-cells are seen in most cases.2 Recently, the markers CD10, CXCL13 and PD1 have been used to establish the diagnosis of AILT, suggesting that this lymphoma arises from follicular helper T-cells.

ALCL is typified by large anaplastic-appearing cells that are strongly CD30+, with hallmark cells seen in the common variant. Anaplastic lymphoma kinase-positive (ALK+) ALCL is characterized by the nucleophosmin (NPM)-ALK fusion protein, generated by the t(2;5)(p23;q35) translocation. This fusion protein can be detected immunohistochemically and has clinical relevance, as outlined below.

Enteropathy-associated T-cell lymphoma (EATL), hepato-splenic T-cell lymphoma (HTCL) and subcutaneous pannic-ulitis-like TCL (SPTCL) are rarely encountered in clinical practice. Cytologically, EATL is typically a monotonous-appearing tumour that is CD3+ and CD7+. It is generally found in individuals with gluten sensitivity, although a recently described monomorphic form, the type II variant, is often CD56+ and may not be associated with celiac disease. HTCL is a rare, aggressive, extranodal cytotoxic lymphoma, usually of T-cell receptor phenotype, that often occurs in the setting of immunosuppression.5 With standard chemo-therapy, it is an incurable disease. SPTCL has been revised in the 2008 World Health Organization (WHO) classification to include only cases with an αβ phenotype. This lymphoma has a favourable prognosis, with 5-year overall survival (OS) exceeding 80%.6 In contrast, cases with phenotypes are now grouped together with the cutaneous TCLs due to similarly poor prognosis.6 Other uncommon subtypes of primary cutaneous PTCL have also been separated as dis-tinct entities, including an indolent CD4+ variant and an aggressive CD8+ variant.2

Two types of PTCL are much more commonly found in Asia than in North America and Europe: extranodal natural killer T-cell lymphoma (NK/TCL) (nasal type) and adult T-cell leukemia/lymphoma (ATLL).1,2 NK/TCL is typified by angiodestructive growth pattern and EBV+ tumour cells. ATLL, which is always associated with human T-lympho-tropic virus type I (HTLV-I) infection, carries a high risk of opportunistic infections; antiretroviral treatment is an important part of therapy.7

sponsorship of distribution of this article was supported through an unrestricted educational grant from Celgene Inc.© 2012 Parkhurst, publisher of Oncology xchange. All rights reserved.

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PRognoSiS of PTclSIt has long been recognized that the majority of PTCLs have an inferior prognosis in comparison to their B-cell counter-parts. This is particularly evident for rare subtypes such as EATL and HTCL, where 5-year failure-free survival (FFS) is <5% with standard chemotherapy (Figure 1).1,8 Treatment approaches have paralleled those for diffuse large B-cell lymphoma (DLBCL); as a result, CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) is considered the standard therapy, despite consistent evidence that it is largely ineffective. The landmark SWOG (Southwest Oncology Group) trial comparing CHOP to 2nd- and 3rd-generation dose-intensive regimens in aggressive lymphomas, as diag-nosed by the Working Formulation classification, established that CHOP had equivalent efficacy but less toxicity. However, since immunophenotyping was not performed, the impact of more intensive chemotherapy in PTCL is unknown.9 A comprehensive assessment of the outcome of 3,287 PTCL patients diagnosed from 1992 to 1995 and in 13 SEER (Surveillance, Epidemiology and End Results) registries treated with CHOP or CHOP-like regimens reported a 5-year OS of 37.5% for PTCL-NOS.10 Although there was no centralized pathology review, the results are comparable with those of other studies, including the large collaborative International Peripheral T-cell Lymphoma (ITCL) project, which reported a 5-year OS of 32% and an FFS of 22% in this subgroup.11 Further, patients with PTCL-NOS with multiple risk factors according to the International Prog-nostic Index (IPI) can have a 5-year OS as low as 10–15%.11

These results are far inferior to those seen with aggressive B-cell lymphoma, even in the pre-rituximab treatment era.12

It also appears that the use of anthracyclines, a key compo-nent of CHOP, may not impact outcome in PTCL-NOS.13 The one exception is ALK+ ALCL, which has a relatively high cure rate with CHOP-type chemotherapy (5-year FFS 60% vs 36% for ALK+ vs ALK-negative [ALK–] disease).14

cAn WE iMPRoVE on choP AS PRiMARy ThERAPy?A number of largely retrospective studies evaluated new upfront chemotherapy regimens for PTCL as alternatives to CHOP. The GOELAMS (Groupe Ouest-Est des Leucémies Aiguës et autres Maladies du Sang) group compared alternating VIP (etoposide, ifosfamide, cisplatin)/ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) for a total of 6 cycles against CHOP for 8 cycles in a Phase III study of patients with newly diagnosed PTCL. There was no outcome difference, with overlapping survival curves (p=0.4522). The 5-year event-free survival (EFS) in CHOP-treated patients was ~35%, providing a useful benchmark for comparison with other novel combination therapies.15

The German Non-Hodgkin’s Lymphoma Study Group (DSHNHL) retrospectively analyzed the outcome of PTCL patients (n=331) who had been enrolled in Phase II or III aggressive lymphoma studies. The impact of adding etoposide and shortening the chemotherapy interval was determined in the most common subtypes (PTCL-NOS, ALCL and AILT; total n=289).16 In patients over age 60,

neither intervention improved outcome. In younger patients, specifically those with normal lactate dehydroge-nase (LDH) levels, EFS was extended significantly with etoposide (p=0.003), while OS did not improve significantly (p=0.176). Similar improvement in EFS with etoposide (3-year EFS 71% vs 51%; p=0.004) was seen in an analysis of combined data from the NHL-B1 and the Hi-CHOEP (dose-escalated CHOP plus etoposide) Phase II/III trials, again selecting the younger, lower-risk patients from these patient populations. However, the addition of etoposide appeared to have the greatest impact in patients with ALK+ ALCL (3-year EFS 91% vs 82%; p=0.012). In patients with other common subtypes, there was only a trend to improved 3-year EFS (61% vs 48%; p=0.057), with no OS difference observed; however, patient numbers were small.

Table 1. World Health Organization classifications of mature T-cell and NK-cell neoplasms2

T-cell prolymphocytic leukemia

T-cell large granular lymphocytic leukemia

Aggressive NK-cell leukemia

Adult T-cell leukemia/lymphoma

Chronic lymphoproliferative disorders of NK cells

ebV+ T-cell lymphoproliferative disorders of childhood

Systemic EBV + T-cell lymphoproliferative disease of childhood

Hydroa vacciniforme-like lymphoma

Extranodal NK/T-cell lymphoma, nasal type

Enteropathy-associated T-cell lymphoma

Hepatosplenic T-cell lymphoma

Subcutaneous panniculitis-like T-cell lymphoma (αβ subtype only)

Mycosis fungoides

Sézary syndrome

Primary cutaneous CD30+ T-cell lymphoproliferative disorders

Primary cutaneous anaplastic large cell lymphoma

Lymphomatoid papulosis*

Borderline lesions

Primary cutaneous peripheral T-cell lymphomas, rare subtypes

Primary cutaneous gamma/delta T-cell lymphoma

Primary cutaneous CD8+ aggressive epidermotropic T-cell lymphoma

Primary cutaneous CD4+ small/medium T-cell lymphoma

Peripheral T-cell lymphoma, not otherwise specified

Angi-immunoblastic T-cell lymphoma

anaplastic large cell lymphoma, alK+ positive

Anaplastic large cell lymphoma, ALK+ negative

Note: New distinct categories in bold; provisional categories in bold italics.*Not considered a neoplastic lesion.NK=natural killer; ALK=anaplastic lymphoma kinase; EBV=Epstein-Barr virus.

© 2012 Parkhurst, publisher of Oncology xchange. All rights reserved.

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Figure 1. Overall survival in various subtypes PTCl

PTCL= peripheral T-cell lymphoma; ALCL= anaplastic large cell lymphoma; ALK=anaplastic lymphoma kinase; SCPTCL=subcutaneous panniculitis-like T-cell lymphoma; NKTCL=natural killer cell/T-cell lymphoma; AILT= angioimmunoblastic T-cell lymphoma; NOS=not otherwise specified; ETTL=enteropathy-type T-cell lymphoma; HSTCL=hepatosplenic T-cell lymphoma. Reprinted with permission © 2008. American Society of Clinical Oncology. All rights reserved.

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choP WiTh AlEMTuzuMAbAlemtuzumab is a humanized monoclonal antibody that selectively binds to the CD52 antigen (Figure 2). This surface protein is expressed on most normal and malignant lympho-cytes, making it an attractive target for both T- and B-cell lymphomas. Because CD52 is also expressed on many other immune cells, this treatment may result in significant immuno-suppression and a high risk of opportunistic infection. Alemtu-zumab had a modest overall response rate (ORR) in relapsed/refractory PTCL (36%),17 but treatment-related mortality was unacceptably high (36%).17 It also appears that CD52 expression in PTCLs is heterogeneous; in PTCL-NOS, only 35–40% of cases appear to be CD52+ by immunohistochemistry.18,19 Higher rates are found with detection of CD52 by flow cytometry, but it is not known whether this more sensitive measure correlates with alemtuzumab sensitivity.20

Three Phase II studies have been published evaluating CHOP together with alemtuzumab combinations. In the first, 20 patients were treated with CHOP and alemtuzumab (30 mg IV); the ORR was 80% (65% complete response [CR]) and the 1-year EFS was 43%, not strikingly different from CHOP alone. The toxicity of this combination was prohibitive (90% Grade 4 neutropenia; 55% febrile neutro-penia), and 2 treatment-related deaths resulted in early study closure.21 To reduce toxicity, the GITIL (Gruppo Italiano Terapie Innovative nei Linfomi) lengthened the CHOP cycles to every 4 weeks (alemtuzumab 30 mg/day).22 Toxicity was improved but opportunistic infections remained prob-lematic. With a median followup of 16 months, the estimated 2-year FFS was projected to be 48%. The HOVON (Dutch Belgian Hematology-Oncology Cooperative) group recently reported results of CHOP-14–alemtuzumab (days 1, 5, 10), and although the ORR was high (90%), the 2-year EFS was comparable to that of CHOP alone (27%). Further, febrile neutropenia occurred in 43%, and EBV+ lymphoprolifera-tive disorder was reported in two patients as a result of the immunosuppression. Similarly, a novel regimen of alemtu-zumab with fludarabine, cyclophosphamide and doxorubicin

(Campath-FCD) has been explored in relapsed/refractory and newly diagnosed PTCL. This treatment was also associ-ated with EBV+ lymphoma and poor efficacy.23

Currently, there are two ongoing Phase III trials in Europe comparing dose-dense CHOP-14 to CHOP-14 with subcu-taneous alemtuzumab in younger patients (<60 years, ACT-1) and older patients (>60 years, ACT-2). Both trials include growth factor support and ACT-1 also includes high-dose chemotherapy/autologous stem cell transplant (HDC/ASCT) in responding patients. These landmark studies should help clarify the role of alemtuzumab in the manage-ment of PTCL patients (clinicaltrials.gov).

choP AnD DEnilEuKin DifTiToxDenileukin diftitox (DAB389 interleukin [IL]-2) is a genetically engineered fusion protein that combines the enzymatically active A and B fragments of diphtheria toxin with the sequence of IL-2 (Figure 2). The IL-2 domain targets the fusion toxin to tumour cells bearing high-affinity IL-2 receptors (IL-2R), resulting in endocytosis of the fusion toxin and rapid cell death.24 As a single agent in relapsed/refractory PTCL,25 denileukin diftitox led to an ORR of 48% (CR 22%), with a median progression-free survival (PFS) of 6 months.

Denileukin diftitox has a non-cross-resistant mechanism of action and does not appear to be myelosuppressive, making it an appealing drug to combine with CHOP. In a now-completed Phase II study, the ORR was 65% (CR 51%). Toxicities were mostly infusion-related with vascular leak; however, there were 3 deaths following cycle 1 (2 cardiac, 1 rhabdomyolysis).26 Interestingly, the ORR was only 47% in PTCL-NOS (n=19), compared to 80% in AITL (n=10) and 87% in ALCL (n=8), suggesting selective sensitivity to this combination. A Phase III trial is planned comparing this novel combination with CHOP.

oThER choP coMbinATionSBevacizumab is a humanized monoclonal antibody against vascular endothelial growth factor (VEGF)-A, which is

strongly expressed in PTCL. The ECOG (Eastern Cooperative Oncology Group) initiated a Phase II study in newly diagnosed PTCL patients, combining CHOP with bevacizumab followed by maintenance beva-cizumab. However, this combination caused significant cardiac toxicity, including 4 cases of congestive heart failure, indicating that further development will be limited.27

Bortezomib is a proteasome inhibitor that downregulates NF-B transcriptional activation, potentially sensitizing cells to chemotherapy. A Phase I study performed in PTCLs established the optimal schedule of bortezomib of 1.6 mg/m2 on days 1 and 8.28 A Phase II study combining CHOP and bortezomib in PTCL (including 5 patients with cutaneous T-cell lymphoma [CTCL]) recently demonstrated an ORR of 76% (CR 65%). The GELA (Groupe d’Étude

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des Lymphomes de l’Adulte) trial evaluated the dose-intensive regimen ACVBP (doxorubicin, cyclophosphamide, vindesine, bleomycin, prednisone) and bortezomib in newly diagnosed PTCL patients (n=57), but toxicity was high and the response rate was comparable to that of ACVBP alone (CR 46%).29

noVEl chEMoThERAPy AnD coMbinATionS in PRiMARy ThERAPyGemcitabine combinationsWith some evidence that anthracyclines may not be optimal in PTCL, new chemotherapy agents and combinations are being evaluated. It has been speculated that the chemoresis-tance may in part be due to overexpression of P-glycoprotein (Pgp), known to contribute to anthracycline resistance.

Gemcitabine demonstrated encouraging activity in heavily pretreated relapsed PTCLs, with an ORR of 55% (CR 30%). The fact that this agent bypasses the Pgp efflux pump pro-vides rationale to move it to front-line therapy.30 SWOG has completed a Phase II study evaluating a novel regimen in PTCLs called PEGS (cisplatin, etoposide, gemcitabine, methylprednisolone), incorporating drugs that are not Pgp substrates. Most patients (79%) were newly diagnosed, but the 1-year PFS was only 38%. With gemcitabine given on day 1 only, the dosing may not have been optimised.31

An Italian study of high-risk PTCL evaluated front-line use of a novel regimen incorporating gemcitabine, ifosfamide and oxaliplatin (GIFOX) (including ASCT in young, chemo-sensitive patients). ORR was 86% (CR + unconfirmed CR [CRu], 67%) unconfirmed CR [CRu] 67%) and 5-year EFS 49%, but toxicity was moderate, with Grade 4 thrombocy-topenia and anemia observed in 38% and 24%, respectively; 33% had a Grade 3 infection.32

DoSE EScAlATion in PRiMARy ThERAPyIt is unclear whether dose escalation, with or without stem cell support, improves outcome in PTCLs. The MD Anderson Cancer Center retrospectively evaluated outcomes in 135 patients with PTCL treated with CHOP, compared with a variety of more dose-intensive approaches including early autologous and allogeneic transplant. No difference in out-comes was evident, although the number of patients receiving each regimen was small.33

Although the German retrospective study suggested that the addition of etoposide might improve cure rates in PTCL in select low-risk patients, a benefit was not observed using simple dose-escalation in high-risk patients. The 3-year EFS of Mega-CHOEP with ASCT was only 26% in newly diag-nosed PTCL patients with an age-adjusted IPI score of 2 or 3 or an elevated LDH.34 These results challenge the use of consolidative HDC/ASCT, a common approach in these high-risk patients.

uPfRonT TRAnSPlAnTATion in ThE MAnAgEMEnT of PTclSMultiple retrospective studies have been published evaluating the impact of upfront transplantation in PTCL, as has been comprehensively reviewed.35,36 Trial interpretation and com-parisons are difficult for a number of reasons, including the

evaluation of heterogeneous patient populations, potential for selection bias and the dearth of intention-to-treat (ITT) data. Since there are no reported prospective randomized Phase III trials comparing HDC/ASCT to conventional-dose chemotherapy specifically for PTCL, it remains challenging to determine the relative impact of patient selection vs true differences in efficacy.

The GELA group performed a retrospective analysis of the impact of upfront autologous transplant in TCLs. Limiting the study to patients who achieved CR, a matched-pair analysis was performed comparing dose-intensive chemotherapy alone (ACVB or NCVB [cyclophosphamide, vinblastine and bleomycin with either doxorubicin or mitoxantrone]) with the same chemotherapy plus HDC/ASCT. No difference in disease-free survival (DFS) or OS was found.37

Several Phase II prospective studies of upfront transplant have been published and represent more homogeneous populations of treated patients. With rare exceptions, patients with ALK+ ALCL were excluded.35,36 The transplant rate varied from approximately 40% to 70%, and EFS ranged from 30% to 50% in ITT analysis.35,36 The Nordic group completed the largest prospective Phase II trial of upfront transplant (NLG-T-01) in 160 patients with PTCL, excluding ALK+ ALCL. The planned treatment scheduled was CHOEP-14 for 6 cycles, followed by BEAM (carmustine, etoposide, cytarabine, melphalan/ASCT) in responding patients.38 Most patients had good functional status (71% with PS [perfor-mance status] scores of 0 or 1), and the overall transplant rate was 70%. With median followup of 5 years, 5-year PFS was 44% and 5-year OS was 51%. Interestingly, patients with ALK– ALCL (n=31) appeared to have a superior 5-year PFS (64%) compared to PTCL-NOS (38%), EATL (38%) or AILT (49%). Outcomes were also better than historical comparisons, suggesting that this group may have a greater benefit from this approach (personal communication).38

ThE RolE of hDc/AScT in RElAPSED/REfRAcToRy PTclIn eligible patients, HDC/ASCT represents the standard of care for relapsed/refractory PTCL. In the original PARMA Phase III randomized controlled study, HDC/ASCT emerged as superior to second-line chemotherapy for relapsed aggres-sive NHL with diagnoses based on the Working Formulation classification.39 There has been no similar study in PTCLs, but retrospective studies report EFS in this setting ranging from 18% to 60%, with salvage rates comparable to those seen in DLBCL, especially for ALCL.35,36 Given the overall body of evidence, ASCT is frequently offered to patients with PTCL with relapsed, chemosensitive disease.

AllogEnEic TRAnSPlAnT AnD ThE gRAfT-VS-lyMPhoMA EffEcTAllogeneic stem cell transplantation (AlloSCT), with either myeloablative or reduced-intensity conditioning (RIC), has also been reported to yield durable remission in many cases (3-year EFS 23–64%).35,40,41 Evidence supporting a graft-vs-PTCL effect comes from studies with donor lymphocyte infusions.40,41 The largest study published to date evaluated

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in clinical trials. This approach obscures differences in treat-ment sensitivity of the PTCL subtypes and can make trial comparisons difficult. Further, there is some evidence to sup-port tailoring treatment for at least some subtypes.

The outcome of nasal NK/TCL is poor with anthracycline-based chemotherapy, particularly for those with advanced-stage disease and those with extranasal disease,42 which may reflect an inherent resistance due to Pgp expression. L-aspara-ginase has emerged as an extremely active agent in NK/TCLs. In vitro studies suggest that L-asparagine depletion results in NK cell apoptosis. A retrospective study of 15 patients with relapsed/refractory NK/TCL treated with L-asparaginase, methotrexate (3 g/m2) and dexamethasone demonstrated an ORR of 87% (CR 50%) (Table 2), but toxicity can be problematic and antithrombin levels need close monitoring.43

77 previously treated patients with mainly myeloablative conditioning (74%). The 5-year PFS was 53%, but treatment-related mortality (TRM) was 34% at 5 years.41 A Phase II trial evaluating RIC and AlloSCT in 17 patients, including 8 who had failed front-line HDC/ASCT, demonstrated a 3-year PFS of 64% with a TRM of 6%.40 Allogeneic transplan-tation is promising in the treatment of PTCL but is limited by the availability of stem cell donors and toxicity related to graft-vs-host disease.

ShoulD TREATMEnT bE TAiloRED foR SPEcific PTcl SubTyPES?Generally, treatment approaches to date have been similar among the PTCL subtypes and, because of disease rarity, it is common to include subtypes other than cutaneous PTCLs

Table 2: Studies of novel drugs currently under investigation in the treatment of relapsed/refractory PTCl

agent N Orr% (Cr)a Median survival and duration of response Main toxicities

Novel chemotherapy

gemcitabine Phase II30

20 55 (30) DoR for CR pts (7/9) 34 mos Neutropenia Thrombocytopenia

Pralatrexate Phase II50

111 29 (11) PFS 3.5 mosOS 14.5 mosDoR 10.1 mos

ThrombocytopeniaMucositisNeutropenia

l-asparaginase retrospective43

15 (all NK/TCL) 87 (50) Not reported Antithrombin deficiencySepsisHepatitis

bendamustine52 50 50 (28) PFS 4 mosDoR 3.5 mosOS 6 mos

NeutropeniaThrombocytopenia

Histone deacetylase inhibitors

romidepsin (depsipeptide) Phase II (NCI)55

Phase II54

47

130

38 (18)

25 (15)

DoR 8.9 mos

PFS 4 mosDoR 17 mos

NauseaVomitingFatigueThrombocytopeniaNeutropenia

belinostat Phase II56

20 25 (10) DoR ~ 9 Toxicity not detailed in abstract

antibody-directed therapy

brentuximab (SgN-35) anti-CD30-drug conjugate66

58 (all ALCL) 86 (57) PFS 13.3 mosDoR 12.6 mosOS not reached

Peripheral sensory neuropathy

Zanolimumab (HuMax-CD4) Phase II59

21 (CD4+) 24 (9.5) Not reported RashInfusion reactionInfections

Other targeted therapy

lenalidomide Phase II b,62,63

2410 (all PTCL-NOS)

30 (0)30 (30)

PFS ~ 3 mos FatigueConstipationThrombocytopenia

aurora a kinase inhibitor Phase 167

8 57c Not reported NeutropeniaFatigueDiarrheaAlopecia

PTCL=peripheral T-cell lymphoma; NK/TCL=natural killer T-cell lymphoma, nasal type; ALCL=anaplastic large cell lymphoma; ORR=overall response rate; CR=complete response; PFS=progression-free survival; DoR=duration of response; NOS= not otherwise specified; OS=overall survival; mos=months. a Response by central review; b Interim analysis; c Responses described in table are for PTCL patients only.

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A Phase II study evaluating L-asparaginase in combination with methotrexate and dexamethasone (AspaMetDex) was recently reported. The combination appears to be extremely active in this relapsed/refractory population, with an ORR of 78% (CR 61%) and a median duration of response (DoR) of 12 months.44 Additional studies incorporating L-asparagi-nase in front-line treatment of both localized and advanced-stage NK/TCL are ongoing.

It appears that radiotherapy is a key treatment modality in early-stage disease, with more favourable outcomes observed using high doses (50–60 Gy) early in the front-line setting.45 Recently, the use of a platinum as radiosensitizer has been explored and may allow for use of lower, less toxic doses of radiation.46 Further, since systemic relapse can occur with single-modality radiotherapy, other novel combinations have been tested. Concurrent radiation (40 Gy) and cisplatin (30 mg/m2 weekly) followed by 3 cycles of VIPD (etoposide, ifosfamide, cisplatin, dexamethasone), was evaluated in Stage IE/IIE nasal NK/TCL. Although this was a highly selected population, the outcome was encouraging, with a CR rate of 83% and an estimated 3-year PFS of 85%. Similarly, concurrent radiotherapy (50 Gy) and DeVIC (dexametha-sone, etoposide, ifosfamide, carboplatin) was evaluated in a Phase I/II trial in localized nasal NK/TCL with good results (CR 77%, 2-year PFS 67%).47 In the absence of a random-ized trial, the most recent NCCN (National Comprehensive Cancer Network) guidelines suggest either high-dose radio-therapy alone (>50 Gy) (Stage 1, no risk factors) or con-current chemoradiotherapy (Stage 1 or 2) using either of the above regimens.48

HSTCL is a rare PTCL subtype with extremely poor response to CHOP-based treatment, with only occasional survivors. Thus, many investigators have advocated transplant in the primary setting following chemotherapy with a platinum-based regimen. Particularly encouraging results have been seen with allogeneic transplant. A recent review of the literature of 17 HSTCL patients who had undergone allogeneic trans-plant demonstrated 7 (41%) cases alive and in remission.49

noVEl ThERAPiES in RElAPSED/REfRAcToRy PTclChemotherapyPralatrexatePralatrexate is a novel folate analogue with enhanced affinity for the reduced folate carrier (RFC) and is more effectively polyglutamated, resulting in higher intracellular concentra-tions and cellular retention (Figure 2).50 Interest in prala-trexate for the treatment of PTCLs stemmed from a Phase I/II study in patients with multiple relapsed and refractory hematologic malignancies, which suggested that pralatrexate was selective for TCLs.51 The Phase II PROPEL study recently evaluated pralatrexate in combination with vitamin B12 and folate for relapsed/refractory PTCLs. By central review, the ORR was 29% (n=111), with a median PFS of 3.5 months and median DoR of 10.5 months (Table 2).50 The main toxicities were mucositis (Grade 3/4 22%), thrombocytopenia (Grade 3/4 33%) and neutropenia (Grade 3/4 22%). These results led to FDA approval of pralatrexate in September 2009 for the treatment of relapsed/refractory PTCL, repre-

senting the first agent to be approved exclusively in this disease (Table 2). Ongoing studies combine pralatrexate with other agents in the upfront and relapsed settings.

BendamustineBendamustine is a cytotoxic agent with alkylating and anti-metabolite properties. It is extremely active in indolent B-cell lymphomas and has recently been tested in a Phase II study in relapsed/refractory PTCLs. Updated results with 60 patients were recently reported from the BENTLY trial; the ORR in the ITT population was 50% (CR 28%), with median DoR, PFS and OS of 3.5, 4 and 6 months, respectively.52 The most common adverse events were Grade 3/4 neutro-penia (30%), thrombocytopenia (24%) and infections (20%).

HDAC inhibitorsHistones are highly conserved proteins that facilitate DNA compaction, thereby regulating transcriptional activity. They are regulated in part through acetylation, which loosens the chromatin structure, modulating the expression of various genes. Histone deacetylases (HDACs) and histone acetyltransferases regulate chromatin structure and function through the removal and addition, respectively, of an acetyl group from the lysine residues of core nucleosomal his-tones. HDAC inhibitors (HDIs) are epigenetic therapies that increase acetylation of histones and other nuclear pro-teins (Figure 2). By modulating gene expression and by various other effects, HDIs promote cell cycle arrest and apoptosis. Multiple HDIs, including vorinostat, belinostat and romidepsin, are currently under investigation in clinical trials, particularly in CTCL and PTCL, where they appear to exert a class effect.

Romidepsin (depsipeptide, or FK228), a member of this novel class of antineoplastic agents, was one of the first HDIs studied in PTCL. With encouraging results observed in a Phase I study,53 two Phase II studies have now been com-pleted in relapsed/refractory PTCLs evaluating romidepsin (14 mg/m2 IV) administered on days 1, 8 and 15 of a 28-day schedule. The National Cancer Institute (NCI) evaluated 47 patients treated with romidepsin, reporting an ORR of 38% (CR 18%) with median DoR of 9 months; patients with CR had a median DoR of 30 months (Table 2). A second, industry-sponsored Phase IIB study has also reported final results. In total, 130 patients with histologically confirmed relapsed/refractory PTCL were treated; the ORR was 25% (CR 15%) and median DoR was 17 months (Table 2).54 The median PFS was 4 months and was 18 months for patients achieving a CR/CRu.

Romidepsin was generally well tolerated. The most com-mon side effects encountered in these studies were nausea (Grade 3/4 20%), fatigue (Grade 3/4 8%), thrombocytopenia (Grade 3/4 24%) and neutropenia (Grade 3/4 20%).54,55 A Phase IB study is ongoing, combining CHOP with romidepsin for the primary treatment of PTCL.

Belinostat, a pan-HDAC inhibitor (1,000 mg/m2 IV days–5 every 3 weeks), has also been evaluated in 20 patients with relapsed/refractory PTCL, with comparable efficacy (ORR 20%, CR 10%).56

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AnTiboDy-DiREcTED ThERAPyGiven that CD30 is expressed in all ALCLs and is highly restricted, it was an obvious target for an antitumour anti-body. However, efficacy was disappointing with the anti-CD30 monoclonal antibodies SGN-30 and MDX-060.57,58

To enhance antitumour activity, an antibody-drug conjugate, brentuximab vedotin (SGN-35), was designed by conjugating monomethyl auristatin E (MMAE), an antitubulin agent, to a CD30-specific monoclonal antibody, cAC10, by an enzyme-cleavable dipeptide linker. MMAE is released into the cell following endocytosis and interferes with mitosis, causing cell arrest and apoptosis (Figure 2). A Phase I trial was performed in CD30+ hematologic malignancies, most of which were Hodgkin lymphomas (HL), although 2 patients with ALCL were also enrolled. Encouraging efficacy was observed, including responses in both patients with ALCL. Thus, Phase II studies were initiated in both HL and ALCL.

In 58 patients with relapsed/refractory ALCL (72% ALK–) treated with brentuximab vedotin, the ORR was 86% (CR 57%), median PFS 13.3 months and median DoR 12.6 months (Table 2). Given the interference in microtubule formation, the main toxicity was peripheral neuropathy, but Grade 3 events occurred in only 12% of patients. As a result of promising single-agent activity, a study has been initiated combining CHP (CHOP with vincristine omitted due to neurotoxicity) with brentuximab vedotin in newly diagnosed systemic ALCL. Brentuximab vedotin is also being explored in other CD30+ NHLs, including a small number of PTCL cases that are positive for this marker.

The majority of PTCLs, including PTCL-NOS, AITL and ALCL, have a T-helper cell phenotype, expressing CD4 on the cell surface. Zanolimumab (HuMax-CD4) is a human monoclonal antibody directed against CD4 that abrogates signalling by the T-cell receptor and induces killing of CD4+

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Figure 2. Mechanisms of action of novel agents currently in clinical trials for peripheral T-cell lymphoma.

* approved by Health Canada; MMAE=monomethyl auristatin E; DT=diphtheria toxin; IL-2=interleukin 2; TCR=T-cell receptor; dFdCDP=gemcitabine diphosphate; dFdCTP=gemcitabine triphosphate; RR=ribonucleotide reductase; RFC-1=reduced folate carrier; FPGS=folylpolyglutamate synthase; Glu=glutamate; DHFR=dihydrofolate reductase; NK=natural killer; VEGF= vascular endothelial growth factor; TNF-α=tumour necrosis factor-alpha; IL-6=interleukin 6; DSB=double-strand breaks; HAT=histone acetyltransferase; HDAC=histone deacetylase; A=acetyl group.

CD30

Brentuximab vedotin linker

MMAE

Cytoplasm

Cell membrane

Nucleus

CD52

Alemtuzumab*

TCR

CD4

Zanolimumab

MMAE released

MMAE disrupts microtubules

G2/M arrest

Spindle assembly

Apoptosis Senescence

Alisertib

Aurora-A kinase

Bendamustine

DNA DSBs

Apoptosis

p53

Romidepsin Belinostat

HDAC

IL-2 receptor

Denileukin diftitox

Protein synthesis

Cell death

DT

IL-2 DT

IL-2 DT

IL-2

Proteasome

Bortezomib*

HAT

Apoptosis Growth arrest Differentiation

Transcription activation

↑ p21

G0/G1 arrest

G2/M arrest

Relaxed chromatin

Gemcitabine* (dFdC)

dFdCDP

dFdCTP RR

DNA synthesis

Condensed chromatin

Repression

Pralatrexate

DHFR

FPGS

Pralatrexate

RFC-1

Lenalidomide*

TNF-α IL-6

VEGF

Apoptosis

Angiogenesis

T-cell co-stimulation

NK cell activation

Pralatrexate-Glu(n)

CO

PyRI

gH

t PA

RKH

uRs

t LIM

ItED

201

2

© 2012 Parkhurst, publisher of Oncology Exchange. All rights reserved.

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cells by antibody-dependent cellular cytotoxicity (Figure 2). A Phase II trial evaluating this agent in 21 patients with relapsed/refractory PTCL recently reported an ORR of 24% (CRu 10%; Table 2).59 The most frequently encountered toxicities were rash, pyrexia and infusion reactions; the infec-tion rate was moderate (29%).

oThER TARgETED ThERAPyBortezomibThe proteasome inhibitor bortezomib has a non-cross-resis-tant mechanism of action with a variety of agents (Figure 2). A Phase I study of gemcitabine (800 mg/m2) and bortez-omib (1.6 mg/m2 on days 1 and 15 of each 28-day cycle) was evaluated in a variety of hematologic malignancies, with early responses seen in PTCL.60 Bortezomib is also being evaluated in combination with pralatrexate, given evidence of synergy in preclinical models.61

LenalidomideLenalidomide is an immunomodulatory agent with several proposed mechanisms of action, including direct cytotoxicity to the tumour cell and alteration of factors in the microenvi-ronment (Figure 2). It is active in a variety of hematologic malignancies, notably multiple myeloma. Interim results of a Phase II study evaluating 24 patients treated with lenalid-omide in relapsed/refractory PTCLs showed an ORR of 30% with no CRs. Another small study reported CR in 3 of 10 PTCL-NOS patients, for an ORR of 30%.62 The most common side effects were fatigue, constipation and throm-bocytopenia.63

Aurora A kinase inhibitorsAurora A kinase (AAK), a serine-threonine kinase that reg-ulates mitosis and multiple signalling pathways, has recently been explored as a target in hematologic malignancies (Figure 2). A Phase II trial evaluating the efficacy of an oral AAK inhibitor, alisertib (MLN8237), has been initiated in relapsed/refrac-tory aggressive NHLs. Early results suggest some selectivity for PTCLs, with an ORR of 57% compared with 32% for all patients in the study. The most commonly encountered toxicities were neutropenia, fatigue, diarrhea and anemia.

iS ThERE An oPTiMAl ThERAPy in ThE RElAPSED/REfRAcToRy PAlliATiVE SETTing?A recent population-based analysis highlighted poor outcomes in patients with relapsed/refractory PTCL. However, some select patients with good functional status can have more favourable outcomes, even with standard chemotherapy.64

With the multitude of agents available in relapsed/refrac-tory PTCL, it is unclear which therapy to choose. Other than brentuximab vedotin, the drugs are relatively nonspecific. However, there is some evidence that treatment may be tailored by PTCL subtype. For example, durable remissions were observed in AITL using romidepsin where pralatrexate was ineffective.50,65 Further studies are needed to develop markers predicting response to various therapies to guide treatment selection. Overall, physicians must balance efficacy and toxicity in this largely palliative population.

concluSionThe development of optimal treatments to improve outcome for PTCLs remains a challenge, given the rarity and biologic heterogeneity of these cancers. Nevertheless, in the last few years there have been an unprecedented number of trials in PTCL, demonstrating that it is possible to do prospective trials in these rare diseases. The goal of future studies should be to focus on new combinations and the most active agents in PTCL, and ultimately to develop an effective combination regimen for primary treatment.

DiScloSuRES: Dr. savage has received honoraria from Celgene and seattle genetics for consulting. Dr. Reiman has received honoraria from Celgene for consulting.

AcKnoWlEDgEMEnTS: the authors gratefully acknowledge the support of Celgene Canada Inc. and thank John Ashkenas, PhD (sCRIPt, toronto ON) for editorial assistance.

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