Peripheral T-Cell Lymphomas: Progress and Challenges

feature Peripheral T-cell lymphomas: progress and challenges

by Kerry J. Savage, MD, MSc; Tony Reiman, MD, MSc

Abstract

eripheral T-cell lymphomas (PTCLs) represent a com- lymphomas. With disease rarity, studies are small and plex group of diseases that remain a management often retrospective in nature. A number of novel agents P challenge today. Although CHOP (cyclophosphamide, are now being tested exclusively in PTCLs, some with doxorubicin, vincristine and prednisone) is considered promising activity that are moving into the clinical care the standard therapy, outcomes are disappointing and setting. relapses are frequent. Therapeutic progress has lagged Key words: peripheral T-cell lymphoma, CHOP therapy, behind that for the more common and aggressive B-cell B-cell lymphoma

Pathology of PTCLs ALCL is typified by large anaplastic-appearing cells that Peripheral T-cell lymphomas (PTCLs) are derived from post- are strongly CD30+, with hallmark cells seen in the common thymic mature T-cells and represent approximately 10–15% variant. Anaplastic lymphoma kinase-positive (ALK+) ALCL of all non-Hodgkin lymphoma (NHL) in North America. is characterized by the nucleophosmin (NPM)-ALK fusion This broad category encompasses a heterogeneous group of protein, generated by the t(2;5)(p23;q35) translocation. diseases, of which the most commonly encountered subtypes This fusion protein can be detected immunohistochemically are PTCL not otherwise specified (PTCL-NOS), systemic and has clinical relevance, as outlined below. anaplastic large cell lymphoma (ALCL) and angioimmunoblastic Enteropathy-associated T-cell lymphoma (EATL), hepato- T-cell lymphoma (AITL); these subtypes collectively represent splenic T-cell lymphoma (HTCL) and subcutaneous pannic- 66% of all cases of PTCL in North America (Table 1).1 ulitis-like TCL (SPTCL) are rarely encountered in clinical Advances in immunophenotypic and molecular analysis practice. Cytologically, EATL is typically a monotonous- over time have led to the recognition of PTCLs as a distinct appearing tumour that is CD3+ and CD7+. It is generally and heterogeneous group of lymphomas. Given the disease found in individuals with gluten sensitivity, although a complexity, expert review by an experienced hematopathologist recently described monomorphic form, the type II variant, is is essential. Immunophenotyping for standard pan-T-cell often CD56+ and may not be associated with celiac disease. antigens is typically performed and loss of T-cell antigens is HTCL is a rare, aggressive, extranodal cytotoxic lymphoma, considered abnormal. usually of  T-cell receptor phenotype, that often occurs The morphology of PTCL can be quite diverse, particularly in the setting of immunosuppression.5 With standard chemo- for PTCL-NOS, and variation occurs even within a single therapy, it is an incurable disease. SPTCL has been revised in tumour. In some cases, an inflammatory cell background the 2008 World Health Organization (WHO) classification can be seen, with sparse malignant cells. Gene rearrangement to include only cases with an αβ phenotype. This lymphoma studies are used to document a monoclonal T-cell population.2 has a favourable prognosis, with 5-year overall survival (OS) Further biologic characterization of PTCL-NOS is antici- exceeding 80%.6 In contrast, cases with  phenotypes are pated, leading to the recognition of as yet undefined, distinct now grouped together with the cutaneous  TCLs due to PTCL subtypes within this heterogeneous disease category.3,4 similarly poor prognosis.6 Other uncommon subtypes of AILT has a characteristic appearance, with increased vascu- primary cutaneous PTCL have also been separated as dis- larity and expanded CD21+ follicular dendritic cell networks. tinct entities, including an indolent CD4+ variant and an Epstein-Barr virus-positive (EBV+) B-cells are seen in most aggressive CD8+ variant.2 cases.2 Recently, the markers CD10, CXCL13 and PD1 Two types of PTCL are much more commonly found in have been used to establish the diagnosis of AILT, suggesting Asia than in North America and Europe: extranodal natural that this lymphoma arises from follicular helper T-cells. 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. Kerry J. Savage, MD, MSc and Tony Reiman, MD, MSc are ATLL, which is always associated with human T-lympho- Medical Oncologists; Dr Savage is at the BC Cancer Agency in tropic virus type I (HTLV-I) infection, carries a high risk Vancouver, BC, and Dr Reiman is at the Saint John Regional Hospital in Saint John, NB. Corresponding author: Dr. Kerry J. Savage, 600 West of opportunistic infections; antiretroviral treatment is an 10 th Ave, Vancouver, BC V5Z 4E6; Email: [email protected]. 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. 10 oe VOL. 11, No. 3, August 2012 feature

Prognosis of PTCLs Table 1. World Health Organization classifications of It has long been recognized that the majority of PTCLs have mature T-cell and NK-cell neoplasms2 an inferior prognosis in comparison to their B-cell counter- parts. This is particularly evident for rare subtypes such as T-cell prolymphocytic leukemia EATL and HTCL, where 5-year failure-free survival (FFS) is T-cell large granular lymphocytic leukemia <5% with standard chemotherapy (Figure 1).1,8 Treatment approaches have paralleled those for diffuse large B-cell Aggressive NK-cell leukemia lymphoma (DLBCL); as a result, CHOP (cyclophosphamide, Adult T-cell leukemia/lymphoma doxorubicin, vincristine and prednisone) is considered the standard therapy, despite consistent evidence that it is largely Chronic lymphoproliferative disorders of NK cells ineffective. The landmark SWOG (Southwest Oncology EBV+ T-cell lymphoproliferative disorders of childhood nd rd Group) trial comparing CHOP to 2 - and 3 -generation Systemic EBV + T-cell lymphoproliferative disease of childhood dose-intensive regimens in aggressive lymphomas, as diagnosed by the Working Formulation classification, established Hydroa vacciniforme-like lymphoma that CHOP had equivalent efficacy but less toxicity. However, Extranodal NK/T-cell lymphoma, nasal type since immunophenotyping was not performed, the impact Enteropathy-associated T-cell lymphoma of more intensive chemotherapy in PTCL is unknown.9 A comprehensive assessment of the outcome of 3,287 PTCL Hepatosplenic T-cell lymphoma patients diagnosed from 1992 to 1995 and in 13 SEER Subcutaneous panniculitis-like T-cell lymphoma (αβ subtype only) (Surveillance, Epidemiology and End Results) registries treated with CHOP or CHOP-like regimens reported a Mycosis fungoides 5-year OS of 37.5% for PTCL-NOS.10 Although there was Sézary syndrome no centralized pathology review, the results are comparable Primary cutaneous CD30+ T-cell lymphoproliferative disorders with those of other studies, including the large collaborative International Peripheral T-cell Lymphoma (ITCL) project, Primary cutaneous anaplastic large cell lymphoma which reported a 5-year OS of 32% and an FFS of 22% in Lymphomatoid papulosis* this subgroup.11 Further, patients with PTCL-NOS with multiple risk factors according to the International Prog- Borderline lesions nostic Index (IPI) can have a 5-year OS as low as 10–15%.11 Primary cutaneous peripheral T-cell lymphomas, rare subtypes These results are far inferior to those seen with aggressive Primary cutaneous gamma/delta T-cell lymphoma B-cell lymphoma, even in the pre-rituximab treatment era.12 It also appears that the use of anthracyclines, a key compo- Primary cutaneous CD8+ aggressive epidermotropic T-cell lymphoma 13 nent of CHOP, may not impact outcome in PTCL-NOS. Primary cutaneous CD4+ small/medium T-cell lymphoma The one exception is ALK+ ALCL, which has a relatively high cure rate with CHOP-type chemotherapy (5-year FFS Peripheral T-cell lymphoma, not otherwise specified 60% vs 36% for ALK+ vs ALK-negative [ALK–] disease).14 Angi-immunoblastic T-cell lymphoma Anaplastic large cell lymphoma, ALK+ positive CAN WE IMPROVE ON CHOP as + PRIMARY THERAPY? Anaplastic large cell lymphoma, ALK negative A number of largely retrospective studies evaluated new upfront Note: New distinct categories in bold; provisional categories in bold italics. chemotherapy regimens for PTCL as alternatives to CHOP. *Not considered a neoplastic lesion. The GOELAMS (Groupe Ouest-Est des Leucémies Aiguës NK=natural killer; ALK=anaplastic lymphoma kinase; EBV=Epstein-Barr virus. et autres Maladies du Sang) group compared alternating VIP (etoposide, ifosfamide, cisplatin)/ABVD (doxorubicin, neither intervention improved outcome. In younger bleomycin, vinblastine, dacarbazine) for a total of 6 cycles patients, specifically those with normal lactate dehydroge- against CHOP for 8 cycles in a Phase III study of patients with nase (LDH) levels, EFS was extended significantly with newly diagnosed PTCL. There was no outcome difference, etoposide (p=0.003), while OS did not improve significantly with overlapping survival curves (p=0.4522). The 5-year (p=0.176). Similar improvement in EFS with etoposide event-free survival (EFS) in CHOP-treated patients was ~35%, (3-year EFS 71% vs 51%; p=0.004) was seen in an analysis providing a useful benchmark for comparison with other of combined data from the NHL-B1 and the Hi-CHOEP novel combination therapies.15 (dose-escalated CHOP plus etoposide) Phase II/III trials, The German Non-Hodgkin’s Lymphoma Study Group again selecting the younger, lower-risk patients from these (DSHNHL) retrospectively analyzed the outcome of patient populations. However, the addition of etoposide PTCL patients (n=331) who had been enrolled in Phase II appeared to have the greatest impact in patients with ALK+ or III aggressive lymphoma studies. The impact of adding ALCL (3-year EFS 91% vs 82%; p=0.012). In patients with etoposide and shortening the chemotherapy interval was other common subtypes, there was only a trend to improved determined in the most common subtypes (PTCL-NOS, 3-year EFS (61% vs 48%; p=0.057), with no OS difference ALCL and AILT; total n=289).16 In patients over age 60, observed; however, patient numbers were small.

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CHOP with alemtuzumab (Campath-FCD) has been explored in relapsed/refractory Alemtuzumab is a humanized monoclonal antibody that and newly diagnosed PTCL. This treatment was also associ- selectively binds to the CD52 antigen (Figure 2). This surface ated with EBV+ lymphoma and poor efficacy.23 protein is expressed on most normal and malignant lympho- Currently, there are two ongoing Phase III trials in Europe cytes, making it an attractive target for both T- and B-cell comparing dose-dense CHOP-14 to CHOP-14 with subcu- lymphomas. Because CD52 is also expressed on many other taneous alemtuzumab in younger patients (<60 years, ACT-1) immune cells, this treatment may result in significant immuno- and older patients (>60 years, ACT-2). Both trials include suppression and a high risk of opportunistic infection. Alemtu- growth factor support and ACT-1 also includes high-dose zumab had a modest overall response rate (ORR) in relapsed/ chemotherapy/autologous stem cell transplant (HDC/ refractory PTCL (36%),17 but treatment-related mortality was ASCT) in responding patients. These landmark studies unacceptably high (36%).17 It also appears that CD52 expression should help clarify the role of alemtuzumab in the manage- in PTCLs is heterogeneous; in PTCL-NOS, only 35–40% ment of PTCL patients (clinicaltrials.gov). of cases appear to be CD52+ by immunohistochemistry.18,19 Higher rates are found with detection of CD52 by flow CHOP and denileukin diftitox

cytometry, but it is not known whether this more sensitive Denileukin diftitox (DAB389 interleukin [IL]-2) is a genetically measure correlates with alemtuzumab sensitivity.20 engineered fusion protein that combines the enzymatically Three Phase II studies have been published evaluating active A and B fragments of diphtheria toxin with the sequence CHOP together with alemtuzumab combinations. In the of IL-2 (Figure 2). The IL-2 domain targets the fusion toxin first, 20 patients were treated with CHOP and alemtuzumab to tumour cells bearing high-affinity IL-2 receptors (IL-2R), (30 mg IV); the ORR was 80% (65% complete response resulting in endocytosis of the fusion toxin and rapid cell [CR]) and the 1-year EFS was 43%, not strikingly different death.24 As a single agent in relapsed/refractory PTCL,25 from CHOP alone. The toxicity of this combination was denileukin diftitox led to an ORR of 48% (CR 22%), with a prohibitive (90% Grade 4 neutropenia; 55% febrile neutro- median progression-free survival (PFS) of 6 months. penia), and 2 treatment-related deaths resulted in early study Denileukin diftitox has a non-cross-resistant mechanism of closure.21 To reduce toxicity, the GITIL (Gruppo Italiano action and does not appear to be myelosuppressive, making Terapie Innovative nei Linfomi) lengthened the CHOP it an appealing drug to combine with CHOP. In a now- cycles to every 4 weeks (alemtuzumab 30 mg/day).22 Toxicity completed Phase II study, the ORR was 65% (CR 51%). was improved but opportunistic infections remained prob- Toxicities were mostly infusion-related with vascular leak; lematic. With a median followup of 16 months, the estimated however, there were 3 deaths following cycle 1 (2 cardiac, 2-year FFS was projected to be 48%. The HOVON (Dutch 1 rhabdomyolysis).26 Interestingly, the ORR was only 47% Belgian Hematology-Oncology Cooperative) group recently in PTCL-NOS (n=19), compared to 80% in AITL (n=10) reported results of CHOP-14–alemtuzumab (days 1, 5, 10), and 87% in ALCL (n=8), suggesting selective sensitivity to and although the ORR was high (90%), the 2-year EFS was this combination. A Phase III trial is planned comparing comparable to that of CHOP alone (27%). Further, febrile this novel combination with CHOP. neutropenia occurred in 43%, and EBV+ lymphoproliferative disorder was reported in two patients as a result of the Other CHOP combinations immunosuppression. Similarly, a novel regimen of alemtu- Bevacizumab is a humanized monoclonal antibody against zumab with fludarabine, cyclophosphamide and doxorubicin vascular endothelial growth factor (VEGF)-A, which is strongly expressed in PTCL. The ECOG (Eastern Cooperative Oncology Group) Figure 1. Overall survival in various subtypes PTCL initiated a Phase II study in newly diagnosed PTCL patients, combining CHOP with bevacizumab followed by maintenance bevacizumab. 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 PTCL= peripheral T-cell lymphoma; ALCL= anaplastic large cell lymphoma; ALK=anaplastic lymphoma kinase; SCPTCL=subcutaneous panniculitis-like T-cell with cutaneous T-cell lymphoma [CTCL]) lymphoma; NKTCL=natural killer cell/T-cell lymphoma; AILT= angioimmunoblastic T-cell lymphoma; NOS=not otherwise specified; ETTL=enteropathy-type recently demonstrated an ORR of 76% T-cell lymphoma; HSTCL=hepatosplenic T-cell lymphoma. Reprinted with permission © 2008. American Society of Clinical Oncology. All rights reserved. (CR 65%). The GELA (Groupe d’Étude

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des Lymphomes de l’Adulte) trial evaluated the dose-intensive evaluation of heterogeneous patient populations, potential regimen ACVBP (doxorubicin, cyclophosphamide, vindesine, for selection bias and the dearth of intention-to-treat (ITT) bleomycin, prednisone) and bortezomib in newly diagnosed data. Since there are no reported prospective randomized PTCL patients (n=57), but toxicity was high and the response Phase III trials comparing HDC/ASCT to conventional-dose rate was comparable to that of ACVBP alone (CR 46%).29 chemotherapy specifically for PTCL, it remains challenging to determine the relative impact of patient selection vs true NOVEL CHEMOTHERAPY AND differences in efficacy. COMBINATIONS IN PRIMARY THERAPY The GELA group performed a retrospective analysis of the Gemcitabine combinations impact of upfront autologous transplant in TCLs. Limiting With some evidence that anthracyclines may not be optimal the study to patients who achieved CR, a matched-pair analysis in PTCL, new chemotherapy agents and combinations are was performed comparing dose-intensive chemotherapy being evaluated. It has been speculated that the chemoresis- alone (ACVB or NCVB [cyclophosphamide, vinblastine and tance may in part be due to overexpression of P-glycoprotein bleomycin with either doxorubicin or mitoxantrone]) with (Pgp), known to contribute to anthracycline resistance. the same chemotherapy plus HDC/ASCT. No difference Gemcitabine demonstrated encouraging activity in heavily in disease-free survival (DFS) or OS was found.37 pretreated relapsed PTCLs, with an ORR of 55% (CR 30%). Several Phase II prospective studies of upfront transplant The fact that this agent bypasses the Pgp efflux pump pro- have been published and represent more homogeneous vides rationale to move it to front-line therapy.30 SWOG populations of treated patients. With rare exceptions, patients has completed a Phase II study evaluating a novel regimen with ALK+ ALCL were excluded.35,36 The transplant rate in PTCLs called PEGS (cisplatin, etoposide, gemcitabine, varied from approximately 40% to 70%, and EFS ranged from methylprednisolone), incorporating drugs that are not Pgp 30% to 50% in ITT analysis.35,36 The Nordic group completed substrates. Most patients (79%) were newly diagnosed, but the largest prospective Phase II trial of upfront transplant the 1-year PFS was only 38%. With gemcitabine given on (NLG-T-01) in 160 patients with PTCL, excluding ALK+ day 1 only, the dosing may not have been optimised.31 ALCL. The planned treatment scheduled was CHOEP-14 An Italian study of high-risk PTCL evaluated front-line use for 6 cycles, followed by BEAM (carmustine, etoposide, of a novel regimen incorporating gemcitabine, ifosfamide cytarabine, melphalan/ASCT) in responding patients.38 Most and oxaliplatin (GIFOX) (including ASCT in young, chemo- patients had good functional status (71% with PS [perfor- sensitive patients). ORR was 86% (CR + unconfirmed CR mance status] scores of 0 or 1), and the overall transplant [CRu], 67%) unconfirmed CR [CRu] 67%) and 5-year EFS rate was 70%. With median followup of 5 years, 5-year PFS 49%, but toxicity was moderate, with Grade 4 thrombocy- was 44% and 5-year OS was 51%. Interestingly, patients with topenia and anemia observed in 38% and 24%, respectively; ALK– ALCL (n=31) appeared to have a superior 5-year PFS 33% had a Grade 3 infection.32 (64%) compared to PTCL-NOS (38%), EATL (38%) or AILT (49%). Outcomes were also better than historical Dose escalation in primary therapy comparisons, suggesting that this group may have a greater It is unclear whether dose escalation, with or without stem cell benefit from this approach (personal communication).38 support, improves outcome in PTCLs. The MD Anderson Cancer Center retrospectively evaluated outcomes in 135 The role of HDC/ASCT in relapsed/ patients with PTCL treated with CHOP, compared with a refractory PTCL variety of more dose-intensive approaches including early In eligible patients, HDC/ASCT represents the standard of autologous and allogeneic transplant. No difference in out- care for relapsed/refractory PTCL. In the original PARMA comes was evident, although the number of patients receiving Phase III randomized controlled study, HDC/ASCT emerged each regimen was small.33 as superior to second-line chemotherapy for relapsed aggres- Although the German retrospective study suggested that sive NHL with diagnoses based on the Working Formulation the addition of etoposide might improve cure rates in PTCL classification.39 There has been no similar study in PTCLs, in select low-risk patients, a benefit was not observed using but retrospective studies report EFS in this setting ranging simple dose-escalation in high-risk patients. The 3-year EFS from 18% to 60%, with salvage rates comparable to those of Mega-CHOEP with ASCT was only 26% in newly diag- seen in DLBCL, especially for ALCL.35,36 Given the overall nosed PTCL patients with an age-adjusted IPI score of 2 body of evidence, ASCT is frequently offered to patients or 3 or an elevated LDH.34 These results challenge the use with PTCL with relapsed, chemosensitive disease. of consolidative HDC/ASCT, a common approach in these high-risk patients. Allogeneic transplant and the graft-vs-lymphoma effect Upfront transplantation in Allogeneic stem cell transplantation (AlloSCT), with either the management of PTCLs myeloablative or reduced-intensity conditioning (RIC), has Multiple retrospective studies have been published evaluating also been reported to yield durable remission in many cases the impact of upfront transplantation in PTCL, as has been (3-year EFS 23–64%).35,40,41 Evidence supporting a graft-vs- comprehensively reviewed.35,36 Trial interpretation and com- PTCL effect comes from studies with donor lymphocyte parisons are difficult for a number of reasons, including the infusions.40,41 The largest study published to date evaluated

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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 20 55 (30) DoR for CR pts (7/9) 34 mos Neutropenia Phase II30 Thrombocytopenia Pralatrexate 111 29 (11) PFS 3.5 mos Thrombocytopenia Phase II50 OS 14.5 mos Mucositis DoR 10.1 mos Neutropenia L-asparaginase 15 (all NK/TCL) 87 (50) Not reported Antithrombin deficiency retrospective43 Sepsis Hepatitis Bendamustine52 50 50 (28) PFS 4 mos Neutropenia DoR 3.5 mos Thrombocytopenia OS 6 mos Histone deacetylase inhibitors romidepsin (depsipeptide) 47 38 (18) DoR 8.9 mos Nausea Phase II (NCI)55 Vomiting Phase II54 130 25 (15) PFS 4 mos Fatigue DoR 17 mos Thrombocytopenia Neutropenia Belinostat 20 25 (10) DoR ~ 9 Toxicity not detailed in abstract Phase II56 Antibody-directed therapy brentuximab (SGN-35) 58 (all ALCL) 86 (57) PFS 13.3 mos Peripheral sensory anti-CD30-drug conjugate66 DoR 12.6 mos neuropathy OS not reached Zanolimumab 21 (CD4+) 24 (9.5) Not reported Rash (HuMax-CD4) Infusion reaction Phase II59 Infections Other targeted therapy Lenalidomide 24 30 (0) PFS ~ 3 mos Fatigue Phase IIb,62,63 10 (all PTCL-NOS) 30 (30) Constipation Thrombocytopenia

aurora A kinase inhibitor 8 57c Not reported Neutropenia Phase 167 Fatigue Diarrhea Alopecia

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.

77 previously treated patients with mainly myeloablative in clinical trials. This approach obscures differences in treat- conditioning (74%). The 5-year PFS was 53%, but treatment- ment sensitivity of the PTCL subtypes and can make trial related mortality (TRM) was 34% at 5 years.41 A Phase II comparisons difficult. Further, there is some evidence to sup- trial evaluating RIC and AlloSCT in 17 patients, including port tailoring treatment for at least some subtypes. 8 who had failed front-line HDC/ASCT, demonstrated a The outcome of nasal NK/TCL is poor with anthracycline- 3-year PFS of 64% with a TRM of 6%.40 Allogeneic transplan- based chemotherapy, particularly for those with advanced- tation is promising in the treatment of PTCL but is limited stage disease and those with extranasal disease,42 which may by the availability of stem cell donors and toxicity related reflect an inherent resistance due to Pgp expression. L-aspara- to graft-vs-host disease. ginase has emerged as an extremely active agent in NK/TCLs. In vitro studies suggest that L-asparagine depletion results Should treatment be tailored in NK cell apoptosis. A retrospective study of 15 patients with for specific PTCL subtypes? relapsed/refractory NK/TCL treated with L-asparaginase, Generally, treatment approaches to date have been similar methotrexate (3 g/m2) and dexamethasone demonstrated among the PTCL subtypes and, because of disease rarity, it an ORR of 87% (CR 50%) (Table 2), but toxicity can be is common to include subtypes other than cutaneous PTCLs problematic and antithrombin levels need close monitoring.43

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A Phase II study evaluating L-asparaginase in combination senting the first agent to be approved exclusively in this with methotrexate and dexamethasone (AspaMetDex) was disease (Table 2). Ongoing studies combine pralatrexate recently reported. The combination appears to be extremely with other agents in the upfront and relapsed settings. active in this relapsed/refractory population, with an ORR of 78% (CR 61%) and a median duration of response (DoR) Bendamustine of 12 months.44 Additional studies incorporating L-asparagi- Bendamustine is a cytotoxic agent with alkylating and anti- nase in front-line treatment of both localized and advanced- metabolite properties. It is extremely active in indolent B-cell stage NK/TCL are ongoing. lymphomas and has recently been tested in a Phase II study It appears that radiotherapy is a key treatment modality in in relapsed/refractory PTCLs. Updated results with 60 early-stage disease, with more favourable outcomes observed patients were recently reported from the BENTLY trial; the using high doses (50–60 Gy) early in the front-line setting.45 ORR in the ITT population was 50% (CR 28%), with median Recently, the use of a platinum as radiosensitizer has been DoR, PFS and OS of 3.5, 4 and 6 months, respectively.52 explored and may allow for use of lower, less toxic doses of The most common adverse events were Grade 3/4 neutro- radiation.46 Further, since systemic relapse can occur with penia (30%), thrombocytopenia (24%) and infections (20%). single-modality radiotherapy, other novel combinations have been tested. Concurrent radiation (40 Gy) and cisplatin HDAC inhibitors (30 mg/m2 weekly) followed by 3 cycles of VIPD (etoposide, Histones are highly conserved proteins that facilitate DNA ifosfamide, cisplatin, dexamethasone), was evaluated in compaction, thereby regulating transcriptional activity. They Stage IE/IIE nasal NK/TCL. Although this was a highly are regulated in part through acetylation, which loosens selected population, the outcome was encouraging, with a the chromatin structure, modulating the expression of CR rate of 83% and an estimated 3-year PFS of 85%. Similarly, various genes. Histone deacetylases (HDACs) and histone concurrent radiotherapy (50 Gy) and DeVIC (dexametha- acetyltransferases regulate chromatin structure and function sone, etoposide, ifosfamide, carboplatin) was evaluated in a through the removal and addition, respectively, of an acetyl Phase I/II trial in localized nasal NK/TCL with good results group from the lysine residues of core nucleosomal his- (CR 77%, 2-year PFS 67%).47 In the absence of a random- tones. HDAC inhibitors (HDIs) are epigenetic therapies ized trial, the most recent NCCN (National Comprehensive that increase acetylation of histones and other nuclear pro- Cancer Network) guidelines suggest either high-dose radio- teins (Figure 2). By modulating gene expression and by therapy alone (>50 Gy) (Stage 1, no risk factors) or con- various other effects, HDIs promote cell cycle arrest and current chemoradiotherapy (Stage 1 or 2) using either of apoptosis. Multiple HDIs, including vorinostat, belinostat the above regimens.48 and romidepsin, are currently under investigation in clinical HSTCL is a rare PTCL subtype with extremely poor trials, particularly in CTCL and PTCL, where they appear response to CHOP-based treatment, with only occasional to exert a class effect. survivors. Thus, many investigators have advocated transplant Romidepsin (depsipeptide, or FK228), a member of this in the primary setting following chemotherapy with a platinum- novel class of antineoplastic agents, was one of the first HDIs based regimen. Particularly encouraging results have been seen studied in PTCL. With encouraging results observed in a with allogeneic transplant. A recent review of the literature Phase I study,53 two Phase II studies have now been com- of 17 HSTCL patients who had undergone allogeneic trans- pleted in relapsed/refractory PTCLs evaluating romidepsin plant demonstrated 7 (41%) cases alive and in remission.49 (14 mg/m2 IV) administered on days 1, 8 and 15 of a 28-day schedule. The National Cancer Institute (NCI) evaluated NOVEL THERAPIES IN RELAPSED/REFRACTORY PTCL 47 patients treated with romidepsin, reporting an ORR of Chemotherapy 38% (CR 18%) with median DoR of 9 months; patients with Pralatrexate CR had a median DoR of 30 months (Table 2). A second, Pralatrexate is a novel folate analogue with enhanced affinity industry-sponsored Phase IIB study has also reported final for the reduced folate carrier (RFC) and is more effectively results. In total, 130 patients with histologically confirmed polyglutamated, resulting in higher intracellular concentra- relapsed/refractory PTCL were treated; the ORR was 25% tions and cellular retention (Figure 2).50 Interest in prala- (CR 15%) and median DoR was 17 months (Table 2).54 The trexate for the treatment of PTCLs stemmed from a Phase median PFS was 4 months and was 18 months for patients I/II study in patients with multiple relapsed and refractory achieving a CR/CRu. hematologic malignancies, which suggested that pralatrexate Romidepsin was generally well tolerated. The most com- was selective for TCLs.51 The Phase II PROPEL study recently mon side effects encountered in these studies were nausea evaluated pralatrexate in combination with vitamin B12 and (Grade 3/4 20%), fatigue (Grade 3/4 8%), thrombocytopenia folate for relapsed/refractory PTCLs. By central review, the (Grade 3/4 24%) and neutropenia (Grade 3/4 20%).54,55 A ORR was 29% (n=111), with a median PFS of 3.5 months Phase IB study is ongoing, combining CHOP with romidepsin and median DoR of 10.5 months (Table 2).50 The main for the primary treatment of PTCL. toxicities were mucositis (Grade 3/4 22%), thrombocytopenia Belinostat, a pan-HDAC inhibitor (1,000 mg/m2 IV (Grade 3/4 33%) and neutropenia (Grade 3/4 22%). These days–5 every 3 weeks), has also been evaluated in 20 patients results led to FDA approval of pralatrexate in September with relapsed/refractory PTCL, with comparable efficacy 2009 for the treatment of relapsed/refractory PTCL, repre- (ORR 20%, CR 10%).56

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

Alemtuzumab* Zanolimumab Denileukin diftitox Pralatrexate Brentuximab vedotin NK cell linker DT CD4 IL-2 T-cell activation MMAE TCR IL-2 CD52 co-stimulation RFC-1 receptor Angiogenesis CD30 Gemcitabine* Cell Pralatrexate DT (dFdC) membrane IL-2 FPGS VEGF Pralatrexate-Glu(n) Cytoplasm IL-2 dFdCDP DT DHFR Lenalidomide*

RR Protein dFdCTP synthesis Bortezomib* TNF-α IL-6 MMAE released Cell death Proteasome Apoptosis Alisertib DNA synthesis Repression

Spindle Aurora-A Bendamustine Condensed chromatin kinase MMAE disrupts assembly microtubules Romidepsin ↑ p21 HAT HDAC Belinostat 2012 ed p53 DNA DSBs t Nucleus Relaxed chromatin imi G0/G1 st L r arrest u arkh

Apoptosis t P h

G2/M G2/M Apoptosis Transcription g Growth arrest ri

Apoptosis y

arrest arrest Senescence activation op Differentiation C

* 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.

Antibody-directed therapy In 58 patients with relapsed/refractory ALCL (72% ALK–) Given that CD30 is expressed in all ALCLs and is highly treated with brentuximab vedotin, the ORR was 86% restricted, it was an obvious target for an antitumour anti- (CR 57%), median PFS 13.3 months and median DoR 12.6 body. However, efficacy was disappointing with the anti-CD30 months (Table 2). Given the interference in microtubule monoclonal antibodies SGN-30 and MDX-060.57,58 formation, the main toxicity was peripheral neuropathy, but To enhance antitumour activity, an antibody-drug conjugate, Grade 3 events occurred in only 12% of patients. As a result brentuximab vedotin (SGN-35), was designed by conjugating of promising single-agent activity, a study has been initiated monomethyl auristatin E (MMAE), an antitubulin agent, combining CHP (CHOP with vincristine omitted due to to a CD30-specific monoclonal antibody, cAC10, by an neurotoxicity) with brentuximab vedotin in newly diagnosed enzyme-cleavable dipeptide linker. MMAE is released into systemic ALCL. Brentuximab vedotin is also being explored the cell following endocytosis and interferes with mitosis, in other CD30+ NHLs, including a small number of PTCL causing cell arrest and apoptosis (Figure 2). A Phase I trial cases that are positive for this marker. was performed in CD30+ hematologic malignancies, most of The majority of PTCLs, including PTCL-NOS, AITL which were Hodgkin lymphomas (HL), although 2 patients and ALCL, have a T-helper cell phenotype, expressing CD4 with ALCL were also enrolled. Encouraging efficacy was on the cell surface. Zanolimumab (HuMax-CD4) is a human observed, including responses in both patients with ALCL. monoclonal antibody directed against CD4 that abrogates Thus, Phase II studies were initiated in both HL and ALCL. signalling by the T-cell receptor and induces killing of CD4+

16 oe VOL. 11, No. 3, August 2012 feature

cells by antibody-dependent cellular cytotoxicity (Figure 2). CONCLUSION A Phase II trial evaluating this agent in 21 patients with The development of optimal treatments to improve outcome relapsed/refractory PTCL recently reported an ORR of 24% for PTCLs remains a challenge, given the rarity and biologic (CRu 10%; Table 2).59 The most frequently encountered heterogeneity of these cancers. Nevertheless, in the last few toxicities were rash, pyrexia and infusion reactions; the infec- years there have been an unprecedented number of trials in tion rate was moderate (29%). PTCL, demonstrating that it is possible to do prospective trials in these rare diseases. The goal of future studies should Other targeted therapy be to focus on new combinations and the most active agents Bortezomib in PTCL, and ultimately to develop an effective combination The proteasome inhibitor bortezomib has a non-cross-resis- regimen for primary treatment. tant mechanism of action with a variety of agents (Figure 2). A Phase I study of gemcitabine (800 mg/m2) and bortez DISCLOSURES: Dr. Savage has received honoraria from Celgene omib (1.6 mg/m2 on days 1 and 15 of each 28-day cycle) and Seattle Genetics for consulting. Dr. Reiman has received honoraria was evaluated in a variety of hematologic malignancies, with from Celgene for consulting. early responses seen in PTCL.60 Bortezomib is also being evaluated in combination with pralatrexate, given evidence ACKNOWLEDGEMENTS: The authors gratefully acknowledge the of synergy in preclinical models.61 support of Celgene Canada Inc. and thank John Ashkenas, PhD (SCRIPT, Toronto ON) for editorial assistance. 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