New Strategies in Peripheral T-Cell Lymphoma: Understanding Tumor Biology and Developing Novel Therapies

Clinical Cancer CCR New Strategies Research

Kieron Dunleavy1, Richard L. Piekarz1, Jasmine Zain2, John E. Janik1, Wyndham H. Wilson1, Owen A. O’Connor2, and Susan E. Bates1

Abstract Peripheral T-cell lymphomas (PTCL) constitute a group of heterogeneous diseases that are uncommon, representing, in Western countries, only approximately 10% of all non-Hodgkin lymphomas. They are typically associated with a poor prognosis compared with their B-cell counterparts and are much less well understood with respect to tumor biology, owing to their rarity and biologic heterogeneity, and to the fact that characteristic cytogenetic abnormalities are few compared with B-cell lymphomas. Although the outcome for patients with anaplastic large cell lymphoma (ALCL), particularly anaplastic lymphoma kinase (ALK)–positive ALCL, is good, other types of PTCLs are associated with a poor prognosis, even with aggressive anthracycline-based chemotherapy. In this respect, there is a need for new approaches in these diseases, and this review focuses on and explores recent experience with novel therapies in PTCL. Clin Cancer Res; 16(23); 5608–17. 2010 AACR.

Background (ALK-positive and -negative ALCLs showed 5-year overall survivals of 70% and 49%, respectively), overall survivals Peripheral T-cell lymphoma (PTCL) represents a hetero- for patients with PTCL-NOS and AITL were poor, and geneous group of clinicopathologically defined distinct T- interestingly, unaffected by the use of anthracyclines in cell lymphomas, the most common of which are PTCL not the upfront setting. The 5-year overall survival for PTCL- otherwise specified (PTCL-NOS), angioimmunoblastic T- NOS, AITL, and all NKTCLs was 32% compared with 14% cell lymphoma (AITL), and anaplastic large cell lymphoma for ATLL. [ALCL; constituting anaplastic lymphoma kinase (ALK)– positive and –negative cases; Fig. 1]. Rarer subtypes include Biology of peripheral T-cell lymphoma extranodal natural killer T-cell lymphoma (NKTCL), adult The molecular biology of these diseases is poorly under- T-cell leukemia/lymphoma (ATLL), and enteropathy-asso- stood, which is, at least partially, due to the rarity of PTCL, ciated T-cell lymphoma (EATL). PTCL-NOS are nodal and and this has complicated the investigation and develop- extranodal mature T-cell lymphomas that do not fit under ment of new targeted therapies (3). The notable exceptions any of the other specifically defined entities of mature T-cell to this are ALK-positive ALCLs, most commonly character- lymphoma in the current World Health Organization ized by a translocation t(2;5)(p23;q35) between the ALK (WHO) classification and will likely be further categorized gene on chromosome 2 and the nucleophosmin (NPM) as gene expression profiling and DNA sequence analysis of gene on chromosome 5 (1, 4); T-cell prolymphocytic these diseases advances (1). The largest evaluation of PTCL leukemia (PLL) with translocations of the T-cell leukemia to date was done by the International Peripheral T-Cell and 1 (TCL-1) or mature T-cell proliferation 1 (MTCP-1) gene Natural Killer/T-Cell Lymphoma Study in which a cohort to chromosome 14, the site of the alpha chain of the T-cell of 1,314 patients in 22 centers worldwide was studied receptor; and ATLL, the first human neoplasm associated (Fig. 2; ref. 2). Though the study was retrospective and with retroviral infection (5). Although the t(2:5) transloca- therapeutic approaches varied widely, it provided interest- tion is found in more than 80% of cases of ALK-positive ing insights into the outcome of these rare lymphomas. ALCL, variant translocations involving ALK and other Although patients with ALCL (particularly ALK positive) partner genes on various chromosomes can also occur had a good outcome with anthracycline-based therapy (6, 7). The transforming NPM-ALK fusion protein that results from the t(2:5) translocation encodes a tyrosine kinase receptor, resulting in the constitutive activation of 1 Authors' Affiliations: Center for Cancer Research, National Cancer ALK and its downstream pathways (8). ALK can be detected Institute, Bethesda, Maryland; 2New York University Cancer Institute, NYU Langone Medical Center, New York, New York by immunohistochemistry, and whereas in the majority of Corresponding Author: Kieron Dunleavy, National Cancer Institute, cases with the classical t(2;5)/NPM-ALK translocation, ALK Building 10, Room 12N226, 10 Center Drive, Bethesda, MD 20892–1868. staining is both cytoplasmic and nuclear, it may be mem- Phone 3014351007; Fax 3014801105; E-mail [email protected] branous or cytoplasmic in variant cases (1). PLL can occur doi: 10.1158/1078-0432.CCR-09-1995 in an inherited form associated with ataxia telangiectasia or 2010 American Association for Cancer Research. in a sporadic form. In both cases, the majority of patients

5608 Clin Cancer Res; 16(23) December 1, 2010

A Anaplastic large cell lymphoma, ALK+ Anaplastic large cell lymphoma, ALK- All natural killer/T-cell lymphomas 100 Peripheral T-cell lymphoma, not otherwise specified 90 Angioimmunoblastic lymphoma Adult T-cell leukemia/lymphoma 80 70 60 50 40 30

Overall Survival (%) 20 10 P < .001

0 123456789101112131415161817 Time (years) B Primary cutaneous ALCL Subcutaneous panniculitis-like T–cell lymphoma Enteropathy-type T–cell lymphoma Fig. 1. These Kaplan-Meier curves 100 Hepatosplenic T-cell lymphoma show: A, the overall survivals of 90 patients with the most common 80 subtypes of PTCL; B, the overall survivals of patients with the less 70 common subtypes of PTCL; and, 60 C, the overall survivals of patients 50 with NKTCL. Reproduced with 40 permission from the International T-cell Lymphoma Project, Vose 30 et al. (2). Overall Survival (%) 20 10 P < .001

0 12345678910111213 Time (years) C 100 Nasal natural killer/T-cell lymphoma Natural killer/T-cell lymphoma, nasal type 90 Aggressive or unclassifiable natural killer/T-cell 80 lymphoma 70 60 50 40 30

Overall Survival (%) 20 10 P < .001

0 123456789101112 Time (years)

have a translocation of the TCL-1 gene into chromosome the viral RNA and express the tax gene, which induces an 14. TCL-1 and MTCP-1 have a similar protein structure and autocrine growth loop through upregulation of interleukin associate with protein kinase B (Akt) to drive proliferation (IL)-2 and its receptor. This sequence immortalizes of the cells (9). In ATLL, cells infected with HTLV1 integrate the infected T cells and, presumably, over the course of

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2.5% Peripheral T-cell Lymphoma 12.2% 0.9% Angioimmunoblastic 1.4% 25.9% Natural killer/T-cell lymphoma 1.7% Adult T-cell leukemia/lymphoma 4.7% Anaplastic large cell lymphoma, ALK+ Fig. 2. The distribution of 1,314 Anaplastic large cell lymphoma, ALK- cases by consensus diagnosis. 5.5% Enteropathy-type T-cell Reproduced with permission from Primary cutaneous ALCL the International T-cell Lymphoma Project, Vose et al. (2). 6.6% 18.5% Hepatosplenic T-cell Subcutaneous panniculitis-like 9.6% 10.4% Unclassifiable PTCL Other disorders

decades, allows the accumulation of genetic defects that Treatment of peripheral T-cell lymphoma result in overt malignancy. The only other molecular aber- With the exception of ALK-positive ALCL, which is highly ration identified in PTCL is isochromosome 7q, which is curable with CHOP-like therapy and has a 5-year overall associated with hepatosplenic T-cell lymphoma. Most survival that approaches 80%, the outcome for patients with other T-cell lymphomas have not been defined molecularly a new diagnosis of PTCL who receive anthracycline-based (10). ALK-negative ALCL is poorly understood, and its therapy is poor, and most patients relapse soon after initial inferior outcome suggests a derivation distinct from that treatment and die of their disease (2). Although historically, of ALK-positive cases, although gene expression profiling many studies in PTCL have included patients with ALCL, has shown some overlap in expression patterns of kinases studies confined to PTCL-NOS using CHOP or CHOP-like and apoptosis inhibitors, suggesting a common pathogenic regimens show disappointing outcomes with long-term mechanism. Although the pathogenesis of AITL is also survivals in the range of 20% (17). In one study of 36 newly poorly elucidated, recent work has shown overexpression diagnosed patients with PTCL-NOS who received CHOP- of the chemokine CXCL13 by the neoplastic cells, suggest- based chemotherapy, 1- and 2-year overall survivals were ing derivation from follicular helper T cells (11–13). 61% and 25%, respectively. In the International Peripheral Though gene-expression profiling studies in PTCL lag T-Cell and Natural Killer/T-Cell Lymphoma Study, whereas behind those in B-cell lymphomas, some recent studies, more than 85% of patients received an anthracycline-con- albeit with small numbers of patients due to the infre- taining regimen, the 5-year overall survival for patients with quency of these diseases, have suggested that the histo- PTCL-NOS, AITL, and NKTCLs was merely 32%. These pathologically defined PTCL subtypes have distinct results confirm the poor efficacy of current standard thera- molecular profiles (3, 14–16). Molecular classifiers have pies and argue for the evaluation of new agents in these been constructed for AITL, ALK-positive ALCL, and ATLL diseases. Over the past few years, a number of novel thera- (Fig. 3). In a recent study in which gene expression profil- pies with efficacy in the relapsed setting have emerged for ing was done on 144 cases of PTCL, the identification of a PTCL. The suboptimal outcome for newly diagnosed molecular subgroup, with features of cytotoxic T lympho- patients with current standard therapeutic approaches sug- cytes and a poor survival compared with the remaining gests that novel agents should be investigated in clinical PTCL-NOS cases, suggests that PTCL-NOS is a molecularly trials in the upfront setting in a window of opportunity heterogeneous entity (3). This heterogeneity of lympho- approach to define their efficacy and their molecular magenesis makes it challenging to identify selective targets mechanisms. Autologous bone marrow transplantation for drug development. following second line therapy with regimens like ifosfa- The biological basis for the poor treatment outcome for mide, carboplatin and etoposide (ICE) and high-dose cytar- patients with PTCL, in contrast to patients with aggressive abine, cisplatin and dexamethasone (DHAP), can be B-cell lymphomas, is not well understood. In the future, curative for patients with relapsed disease, particularly for studies that incorporate technology such as microarray patients with ALK-positive ALCL (18). The experience of (that can interrogate the expression of thousands of genes) allogeneic transplantation in relapsed PTCL is limited to a or deep DNA sequencing (that can identify all genetic small number of studies, and its role continues to be changes) will likely help elucidate which distinct pathways investigated (19, 20). Further studies to define the optimal are activated and transformed and provide insights into the conditioning regimens and the group of patients who would role of epigenetic changes in these diseases. benefit most from allogeneic transplantation are necessary.

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A D AITL Comparison between the 1 0.9 molecular diagnosis 0.5 AITL Other PTCL and Pathology diagnosis 0 0.1 Bayesian Probability 45 40 35

207 30 25 Probe sets 20 15 No of cases AITL NON-AITL PTCL 10 GEP classified AITL cases with discordant pathologic diagnosis 5 0

B AITL ATLL ATLL PTCL-U 1 0.9 ALK+ALCL ALK-ALCL 0.5 ATLL Other PTCLs Pathology diagnosis 0 0.1 Bayesian Probability Molecular diagnosis AITL ATLL

225 ALK+ALCL

Probe sets PTCLs with cytotoxic T-cell features Not molecularly classified ATLL NON-ATLL PTCL AITL GEP classified ATLL cases, but not by pathology ALK+ALCL C ALK-ALCL PTCL-U ALK (+) ALCL 1 0.9 0.5 ALK+ALCL Other PTCLs 0 0.1 Bayesian Probability 94 Probe sets

ALK+ NON-ALK+ PTCL

Fig. 3. Gene-expression–based molecular predictors of the major subgroups of PTCL from the International Peripheral T-Cell Lymphoma Project. A, AITL, B, ATLL, and C, ALKþ ALCL. D, The correlation between the molecular and the pathology-based diagnoses. Reproduced with permission from Iqbal et al. (3).

On the Horizon On the basis of preclinical modeling in both T- and B-cell lymphoma cell lines, which showed better cytotoxicity for Pralatrexate pralatrexate compared with methotrexate (in lymphoma Pralatrexate was the first drug approved specifically for cytotoxicity assays, pralatrexate had at least a 1-log lower use in PTCL by the U.S. Food and Drug Administration 50% inhibitory concentration than methotrexate), a (FDA) on the basis of its single agent activity in relapsed phase I-II study was undertaken in patients with both T- and/or refractory T-cell lymphoma (21). It is a targeted and B-cell lymphomas (23, 24). Although an every-other- antifolate and specifically, a novel 10-deazaaminopterin, week dose of 135 mg/m2 was associated with problematic structurally similar to methotrexate, but rationally designed stomatitis, a weekly schedule of 30 mg/m2 for 6 of 7 weeks, to have greater affinity for the reduced folate carrier with folate and vitamin B12 supplementation, abrogated (SLC19A1 or RFC-1; a fetal oncoprotein highly expressed significant stomatitis that had been seen with the every- on fetal and malignant tissue and the principal transporter other-week schedule and reduced other toxicities (25). through which folates and antifolates enter the cell), Though minimally effective in B-cell lymphoma, the activ- enabling the drug to be selectively accumulated in tumor ity in T-cell lymphoma was significant with complete and cells (22). partial response rates of 28% and 24%, respectively, in

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25 patients with relapsed and/or refractory T-cell lym- FDA approval of this agent for patients with CTCL. phoma who received the once weekly schedule. Responses Romidepsin was also studied in patients with PTCL in were seen across various types of PTCL, including many a multicenter study; of 46 evaluable patients, the overall patients with PTCL-NOS. In responders, more than 50% response rate was 33% with a complete response rate of achieved a durable remission of at least 6 months. Follow- 11%; the median duration of response was 9 months ing on from the results of this study, an international phase (35). On the basis of these results, a confirmatory inter- II study in PTCL (PROPEL) was carried out (22), and was national study of romidepsin in PTCL is ongoing. The the basis for the accelerated approval granted by the FDA in principal drug-related toxicities were fatigue, nausea, and 2009. In 109 evaluable patients, the overall response rate thrombocytopenia. EKG changes consisting of T-wave was 28% with 9% of patients achieving a complete flattening are noted in a majority of patients but have response; the median duration of response was 9.4 not been associated with cardiac damage (36). Electrolyte months. In this multicenter study, the principal toxicities replacement to maintain high-normal potassium and were thrombocytopenia, mucositis, neutropenia, and ane- magnesium and concurrent administration of antie- mia. Shifting to a weekly schedule and treatment with metics, integral to ongoing studies, have made romidep- folate and vitamin B12 have mitigated the risk of mucositis. sin well tolerated in both the CTCL and PTCL patient The full clinical potential of pralatrexate in combination populations (33). Future clinical trials that will combine with other agents has yet to be determined. Recent studies romidepsin with other agents in PTCL are important to have shown synergy with agents such as gemcitabine, improve efficacy and outcome. paving the way for combination studies (26). Belinostat (PXD101) is another pan-HDAC inhibitor that has shown activity in both CTCL and PTCL. Recently, Histone deacetylase inhibitors its activity in PTCL was reported (37). Patients received Acetylation of proteins is a posttranslational modifica- a dose of 1,000 mg/m2 intravenously on days 1 to 5 of a tion that occurs on the e-amino side chain of lysine amino 3-week cycle, and in 20 patients, the overall response rate acids; deacetylases are a family of enzymes that remove was 25% with a complete response rate of 10%. these acetyl groups. To date, histones have been the most At this point in time, no data are available on the efficacy characterized proteins for the posttranslational modifica- of the other HDACis in patients with PTCL, but it is very tion of acetylation. As a result, agents that block the activity possible that these data will also show efficacy given the of deacetylases are commonly referred to as histone dea- apparent activity of the entire class of agents in T-cell cetylase inhibitors (HDACi). Furthermore, the most com- lymphomas. These agents include vorinostat, already monly accepted hypothesis for the HDACi mechanism of FDA approved for the treatment of refractory CTCL, pano- antitumor activity is thought to be the ability of these binostat, and entinostat (38, 39). agents to regulate gene expression. They have been shown to alter gene expression in a wide variety of tumor types and Denileukin diftitox specifically have been shown to mediate increased expres- Denileukin diftitox (Ontak), a recombinant fusion pro- sion of cell cycle regulators, cell type–specific differentia- tein, consists of IL-2 genetically fused with diptheria toxin. tion genes, tumor antigens, and genes encoding It binds to the IL-2 receptor (IL-2R), and the fusion toxin is proapoptotic proteins (27–30). However, with the discov- endocytosed and cleaved, resulting in the release of the ery that multiple other proteins undergo posttranslational active diptheria toxin. This release leads to ADP ribosyla- modification by acetylation, including numerous nuclear tion of the eukaryotic translation factor, elongation factor and cellular proteins, mechanisms of antitumor activity 2, with subsequent inhibition of protein synthesis and cell independent of regulation of gene expression through death. The limited expression of the IL-2R on activated T histones are potentially as important (31). cells and T-regulatory cells and its high level of expression Romidepin (FK228 or depsipeptide) was the first on many hematologic malignancies make it an attractive HDACi to show efficacy in patients with PTCL or cuta- agent for clinical evaluation. neous T-cell lymphoma (CTCL). In a report of four Denileukin diftitox was approved by the FDA for patients treated in a phase I study, one patient with patients with refractory or relapsed CD25-positive CTCL PTCL-NOS had a complete response, and three patients on the basis of its activity in this disease (40, 41). It has with CTCL a partial response, prompting a phase II trial to alsoshownsomeefficacyinPTCL(42)andiscurrently assess its efficacy in patients with CTCL or PTCL (29, 32). being tested in combination with CHOP chemotherapy. Romidepsin is administered at a dose of 14 mg/m2 given A phase II trial that evaluated a dose of 18 mg/kg daily for on days 1, 8, and 15 of an every-28-day cycle. An overall 5 days every 3 weeks preliminarily reported an overall response rate of 34% and a complete response rate of 6% response rate of 48% and a complete response rate of 22% (with a median duration of response of 13.7 months) in with minimal toxicity (42). A higher response rate was 71 patients with CTCL was reported from a multi-institu- observed in patients with CD25þ tumors (61.5% versus tional study, and in a separate registration trial of 96 45.4%), and the median progression-free survival was 6 patients, a similar overall response rate of 34% and months. At present, denileukin difitoxin administration complete response rate of 6% was observed (33, 34). in the setting of autologous transplantation is also being Thepooleddatafromthesetwotrialswerethebasisofthe investigated in PTCL.

5612 Clin Cancer Res; 16(23) December 1, 2010 Clinical Cancer Research

Novel monoclonal antibodies MDX-060. MDX-060 is a fully human anti-CD30 Alemtuzumab. Alemtuzumab (Campath) is a huma- immunoglobulin (Ig) G1 k monoclonal antibody that nized anti-CD52 monoclonal antibody that is approved binds to the CD30 ligand with nanomolar affinity (57). by the FDA for relapsed and untreated B-cell chronic lym- It has been shown to inhibit growth of CD30-expressing phocytic leukemia (B-CLL), but also has efficacy in T-cell tumor cells in preclinical models (58). It inhibits cellular lymphomas, particularly T-cell PLL. Alemtuzumab was eval- proliferation through modulation of signaling and induces uated in 39 patients with PLL and produced responses in ADCC (58). In a phase I-II study, in patients with recurrent 76% (60% complete response and 16% partial response; ref. Hodgkin lymphoma and ALCL, the drug was administered 43). The median survival of patients was 10 months, but on a once weekly schedule, up to a dose of 15 mg/kg, and reached 16 months for patients who achieved a complete the maximum tolerated dose was not reached (57). response. In a pilot study, it was investigated in 14 patients Although this study only enrolled seven patients with with heavily pretreated relapsed or refractory PTCL (44). ALCL, two (28%) of these had a complete response. Inter- Patients received a rapidly escalating dose during the first estingly, these patients predominantly had skin involve- week followed by 30 mg, three times per week, for a max- ment with their lymphoma. imum of 12 weeks. Though associated with significant SGN-35. SGN-35 (brentuximab vedotin) is an anti- hematologic toxicity and infectious complications (these body-drug conjugate in which anti-CD30 antibody is included military tuberculosis, herpes zoster, and pulmonary attached by an enzyme-cleavable linker to a potent, syn- aspergillosis), the overall response rate was 36%, with 21% of thetic drug payload: monomethyl auristatin E, which inhi- patients achieving a complete response. This study showed bits microtubule polymerization. Preliminary results from that alemtuzumab has antitumor activity in PTCL, but the a phase I weekly dosing study of SGN-35 suggested good toxicity suggests that lower doses and/or different schedules efficacy in systemic ALCL (59). should be explored. Sustained remissions with alemtuzumab Zanolimumab. Zanolimumab is a fully human mono- have been reported in patients with AITL (45). Though its clonal antibody that targets the CD4 antigen present on T- spectrum of activity and mechanism of action have not yet helper lymphocytes (60). The antibody prevents interac- been elucidated, it likely works through a combination of tion between the CD4 receptor and the major histocom- different pathways that include complement-dependent patibility complex class II molecules and in this way cytolysis, antibody-dependent cellular cytotoxicity (ADCC), interferes with T-cell activation. It is very effective in refrac- and apoptosis. Alemtuzumab has been combined with dox- tory CTCL, and preliminary results in a study in patients orubicin-based chemotherapy, and although associated with with PTCL showed encouraging activity with an overall a high response rate, treatment-related toxicity has been response rate of 23%; there were two complete responses, problematic over several studies (46). Intravenously admi- one in a patient with PTCL-NOS and another in AITL (61). nistered alemtuzumab appears to be associated with a higher The development of zanolimumab was recently discontin- mortality rate than subcutaneous administration, again cau- ued by Genmab because of slow patient recruitment into its tioning that dose and schedule need to be optimized (47– pivotal study for zanolimumab in CTCL. 49). A phase III trial of CHOP-14 with or without subcuta- Siplizumab. Siplizumab is a humanized monoclonal neous alemtuzumab is currently ongoing. antibody that targets the CD2 antigen present on most T SGN-30. CD30 is a cell membrane protein of the and NK cells. Siplizumab showed activity in an animal tumor necrosis factor receptor family and a regulator of model of ATLL with 50% of tumor-bearing animals cured cell growth and apoptosis (50). CD30 ligation with mono- with four weekly administrations of the antibody, and clonal antibodies or CD30 ligand produced apoptosis of complete elimination of disease with a 6-month course ALCL cell lines in vitro and in murine xenograft models of treatment. Two separate phase I trials of siplizumab (51–54). On the basis of activity in animal models, anti- showed promising activity in T-cell malignancies with CD30 monoclonal antibodies were tested in CD30-positive partial and complete responses observed in patients with hematologic malignancies. SGN-30 (anti-CD30 mAB) is a PTCL, ATLL, and large granular lymphocyte leukemia, but chimeric anti-CD30 monoclonal antibody that showed the development of Epstein-Barr virus–related lymphopro- potent preclinical antitumor activity in both Hodgkin liferative disease (EBV-LPD) in 5 of 51 patients prompted lymphoma and ALCL (50). In a phase I study in which closure of the single agent trials (62). Siplizumab is under the drug was administered once weekly, there was modest evaluation in combination with rituximab in an attempt to activity in ALCL and Hodgkin lymphoma (55). Adverse prevent EBV-LPD. Downmodulation of the CD2 receptor events were mild, and the maximum tolerated dose was not in response to antibody administration represents another reached. A subsequent phase II study (in which the drug, potential problem in the use of this antibody. again, was administered according to a weekly schedule) KW-0761. KW-0761 is a defucosylated humanized treated 41 patients with ALCL. The objective response rate anti-CCR4 antibody that has been evaluated in a phase I in this group was 17.1%, and, interestingly, all the trial in patients with ATL or PTCL. The antibody is unique responses were in patients with ALK-negative disease, in that defucosylation enhances ADCC and permits a lower who typically have a worse prognosis than ALK-positive dose of antibody to be effective. Responses were observed cases (56). Currently, clinical trials are ongoing combining in patients treated at doses ranging from 0.01 to 1 mg/kg, SGN-30 with combination chemotherapy. with the latter dose being evaluated in phase II trials (63).

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Interestingly, this antibody also depletes T-regulatory cells tumor growth and causing apoptosis. It also causes cell and may exert some of its antitumor effect through this apoptosis through inhibition of ribonucleotide reductase. mechanism. It has shown activity in relapsed T-cell lymphomas Daclizumab. Daclizumab is a humanized monoclonal (71, 72). One study investigated its activity in patients antibody that inhibits IL-2 binding to its receptor IL-2R and with relapsed PTCL; gemcitabine was administered at a is approved by the FDA for the prevention of renal trans- dose of 1,200 mg/m2 on days 1, 8, and 15 of a 28-day cycle plant rejection (64). Basiliximab, a chimeric antibody that for a total of three to six cycles (71, 73). Albeit a small study, binds to the same receptor, would be anticipated to have 55% of patients with PTCL had a response, with 30% similar activity. Neither antibody depletes CD25-expres- achieving a complete response. Response duration ranged sing T cells, but daclizumab has activity in patients with from 15 to 60 months (71, 73). smoldering and chronic ATLL, in which it interferes with Pentostatin was tested at a dose of 3.75 or 5 mg/m2 by the autocrine growth loop stimulated by tax (64). intravenous bolus administration daily for 3 days on an A major difficulty in the use of most monoclonal anti- every-3-weeks schedule in patients with relapsed T-cell bodies directed at T-cell antigens to treat lymphoma resides lymphoma (74). Forty-two patients were evaluable for in the necessary depletion of normal T cells that accom- response, with an overall response rate of 54.8% observed. panies their use. T-cell depletion predisposes to the devel- The median duration of remission was short at 4.3 months, opment of opportunistic infections and secondary but some responses were prolonged to more than 5 years. malignancies and these combinations appear to be greater The major toxicities included nausea, neutropenia, and with the combination of monoclonal antibodies and che- CD4 T-cell depletion. motherapy. The addition of rituximab may prevent the Forodesine is a potent purine nucleoside phosphorylase development of EBV-LPD and the use of antiviral and inhibitor, which leads to T-cell selective intracellular dGTP antifungal prophylaxis may help reduce the incidence of accumulation, causing apoptosis. It has in vitro activity opportunistic infections. against a wide range of B- and T-cell diseases and has shown moderate efficacy in patients with CTCL in a pre- Immunosuppressants and immunomodulatory agents liminary analysis (75). Clofarabine is a deoxyadenosine Cyclosporine A is an antifungal metabolite with immu- analog that has increased stability compared with cladri- nosuppressive effects. It has a suppressive effect on T cells at bine or fludarabine, and is under investigation in PTCL. the early stages of activation and a direct cytotoxic effect on Bortezomib, a proteasome inhibitor, was initially lymphocytes. This rationale led investigators to examine its approved for use in relapsed and/or refractory multiple role in AITL, a disease that is characterized by complex myeloma and, subsequently, was also found to be very immune dysregulation. Cyclosporine was administered effective in mantle-cell lymphoma (76–78). It has also twice daily for 6 to 8 weeks, with gradual tapering over shown activity in T-cell lymphoma, mostly in CTCL but several weeks and responding patients received mainte- also in PTCL-NOS, with skin involvement (79). In pre- nance therapy (65). Considering the poor outcome with viously untreated patients with PTCL and NKTCL, it has standard therapy in this disease, the results with this drug been combined with CHOP and was well tolerated and an were noteworthy. Eight of 12 (67%) patients with AITL active combination (80). experienced a response, with 2 patients achieving a com- A recently published study that evaluated the first clini- plete response; the median duration of response was cally available spleen tyrosine kinase (Syk) inhibitor in 13 months (65). The investigators proposed that cyclos- recurrent B-cell lymphoma showed high objective response porine may act by inhibiting deregulated T-cell activation rates, particularly in patients with CLL and small lympho- through the calcineurin-nuclear factor of activated T-cell cytic leukemia (81). Overexpression of Syk has been shown (NF-AT) signaling pathway. in PTCL, and inhibition of Syk induces apoptosis and Lenalidomide, a derivative of thalidomide, has shown blocks proliferation in T-cell non-Hodgkin lymphoma cell interesting efficacy across a broad range of lymphoid dis- lines (82, 83). Therefore, Syk inhibition is an interesting eases (66–68). Its mechanism of action is poorly under- therapeutic strategy, and fostamatinib disodium is being stood; in vitro it has direct antitumor effects, inhibits investigated in PTCL. angiogenesis, and results in increased NK cells in tumor tissue. Recently, it was tested in patients with relapsed or Bone marrow transplantation refractory PTCL and administered at a dose of 25 mg once Although autologous transplantation has an established daily on days 1 to 21 of a 28-day cycle (69). In a pre- role in relapsed ALK-positive ALCL, as discussed earlier, the liminary report, the overall response rate was 30% in 23 role of this strategy in the setting of other relapsed PTCLs or evaluable patients, suggesting that further investigation of as frontline consolidation in PTCL has not been well this drug in PTCL is warranted (69). Thalidomide, in a case established (84, 85). Allogeneic transplantation is a poten- report, showed efficacy in AITL (70). tially effective therapy for some patients with relapsed T- cell lymphoma and is under investigation in prospective Other agents in peripheral T-cell lymphoma studies (86). For histologies like EATL and hepatosplenic Gemcitabine is a novel nucleoside analog that com- g-d T-cell lymphoma, in which outcomes with conven- petes with the natural nucleotide deoxycytidine, arresting tional approaches are extremely poor and survivals short,

5614 Clin Cancer Res; 16(23) December 1, 2010 Clinical Cancer Research

consolidation allogeneic transplantation following induc- extensive in oncology. The fundamental question is how to tion therapy should be investigated in clinical trials. move these compounds forward. At the present time, only one of these (pralatrexate) is FDA approved for PTCL. The Conclusions approval was accelerated, indicating that further studies are required to confirm clinical benefit. Trials with HDACis With the exception of ALK-positive ALCL, the outcome are completed, and submission to the FDA expected. For for most patients with PTCL is poor and significantly these therapeutic advances to be translated into long-term inferior to that of patients with aggressive B-cell lympho- clinical benefit for patients with PTCL, it is imperative mas. Therapeutic advancement in T-cell lymphoma has that a systematic clinical trial effort is instituted in this been curtailed, at least in part, by the rarity of these tumors, disease. Given its rarity and generally poor prognosis, most which has made instituting large-scale clinical trials chal- patients with PTCL should be considered for enrollment in lenging. Additionally, there is a lack of reagents to do clinical trials. In the context of these trials, it is critical to preclinical studies. While cell lines are limited from further develop international consortiums, and attempt to patients with T-cell neoplasms, efforts to develop these pair molecular characterization of tumors with drug devel- lines have the potential to increase our understanding of opment and investigation. Novel agents with activity in these diseases. Whereas the biology of many B-cell lym- the relapsed setting need to be incorporated into upfront phomas has been well elucidated, the pathogenesis and clinical trials, given the aggressiveness and frequently pivotal pathways that characterize distinct T-cell lympho- poor outcome of PTCL subtypes other than ALK-positive mas remain poorly understood at present. Recent gene- ALCL. Novel clinical trial designs, including adaptive expression profiling studies, albeit in small numbers of designs, also need to be considered to increase efficiency. patients, have shown that certain key signatures are asso- Window of opportunity trials offer the opportunity to ciated with PTCL subtypes and suggest that more extensive test agents in newly diagnosed patients. The goal is to and expansive molecular analyses are critical to advance- move agents from the long list of potential agents either ment of the field. It is likely that defining the molecular off the list, or into their appropriate places in the arma- abnormalities in T-cell lymphomas will provide an oppor- mentarium, and to bring the outcome for patients with tunity to develop specifically targeted agents. PTCL up to that expected for patients with more curable In the preceding paragraphs, we have discussed a long list types of lymphoma. of agents with potential utility in PTCL: novel agents that are under study prior to registration and previously FDA- Disclosure of Potential Conflicts of Interest approved agents in which PTCL would represent an expanded indication. These agents include small mole- No potential conflicts of interest were disclosed. cules, monoclonal antibodies, immunomodulators, and Received 04/26/2010; revised 08/05/2010; accepted 09/06/2010; conjugates, and represent a pipeline that is one of the most published online 12/07/2010.

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