Peripheral T-cell lymphomas (PTCLs) are a heterogeneous

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1 Novel Treatments for T-Cell Lymphoma Chan Yoon Cheah, MBBS, DMedSc, Yasuhiro Oki, MD, and Michelle A. Fanale, MD OVERVIEW T-cell lymphomas are a biologically and clinically diverse collection of diseases that collectively account for 10% to 15% of non-hodgkin lymphomas. Unlike B-cell lymphomas, the response of T-cell lymphomas to standard anthracycline-containing chemotherapy regimens is suboptimal and the prognosis of patients is accordingly poor. To address these shortcomings, there has been a proliferation in biologic agents with novel mechanisms of action that target surface antigens, signaling pathways, or cellular processes. Given the large number of candidate molecules showing preclinical promise and the rarity of these diseases, drug development for peripheral T-cell lymphoma is challenging. We provide an overview of agents that have recently been approved for relapsed/refractory T-cell lymphoma and highlight efforts to introduce these agents into front-line treatment protocols in combination with chemotherapy. We discuss biologic doublets currently being evaluated as chemotherapy-free salvage regimens and highlight some of the most promising investigational agents in early clinical development. Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of diseases that account for 10 to 15% of non-hodgkin lymphomas (NHLs) in most Western countries. Although the WHO 2008 classifıcation system includes 22 distinct mature T-cell and natural killer (NK) cell neoplasms, 1 they can be functionally grouped according to typical presentation as nodal, extranodal, leukemic, and cutaneous (Fig. 1). Three entities account for approximately 60% of T-cell lymphomas: PTCL not otherwise specifıed (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), and systemic anaplastic large cell lymphoma (ALCL), which may be positive or negative for anaplastic lymphoma kinase (ALK). 2 For the purpose of this review, we will focus primarily on these most common subtypes. CURRENT TREATMENT OUTCOMES Unfortunately, the majority of patients with PTCL do not experience durable remissions following multiagent chemotherapy. The exception is patients with ALK ALCL, in whom outcomes can be favorable even when they are treated with cyclophosphamide/doxorubicin/vincristine/ prednisone (CHOP). 2 The International T-cell Lymphoma Project described outcomes for 340 patients with PTCL- NOS: 5-year overall survival (OS) and failure-free survival (FFS) were 32% and 20% respectively, with no clear benefıt for patients treated with anthracyclines. 3 Despite these data, CHOP remains the most common induction therapy used. Attempts to improve on CHOP with intensive induction such as VIP/ABVD (etoposide/ifosfamide/cisplatin doxorubicin/bleomycin/ vinblastine/dacarbazine) and other highdose sequential chemotherapy regimens have been mostly unsuccessful. 4-6 In one retrospective study, Hyper-CVAD/MA (hyper-fractionated cyclophosphamide/doxorubicin/vincristine/dexamethasone alternating with methotrexate/cytarabine) showed higher overall response rate (ORR) and progression-free survival (PFS), but not higher OS, than CHOP, 7 although this fınding has not been replicated in other retrospective studies. 5 Given the substantially greater toxicity associated with this regimen, we recommend that Hyper-CVAD be used with caution. The German High-Grade Lymphoma Study Group (DSHNHL) retrospectively analyzed the outcomes of patients with PTCL who were treated in prospective studies using CHOP-like regimens to address whether (1) shortening the interval from 21 to 14 days, or (2) adding etoposide to CHOP (CHOEP) affected outcomes. 8 In a subgroup analysis, patients age 60 or older with normal serum lactate dehydrogenase (LDH) levels achieved superior event-free survival (EFS) when treated with etoposide-containing regimens; this was largely the result of a signifıcant benefıt in patients with ALK ALCL (3- year EFS 92% for CHOEP vs. 57% for CHOP; p 0.012) whereas those with other histologies displayed a nonsignifıcant trend toward improvement (3-year EFS 61% for CHOEP vs. 48% for CHOP; p 0.057). 8 The benefıt of etoposide in younger patients was supported by a recent large Swedish registry analysis, which found that use of CHOEP (vs. CHOP) was associated with improved PFS in patients younger than UP-FRONT TRANSPLANTATION IN PTCL Because of the poor outcomes described using chemotherapy alone, up-front consolidation using high-dose chemotherapy From the Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX. Disclosures of potential conflicts of interest are found at the end of this article. Corresponding author: Michelle A. Fanale, MD, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd #429, Houston, TX 77030; mfanale@mdanderson.org by American Society of Clinical Oncology. e468

2 NOVEL TREATMENTS FOR T-CELL LYMPHOMA FIGURE 1. WHO 2008 Classification of Mature T-Cell Neoplasms According to Typical Presentation mature T-cell and NK-cell neoplasms nodal extranodal leukemic cutaneous Peripheral T-cell lymphoma, NOS Angioimmunoblastic T-cell lymphoma Anaplastic large cell lymphoma, ALK positive Anaplastic large cell lymphoma, ALK negative Extranodal NK/T-cell lymphoma, nasal type Enteropathy-associated T-cell lymphoma Hepatosplenic T-cell lymphoma Subcutaneous panniculitis-like T- cell lymphoma ( subtype only) T-cell prolymphocytic leukemia T-cell large granular lymphocytic leukemia Aggressive NK-cell leukemia Adult T-cell leukemia/lymphoma Mycosis fungoides Sézary syndrome Primary cutaneous CD30-positive T- cell lymphoproliferative disorders Primary cutaneous anaplastic large cell lymphoma Lymphomatoid papulosis Primary cutaneous peripheral T-cell lymphomas, rare subtypes Primary cutaneous gamma-delta T-cell lymphoma Primary cutaneous CD8 aggressive epidermotropic T-cell lymphoma Primary cutaneous CD4 small/medium T-cell lymp homa KEY POINTS Outcomes for patients with peripheral T-cell lymphoma treated with cyclophosphamide/doxorubicin/vincristine/ prednisone (CHOP)-like induction regimens with and without front-line consolidative stem cell transplantation will be summarized. Clinical data supporting the regulatory approval of pralatrexate, romidepsin, brentuximab vedotin, and belinostat for patients with relapsed/refractory disease will be reviewed. Trials combining these novel agents in combination with CHOP-like chemotherapy in previously untreated patients will be outlined. Studies using combinations of new agents in biologic doublets as salvage regimens will be described. Emerging clinical data on agents with promising clinical efficacy in phase I studies will be highlighted. and autologous stem cell transplantation (ASCT) in patients who achieve a response has been explored. The ORR following induction ranged from 66% to 82%, 41% to 72% of patients received ASCT, and the median OS was 3 to 5 years. 6,10-14 Reimer et al treated 83 patients (32 with PTCL- NOS) with CHOP induction followed by cyclophosphamidetotal body irradiation conditioning and ASCT. At a median follow-up of 33 months, the 3-year PFS and OS were 36% and 48% respectively. 13 The Nordic Lymphoma Group treated 160 patients with PTCL (excluding ALK ALCL) with biweekly CHOP with etoposide (CHOEP-14). 11 At a median follow-up of 60.5 months, the 5-year PFS and OS were 44% and 51% respectively, with marginal improvement in PFS (p 0.04) and OS (p 0.03) among patients with ALK ALCL compared with other PTCL subtypes. In both studies, patients who had transplants had markedly superior outcomes compared with those who did not; however, the latter group consisted mostly of patients whose disease did not respond to induction therapy or had comorbidities precluding SCT. The U.S. multicenter consortium reported that outside of clinical trials, only 33/341 patients (10%) treated at large academic centers received ASCT in fırst remission; this was associated with improvement in both PFS (hazard ratio [HR] 0.48; 95% CI, 0.27 to 0.84, p 0.01) and OS (HR 0.48, 95% CI, 0.24 to 0.98, p 0.04), although the typical limitations of a retrospective study apply. 7 Smith et al analyzed data collected by the Center for International Blood and Bone Marrow Transplant Research (CIBMTR) for 241 patients with mature T-cell lymphomas who underwent transplantation. 15 Patients in complete response (CR)1 had favorable outcomes (3-year PFS and OS of 58% and 70% respectively), indicating a major role for ASCT in patients with PTCL (other than those with primary cutaneous or ALK ALCL) who are in fırst remission. However, it should be noted that no prospective randomized data demonstrating a clear advantage for transplant over induction chemotherapy alone currently exist. Up-front allogeneic stem cell transplantation (allosct) has been explored in a prospective phase II study in which Corradini et al randomly assigned patients age 60 or older whose disease responded to induction therapy to either ASCT (14 patients) or allosct (23 patients) based on donor availability. 10 The reported 4-year OS (92% vs. 69%, p 0.10) and PFS (70% vs. 69%, p 0.92) were not signifıcantly different; however, the study was neither designed nor powered for this comparison. The CIBMTR multicenter retrospective study attempted to compare outcomes for 115 patients who received ASCT and 126 who received allosct; patients in the allosct group were younger, but had more unfavorable features. The 3-year PFS for ASCT versus allosct in this analysis was 47% versus 33%, but only 17% of the patients who received ASCT and 14% of those with allosct had received just one prior line of treatment. 15 Thus, whether allosct as front-line consolidation offers additional disease control over ASCT remains controversial and is being addressed by asco.org/edbook 2015 ASCO EDUCATIONAL BOOK e469

3 an ongoing German cooperative group study (EudraCT number: ). NEW AGENTS FOR RELAPSED AND REFRACTORY DISEASE When treated using conventional chemotherapy alone, the outcome of patients with relapsed or refractory PTCL is particularly poor a population-based registry study from the British Columbia Cancer Agency found that the median OS of patients with PTCL was only 5.5 months. 16 When used as a single agent in pretreated patients, bendamustine results in an ORR of approximately 50% with a median duration of response (DOR) of 3.5 months. 17 Gemcitabine has a similar ORR and the responses appear more durable. 18,19 However, there is a substantial unmet need for more options for patients whose disease does not respond to these therapies. Fortunately, several agents with novel mechanisms of action have been approved for this setting in the last 5 years, with several others undergoing evaluation in trials for potential future approval (Table 1). Pralatrexate Folates are critical for DNA synthesis and folate antagonism was one of the earliest successful chemotherapeutic pathways. 20 Pralatrexate is an inhibitor of dihydrofolate reductase that was designed to have increased affınity for the reduced folate carrier and therefore accumulates within cells and exhibits increased potency compared with methotrexate. 21 A phase I study demonstrated promising activity in T-cell lymphomas, 22 prompting an international phase II study (PROPEL). In this trial, 111 patients with relapsed or refractory aggressive PTCL were treated with single-agent pralatrexate (30 mg/m 2 administered intravenously once weekly), achieving an ORR of 29% (CR 11%) with median DOR of 10.1 months. 23 The major toxicities seen with this agent are cytopenias (particularly thrombocytopenia, which may be dose limiting) and mucositis (any grade, 70%; grade 3, 22%), although there are data suggesting that prophylactic use of leucovorin may ameliorate the latter without compromising effıcacy. 24 On the basis of this study, in 2009 pralatrexate gained U.S. Food and Drug Administration (FDA) approval for patients with PTCL who have received one or more systemic therapies. Histone Deacetylase Inhibitors Epigenetic therapies are useful for a range of hematologic malignancies, particularly PTCL. Recent publications have shown that histone deacetylase (HDAC) inhibitors have pleiotropic downstream effects including apoptosis, senescence, immune suppression, and angiogenesis. 25 HDACs are a group of enzymes with both histone and nonhistone targets that together govern chromatin conformation and gene expression. 26 Several agents in this class are effective in PTCL. Romidepsin. Romidepsin is a cyclic, class 1-selective HDAC inhibitor that has been used as monotherapy for relapsed or refractory PTCL in two phase II studies. 27,28 Coiffıer et al reported the larger study, in which 130 patients (53% PTCL- NOS) with a median of two prior treatments received 14 mg/m 2 romidepsin intravenously once weekly for 3 of 4 weeks. 28 Responses occurred at a median of 1.8 months; the ORR of 25% (CR 15%) was comparable across major histologic subtypes. Responses were durable, and a recent update of this study reported a median DOR of 28 months. 29 The most common toxicities included fatigue, thrombocytopenia, and gastrointestinal (GI) disturbance. Early reports suggesting prolongation of corrected QT interval were sub- TABLE 1. Summary of Selected Novel Agents Currently Being Evaluated for Efficacy in Peripheral T-Cell Lymphoma Agent Mechanism Phase n Grade 3 Toxicities ORR CRR DOR FDA-approved agents for PTCL Pralatrexate 23 Folate antagonist II 111 Mucositis 29% 11% 10.3 mo Romidepsin 27,28 HDAC inhibitor II 47 Nausea, fatigue, thrombocytopenia 38% 17% 8.9 mo II 130 Thrombocytopenia, neutropenia, infection 25% 15% 28 mo* Brentuximab vedotin 38 Antibody-drug conjugate II 35 Neutropenia, peripheral neuropathy 41% 24% 7.6 mo Belinostat 31 HDAC inhibitor II 129 Hematologic 26% 10% 13.6 mo Agents under investigation in PTCL Mogamulizumab 43 Anti-CCR4 mab II 37 Neutropenia, rash 34% 17% 8.2 mo** Alisertib (MLN8237) 54 Aurora A kinase inhibitor II 37 Hematologic, febrile neutropenia 24% 5% NR Duvelisib (IPI145) 69 PI3K inhibitor I 33 Transaminitis, rash, neutropenia 47% 12% NR Crizotinib 89 ALK inhibitor II 14 Diarrhea, vomiting, visual impairment 60% 36% 8.3 mo Nivolumab 88 Anti-PD1 mab I 5 Pneumonitis, rash, sepsis 40% 0% NR Abbreviations: ORR, objective response rate; CRR, complete response rate; DOR, duration of response; PI3K, phosphoinositide-3-kinase; CCR4, chemokine receptor-4; HDAC, histone deacetylase; ALK, anaplastic lymphoma kinase; NR, not reported; PD-1, programmed cell death-1; mab, monoclonal antibody. Response rates refer to patients with nodal PTCL subtypes where information available. *Duration of response reported from updated report. 29 **Median progression-free survival of patients with PTCL achieving response. e470

4 NOVEL TREATMENTS FOR T-CELL LYMPHOMA sequently attributed to antiemetic therapy and clinically signifıcant dysrhythmias were not seen. Romidepsin gained FDA approval in 2011 for patients with PTCL who have at least one prior systemic therapy. Chihara et al reported a single-center phase I study to determine the safety profıle of romidepsin administered on days 1 and 4 with ifosfamide/ carboplatin/etoposide (ICE), with the hope that this combination would improve the CR rate over ICE alone and thus facilitate a greater proportion of patients receiving SCT. 30 The main toxicities were hematologic, with reversible grade 3 or greater thrombocytopenia in 87% of patients, and 5/7 (71%) response-evaluable patients achieved CR. This encouraging preliminary observation requires further confırmation in an expanded cohort and enrollment is ongoing. Belinostat. Belinostat is a pan-hdac inhibitor derived from hydroxamic acid that was evaluated in a single-arm phase II study with a dosing schedule of 1,000 mg/m 2 for days 1 through 5 in a 3-week cycle until progression or unacceptable toxicity. 31 Among 120 patients with PTCL confırmed by central pathology review, the ORR was 26% (CR 10%). As with romidepsin, responses were rapid (median time to response 5.6 weeks) and the median DOR was 8.3 months at the time of initial reporting. The major toxicities were hematologic (grade 3 anemia, neutropenia, and thrombocytopenia in 10, 13, and 13%, respectively). 31 Of note, belinostat appears to induce grade 3 or greater thrombocytopenia less frequently than romidepsin. On the basis of this study, in 2014 belinostat received accelerated FDA approval for patients with relapsed/refractory PTCL. Brentuximab Vedotin Although naked monoclonal antibodies (mabs) against CD30 showed preclinical promise, clinical activity in patients with CD30 lymphomas was disappointing. 32 Brentuximab vedotin (BV) was designed to improve effıcacy by conjugating the anti-cd30 mab to the antimicrotubule agent monomethylauristatin E (MMAE). Binding to CD30 on the cell surface results in proteolytic release, internalization, and lysosomal uptake of MMAE, and tubule disruption, cell cycle arrest, and apoptosis. 33 ALCL has uniform strong CD30 expression, and on the basis of positive data from BV phase I trials, 34,35 a multicenter phase II study in patients with relapsed/refractory systemic ALCL (ALK-positive and -negative) was conducted. 36 Fifty-eight patients with a median number of two prior treatments were treated with 1.8 mg/kg BV intravenously every 3 weeks for up to 16 doses. The ORR was 86% (CR 57%) with 97% of patients having a reduction in tumor volume; responses occurred after a median of 6 weeks and the median DOR was 12.3 months. The most common toxicities were nausea, fatigue, GI disturbance, rash, and neutropenia (mostly grade 1 to 2). Peripheral sensory neuropathy was mainly grade 1 (all grades, 41%; grade 3, 12%) and was manageable with dose reductions and delays. Rare but potentially fatal adverse events reported include posterior multifocal leukoencephalopathy and pancreatitis. 37 Horwitz et al treated 35 patients with non-alcl PTCL subtypes (which have variable CD30 expression) using a similar study design. 38 The patients included in this study had either AITL (13 patients) or PTCL-NOS (22 patients); among these two histologic subtypes the ORR was 54% and 33% and the CR was 38% and 14%, respectively. Interestingly, CD30 expression by immunohistochemistry did not correlate with clinical outcomes, thus it could be hypothesized that MMAE diffuses out of the apoptotic tumor cell and exerts local effects on the tumor microenvironment. BV was approved by the FDA in 2011 for patients with systemic ALCL having failed at least one prior systemic therapy, and at the time of writing has National Comprehensive Cancer Network compendium class 2A listing for the treatment of patients with relapsed non-alcl CD30 PTCL. Alemtuzumab CD52 is a pan-lymphoid antigen with variable expression in PTCL. 39 The anti-cd52 mab alemtuzumab was used as a single agent in two small European studies in patients with pretreated PTCL. 40,41 Enblad et al treated 14 patients with 30 mg alemtuzumab administered intravenously three times weekly for up to 12 weeks. 40 Despite chemoprophylaxis with trimethoprim/sulfamethoxazole and valaciclovir, fatal opportunistic infections occurred in 5/14 (35%) patients, resulting in early study termination. The observed ORR was 36%. Interestingly, Zinzani et al showed that a reduced dose (10 mg) and a shorter schedule was better tolerated and effective, with an ORR of 50% in six patients with PTCL. 41 However, the toxic deaths that occurred in the fırst study have dampened enthusiasm for further development in patients with pretreated PTCL. Mogamulizumab Mogamulizumab, a defucoslyated mab against chemokine receptor-4 (CCR4), was found to have single-agent activity in patients with relapsed/refractory T-cell lymphomas in a phase I study. 42 Ogura et al performed a phase II study in Japanese patients with relapsed/refractory T-cell lymphoma with 1.0 mg/kg mogamulizumab administered intravenously weekly for 8 weeks. 43 Among 37 patients treated, the median number of prior therapies was two and the main histologic subtypes were PTCL-NOS (16 patients), AITL (12 patients), and CTCL (8 patients). The ORR was 35% (CR 13%), with a median PFS of 3.0 months. The main toxicities reported were neutropenia (any grade, 38%; grade 3, 19%), fever (grade 1 2, 30%), infusion reaction (grade 1 2, 24%), and skin disorders (any grade, 51%; grade 3, 11%). Although CCR4 expression by immunohistochemistry was required for study entry, there was little correlation between expression of target antigen and response, similar to the data for BV and CD30. The authors hypothesized depletion of CCR4 regulatory T (T reg ) cells, resulting in an increase in the number of CD8 cytotoxic T-cells, as a mechanism of tumor control, and on the basis of these data mogamulizumab gained approval for the treatment of relapsed PTCL in Japan in Zinzani et al performed a multicenter European phase II study with 38 patients and reported a lower ORR of 11% with asco.org/edbook 2015 ASCO EDUCATIONAL BOOK e471

5 a similar median PFS of 2 months, 44 although the limited DOR suggests that mogamulizumab might be best suited for combination studies. However, one possible exception may be the highly aggressive and chemorefractory disease adult T-cell lymphoma/leukemia. Ishida et al performed a phase II study of mogamulizumab in 28 patients with relapsed/refractory disease, in which the ORR was 50% with median PFS and OS of 5.2 and 13.7 months respectively. 45 Lenalidomide The immunomodulatory drug lenalidomide has substantial activity in myeloma and B-cell lymphomas. 46,47 Three small studies have explored lenalidomide (25 mg administered orally for days 1 to 21 of a 28-day cycle) in patients with relapsed/refractory PTCL, with a reported ORR of 22% to 39% (CR 8% to 30%) Although the median DOR in the largest study of 54 patients was only 3.6 months, there was a nonsignifıcant trend toward higher response rates among the subset of patients with AITL. 48 Alisertib Aurora A kinase regulates mitotic entry and spindle formation; it is overexpressed in aggressive lymphomas and has a potential role in oncogenesis. 51 The orally available, smallmolecule competitive inhibitor alisertib induces cytotoxicity in a range of solid and hematologic tumors. 52 Friedberg et al performed a multicenter phase II study of alisertib in 48 patients with heavily pretreated aggressive lymphomas. 53 Although the ORR was 27% overall, it was 4/8 (50%) among patients with T-cell lymphoma, with 3/4 (75%) maintaining a response for more than 1 year at the time of reporting. Subsequently, the SWOG1108 phase II study extended this observation in an additional 37 heavily pretreated patients with a range of PTCL subtypes. 54 Alisertib was administered at a dosage of 50 mg twice daily for 7 days in a 21-day cycle. The most common adverse events (AEs) of grade 3 or greater were hematologic, observed in approximately one-third of patients; febrile neutropenia was seen in 14%. The ORR was 24% overall and 31% in patients with PTCL-NOS. As a pathway to potential approval, an ongoing international phase III registration study is comparing alisertib to investigators choice (gemcitabine, pralatrexate, or romidepsin) in patients with PCTL (NCT ). MOVING NOVEL AGENTS INTO THE FRONT LINE With many drugs demonstrating effıcacy in relapsed/refractory PTCL, integrating agents into front-line therapy is a major focus of drug development efforts. The conventional approach has been to be combine novel agents with chemotherapy in an attempt to discover an R-CHOP equivalent for PTCL; a summary of these studies is provided in Table 2. CHOP/CHP Plus Brentuximab Vedotin Because of the promising single-agent activity of brentuximab, a phase I study of CHOP without vincristine (CHP) and with brentuximab was designed to minimize the overlapping toxicity of peripheral sensory neuropathy. This study enrolled 39 patients with CD30 PTCL, although most (32 patients) had ALCL. 55 Two schedules of administration were used: BV 2 followed by CHOP 6 (sequential, 13 patients) or BV given concurrently with CHP (combination, 26 patients). The sequential arm was closed by the sponsor after two patients who responded to BV progressed during CHOP. Toxicity was similar between the schedules and manageable; the most common AE overall was peripheral neuropathy (31% with grade 3 in the combination group), followed by hematologic febrile neutropenia (21% in the combination group), fatigue, nausea, and GI disturbance. The combination was highly active, with an ORR of 85% and 100% (CR, 62% and 88%) and 1-year PFS of 77% and 71% in the sequential and combination groups, respectively, and none of these TABLE 2. Summary of Selected Chemotherapy/Novel Agent Combinations for Untreated Peripheral T-Cell Lymphoma Combination Study Group Major Histologies Phase n ORR CRR PFS OS CHOP romidepsin 57 LYSARC NR Ib/II 35 68% 51% 18 mo 57% 18 mo 76% CHOP vorinostat 60 MDACC PTCL-NOS 5, AITL 5, ALCL 4 I 14 93% 93% 2 yr 79% 2 yr 81% CHOP-14 alemtuzumab 62 GITIL PTCL-NOS 14, AITL 6, ALCL 3 II 24 75% 71% 2 yr 48% 2 yr 53% CHOP alemtuzumab 63 HOVON PTCL-NOS 10, AITL 6 II 20 90% 60% 2 yr 27%* 2 yr 55% CHO(E)P alemtuzumab 61 DSHNHL PTCL-NOS 21, AITL 11, ALCL 4 II 41 61% 58% 3 yr 32% 3 yr 62% CHP brentuximab vedotin 55 U.S./European multicenter ALCL 32, PTCL-NOS 2, ATLL 2, AITL 2 I %** 88%** 1 yr 71%** 1 yr 88%** CEOP pralatrexate 56 T-cell consortium PTCL-NOS 21, AITL 8, ALCL 4 II 33 70% 45% 1 yr 48%ˆ 1 yr 80% CHOP denileukin diffitox 99 U.S. multicenter PTCL-NOS 19, AITL 10, ALCL 8 II 49 65% 50% 2 yr 43% 2 yr 65% CHOP bortezomib 74 CISL PTCL-NOS 16, ENKTL 10, AITL 8 II 46 76% 65% 3 yr 35% 3 yr 47% Abbreviations: ORR, objective response rate; CRR, complete response rate; DOR, duration of response; NR, not reported; CHOP, cyclophosphamide/doxorubicin/vincristine/prednisone; ICE, ifosfamide/carboplatin/etoposide; CHP, cyclophosphamide/doxorubicin/prednisone; CEOP, cyclophosphamide/etoposide/doxorubicin, prednisone; CHOEP, cyclophosphamide, doxorubicin, vincristine/ etoposide/prednisone; LYSARC, Lymphoma Academic Research Organization; MDACC, MD Anderson Cancer Center; GITIL, Italian Group for Innovative Lymphoma Therapies; HOVON, Dutch-Belgian Haemato-Oncology Group; CISL, Consortium for Improving the Survival of Lymphoma; PTCL-NOS, peripheral T-cell lymphoma not otherwise specified; AITL, angioimmunoblastic T-cell lymphoma; ALCL, anaplastic large cell lymphoma; ATLL, adult T-cell leukemia/lymphoma; ENKTL, extranodal NK/T-cell lymphoma. *Event-free survival. **Results for combination CHP brentuximab arm. e472

6 NOVEL TREATMENTS FOR T-CELL LYMPHOMA patients underwent front-line consolidative ASCT. 55 The combination schedule is currently being compared with CHOP for patients with CD30 PTCL in the phase III ECHELON-2 study (NCT ). CEOP Plus Pralatrexate Advani et al reported preliminary results from the T-cell consortium trial of CEOP (cyclophosphamide/etoposide/vincristine/ prednisone) alternating with pralatrexate in newly diagnosed patients with PTCL. 56 Etoposide was substituted for doxorubicin because of data suggesting improved effıcacy (discussed above) and the lack of proven benefıt for anthracyclines. CEOP was administered in the standard fashion, with pralatrexate administered at 30 mg/m 2 intravenously on days 15, 22, 29; up to 6 cycles in total were planned and growth factor support was mandatory. The goal was to improve the CR rate to facilitate optional ASCT, which was allowed at the investigator s discretion. The ORR was 70% (CR 45%) and the 1-year EFS was 48%. Observed toxicities of grade 3 or greater included hematologic events, sepsis, and mucositis. CHOEP Plus HDAC Inhibitors The French cooperative group LYSARC (Lymphoma Academic Research Organization) performed a phase Ib/II study of CHOP with romidepsin in 35 patients with treatmentnaive PTCL. CHOP21 8 was given at standard doses, with the dose of romidepsin escalated (phase II dose 12 mg/m 2 on days 1 and 8 in a 21-day cycle). The major adverse events were, predictably, hematologic: grade 3 or greater neutropenia (38%), thrombocytopenia (19%), and anemia (9%). The ORR was 68% (CR 51%) and the estimated PFS at 18 months was 57%. 57 This combination is being tested in a randomized phase III study (NCT ). The Italian Cooperative Group is performing an ongoing phase I/II study of romidepsin in combination with CHOEP followed by ASCT (NCT ). Because of its activity in cutaneous T-cell lymphoma, 58,59 Oki et al. tested the combination of the orally available pan-hdac inhibitor vorinostat with CHOP in a small phase I study of 14 newly diagnosed patients with PTCL. 60 Toxicities were comparable to those expected from standard CHOP, with the exception of mild diarrhea in approximately half of all patients treated. All 12 patients who completed therapy achieved a CR (93% of total population) suggesting that this promising combination warrants further evaluation. A multicenter phase I study evaluating the combination of CHOP with belinostat is in progress (NCT ). CHOP Plus Alemtuzumab Alemtuzumab has also been explored in combination with CHOP-like therapy in three separate phase II multicenter European studies with markedly different treatment schedules The Italian study used 8 doses of CHOP-14 with 30 mg alemtuzumab given intravenously at 2-week intervals (total 240 mg) 62 ; the HOVON (Dutch-Belgian Hemato-Oncology Group) study also used CHOP-14, but intensifıed alemtuzumab with three 30-mg doses per cycle (total 720 mg) 63 ; the DSHNHL study used alemtuzumab (133 mg over 4 weeks) as consolidation following CHOP induction (with etoposide for patients older than 60) in 41 patients with newly diagnosed PTCL. 61 In all three studies, serious opportunistic infectious complications such as CMV reactivation, disseminated zoster and tuberculosis JC virus encephalitis, invasive fungal infections, and EBV-associated lymphoproliferative disease were observed despite aggressive chemoprophylaxis. Although comparisons between small phase II studies in heterogeneous disease groups are diffıcult, it appeared that both the ORR and rate of infection of grade 3 or greater were proportional to the cumulative dose of alemtuzumab administered. The ongoing ACT-1 (NCT ) and ACT-2 (EudraCT ) phase III studies are randomized comparisons of CHOP alemtuzumab in PTCL in younger (with ASCT consolidation) and older patients respectively. BIOLOGIC DOUBLETS IN THE RELAPSED SETTING Moving beyond the traditional CHOP X development pathway are a plethora of studies testing combinations of novel agents and eschewing chemotherapy altogether. At present, these biologic doublets are mostly being tested in the relapsed/refractory setting. A selection of such studies is presented in Table 3. We anticipate that the most promising combinations will be investigated in chemotherapy-free front-line protocols, as is currently underway in B-cell lymphoma. At the present time, results from most of these protocols are not mature. Hopfınger et al explored the combination of lenalidomide, vorinostat (400 mg daily, fıxed dose), and dexamethasone in a phase I/II study and found that the maximum tolerated dose (MTD) of lenalidomide in the combination was only 5 mg daily. 64 Planned dose escalation was aborted because of grade 3 thrombocytopenia and stroke at the 10-mg dose of lenalidomide. Probably because of the low tolerated dose of lenalidomide, activity was modest (ORR 25%, median PFS 2.2 months). Tan et al recently reported on a phase II study of the HDAC inhibitor panobinostat with the proteasome inhibitor bortezomib in patients with pretreated PTCL. 65 The main toxicities were hematologic, diarrhea, fatigue, and peripheral sensory neuropathy; among 23 evaluable patients, the ORR was 43% (CR 22%) with fıve patients successfully bridged to allogeneic stem cell transplantation. Several combination studies are underway using romidepsin in combination with other biologic agents. There are preclinical data suggesting potent synergism between romidepsin and alisertib in T-cell lymphomas, 66 an observation supported by preliminary results from a phase I study of the combination being performed at The University of Texas MD Anderson Cancer Center. 67 Among the included histologies, activity seems most promising in PTCL, with a CR observed at the lowest dose level and ORR of 1/3 (33%). This study is ongoing and the expansion cohort will be restricted to patients with PTCL. Romidepsin is also being explored in combination with several other nonchemotherapic agents, including lenalidomide, 5-azacitidine, and pralatrexate, with promising early results. Preliminary results from a phase I/II asco.org/edbook 2015 ASCO EDUCATIONAL BOOK e473

7 TABLE 3. Selected Ongoing Studies Testing Biologic Doublets in Peripheral T-Cell Lymphoma Agents Phase Population Sponsor/Site ClinicalTrials.gov Romidepsin lenalidomide I Untreated PTCL Northwestern University NCT I RR lymphoma/myeloma Yale/Peter MacCallum Cancer Centre NCT I RR lymphoma/myeloma Memorial Sloan Kettering Cancer Center NCT Romidepsin oral 5-azacitidine I RR lymphoid malignancies Columbia University NCT Romidepsin alisertib 67 I RR aggressive NHL National Cancer Institute NCT MD Anderson Cancer Center Alisertib vorinostat I RR lymphoma National Cancer Institute NCT Carflizomib belinostat I RR NHL Massachusetts General Hospital NCT Carfilzomib vorinostat I RR lymphoma University of Rochester NCT Pralatrexate romidepsin I/II RR lymphoid malignancies Columbia University NCT Bortezomib romidepsin I RR indolent lymphoid malignancies Virginia Commonwealth University NCT Abbreviations: PTCL, peripheral T-cell lymphoma; NHL, non-hodgkin lymphoma; RR, relapsed/refractory. combination of romidepsin/lenalidomide suggested that the combination is active, with ORR in relapsed PTCL of 58% but only 1 of 12 patients entering into CR. 68 Phase II studies are planned and Petrich et al will be conducting a front-line PTCL phase II trial of romidepsin plus lenalidomide. As these biologic doublets move into the front-line setting further information will be gained in terms of their effıcacy, although challenges remain with respect to which components of effıcacy (ORR, CR, or PFS) are most important to determine which biologic regimens should be selected for front-line randomized comparative trials against standard chemotherapy regimens such as CHOP or CHOEP. AGENTS IN EARLY CLINICAL DEVELOPMENT PI3K Inhibitors The orally administered phosphoinositide-3-kinase (PI3K) gamma/delta inhibitor duvelisib (IPI-145) was assessed in a phase I study of 33 heavily pretreated patients with T-cell lymphoma (CTCL 17, PTCL 16). 69 Most patients were treated at the MTD of 75 mg twice daily; among patients with PTCL the ORR was 47% (CR 12%) with a favorable toxicity profıle (the most common AEs were transaminitis, rash, and neutropenia). These highly promising results warrant further evaluation. Based on preclinical data, 70 another PI3K gamma/delta inhibitor, RP-6530, is currently being evaluated in a phase I study of patients with relapsed/refractory lymphomas and appears to be well tolerated, although no patients with PTCL were included in the preliminary report. 71 Another interesting approach to improve the effıcacy of novel therapeutics is the design of bifunctional molecules through medicinal chemistry. One such agent, CUDC-907, is both a pan-hdac and PI3K inhibitor and has shown greater preclinical activity than single-agent HDAC or PI3K inhibitors. 72 The compound is currently in a phase I clinical trial of refractory lymphoid malignancies (NCT ). Proteasome Inhibitors The fırst agent in this class, bortezomib, had moderate activity as a single agent in CTCL 73 and in combination with CHOP in untreated patients with PTCL. 74 The secondgeneration proteasome inhibitor carfılzomib is being investigated in an ongoing phase I study (NCT ). IDH2 Inhibitors Gain-of-function mutations in the genes encoding the metabolic enzymes isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) result in accumulation of R-2-hydroxyglutarate, a metabolite that induces epigenetic changes that drive oncogenesis. 75 Mutations in IDH1 and IDH2 have been reported in a range of hematologic and solid tumors, including 45% of cases of AITL. 76,77 AG-221 is a fırst-in-class, oral selective inhibitor of mutant IDH2 enzyme that appears to be well tolerated, with promising activity and durable responses in a preliminary report of a phase I study in advanced IDH2-positive hematologic malignancies. 78 It is being evaluated in a phase I/II study including patients with IDH2-positive AITL (NCT ). Retinoids Vitamin A derivatives have demonstrated a range of anticancer functions including antiangiogenesis activity and induction of apoptosis and differentiation. 79 With the exception of acute promyelocytic leukemia, their clinical development has been limited by their toxicity profıle. The synthetic retinoic acid (fenretinide) appears to be better tolerated than all-trans retinoic acid, and a phase I study using a pharmacologically optimized emulsion formulation resulted in a clinical benefıt rate (CR PR SD) of 64% among 11 patients with relapsed T-cell lymphomas. 80 Selective Inhibitors of Nuclear Export Selinexor (KPT-330) is a fırst-in-class, selective, reversible inhibitor of nuclear export that binds to the nuclear export protein XPO1, forcing its nuclear retention and activation of tumor suppressor proteins. 81 It has shown preclinical activity in a range of malignancies Preliminary data from a phase I study in patients with relapsed/refractory hematologic malignancies suggest that it is well tolerated and has potential effıcacy in T-cell lymphoma with one outcome of CR and two e474

8 NOVEL TREATMENTS FOR T-CELL LYMPHOMA of stable disease (SD) among three evaluable patients. 85 A phase II study in PTCL (and other histologies) is planned. Immune Checkpoint Inhibitors PD-1 is an immune checkpoint receptor that inhibits T-cell activation upon binding to its ligand PD-L1, which is overexpressed in many lymphoid malignancies. Antibodies specifıc for PD-1, such as nivolumab, thus induce antitumor T-cell activation and are highly active in Hodgkin lymphoma. 86 PD-L1 is known to play an important role in the tumor microenvironment in PTCL, providing a preclinical rationale for PD-1 inhibitors in these conditions. 87 A phase I study in heavily pretreated patients with NHL including 23 patients with T-cell lymphoma recently reported a favorable toxicity profıle and ORR of 17%. However, among patients with PTCL, the ORR was 2/5 (40%). 88 ALK Inhibitors For patients with ALK ALCL, the EML4-ALK fusion oncogene provides an attractive target. Crizotinib, the fırstgeneration ALK inhibitor, was used in a phase Ib study of 15 patients with ALK lymphomas (14 with ALK ALCL). 89 The main toxicities were diarrhea, vomiting, and visual impairment; the ORR was 60%. This agent is being tested in a phase I/II study in combination with chemotherapy in untreated patients (NCT ) and in a study of relapsed/ refractory ALK ALCL (NCT ). As with many tyrosine kinase inhibitors, secondary resistance has been reported and second-generation agents such as ceritinib (LDK378) will undoubtedly be explored in patients who experience treatment failure A phase I study that includes an arm enrolling patients with ALK malignancies other than lung cancer is in progress (NCT ). TOWARD MOLECULAR STRATIFICATION IN PTCL Gene expression profıling (GEP) has advanced our understanding of the classifıcation, 92 prognostic stratifıcation, and molecular pathogenesis of T-cell lymphomas. The Mayo group recently described two genetic subsets of ALK ALCL with disparate clinical outcomes: patients with rearrangements in DUSP22 (at the 6p25.3 locus, found in 30% of cases) had excellent outcomes, comparable to those of ALK ALCL, whereas those with TP63 rearrangement (on 3q28, seen in 8% cases) had dismal prognosis. 93 Several recurrent somatic mutations in genes such as TET2, 94 IDH2, 77 and RHOA 95,96 have been described, although their clinical relevance requires further investigation. In PTCL-NOS, a recurrent t(5;9)(q33;q22) translocation resulting in a ITK-SYK fusion gene and SYK overexpression was described in a subset of patients with follicular histology. 97 Finally, small nucleolar RNA (snornas) have been shown to have potential diagnostic and prognostic signifıcance in PTCL. 98 Further development and more widespread utilization of these technologies are clearly needed to deliver on the promise of true precision medicine for patients with T-cell lymphomas. CONCLUSION Cooperative studies in the last 5 years have successfully enabled the rapid completion of phase I/II studies and brought four new drugs for patients with T-cell lymphoma to the clinic. Continuing efforts are needed to complete confırmatory randomized phase III studies in combination with chemotherapy. The development of chemotherapy-free regimens using the most active biologic agents in PTCL will be a critical focus of research efforts in the future. Additional efforts to develop molecular targeted approaches are also clearly needed in order to rationally select a treatment plan that would be predicted to have the highest effıcacy for a particular patient. Disclosures of Potential Conflicts of Interest Relationships are considered self-held and compensated unless otherwise noted. Relationships marked L indicate leadership positions. Relationships marked I are those held by an immediate family member; those marked B are held by the author and an immediate family member. Institutional relationships are marked Inst. Relationships marked U are uncompensated. Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: Michelle A. Fanale, Plexus, Research to Practice, Seattle Genetics, Takeda. Consulting or Advisory Role: Michelle A. Fanale, Acetylon Pharmaceuticals, Amgen, Clarient, Spectrum Pharmaceuticals. Speakers Bureau: None. Research Funding: Michelle A. Fanale, Bristol-Myers Squibb, Celgene, Genentech, Gilead Sciences, MedImmune, Millennium, Molecular Templates, Novartis, Seattle Genetics. Yasuhiro Oki, Curis, Seattle Genetics, Novartis, Janssen Pharmaceuticals, Infinity, Millennium, Cell Medica, Spectrum Pharmaceuticals. Patents, Royalties, or Other Intellectual Property: None. Expert Testimony: None. Travel, Accommodations, Expenses: Michelle A. Fanale, Plexus, Research to Practice, Spectrum Pharmaceuticals, Takeda. Yasuhiro Oki, DAVAOncology. Other Relationships: None. References 1. 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