Welcome international healthcare professionals

This site is no longer supported and will not be updated with new content. You are welcome to browse and download all content already included in the site. Please note you will have to register your email address to access the site.

You are here

Treatment strategies for peripheral T-cell lymphomas

Best Practice & Research Clinical Haematology, 1, 26, pages 43 - 56

Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of clinically aggressive diseases historically associated with inferior outcomes using conventional lymphoma therapies. Aggressive first line therapy and consolidation with autologous stem cell transplantation has led to improved survival, but the majority of patients either fails to respond to therapy or are not transplant candidates. Novel approaches have included new classes of drug and biological agents, including antifolates, immunoconjugates, histone deacetylase (HDAC) inhibitors, monoclonal antibodies, and signal transduction inhibitors. Molecular profiling has led to identification of relevant pathways for future novel approaches.

Keywords: peripheral T cell lymphoma, angioimmunoblastic T-cell lymphoma, HTLV-1 associated T cell lymphoma, enteropathy associated T-cell lymphoma, panniculitis-like T-cell lymphoma, monoclonal antibodies, denileukin diftitox, brentuximab vedotin, pralatrexate, histone deacetylase inhibitors.

Introduction

The aggressive T-cell lymphomas are a diverse group of disorders that are associated with a poor prognosis. Classification of PTCL is complex and has been further hampered by a paucity of molecular markers. The WHO classification of non-Hodgkin's lymphomas includes many subtypes of aggressive T-cell lymphomas ( Table 1 ) characterized based primarily on their clinical and histopathologic features and subgroups them into the cutaneous, nodal, extranodal, and leukemic groups [1] .

Table 1 The WHO classification for PTCLs was updated in 2008. The new classification expanded some existing disease types and added several new provisional diseases.

Old WHO classification [7] New WHO classification [9]
Precursor T-cell lymphoma  
T-lymphoblastic lymphoma/leukemia  
Mature T-cell lymphomas  
T-cell prolymphocytic leukemia T-cell prolymphocytic leukemia
T-cell granular lymphocytic leukemia T-cell large granular lymphocytic leukemia
Aggressive NK-cell leukemia Aggressive NK-cell leukemia
  Indolent large granular NK-cell lymphoproliferative disorder (provisional)
Adult T-cell lymphoma/leukemia (HTLV1+) Adult T-cell leukemia/lymphoma
Extranodal NK/T-cell lymphoma, nasal type Extranodal NK/T-cell lymphoma, nasal type
Enteropathy-type T-cell lymphoma Enteropathy-associated T-cell lymphoma
Hepatosplenic T-cell lymphoma Hepatosplenic T-cell lymphoma
Subcutaneous panniculitis-like T-cell lymphoma Subcutaneous panniculitis-like T-cell lymphoma (αβ only)
  Primary cutaneous γδ T-cell lymphoma
Mycosis fungoides/Sézary syndrome Mycosis fungoides & Sézary syndrome
Anaplastic large-cell lymphoma, systemic or cutaneous Anaplastic large cell lymphoma- ALK+
  Anaplastic large cell lymphoma- ALK- (provisional)
Peripheral T-cell lymphoma, unspecified Peripheral T-cell lymphoma, not otherwise specified
Angioimmunoblastic T-cell lymphoma Angioimmunoblastic T-cell lymphoma
  Primary cutaneous CD30+ T-cell LPD
  LYP and primary cutaneous ALC
  Primary cutaneous CD4+ small/medium T-cell lymphoma (provisional)
  Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma (provisional)
  Systemic EBV+ T-cell LPD of childhood
  Hydroa vacciniforme-like lymphoma

The nodal lymphoma group includes PTCL, not otherwise specified (NOS), anaplastic large cell lymphoma (ALCL), and angioimmunoblastic T-cell lymphoma (AITL). ALCL is further separated into the ALK+ and ALK entities. According to the International PTCL study, PTCLnos accounts for 26% of cases, angioimmunoblastic T-cell lymphoma accounts for 18.5%, ALK+ ALCL accounts for 6.6% and ALK ALCL for 5.5% of cases [2] . The nodal T cell lymphomas are treated similarly with the exception of the ALK+ ALCL patients who have a more favorable outcome.

The extranodal T-cell lymphomas comprise a group of less well understood diseases identified based on their tissue trophism. Hepatosplenic gamma-delta T-cell comprises 1.4% of cases and is characterized by gamma-delta T-cell infiltration of the liver, spleen, and bone marrow sinusoids. Outcomes are poor with a median survival of less than 2 years. Enteropathy-associated T-cell lymphoma (EATL) accounts for 4.7% of cases and is comprised of two morphologic variants, the pleomorphic type, usually associated with celiac sprue, and the monomorphic type, which is CD56+ and often not associated with celiac disease [3] . Panniculitis-like T-cell lymphomas constitute only 0.9% of PTCL and presents with subcutaneous nodules that are typically CD3+, CD4, and CD8+, with TCR-[alpha]/[beta]+ expression. The cutaneous panniculitis-like T-cell lymphomas with TCR-[gamma]/[delta]+ expression have now been reclassified as cutaneous gamma/delta T-cell lymphoma [4] . NK-cell lymphomas include extranodal NK/T-cell lymphoma, nasal type, blastic NK-cell lymphoma, and aggressive NK-cell leukemia account for 10.4% of PTCL cases.

The leukemic group of T-cell lymphomas consists of adult T-cell lymphoma (ATLL) associated with human T-lymphotropic virus type I (HTLV-1), T-cell chronic large granular lymphocytic (LGL) leukemia, aggressive NK-cell leukemia, and T-cell prolymphocytic leukemia. LGL leukemia often has an indolent clinical course and is associated with neutropenia, while aggressive NK cell leukemia and ATLL often have a poor outcome even with systemic therapy. HTLV-1-associated lymphomas include several entities. Adult T-cell leukemia-lymphoma (ATL) is a fulminant disease with a leukemic component, lymphadenopathy, hepatosplenomegaly, skin involvement, high LDH, and hypercalcemia. Smoldering ATL is characterized by circulating leukemia cells without nodal involvement. Lymphomatous ATL presents with lymphadenopathy without leukemic involvement, and chronic ATL is characterized by skin lesions, leukemic, nodal and visceral disease without hypercalcemia, GI involvement, bone, or CNS disease. HTLV-1 infection is prevalent in Japan and the Caribbean basin, but only a small proportion of patients carrying the virus develop a malignancy.

Therapeutic approaches for aggressive T-cell lymphomas

Standard first-line therapy

T-cell lymphomas have traditionally been treated much like aggressive diffuse large B-cell lymphomas. A meta-analysis of 2912 patients treated with CHOP or CHOP-like regimens reported a 5-year overall survival of 37%, inferior to that of B-cell patients [5] . Further, retrospective data reported no difference in outcome when more aggressive regimens such as HyperCVAD and ESHAP were used in 135 patients with PTCL (3-year OS: 43% vs. 49% for CHOP) [6] . A prospective study addressing the role of dose intensive therapy was completed and demonstrated that mega CHOP/ESHAP regimen (cyclophosphamide 2000 mg/m(2)/day, adriamycin 90 mg/m(2)/day, vincristine and prednisone alternating with three courses of etoposide, cisplatin, cytarabine and prednisone (ESHAP)) administered first line with the intent to transplant patients in first remission demonstrated that patients fared no better than those with CHOP alone by historical comparison, and the median survival of patients who demonstrated primary refractory disease was poor at 8 months [7] .

The German High Grade Non-Hodgkin's Lymphoma Study group explored the role of dose intensive therapy with the addition of etoposide to CHOP regimens and reported their results in aggressive T-cell lymphomas [8] . There were 343 T-cell patients enrolled in these studies (70 with PTCLnos, 28 with AITL, 78 with ALK+ ALCL, and 113 with ALK ALCL. While response rates were more favorable for the etoposide containing regimen, there was no improvement in event-free survival with the addition of etoposide to first line CHOP except in the younger patients (75% vs. 51%, favoring CHOEP); however, there was no overall survival difference. Further, the impact of etoposide on EFS was seen only in the most favorable ALK+ patients who were under age 60 and not in patients with less favorable histologies, such as PTCLnos or AITL. In the elderly population, neither shortening of the time interval between cycles from 3 to 2 weeks (CHOP-21 vs. CHOP-14), administration of 8 instead of 6 courses of CHOP-14, nor the addition of etoposide (CHOEP) significantly improved EFS or OS, but toxicity was increased. One important prognostic factor in these studies was the International Prognostic Index (IPI). Overall, patients with a low IPI of 0–1 had a 3-year EFS above 50%, while those with IPI ≥ 2 had an EFS of 34%. When dose intense therapy (MegaCHOEP) was used, results were inferior to those of standard dose CHOP.

Alternative regimens to CHOP have also been explored in multicenter trials. The French used ACVBP (doxorubicin 75 mg/m2 D1, cyclophosphamide 1200 mg/m2 D1, vindesine 2 mg/m2 D1 and D5, bleomycin 10 mg D1 and D5 and prednisone D1 to D5, followed by a sequential consolidation consisting of methotrexate (2 courses), etoposide + ifosfamide (4 courses) and cytarabine (2 courses) at 2 weeks intervals) in a randomized trial and results were slightly better than with CHOP [9] However, the addition of bortezomib on days 1 and 5 of each ACVBP cycle and then days 1,8,15 every 4 weeks as a consolidation showed no further benefit with this regimen.

Another alternative first line regimen, etoposide, ifosfamide, cisplatin alternating with doxorubicin, bleomycin, vinblastine, dacarbazine (VIP-reinforced-ABVD; VIP-rABVD) was compared to CHOP/21 in 88 patients with PTCL [10] . The Groupe Ouest Est d'Etude des Leucemies et Autres Maladies du Sang (GOELAMS) treated 88 patients with this regimen and reported a 2-year EFS of 41% vs. 45% for CHOP-21 with a similar median overall survival of 42 months for each of the arms.

New combination therapies for PTCL

CHOP-based regimens

Based on the demonstration of CD52 by expression on up to 42% of patients with PTCL, alemtuzumab has been used as a single agent in relapsed PTCL and in combination with chemotherapy in the front line [11] . One phase II study by Kim et al. enrolled 20 patients treated with CHOP combined with intravenous alemtuzumab in 3-week cycles (cycle 1: 10 mg on day 1, 20 mg on day 2; subsequent cycles: 30 mg on day 1) as frontline therapy [12] . Responses were seen in all 10 pts. With PTCLnos, 1 of 3 with extranodal NK/T cell lymphoma, 2 of 3 with AITL, and 1 of 2 with ALK ALK ALCL and SPTCL respectively, and toxicities included grade 4 neutropenia in 90% of patients, cytomegalovirus (CMV) reactivation in 25%, and 2 treatment-related deaths. When alemtuzumab was given subcutaneously in a subsequent study by Gallamini et al., the incidence of serious infections was reduced [13] . Of 24 evaluable patients, 71% had a complete response, including all 6 with AITL, all 3 with ALK-ALCL, 7 of 14 with PTCLnos, and one with enteropathy associated T-cell lymphoma. Cytomegalovirus reactivation occurred in 9% of patients, and serious infections included one patient with Jacob-Creutzfeldt virus and two with aspergillosis. The overall median duration of response was 11 months. Based on these results, the alemtuzumab-CHOP combination is being compared to CHOP-21 in by the Nordic Lymphoma Group and the German High Grade Lymphoma Groups (the ACT Trial). Patients over age 60 are randomized and followed until progression. Patients under age 60 are randomized to either 6 cycles of CHOP-14 or 4 cycles of alemtuzumab-CHOP-14 or 2 cycles of CHOP-14 without alemtuzumab vs. 6 cycles of CHOP-14. Patients in remission will then undergo an autologous stem cell transplant.

The combination of alemtuzumab with dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) has been explored in patients with aggressive T-cell lymphomas [14] . Infections were reported in 11 of 14 patients from bacterial, fungal and viral pathogens.

Denileukin diftitox, the interleukin-2 receptor targeted fusion protein, has also been combined with CHOP for first line therapy of aggressive T-cell lymphomas. Denileukin diftitox has shown activity as a single agent in relapsed aggressive T-cell lymphomas, with a response rate of 48% in 27 heavily pretreated patients [15] . In a multi-center prospective phase II trial, denileukin diftitox was administered at a dose of 18 μg/kg/day on days 1 and 2 with CHOP on day 3; all patients received growth factor support [16] The ORR in 47 pts. was 68% with 57% CR. The median PFS was 12 mo. and 2-year estimated OS was 60%. The most frequent grade 3 or 4 adverse events were bone marrow suppression and febrile neutropenia. A multi-center study randomizing CHOP-denileukin diftitox with CHOP alone is underway.

Studies incorporating other targeting antibodies with CHOP have also been reported. For patients with angioimmunoblastic T-cell lymphoma in whom the microenvironment is rich in B-lymphocytes, rituximab was added to CHOP in elderly patients (age 59–79). The overall response rate was 80%, with 44% achieving a complete response. With a median follow up of 24 months, the progression free survival was 42% and the 2-year-overall survival was 62%; the authors stated that these results were no different than their previous experience with CHOP alone in this population.

Another attempt to target microenvironment in aggressive T-cell lymphoma was a Phase II study conducted by the Eastern Cooperative Oncology Group combining the anti-VEGF receptor monoclonal antibody, bevacizumab, with CHOP as first line therapy. The rational for this combination is that VEGF has been shown to be overexpressed by several PTCL subtypes, especially AITL and PTCLnos and responses have been seen in relapsed AITLs patients who received bevacizumab [17] . A preliminary analysis of this study demonstrated a high incidence of cardiac events related to the therapy, including 4 cases of congestive heart failure, and the study has been halted [18] .

Gemcitabine-based regimens

Because results with CHOP and traditional anthracycline based regimens have overall been inferior in aggressive T-cell lymphomas, regimens utilizing gemcitabine have been explored. Gemcitabine is not metabolized by the multi-drug resistance p-glycoprotein pathway and has demonstrated efficacy in T-cell lymphomas as a single agent [19] . Gemcitabine combined with cisplatin (GEM-P, gemcitabine 1000 mg/m2 days 1,8,15, cisplatin 100 mg/m2 on day 8) demonstrated a response rate of 73% with grade 3 or 4 neutropenia in 41% of patients [20] . The combination vinorelbine 25 mg/m2 and gemcitabine 1000 mg/m2 on days 1 and 8 of each 21-day had a reported 70% response rate in a pilot study [21] . A regimen of CHOP plus etoposide 100 mg/m2 day 1 and gemcitabine 600 mg/m2 every 21 days was explored in 26 enrolled patients, with an overall response rate of 76.9% and a median event free survival of 7 months [22] . While results with this regimen were similar to CHOP, the incidence of febrile neutropenia was 15.4%. While active, this regimen did not appear to be superior to studies with CHOP-etoposide and incidence of myelosuppression was higher.

The PEGS regimen (gemcitabine, cisplatin etoposide, solu-medrol) has been reported Southwest Oncology Group in untreated and relapsed PTCL patients. The one year event-free survival was lower than expected at 38%. Another regimen incorporating gemcitabine, the GIVOX regimen (gemcitabine, ifosfamide, and oxaliplatin), reported a response rate of 86% with 67% CR and the 5-year EFS was 49%. Toxicities were primarily hematologic, with grade 4 thrombocytopenia and anemia occurring in 38% and 24% of patients respectively. Overall, gemcitabine based regimens have been shown to be active but there are no randomized trials comparing this approach to CHOP in the first line setting.

Transplantation as a consolidation therapy

Because of the historically poor outcomes and high relapse rates after first line chemotherapy in aggressive T-cell lymphomas, the role of autologous or allogeneic stem cell transplantation in first remission has been explored in a number of small series and more recently in prospective nonrandomized trials. The largest studies from the Nordic and German study groups report overall EFS ranging from 30 to 50% and transplant rates of 40–70% based on intent to treat analysis. The Nordic group reported results from 160 patients treated with an etoposide based regimen (CHOEP-14) followed by BEAM conditioning [23] . At a median follow up of 4 years, the OS was 50% and the PFS was 48%. In the German study reported by Reimer et al., 83 patients were treated with CHOP × 4, followed by Dexa BEAM or ESHAP [24] . The conditioning regimen was total body irradiation and high dose cyclophosphamide. In this study, only 66% of patients were able to be transplanted. At a mean follow up of 33 months, the OS was 48% and the EFS were 53%. Comparison of these two different approaches suggests that there may be no benefit for total body irradiation in this setting, and BEAM or chemotherapy based conditioning regimens remains the standard. To date there are no randomized trials exploring the role of transplantation compared to no further therapy or maintenance chemotherapy in aggressive T-cell lymphomas.

 

  • Expert hematopathology review is essential to establish histopathologic subtype of PTCL
  • IPI score is important in treatment planning. Patients with Stage II/II disease and a low IPI may be treated with chemotherapy and involved field radiotherapy and do not need a transplant
  • ALK+ ALCL has a better prognosis and is treated with chemotherapy alone; for ALK+ ALCL with high IPI score, may consider transplant
  • Enteropathy associated T cell lymphomas and NK/T cell lymphomas have different treatment paradigms
  • High consideration for clinical trials and novel agents in any of these subtypes with poor clinical outcomes

Novel agents

A number of novel agents have shown efficacy in aggressive T-cell lymphomas ( Table 2 ). Several agents with activity in the relapsed setting are finding their way into combination approaches for first line treatments, including the histone deacetylases, pralatrexate, and the CD 30 targeted toxin brentuximab vedotin. Response rates have been similar for many of the novel agents when used in the relapsed and refractory setting ( Table 3 ).

Table 2 Novel agents in use or trials in PTCL. a

Type of agent Name Description Disease(s)
Antifolates Pralatrexate 10-deazaminopoterin PTCL, CTCL
Conjugates LMB-2 Anti-Tac)anti-CD25 fused to Pseudomonas toxin CTCL, PTCL (esp ATL)
Denileukin diftitox IL-2 targeting domain fused with diphtheria toxin CTCL, PTCL
  Brentuximab vedotin CD30 antibody conjugated to monomethylauristan-E CD30+ T-cell lymphoma
HDAC inhibitors Belinostat PXD101 CTCL, PTCL
Panobinostat LBH589 CTCL, ATL
Romidepsin Depsipeptide CTCL, PTCL
Vorinostat Suberoylanilide hydroxamic acid (SAHA) CTCL
Immunomodulatory agents Lenalidomide Derivative of thalidomide PTCL, CTCL
Immunosuppressive agents Cyclosporine Inhibitor of the NF-AT transcription complex AITL
Monoclonal antibodies Alemtuzumab Anti-CD52 PTCL
Bevacizumab Anti-VEGF PTCL (esp AITL), NK-cell
Iratumumab Anti-CD30 CD30+ ALCL
KW-0761 Anti-CCR4 ATL, PTCL
SGN-30 Anti-CD30 CD30+ ALCL
Siplizumab Anti-CD2 PTCL, NK-cell, ATL
Zanolimumab Anti-CD4 CTCL, PTCL
Nucleoside analogs Gemcitabine Pyrimidine nucleoside analog PTCL
Nelarabine Purine nucleoside analog T-ALL, T-NHL
Pentostatin Metabolic enzyme inhibitor PTCL
Signaling inhibitors Enzastaurin Selective inhibitor of protein kinase C PTCL, CTCL
Signaling inhibitors R788 Syk inhibitor PTCL
IPI-145 Phosphatidyl-inositol 3 kinase inhibitor T cell lymphoma
Alisertib Aurora Kinase Inhibitor PTCL
Other drugs Bendamustine Novel mechanism PTCL
  Bortezomib Proteasome inhibitor PTCL, CTCL

a There are several other experimental agents in various stages clinical trials for T-cell lymphoma.

Abbreviations: AITL, angioimmunoblastic T-cell lymphoma; ALL, acute lymphoblastic leukemia; ATL, adult T-cell leukemia-lymphoma; CTCL, cutaneous T-cell lymphoma; esp, especially; IL-2, interleukin-2; MAb, monoclonal antibody; NHL, non-Hodgkin’s lymphoma; Ph, phase; PTCL, peripheral T-cell lymphoma.

Table 3 Response rates for new therapies in T-cell lymphoma.

Drug Author, year No of PTCL pts Response duration ORR
Alemtuzumab Enblad Blood 2004 14 2, 6, 12 mo 5/14
Zinzani 2005 10 7 mo 6/10
Gemcitabine Zinzani Ann Oncol 2010 20 15–60 mo (only CCRs) 55%
Zanolimumab D’amore BJH 2010 21   27%
Lenalidomide Dueck Cancer 2010 23 OS: 241 dys 7/23
Denileukin Dang Br J Haematol 2004 27 PFS: 6 mo 13/27
Pentostatin Tsimberidiou Cancer 2004 42 DOR: 4.5 mo 55%
Brentuximab vedotin Pro, J Clin Oncol 2012 58 (ALCL) DOR: 13.2 mo 86%
Pralatrexate O'Connor JCO 2011 115 (109) DOR: 10.1 mo PFS: 3.5 mo 32/109
Romidepsin Piekarz Blood 2011 45 DOR: 8.9 mo (CR: 29.7 mo) 17/45
Coiffier et al., JCO 2012 130 DOR: 17 mo 34/130

Monoclonal antibodies and immunoconjugates

Siplizumab, an antibody targeting CD2, demonstrated activity with 2 CR in patients with large granular lymphocyte leukemia (LGL), 3 partial responses (PRs) in patients with adult T-cell leukemia, and 1 PR in a patient with CTCL [25] and [26]. Several cases of EBV-associated lymphoproliferative disease occurred, resulting in the combination of this antibody with rituximab to prevent EBV emergence [26] . Zanolimumab, a humanized anti-CD4 antibody, was shown to be active in patients with cutaneous T-cell lymphomas and in PTCL with a response rate of 24% in early studies [27] and [28].

Interleukin-2 receptor targeted agents include denileukin diftitox, a fusion protein that combines interleukin-2 receptor-binding domain with diphtheria toxin, and LMB 2, a single chain anti-CD25 antibody conjugated to Pseudomonas exotoxin. Denileukin diftitox was shown to be highly active in relapsed PTCL with a response rate of 48% in heavily pretreated patients irrespective of CD25 expression on the tumor cells as determined by immunohistochemistry [15] . LMB-2 has shown clinical activity in phase II trials in CLL, CTCL, and hairy cell leukemia. ATL is the PTCL subtype that is most sensitive to LMB-2, but clinical responses have been limited to do rapid disease progression after >95% tumor reduction and immunogenic reactions [29] . A phase II clinical trial combines LMB-2 with fludarabine and cyclophosphamide.

Antibodies and conjugates targeting the CD30 receptor have been highly active in anaplastic large cell lymphoma and in other subsets of CD30 expressing T-cell lymphomas. Two monoclonal antibodies, iratumumab and SGN-30, have shown efficacy as single agents in patients with relapsed and refractory CD30+ ALCL [30] and [31]. In vitro studies further demonstrated additive or synergistic effects when the antibodies were combined with conventional chemotherapy [32] . SGN-35, or brentuximab vedotin, an immunoconjugate consisting of the SGN-30 antibody and monomethyl auristatin, a microtubule inhibitor, has recently been FDA approved for the treatment of relapsed and refractory anaplastic large cell lymphoma and Hodgkin's disease [33], [34], and [35]. In a phase II multicenter trial of brentuximab vedotin in relapsed or refractory ALCL, the overall response rate was 86% (50 of 58 patients), with CR in 53%. Patients received brentuximab vedotin 1.8 mg/kg q3 weeks for up to 16 cycles. Peripheral sensory neuropathy was the most frequent side effect and occurred in 36% of patients. Brentuximab vedotin has been incorporated into first line therapy with a CHP regimen (cyclophosphamide, Adriamycin, prednisone) and shown to be safe. A randomized study comparing this regimen to CHOP is underway in untreated patients with systemic anaplastic large cell lymphoma and other subsets of peripheral T-cell lymphomas which express CD30 by immunohistochemistry.

A novel approach for patients with T-cell lymphomas is the use of chemokine targeting agents. A humanized anti-CCR4 antibody, KW-0761, has shown promise as a single agent in Japan for the treatment of T-cell leukemia and lymphomas. In a phase I study, the ORR was 31%, there were no dose-limiting toxicities, and no anti-KW-0761 antibodies were detected [36] . A phase II trial for patients with relapsed HTLV-1 associated T-cell leukemia/lymphoma was completed and reported a 54% overall response rate in 27 patients with relapsed or refractory disease [37] . Toxicities included cytopenias (lymphopenia 96%, neutropenia 33%), skin rash (52%), and mild transaminitis. KW-0761 is now being combined with CHOP chemotherapy for first line treatment of patients with ATL.

Histone deacetylase inhibitors

Histone deacetylase (HDAC) inhibitors are a novel class of drugs which are potent inducers of protein and histone acetylation and modulate expression of a number of cellular genes and pathways [38] . HDAC inhibitors increase the acetylation of histones, as well as other nuclear factors and result in modulation of gene transcription, affecting a panoply of cellular pathways, including apoptosis, and cell survival, angiogenesis, and cell cycle genes. The oral HDAC inhibitor vorinostat has demonstrated activity in relapsed and refractory cutaneous T-cell lymphoma patients at a dose of 400 mg daily, with a response rate of 30% [39] . Panobinostat is an oral HDAC inhibitor with modest activity in cutaneous T-cell lymphoma; this agent is being explored in combination studies for patients with aggressive T-cell lymphomas [40] .

Romidepsin is an intravenous HDAC inhibitor which is administered at a dose of 14 m/m2 weekly for 3 weeks on a 4 week cycle. Romidepsin demonstrated activity in a Phase II study of relapsed and refractory CTCL patients, an overall response rate of 34% and a median response duration of 15 months (range 1–20+) [41] . Romidepsin was subsequently explored in patients with relapsed and refractory PTCL with an objective response rate of 39% in patients with relapsed and refractory disease [42] . A phase IIB study of romidepsin in relapsed and refractory PTCL enrolled 130 patients with a median of 2 prior therapies and reported an overall response rate of 26% with 15% CR [43] . The median OR for all responders was significant at 28 months. Toxicities included gastrointestinal and constitutional events and thrombocytopenia. A combination study of romidepsin with CHOP as first line therapy is now being conducted.

Belinostat is a hydroxamic acid-derived HDACi which has been studied in both intravenous and oral formulations. Belinostat was administered intravenously at 1000 mg/m2/daily for 5 days every 3 weeks in 53 patients including 19 with refractory PTCL and 29 with refractory CTCL [44] . The objective response rate in PTCL was 32% with 2 CR and median response duration of 8.9+ mo., and 14% in CTCL, with response duration of 9.1 months. A multicenter phase II registration trial of belinostat in relapsed PTCL patients has been completed.

Additive and synergistic activity has been demonstrated in vitro for combinations of HDACi with a number of agents, including topoisomerase inhibitors, bortezomib, and cytotoxic chemotherapy drugs and clinical trials are underway to explore the activity of these combinations in T-cell lymphomas. In one study, the combination of HDAC inhibitors and demethylating agents has been shown to be synergistic in vitro [45] .

Pralatrexate

Pralatrexate is a novel folate antagonist whose activity is associated with binding to the reduced folate carrier. A number of studies demonstrated activity of pralatrexate in PTCL with the PROPEL trial enrolling 111 patients with relapsed or refractory disease [46] and [47]. Patients received pralatrexate at a dose of 30mg/m2 weekly for 6 weeks of a 7 week cycle. The ORR was 29% and the median response duration was 10.1 months [48] . Drug-related adverse events included mucusitis in70% of patients and thrombocytopenia in 40%. The incidence of mucusitis with pralatrexate is ameliorated to some degree by the administration of cyanocobalamin and folic acid during the course of therapy [49] . A multi-center study is underway to explore the use of pralatrexate as a maintenance agent after CHOP chemotherapy in untreated patients. Another ongoing study administers pralatrexate sequentially with a CHOP based regimen as a front line therapy, with patients receiving cyclophosphamide, vincristine, prednisone and etoposide, alternating with weekly pralatrexate for 3 of 4 weeks, with repeating cycles. Preliminary data has shown that this regimen is well tolerated.

Immunomodulators and immunosuppressants

Cyclosporine is an immunosuppressive agent that inhibits the NF-AT transcription complex, which activates the genes encoding cytokines and cell surface molecules involved in cell-to-cell communication and death. The efficacy of single agent cyclosporine was explored in patients with AITL because this subtype of T-cell lymphoma is characterized by immune deregulation. Of 12 patients treated in a Phase II trial, two thirds had a response, but there were 4 deaths [50] . Other immune modulating and antiangiogenic agents, including bevacizumab, rituximab, lenalidomide, and thalidomide, are also being explored as single agents and in combination with chemotherapy. A phase II study of lenalidomide at a dose of 25 mg/m2 daily for 21 days of a 28 day cycle was conducted in 24 relapsed PTCL patients [51] . The overall response rate was 30% with a PFS of 95 days. Toxicities included neutropenia and thrombocytopenia in 20% and 33% of patients, respectively. Combinations with lenalidomide are currently being planned, and an ongoing trial is exploring the combination of lenalidomide with romidepsin in relapsed and refractory disease.

Nucleoside analogs

Deoxycoformycin (pentostatin) and forodesine are nucleoside analogs which have shown activity in both cutaneous and aggressive T-cell malignancies. Deoxycoformycin is an inhibitor of adenosine deaminase and as such it does not incorporate into DNA, unlike the other nucleoside analogs. A study conducted at the Royal Marsden reported 145 patients with T-cell malignancies who received pentostatin 4 mg/m2/wk. for the first 4 weeks and then every 2 weeks until maximal response. The overall response rate was 32%, but a response rate was observed in 27 patients with peripheral T-cell lymphomas (19%) and in 25 with adult T-cell leukemia/lymphoma (ATLL) (12%) [52] and [53].

Proteasome inhibitors

Bortezomib, a proteasome inhibitor, has been well tolerated and active as a single agent in relapsed or refractory CTCL patients [54] . In a phase II study of bortezomib in relapsed CTCL or PTCL patients, the ORR was 67% with 2 CR and no grade 4 toxicity [54] . Bortezomib was also shown to potentially synergize with pralatrexate in an in-vitro system [55] .

Signaling inhibitors

Enzastaurin is a selective inhibitor of protein kinase C which inhibits cell proliferation, induces tumor cell apoptosis, and suppresses tumor-induced angiogenesis in CTCL cell lines [56] . Enzastaurin is currently being explored in two phase II trials: one for patients with several types of NHL, including PTCL and CTCL, and another for relapsed CTCL patients. The PI3 kinase inhibitor IPI-145 is being explored and has demonstrated early activity in aggressive T-cell lymphoma [57] . Studies to explore the role of PI3 kinase inhibitors in T-cell lymphomas are underway.

Treatment strategies for individual subtypes of T-cell lymphomas

Enteropathy associated T-cell lymphomas

Enteropathy-type T-cell lymphoma (ETCL) is a rare primary extranodal T-cell lymphoma characterized by infiltration of malignant T-cell within the gastrointestinal epithelium. EATL type 1 occurs with higher frequency (80–90% of cases) and is associated with a history of celiac sprue. EATL Type 2 occurs sporadically and is composed of monomorphic populations of T-cells which are characteristically CD3+, CD8+ and CD56+. With conventional CHOP chemotherapy, the 5 year OS and PFS for patients with EATL historically were reported to be dismal at 20% and 4% respectively. Recent strategies to improve outcomes have included more aggressive treatment regimens and introduction of non-anthracycline based regimens in the first line. The Nordic group reported results from 21 patients treated with CHOEP-14 followed by stem cell transplant. On that study, 33% of patients never made it to transplant due to progressive disease, and at 45 month follow up, 10 (45%) of patients were still alive [58] . Lennerd et al. have reported the use of CHOP × 1 cycle followed by 3 cycles of non-cross resistant chemotherapy consisting of Ifosfamide/etoposide/epirubicin with intermediate dose methotrexate and then autologous stem cell transplantation. With this regimen, they have reported a response rate of 69% with a 5-year survival of 60%. Thus far there has been no data comparing outcomes with autologous vs. allogeneic stem cell transplantation in EATL, but patients with high IPI should be considered for clinical trials testing this approach. There is little data on efficacy of salvage therapy in EATL, so the treatment focus should be on effective first line therapy followed by a consolidation with stem cell transplantation.

Subcutaneous panniculitis-like T-cell lymphoma

Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is characterized by infiltration of malignant T-lymphocytes in subcutaneous tissue, often rimming the fat lobules. Although subcutaneous panniculitis-like T-cell lymphoma has been recognized as a distinctive entity in the category of peripheral T-cell lymphoma in the World Health Organization classification, its diagnostic criteria has been redefined by the recent World Health Organization-European Organization for Research and Treatment of Cancer classification for primary cutaneous lymphomas. The term subcutaneous panniculitis-like T-cell lymphoma is now restricted to primary tumors expressing the alpha/beta T-cell receptor phenotype. These lymphomas are usually CD3(+), CD4(−), CD8(+), and CD56(−), and usually have an indolent clinical course. The tumors expressing the gamma/delta phenotype have been reclassified as primary cutaneous gamma/delta T-cell lymphoma (PCGD-TCL).

SPTCL usually presents with one or multiple subcutaneous nodules involving one or multiple areas of the body and may be associated with fevers, weight loss, and pancytopenia. The pancytopenia is often cytokine-mediated, as bone marrow involvement is rare [59] and [60]. The hemophagocytic syndrome may occur in up to one third of patients and in some cases may be fulminant. The clinical course for patients with SPTCL has been highly variable, due in part to the small number of cases reported and to the fact that until recently the distinction between the alpha/beta and gamma/delta subtypes had not been uniformly made at diagnosis. PCGD-TCL accounts for less than 1% of all cutaneous TCL and presents as diffuse skin involvement with disseminated lesions that mainly affect the extremities and frequently are associated with ulceration and necrosis. The phenotype of PCGD patients is CD3+, CD8− with expression of cytotoxic markers in most cases (TIA-1, granzyme B, perforin). Unlike alpha/beta SPTCL, dissemination to other extranodal sites is frequently, and the majority of patients present with B-symptoms.

A retrospective review by Willemze et al. and the EORTC Cutaneous Lymphoma Group describes clinical features and outcomes of 63 patients with SPTCL and 20 with PCGD-TCL based on careful pathological review of the cases [4] . When treatment and outcomes were reviewed, it was noted that 50–70% of patients received CHOP like regimens, 10–38% had immunosuppressive therapies, and a small number were treated with radiation or local excision of the nodules. With initial therapy, 80% of patients in the SPTCL group had a response, compared to 65% in the PCGD group. The 5-year OS for the SPTCL patients was 82% vs 11% for the PCGD patients.

Treatment approaches for SPTCL and PCGD-TCL have not been clearly established. In the retrospective EORTC review, half of the patients were treated with aggressive chemotherapy and several had autologous stem cell transplantation as a consolidation. One third of the patients were treated with single agent therapies such as methotrexate, prednisone, cyclosporine, chlorambucil, or cyclophosphamide. Sixteen of 24 had a complete response, but 9 of these relapsed and 5 subsequently had a durable response on reinstitution of the same therapy. Eight of the patients received CHOP in relapse and 3 had a CR. Of 5 patients presenting with a solitary skin relapse, all were treated with local therapy (radiotherapy or surgery) and are in remission. In the PCGD group, 14 of 20 patients received multi-agent chemotherapy and only 3 had a CR; one patient went on to allogeneic transplant and had a CR after transplant. Seven patients developed visceral disease and at 12 months, 15 of 20 had died of hemophagocytic syndrome or progressive disease.

Other case reports and small series have described responses in SPTCL and PCGD patients. In one single institution review of 10 consecutive patients, 3 (2 SPTCL and one PCGD) were treated initially with denileukin diftitox; one each with SPTCL- and PCGD-disease had PR on therapy and have been maintained without PD [61] . Seven patients were treated with cytotoxic chemotherapy regimens. Four of 7 achieved a remission after EPOCH (2), denileukin diftitox-CHOP (1) or pentostatin/cyclophosphamide followed by alemtuzumab (1). Four patients (1 with refractory-SPTCL, 2 with refractory PCGD and 1 with PCGD in first CR after denileukin diftitox-CHOP) underwent allogeneic hematopoietic stem cell (HSCT) from matched-related donors. Two patients are alive 6 and 13 months after HSCT with no evidence of disease; 1 patient died in CR from infectious complications of HSCT, and 1 relapsed 6 mo. after HSCT and died from PD. At a median follow up of 3 years from diagnosis, 8 patients (80%) are alive, including the 2 patients with SPTCL and 6 of 8 patients with PCGD. In patients who were refractory to CHOP in one series, response to cyclosporine was reported in four [62] .

On the basis of these findings, the treatment approach to PCGD-TCL should be similar to that of other aggressive poor prognosis T-cell lymphomas and should include multi-agent chemotherapy followed by stem cell transplantation from an allogeneic donor if one is available. Patients with SPTCL with a benign clinical behavior may be managed with single agent therapies. For those with progressive or disseminated disease or with the hemophagocytic syndrome, multi-agents chemotherapy followed by autologous stem cell transplantation should be considered.

The role of transplantation in aggressive T-cell lymphomas

Several retrospective studies suggest that there are populations of patients with PTCL that will benefit from transplantation. The National Cancer Consortium Network (NCCN) guideline includes transplant as an option for consolidation after first remission in patients with histologies other than ALK+ ALCL with advanced stage disease. The role of autologous transplantation in relapsed or primary refractory disease is less well defined. Disease status at transplant is a major predictor of success, with inferior results reported for patients who are not chemosensitive. The single center experience at Stanford reported only a modest benefit after autologous transplant (5-year OS of 36%) for patients with relapsed disease and a 5-year OS of 76% in patients transplanted in first remission [63] .

A prospective study from Germany using chemotherapy and up-front autologous transplantation for PTCL has demonstrated that a significant number of patients were never able to be transplanted due to progression of disease on first line therapy. The treatment regimen consisted of 4–6 cycles of CHOP, followed by either dexa BEAM (dexamethasone, carmustine, melphalan, etoposide, and cytarabine) or ESHAP (etoposide, methylprednisolone, cytarabine, and cisplatin) [24] . Patients in complete or partial remission then underwent myeloablative chemoradiotherapy and autologous stem cell transplant (ASCT). Two thirds (66%) of the patients were chemosensitive and went on to ASCT. At a median follow-up time of 33 months, the estimated 3-year OS and PFS for patients in complete response were 48% and 36%, respectively. Patients who did not experience a response to chemotherapy and therefore did not undergo ASCT had a very poor outcome, with a median survival of less than 2 years. In a similar study by the Nordic group (NLG-T-01), treatment naïve patients were treated with CHOPE or CHOP for those over age 60, followed by high dose therapy and autologous transplant [64] . OF 115 patients who underwent transplant, 90 were in a CR at 3 months post-transplant. The 5 year OS and PFS were 51% and 44% respectively, with best results obtained in the ALK-group. In summary, autologous transplantation in first remission benefits a subset of patients with aggressive T cell lymphomas. Review of prognostic factors in the existing prospective trials has demonstrated that patients with high IPI tended to have a higher relapse rate and perhaps would benefit from alternative approaches. Further prospective studies are needed to define which subsets of PTCL patients will optimally benefit from allogeneic or autologous stem cell transplant.

Evidence-based treatment approaches for PTCL

Because of the inferior outcomes with CHOP-based regimens, novel strategies are needed for patients with aggressive T-cell lymphomas. The NCCN has established evidence-based treatment approaches for T-cell lymphoma and stratifies patients based on stage ( Table 4 ). For early stage patients with localized disease, chemotherapy should be followed by involved field radiotherapy. It is recommended that all patients except for those with low IPI be considered for consolidation with autologous stem cell transplant if they are a candidate. ALK+ ALCL is identified as the one subtype which has an excellent outcome and should not be transplanted in first remission. Recent data suggest that ALK+ patients with high IPI could be an exception to this rule. In prospective trials where up to 40% of patients do not undergo a complete remission and therefore cannot be consolidated with transplant, new approaches are necessary.

Table 4 NCCN guidelines for the treatment of aggressive T-cell lymphomas.

First-line therapy
  • Clinical trial (preferred)
  • ALCL, ALK+ histology
    • CHOP-21
    • CHOEP-21
  • Other histologies (ALCL, ALK-; PTCL-NOS; AITL; EATL), regimens that can be used include:
    • CHOEP
    • CHOP-14
    • CHOP-21
    • CHOP followed by ICE
    • CHOP followed by IVE, alternating with intermediate-dose methotrexate (Newcastle regimen)
    • HyperCVAD, alternating with high-dose methotrexate and cytarabine
First-line consolidation All patients except low risk (aalPI) should be considered for high-dose therapy and stem cell rescue; ALCL, ALK+ is a subtype with good prognosis and does not need consolidative transplant if in remission

Selection of first-line therapy based on histopathologic features has not yet been widely employed but should be considered, including individualized approaches for enteropathy and NK/T cell lymphomas. For other rare extranodal subtypes, including hepatosplenic T-cell lymphomas, the evidence base to direct treatment algorithms is modest. The overall recommendations of the NCCN for all patients with the poor prognosis subtypes of aggressive T-cell lymphomas is that clinical trials should be considered a first option if available.

Conflict of interest

None.

References

  • [1] The Non-Hodgkin's Lymphoma Classification Project. A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin's lymphoma. Blood. 1997;89(11):3909-3918
  • [2] The International T-Cell Lymphoma Project. International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes. J Clin Oncol. 2008;26(25):4124-4130
  • [3] A. Zettl, R. deLeeuw, E. Haralambieva, et al. Enteropathy-type T-cell lymphoma. Am J Clin Pathol. 2007;127(5):701-706 Crossref.
  • [4] R. Willemze, P.M. Jansen, L. Cerroni, et al. Subcutaneous panniculitis-like T-cell lymphoma: definition, classification, and prognostic factors: an EORTC Cutaneous Lymphoma Group Study of 83 cases. Blood. 2008;111(2):838-845 Crossref.
  • [5] A.N. Abouyabis, P.J. Shenoy, M.J. Lechowicz, et al. Incidence and outcomes of the peripheral T-cell lymphoma subtypes in the United States. Leuk Lymphoma. 2008;49(11):2099-2107 Crossref.
  • [6] M.P. Escalon, N.S. Liu, Y. Yang, et al. Prognostic factors and treatment of patients with T-cell non-Hodgkin lymphoma: the M. D. Anderson Cancer Center experience. Cancer. 2005;103(10):2091-2098 Crossref.
  • [7] S. Mercadal, J. Briones, B. Xicoy, et al. Intensive chemotherapy (high-dose CHOP/ESHAP regimen) followed by autologous stem-cell transplantation in previously untreated patients with peripheral T-cell lymphoma. Ann Oncol. 2008;19(5):958-963 Crossref.
  • [8] N. Schmitz, L. Trumper, M. Ziepert, et al. Treatment and prognosis of mature T-cell and NK-cell lymphoma: an analysis of patients with T-cell lymphoma treated in studies of the German High-Grade Non-Hodgkin Lymphoma Study Group. Blood. 2010;116(18):3418-3425 Crossref.
  • [9] H. Tilly, E. Lepage, B. Coiffier, et al. Intensive conventional chemotherapy (ACVBP regimen) compared with standard CHOP for poor-prognosis aggressive non-Hodgkin lymphoma. Blood. 2003;102(13):4284-4289 Crossref.
  • [10] A. Simon, M. Peoch, P. Casassus, et al. Upfront VIP-reinforced-ABVD (VIP-rABVD) is not superior to CHOP/21 in newly diagnosed peripheral T cell lymphoma. Results of the randomized phase III trial GOELAMS-LTP95. Br J Haematol. 2010;151(2):159-166 Crossref.
  • [11] P.P. Piccaluga, C. Agostinelli, S. Righi, et al. Expression of CD52 in peripheral T-cell lymphoma. Haematologica. 2007;92(4):566-567 Crossref.
  • [12] J.G. Kim, S.K. Sohn, Y.S. Chae, et al. Alemtuzumab plus CHOP as front-line chemotherapy for patients with peripheral T-cell lymphomas: a phase II study. Cancer Chemother Pharmacol. 2007;60(1):129-134 Crossref.
  • [13] A. Gallamini, F. Zaja, C. Patti, et al. Alemtuzumab (Campath-1H) and CHOP chemotherapy as first-line treatment of peripheral T-cell lymphoma: results of a GITIL (Gruppo Italiano Terapie Innovative nei Linfomi) prospective multicenter trial. Blood. 2007;110(7):2316-2323 Crossref.
  • [14] J. Janik, K. Dunleauy, S. Pittaluga, et al. A pilot study of Campath-1 with dose-adjusted EPOCH in CD52 expressing aggressive T-cell malignancies. Blood. 2005;106:33348
  • [15] N.H. Dang, B. Pro, F.B. Hagemeister, et al. Phase II trial of denileukin diftitox for relapsed/refractory T-cell non-Hodgkin lymphoma. Br J Haematol. 2007;136(3):439-447
  • [16] Foss FM, Sjak-Shie NN, Goy A, Advani R, Jacobsen ED. Phase II study of denileukin diftitox with CHOP chemotherapy in newly-diagnosed PTCL: CONCEPT trial. ASCO Meet Abstr;28(15_suppl):8045.
  • [17] I. Bruns, F. Fox, P. Reinecke, et al. Complete remission in a patient with relapsed angioimmunoblastic T-cell lymphoma following treatment with bevacizumab. Leukemia. 2005;19(11):1993-1995 Crossref.
  • [18] R.H. Advani, F. Hong, K.N. Ganjoo, et al. Cardiac toxicity associated with the anti-VEGF monoclonal antibody bevacizumab (Avastin) in combination with CHOP (A-CHOP) chemotherapy for peripheral T cell lymphoma (PTCL): the ECOG 2404 trial. Blood (ASH Annu Meet Abstr). 2009;114(22):1671
  • [19] P.L. Zinzani, F. Venturini, V. Stefoni, et al. Gemcitabine as single agent in pretreated T-cell lymphoma patients: evaluation of the long-term outcome. Ann Oncol. 2010;21(4):860-863 Crossref.
  • [20] H.T. Arkenau, G. Chong, D. Cunningham, et al. Gemcitabine, cisplatin and methylprednisolone for the treatment of patients with peripheral T-cell lymphoma: the Royal Marsden Hospital experience. Haematologica. 2007;92(2):271-272 Crossref.
  • [21] A. Spencer, K. Reed, C. Arthur. Pilot study of an outpatient-based approach for advanced lymphoma using vinorelbine, gemcitabine and filgrastim. Intern Med J. 2007;37(11):760-766
  • [22] J.G. Kim, S.K. Sohn, Y.S. Chae, et al. CHOP plus etoposide and gemcitabine (CHOP-EG) as front-line chemotherapy for patients with peripheral T cell lymphomas. Cancer Chemother Pharmacol. 2006;58(1):35-39 Crossref.
  • [23] F. d'Amore, E. Jantunen, T. Relander. Hemopoietic stem cell transplantation in T-cell malignancies: who, when, and how?. Curr Hematol Malig Rep. 2009;4(4):236-244 Crossref.
  • [24] P. Reimer, T. Rudiger, E. Geissinger, et al. Autologous stem-cell transplantation as first-line therapy in peripheral T-cell lymphomas: results of a prospective multicenter study. J Clin Oncol. 2009;27(1):106-113
  • [25] D. O'Mahony, J. Morris, L. Moses, et al. Phase I trial of siplizumab in CD2-positive lymphoproliferative disease. Blood. 2005;106:937a
  • [26] D.M.J. O'Mahony, J. Morris, M. Stetler-Stevenson, et al. EBV-related lymphoproliferative disease complicating therapy with siplizumab, a novel anti-CD2 mediated T- and NK-cell depleting agent, in patients with T-cell malignancies. Blood. 2007;110:1043a
  • [27] D. Casale, N. Bartlett, D. Hurd, et al. A phase I open label dose escalation study to evaluate MEDI-507 in patients with CD2-positive T-cell lymphoma/leukemia. Blood. 2006;108:771a
  • [28] F. d'Amore, J. Radford, M. Jerkeman, et al. Zanolimumab (HuMax-CD4™), a fully human monoclonal antibody: efficacy and safety in patients with relapsed or treatment-refractory non-cutaneous CD4+ T-cell lymphoma. Blood. 2007;110:999z
  • [29] R.J. Kreitman, W.H. Wilson, J.D. White, et al. Phase I trial of recombinant immunotoxin anti-Tac(Fv)-PE38 (LMB-2) in patients with hematologic malignancies. J Clin Oncol. 2000;18(8):1622-1636
  • [30] A. Forero-Torres, J.P. Leonard, A. Younes, et al. A phase II study of SGN-30 (anti-CD30 mAb) in Hodgkin lymphoma or systemic anaplastic large cell lymphoma. Br J Haematol. 2009;146(2):171-179 Crossref.
  • [31] S.M. Ansell, S.M. Horwitz, A. Engert, et al. Phase I/II study of an anti-CD30 monoclonal antibody (MDX-060) in Hodgkin's lymphoma and anaplastic large-cell lymphoma. J Clin Oncol. 2007;25(19):2764-2769 Crossref.
  • [32] P. Borchmann, J.F. Treml, H. Hansen, et al. The human anti-CD30 antibody 5F11 shows in vitro and in vivo activity against malignant lymphoma. Blood. 2003;102(10):3737-3742 Crossref.
  • [33] B. Pro, R. Advani, P. Brice, et al. Brentuximab vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic large-cell lymphoma: results of a phase II study. J Clin Oncol. 2012;30(18):2190-2196 Crossref.
  • [34] N.L. Bartlett, A. Younes, M.H. Carabasi, et al. A phase 1 multidose study of SGN-30 immunotherapy in patients with refractory or recurrent CD30+ hematologic malignancies. Blood. 2008;111(4):1848-1854 Crossref.
  • [35] A. Younes, N.L. Bartlett, J.P. Leonard, et al. Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas. N Engl J Med. 2010;363(19):1812-1821 Crossref.
  • [36] K. Yamamoto, A. Utsunomiya, K. Tobinai, et al. Phase I study of KW-0761, a defucosylated humanized anti-CCR4 antibody, in relapsed patients with adult T-cell leukemia-lymphoma and peripheral T-cell lymphoma. J Clin Oncol. 2010;28:1591-1598 Crossref.
  • [37] Ishida T, Joh T, Uike N, et al. Multicenter phase II study of KW-0761, a defucosylated anti-CCR4 antibody, in relapsed patients with adult T-cell leukemia-lymphoma (ATL). Blood (ASH Annu Meet Abstr);116(21):285.
  • [38] O. Martinez-Iglesias, L. Ruiz-Llorente, R. Sanchez-Martinez, et al. Histone deacetylase inhibitors: mechanism of action and therapeutic use in cancer. Clin Transl Oncol. 2008;10(7):395-398 Crossref.
  • [39] E.A. Olsen, Y.H. Kim, T.M. Kuzel, et al. Phase IIb multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T-cell lymphoma. J Clin Oncol. 2007;25(21):3109-3115 Crossref.
  • [40] D.J. Deangelo, A. Spencer, K.N. Bhalla, et al. Phase Ia/II, 2-arm, open-label, dose-escalation study of oral panobinostat administered via 2 dosing schedules in patients with advanced hematologic malignancies. Leukemia. 2013;
  • [41] S.J. Whittaker, M.F. Demierre, E.J. Kim, et al. Final results from a multicenter, international, pivotal study of romidepsin in refractory cutaneous T-cell lymphoma. J Clin Oncol. 2010;28(29):4485-4491 Crossref.
  • [42] R. Piekarz, J. Wright, R. Frye, et al. Final results of a phase 2 NCI multicenter study of romidepsin in patients with relapsed peripheral T-cell lymphoma (PTCL). Blood (ASH Annu Meet Abstr). 2009;114(22):1657
  • [43] B. Coiffier, B. Pro, H.M. Prince, et al. Results from a pivotal, open-label, phase II study of romidepsin in relapsed or refractory peripheral T-cell lymphoma after prior systemic therapy. J Clin Oncol. 2012;30(6):631-636 Crossref.
  • [44] B. Pohlman, R. Advani, M. Duvic, et al. Final results of a phase II trial of belinostat (PXD101) in patients with recurrent or refractory peripheral or cutaneous T-cell lymphoma. Blood (ASH Annu Meet Abstr). 2009;114(22):920
  • [45] Marchi E, Bongero DC, Kalac M, Scotto L, O'Connor OA. The combination of histone deacetylase inhibitors and hypomethylating agents exhibits marked synergy in preclinical models of T-cell lymphoma. Blood (ASH Annu Meet Abstr);116(21):3937.
  • [46] O.A. O'Connor, P.A. Hamlin, C. Portlock, et al. Pralatrexate, a novel class of antifol with high affinity for the reduced folate carrier-type 1, produces marked complete and durable remissions in a diversity of chemotherapy refractory cases of T-cell lymphoma. Br J Haematol. 2007;139(3):425-428 Crossref.
  • [47] O.A. O'Connor, S. Horwitz, P. Hamlin, et al. Phase II-I-II study of two different doses and schedules of pralatrexate, a high-affinity substrate for the reduced folate carrier, in patients with relapsed or refractory lymphoma reveals marked activity in T-cell malignancies. J Clin Oncol. 2009;27(26):4357-4364 Crossref.
  • [48] O.A. O'Connor, B. Pro, L. Pinter-Brown, et al. Pralatrexate in patients with relapsed or refractory peripheral T-cell lymphoma: results from the pivotal PROPEL study. J Clin Oncol. 2011;29(9):11
  • [49] B. Pro, B. Coiffier, S.M. Horwitz, et al. Correlation between baseline methylmalonic acid status and mucositis severity in the PROPEL Study: implications for vitamin prophylaxis. Blood (ASH Annu Meet Abstr). 2009;114(22):1681
  • [50] R. Advani, S. Horwitz, A. Zelenetz, et al. Angioimmunoblastic T cell lymphoma: treatment experience with cyclosporine. Leuk Lymphoma. 2007;48(3):521-525 Crossref.
  • [51] G.S. Dueck, N. Chua, A. Prasad, et al. Activity of lenalidomide in a phase II trial for T-cell lymphoma: report on the first 24 cases. ASCO Meet Abstr. 2009;27(15S):8524
  • [52] D. Catovsky. Clinical experience with 2′-deoxycoformycin. Hematol Cell Ther. 1996;38(Suppl. 2):S103-S107
  • [53] C.E. Dearden. Role of single-agent purine analogues in therapy of peripheral T-cell lymphomas. Semin Hematol. 2006;43(2 Suppl. 2):S22-S26 Crossref.
  • [54] P.L. Zinzani, G. Musuraca, M. Tani, et al. Phase II trial of proteasome inhibitor bortezomib in patients with relapsed or refractory cutaneous T-cell lymphoma. J Clin Oncol. 2007;25(27):4293-4297 Crossref.
  • [55] E.P.L. Marchi, S.E. Venkatraman, O.A. O'Connor. Pralatrexate (PDX) compliments the activity of the proteasome inhibitor bortezomib (B) in in vitro models of lymphoid T-cell malignancies. Blood. 2008;:112
  • [56] C. Querfeld, M.A. Rizvi, T.M. Kuzel, et al. The selective protein kinase C beta inhibitor enzastaurin induces apoptosis in cutaneous T-cell lymphoma cell lines through the AKT pathway. J Invest Dermatol. 2006;126(7):1641-1647 Crossref.
  • [57] S.E.B.J. Coutre, R.R. Furman, J.R. Brown, et al. Phase 1 study of CAL-101, an isoform-selective inhibitor of phosphatidylinositol 3 kinase P110δ, in patients with previously treated chronic lymphocytic leukemia. J Clin Oncol. 2011;29:201
  • [58] Jantunen E, Relander T, Lauritzsen GF, et al. Intensive induction chemotherapy followed by autologous stem cell transplantation (ASCT) in patients with enteropathy-associated T-cell lymphoma: a prospective Study by the Nordic Lymphoma Group (NLG-T-01). Blood (ASH Annu Meet Abstr);116(21):3565.
  • [59] R.S. Go, S.M. Wester. Immunophenotypic and molecular features, clinical outcomes, treatments, and prognostic factors associated with subcutaneous panniculitis-like T-cell lymphoma: a systematic analysis of 156 patients reported in the literature. Cancer. 2004;101(6):1404-1413 Crossref.
  • [60] K.E. Salhany, W.R. Macon, J.K. Choi, et al. Subcutaneous panniculitis-like T-cell lymphoma: clinicopathologic, immunophenotypic, and genotypic analysis of alpha/beta and gamma/delta subtypes. Am J Surg Pathol. 1998;22(7):881-893 Crossref.
  • [61] O. Alpdogan, D. Ornstein, T. Subtil, et al. Outcomes in subcutaneous panniculitis-like T-cell lymphoma (STCL). Blood (ASH Annu Meet Abstr). 2008;112(11):3750
  • [62] P. Rojnuckarin, T.N. Nakorn, T. Assanasen, et al. Cyclosporin in subcutaneous panniculitis-like T-cell lymphoma. Leuk Lymphoma. 2007;48(3):560-563 Crossref.
  • [63] A.I. Chen, A. McMillan, R.S. Negrin, et al. Long-term results of autologous hematopoietic cell transplantation for peripheral T cell lymphoma: the Stanford experience. Biol Blood Marrow Transplant. 2008;14(7):741-747 Crossref.
  • [64] F. d'Amore, T. Relander, G.F. Lauritzsen, et al. Up-front autologous stem-cell transplantation in peripheral T-cell lymphoma: NLG-T-01. J Clin Oncol. 2012;30(25):3093-3099 Crossref.

Footnotes

Yale University School of Medicine, New Haven, CT, USA

Yale Cancer Center, 333 Cedar Street, FMP 112, PO Box 208032, New Haven, CT 06520-8032, USA. Tel.: +1 203 737 5312.