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Novel Therapeutic Strategies for Cutaneous T-Cell Lymphoma in Advanced Stages

Seminars in Hematology, 1, 51, pages 35 - 41

The term cutaneous T-cell lymphoma (CTCL), introduced in 1975, was used to describe a spectrum of skin-based malignant tumors of T-cell origin. Immunological studies identified the complex interaction of cytokines released from infiltrating accessory or malignant cells and how such cytokines aid in the maintenance and proliferation of malignant cells. Though the etiology remains unknown, an association with rare retrovirus in some cases has been described. The mainstay of therapy has been to control the cutaneous presentation with topical therapies in patients with early limited-stage disease. However, a significant number of patients develop refractory disease to skin-directed therapies with or without clinical progression to advanced stages requiring systemic therapy. Over the last two decades a wide number of novel agents such as monoclonal antibodies, small molecule inhibitors, and chemotherapy agents have been developed and are used in patients with advanced disease or those who have exhausted topical treatment options and/or radiation. In this contribution we review the results of clinical studies evaluating emerging therapeutic strategies for patients with CTCL that had developed from ongoing translational research programs focused on understanding the biology of different subtypes of CTCL and identifying disease-specific biomarkers suitable for targeting.

Cutaneous T-cell lymphoma (CTCL) is a heterogeneous group of non-Hodgkin lymphoma (NHL) subtypes characterized by the tropism of CD4 positive lymphocytes to the skin. A significant amount of work had been focused in the characterization of each subtype of CTCL at the pathological and clinical levels in an attempt to guide physicians in the management of this group of malignancies. 1 CTCL includes lymphoid malignancies involving primarily the skin and is a completely separate entity (for clinical and therapeutic purposes) from systemic lymphoma exhibiting secondary skin involvement.

The European Organization for Research and Treatment of Cancer (EORTC) recognized several forms of CTCL with distinct clinical behavior and prognosis (5-year survival rates; ranging between 16% and 100% depending on specific subtypes). The most common types of CTCL include mycosis fungoides (MF) and its more aggressive clinical forms Sezary syndrome (SS) and transformed MF. Some of the challenges observed by physicians managing CTCL patients are the long-term survival of indolent CTCL patients, stressing the need for balancing the risk/benefit ratio for each therapeutic intervention; the low incidence of more aggressive forms, limiting the establishment of robust evidence-based guidelines; the diverse clinical scenarios observed within specific subtypes of CTCL, affecting treatment selection; and the physiological age, pre-existing comorbid conditions or degree of skin involvement, predisposing patients to treatment-related toxicities.

A significant number of CTCL patients (especially those with early-stage and non-aggressive subtypes) have an excellent 5-year survival rate (65%) and in some patients disease can be controlled with topical agents. 2 On the other hand, for patients with advanced-stage MF, SS, transformed MF or other aggressive histologies, disease control with topical or oral biological/chemotherapy agents is suboptimal. For CTCL patients that had become resistant to retinoic acid, systemic chemotherapy offers low overall response rates (ORRs) and/or short duration of response, stressing the need for the development of novel targeted agents. In addition, assessing the response to a given therapy continues to be a challenge and requires the development and implementation of standardized disease response criteria. To this end, the International Society for Cutaneous Lymphomas, the United States Cutaneous Lymphoma Consortium, and the Cutaneous Lymphoma Task Force of the EORTC developed specific guidelines to score the disease burden, to define clinical response, to facilitate the conduction of clinical trials, and to interpret clinical outcomes. 3

In general, novel therapeutic agents currently developed for CTCL patients can be divided into three categories: (1) monoclonal antibodies (mAbs) or antibody-drug conjugates (ADCs), (2) small-molecule inhibitors, and (3) chemotherapy agents.

Monoclonal Antibodies In Ctcl

mAbs and ADCs have become an important therapeutic strategy for cancer patients, including CTCL patients. The identification of cell surface antigen/receptors restricted to cancer cells has served as the basis for the generation of mAbs and ADCs. Over the last 4 decades the generation of mAbs improved significantly as a result of better targeted antigen selection and engineering technologies that allowed the production of chimeric and/or humanized antibodies with less immunogenicity and longer half-lives. Multiple mAbs and to a lesser degree ADCs have significant anti-tumor activity with a favorable toxicity profile. 4 Several mAbs and ADC had been studied in CTCL patients ( Table 1 ).

Table 1 Monoclonal Antibodies in Cutaneous T-Cell Lymphoma

Monoclonal Antibody Immunoconjugate Mechanism of Action Phase of Clinical Trial Comments
LMB-2 Recombinant immunotoxin Anti-CD25 Phase I/II Minimal activity with ORR 10%
Alemtuzumab humanized mAb Anti-CD52 Phase II Increased risk of opportunistic infections
Brentuximab-vedotin Tubulin inhibitor Anti-CD30 Phase II/III Ongoing phase III comparing B-vedotin to investigators choice
Mogamulizumab Humanized mAb Anti-CCR4 Phase II/III Ongoing Phase III study with vorinostat
Zonalimumab Human mAb Anti-CD4 Phase II Clinical development on hold
Siplizumab Humanized mAb Anti-CD2 Phase I/II Further development halted due to risk of EBV-related LPD

Abbreviations: ORR, overall response rate; mAb, monoclonal antibody; Epstein-Barr virus–related B-cell lymphoproliferative disorder, EBV-LPD.

Denileukin Diftitox

A potent immunotoxin, denileukin diftitox, delays disease progression in CTCL. Although not a mAb, denileukin diftitox, an interleukin-2 (IL-2) diphtheria exotoxin recombinant fusion protein, is commonly grouped under this category. Denileukin diftitox was granted accelerated approval by the US Food and Drug Administration (FDA) in February 1999 for the treatment of CD25(+) CTCL patients. Upon binding to the IL-2 receptor (CD25), denileukin diftitox is internalized via receptor-mediated endocytosis and the diphtheria toxin component ADP-ribosylates elongation factor 2 is released into the cytosol, inhibiting protein synthesis and inducing apoptotic cell death. 5 The IL-2 receptor is expressed in 50% of CTCL patients. 6 It is composed of three non-covalently associated subunits: α (CD25), β (CD122), κ, and γ (CD132), and there are four isoforms in which they exist: low-affinity (CD25), intermediate-affinity (CD122/CD132), high-affinity (CD25/CD122/CD132), and pseudo high-affinity (CD25/CD122) isoforms. Denileukin diftitox binds more efficiently to the high- and intermediate-affinity receptors.7 and 8 Three clinical studies supported the accelerated FDA approval of denileukin diftitox in CTCL patients. LeMaistre et al conducted a phase I/II clinical trial seeking to define the maximum tolerated dose (MTD) of denileukin diftitox in patients with relapsed/refractory CD25(+) or CD122(+) lymphoid malignancies. The study included patients with Hodgkin lymphoma (HL, N = 21), NHL (N = 17), and CTCL (N = 35). Clinical activity was observed in 37% of CTCL patients (five complete responses [CRs] and eight partial responses [PRs]). 9 Subsequently, Olsen et al reported the results of the first randomized clinical trial evaluating two denileukin diftitox dose-schedules in CTCL patients. A total of 71 CD25(+) CTCL patients were randomized to receive denileukin diftitox at 9 μg/kg/dose or 18 μg/kg/dose on days 1–5 every 21 days. Treatment with denileukin diftitox was well tolerated at the two doses tested and the ORR was higher in patients receiving higher doses: 36% versus 23%. 10 Finally Prince et al reported the results of a phase III randomized double blinded, placebo control study evaluating the efficacy and safety of denileukin diftitox in CD25(+) CTCL patients (N=144).(11) Patients were randomized to placebo control or denileukin diftitox at 9 μg/kg/dose or 18 μg/kg/dose on days 1-5 every 21 days for up to 8 cycles. Treatment with denileukin diftitox at either doses resulted in higher anti-tumor activity than placebo. The ORR was 49% (27/55) at 18 μg/kg/dose, 38% (17/45) at 9 μg/kg/dose, and 16% (7/44) for the placebo-control arms respectively. 11 In early denileukin diftitox clinical studies, a minimal surface expression of CD25 (20% of malignant cells by immunohistochemistry [IHC]) was required for patient eligibility. However, anti-tumor activity has been observed in patients with less CD25 antigen density expression (ORR 31% for CD25[-] CTCL patients). 12 In recent years, there has been a shortage in the availability of denileukin diftitox in the United States, stressing the need to develop alternative therapeutic strategies.

LMB-2 (Anti-Tac(Fv)-PE38) is a recombinant immunotoxin composed of the variable region (Fv portion) of an anti-CD25 mAb linked to the Pseudomonas exotoxin A (PE38) and was designed to target CD25(+) cells. Unlike denileukin diftitox, LMB-2 is able to bind and internalize without requiring the presence of two other IL-2 receptor subtypes (CD122 or CD132). 13 LMB-2 was initially evaluated in a phase I clinical trial seeking to define its MTD in patients with hematologic malignancies. One patient with CTCL exhibited a PR. Subsequently, the National Cancer Institute (NCI) conducted a phase II clinical trial in stage IB–IV CTCL that had disease progression within 2 years on systemic or topical therapy (N-10). LMB-2 was administered at 18 μg/kg/dose on days 1, 3, and 5 every 21 days. While LMB-2 was well tolerated, activity was minimal at best with only one patient achieving a PR (ORR = 10%). 13

Alemtuzumab (Campath-1H), a humanized anti-CD52 mAb, was the first mAb approved by the FDA for the treatment for B-cell chronic lymphocytic leukemia (B-CLL). It has been used in patients with refractory and advanced-stage (IIB–IV) MF and SS. Several studies have been published demonstrating the clinical activity of alemtuzumab in CTCL patients.14, 15, and 16 Lundin et al reported the results of a phase II clinical trial evaluating alemtuzumab as a single agent in 22 CTCL patients with advanced MF/SS. Clinical activity was observed in 55% of the patients with seven patients achieving a PR and five a CR. 14 Similarly, Bernengo et al reported the results of a clinical study of 19 CTCL patients treated with alemtuzumab. In this small cohort of patients, alemtuzumab therapy resulted in an ORR of 84% with 47% of the patients achieving a CR.15 In addition, the median duration of response/median time to treatment failure (DR/TTF) was 12 months in these clinical studies.14, 15, and 16 On the other hand, significant and serious opportunistic infections (ie, cytomegalovirus infection, Mycobacterium pneumonia, disseminated Herpes simplex infection, etc) were observed in CTCL patients treated with alemtuzumab, impairing the wide utilization of this mAb in clinical practice.14, 15, and 16 Alternative dose-route of administration schedules and/or infectious disease monitoring with preemptive implementation of aggressive anti-viral/anti-bacterial prophylaxis or treatment had reduced the risk of opportunistic infections in patients receiving alemtuzumab.

Brentuximab vedotin (SGN-35) is an ADC composed of an anti-CD30 mAb linked to the tubulin polymerization inhibitor, monomethyl auristatin E (MMAE). Clinical activity had been observed in CD30(+) lymphoma patients (including some patients with CD30[+] CTCL) treated with brentuximab vedotin, and is currently approved for the treatment of relapsed/refractory HL, anaplastic large cell T-cell lymphoma (ALCL), or CD30(+) MF/SS/transformed mycosis fungoides (TMF). CD30 expression in MF and SS is variable and correlates with high-grade large cell transformation (TMF).17 and 18 Moreover, it appears that the degree of CD30 in MF/SS or TMF correlate with clinical outcome. 19 Apart from MF and its variants (ie, SS or TMF), primary cutaneous CD30(+) lymphoproliferative disorders (PCLD) account for approximately 25% of CTCL patients. 20 Brentuximab vedotin is being formally studied in CTCL patients. Two clinical studies evaluated the efficacy and safety of brentuximab vedotin in CTCL patients and investigators from both studies had presented interim results demonstrating significant anti-tumor activity. In the first study, 17 patients with CD30(+) CTCL (including lymphomatous papulosis [LP], primary cutaneous ALCL) demonstrated an objective response in 65% of the treated patients and seven patients achieved a CR. The second exploratory study (NCT01396070) was designed to evaluate the clinical response to brentuximab vedotin as a single agent in MF and SS where tumor cells express variable levels of CD30. Interim data reported last year demonstrated that brentuximab vedotin was active in CTCL with 68% of the patients exhibiting a PR. Moreover, clinical activity did not correlate with CD30 expression levels. 21 A randomized, open-label, phase III clinical trial (NCT01578499, ALCANZA study) is currently enrolling participants to compare brentuximab vedotin against investigator's choice (methotrexate or bexarotene) in patients with relapsed CD30(+) CTCL, including primary cutaneous anaplastic large cell lymphoma (pcALCL) or MF. The results of this study will further define the role of brentuximab vedotin in the management of CTCL patients.

Mogamulizumab (KW-0761) is a defucosylated, humanized anti-CCR4 mAb capable of inducing antibody-dependent cellular cytotoxicity (ADCC). 22 CCR4 is uniformly overexpressed at all disease stages and plays an important role in the epidermotropism observed in CD4(+) malignant cells of CTCL patients. 23 Mogamulizumab is currently been investigated in CTCL patients but has been approved for clinical use in Japan for patients with relapsed/refractory CCR4(+) adult T-cell leukemia-lymphoma (ATL). A phase I/II study (NCT00888927) evaluated the MTD of mogamulizumab in patients with relapsed/refractory peripheral T-cell lymphoma (PTCL) and CTCL. 24 Clinical activity was observed in 16 patients (13 PRs and three CRs) for an ORR of 42%. 24 Subsequently, a follow-up phase II clinical study (NCT01192984) conducted in Japan evaluated the anti-tumor activity of mogamulizumab (administered at 1 mg/kg/dose weekly x 8) in patients with relapsed CCR4(+) PTCL and CTCL. PRs were seen in 38% of the CTCL patients (3/8). 24 An ongoing US phase III clinical study (NCT01728805) is comparing mogamulizumab (1 mg/kg/dose weekly x 4 and then one dose every other week) with single-agent vorinostat in relapsed/refractory CTCL patients.

A-dmDT390-bisFv (UCHT1) is a recombinant diphtheria immunotoxin, composed of two single-chain Fv fragments of the anti-CD3 mAb (UCHT1), connected to each other by a disulfide bond, and fused to the first 390 amino acid residues of the diphtheria toxin. The most common CTCL variants are CD3(+) and therefore suitable to targeted therapy with this immunotoxin. 25 In preclinical models, A-dmDT390-bisFv (UCHT1) kills CD3(+) T-lymphoma cells and transiently depletes normal T cells in a small cohort of CTCL patients. 26 An ongoing phase I/II clinical study (NCT00611208) is evaluating UCHT1 at several dose-escalation/dose schedule cohorts and is open to enrollment for relapsed/refractory PTCL and stage IB–IV CTCL patients. Preliminary results on the first 12 patients suggest that A-dmDT390-bisFv (UCHT1) is active in CTCL patients (two CRs and four CRs for an ORR of 60%). 27

Zanolimumab (HuMax-CD4) is a high-affinity human mAb against CD4. Zanolimumab has several mechanisms of action. It is able to inhibit T cells through Fc-dependent CD4 receptor down-modulation and alteration of T-cell receptor signal transduction. In addition, zanolimumab can induce ADCC. 28 Two open-label, single-group phase II trials evaluated zanolimumab in refractory CTCL patients (study Hx-CD4-007; NCT00071071 and study Hx-CD4-008; NCT00071084, N=38). Refractory CTCL patients were treated with zanolimumab at either low dose (280 mg) or high dose (560 mg or 980 mg) weekly x 17 infusions. An ORR of 56% was achieved in the high-dose groups. 29 As expected, opportunistic infections were observed in treated patients. Currently the clinical development of zanolimumab is on hold as this molecule was acquired by a new pharmaceutical company.

Siplizumab (MEDI-507) is a humanized anti-CD2 mAb that can induce ADCC and is active in T-cell lymphoma mouse models. 30 O’Mahony et al reported the preliminary results of the first phase I/II clinical trials in patients with T-cell malignancies including CTCL (N = 29). 31 Treatment with siplizumab resulted in significant anti-tumor activity, with two and nine patients achieving a CR and PR, respectively. While the results were promising, the clinical development of siplizumab was halted after four patients in this clinical study developed Epstein-Barr virus–related B-cell lymphoproliferative disorder (EBV-LPD). 31

Small Molecule Inhibitors


The discovery and functional characterization of the ubiquitin-proteasome pathway as the major system for extra-lysosomal protein degradation has delineated its importance for regulating the selective proteolysis of key regulatory proteins. 32 A significant number of proteins that regulate cell cycle, apoptosis, cell proliferation, and differentiation are now known to undergo processing and functional limitation by entering the ubiquitin-proteasome pathway. The degradation of intracellular proteins by the proteasome is a multi-step process in which proteins must be “flagged” for recognition and subsequently destroyed by the 26S proteasome. Targeting of proteins for degradation occurs by a process known as ubiquitination and consists of the covalent attachment of multiple monomers of the polypeptide, ubiquitin, to a given protein. The ubiquitination of proteins is controlled by three classes of enzymes: (1) ubiquitin-activating enzymes (E1), (2) ubiquitin-conjugating enzymes (E2), and (3) ubiquitin-protein ligases (E3).33 and 34 Cytotoxic effects of proteasome inhibition have long been appreciated, but only more recently has this phenomenon been taken advantage of clinically. In addition to a central role in degrading misfolded or unfolded proteins, the proteasome has also been implicated in DNA repair and cell cycle control.35, 36, and 37 Bortezomib was the first proteasome inhibitor approved by the FDA for the treatment of multiple myeloma and mantle cell lymphoma (MCL). Clinically, anti-tumor activity has also been observed in other lymphoma subtypes (ie, follicular lymphoma or activated B-cell diffuse large B-cell lymphoma). Zinzani et al reported the results of a phase II clinical trial evaluating bortezomib administered at the standard dose-schedule (1.3 mg/m2 on days 1, 4, 8, and 11 every 21 days) in patients with CTCL (N = 15). For patients receiving at least six cycles of therapy (N = 10), bortezomib therapy led to clinical response in 70% of cases (one CR and six PRs). In responding patients, the duration of response ranged between 7 and 14 months. Toxicity was similar to what has been observed in other bortezomib clinical trials (ie, peripheral neuropathy or myelosupression). 38 Ongoing preclinical and clinical studies are seeking to optimize its anti-tumor activity by developing novel combination strategies in CTCL.

Immunomodulatory Drugs (IMiDs)


Lenalidomide has been approved for the management of multiple myeloma patients and myelodysplastic syndromes. In addition, it is emerging as an attractive therapeutic strategy in patients with B-cell lymphoproliferative disorders and was recently approved for the management of relapsed/refractory MCL. While the mechanisms of action have not been well defined, several effects have been observed in preclinical and/or clinical studies such as direct cell cycle arrest and to a lesser degree apoptosis in cancer cells, decrease in angiogenesis, and a unique capacity to enhance the innate immune system (ie, activation of natural killer [NK] cells and production of IL-2), enhance the anti-tumor activity of mAbs. Lenalidomide was evaluated in patients with relapsed/refractory CTCL (N = 15). Patients with relapsed/refractory MF/SS received oral lenalidomide at 25 mg daily for 21 days every 28 days. Six patients had minimal response. On the other hand, lenalidomide was well tolerable and no significant side effects were observed. Currently, lenalidomide is been studied in the maintenance setting following induction therapy with more active chemotherapy agents (ie, gemcitabine or liposomal doxorubicin) in CTCL patients.

Histone Deacetylase Inhibitors (HDACi)

Histone deacetylases (HDACs) are a family of enzymes that target both histone and non-histone substrates in chromatin and other cellular proteins. These substrates include proteins that are involved in cell cycle, cell death, cell invasion, and angiogenesis. 39 A total of 18 HDAC enzymes had been described thus far and are divided into three families based on their homology to yeast HDAC proteins. As aberrant acetylation is implicated in tumorgenesis, modulating the epigenetic process via deacetylation holds promise in cancer therapeutics. Currently, romidepsin and vorinostat are the two HDACi that have received FDA approval for the treatment of CTCL. These agents inhibit various classes of HDAC proteins.

Romidepsin in CTCL. In preclinical studies, romidepsin induces apoptosis in xenograft models. 40 Romidepsin inhibits class I HDAC proteins with greater potency than class II. Romidepsin administration resulted in induction of p21 expression, IL-2 receptor expression, and apoptosis in cancer cells. 41 Results from two large international phase II studies support the role of romidepsin in CTCL. Piekarz et al administered romidepsin on a three weekly schedule of a 28-day cycle in 71 CTCL patients. The median number of prior regimens was four. The ORR was 34% with 6% of patients attaining a CR. Median time to clinical response was 8 weeks and the median DR was 15 months. 42 Similar results were presented by Whittaker et al. A total of 96 CTCL patients received romidepsin as a single agent and clinical response was observed in 34%. It is important to note that in these studies, different methods were used to assess clinical response. Nevertheless, similar results were noted in both of these studies. 43

The most common adverse events (AEs) observed included fatigue, nausea, vomiting, and thrombocytopenia. Few studies have shown that HDACi may cause QTc prolongation in 9% of patients treated. A case of sudden cardiac death was reported in a patient with multiple cardiac risk factors. Romidepsin use was also associated with T-wave flattening and ST depressions with no changes in troponin level or left ventricular ejection fraction.44 and 45 It is important to also recognize that concomitant anti-emetics may be contributory. Therefore it is crucial that serial electrocardiogram (EKG) evaluation and electrolyte replacement be part of the treatment schedule protocols.

Vorinostat in CTCL. During its early studies, vorinostat was found to be effective in CTCL. Vorinostat is an organic hydroxamic acid. Vorinostat inhibits both class I and II HDAC proteins.46 and 47 In 2006, vorinostat received FDA approval for its use in CTCL based on a single-arm, multicenter, phase IIB trial in relapsed refractory CTCL. A total of 74 patients with stage IB–IVA disease were treated with vorinostat 400 mg daily with ORRs of 29.7% in all patients and 29.5% in MF/SS patients with stage IIB or higher disease. The median time to response in this study was 2 months. The estimated DR was 6 months. 48 In a second phase II study of vorinostat in 33 patients, the ORR was reported at 24% with a median time to response of 3 months and median DR of 3.7 months. The most common side effects included diarrhea, nausea, and fatigue.49 and 50 In the post hoc subset analysis, six of the 74 patients enrolled in the phase II study received vorinostat for more than 2 years. Five of the 6six patients achieved a response and one patient had stable disease. Therefore, in responding patients, this agent may be continued until disease progression. Resistance to vorinostat may occur due to inhibition of apoptosis induction and increased anti-oxidant levels. 51

Other HDACi in CTCL: Panobinostat and Belinostat

Panobinostat is another novel HDACi that has shown clinical efficacy. This agent belongs to the cinnamic hydroxamic class of compounds. 52 The anti-tumor activity of panobinostat administered orally at dose of 20 mg three times per week was recently reported. CTCL patients were grouped into bexarotene-naïve and bexarotene-treated arms. Of the 62 patients in the bexarotene-treated group, 17.7% achieved a response, whereas in the bexarotene-naïve group of 35 patients, 12.5% achieved a response. Cytopenias, particularly thrombocytopenia and neutropenia, were the most common grade 3 and 4 toxicities and observed in >5% of patients. 53 Belinostat is another HDACi that is being evaluated in a phase II clinical trial in patients with relapsed refractory CTCL. There are no studies comparing the efficacy of across HDACi or with other standard and routinely used approaches (photopheresis, interferon [IFN], etc) in CTCL.

Novel Chemotherapy Agents

Multiple chemotherapy agents have shown activity in patients with CTCL. Chemotherapy drugs with known activity against CTCL include liposomal doxorubicin, gemcitabine, nitrogen mustard (topical), and methotrexate. Previous studies evaluated the efficacy and safety of multiple-drug regimens versus single-agent treatments. In general, the use of poly-chemotherapy regimens in CTCL patients results in more toxicity and no better clinical activity/outcomes (progression-free survival or overall survival). Novel chemotherapy agents with unique mechanisms of action and/or pharmacological properties are been tested in clinical studies for CTCL patients.


Pralatrexate is a novel antifolate designed to have a higher affinity for the reduced folate carrier. As a result of this pharmacological property, pralatrexate accumulates at higher intracellular concentration in cancer cells and is more active than methotrexate in preclinical studies.54 and 55 Pralatrexate was approved by the FDA for the treatment of relapsed/refractory T-cell lymphoma on the basis of the pivotal multicenter international registration study. In this particular trial activity was seen not only in systemic T-cell lymphoma but also in patients with refractory TMF (58%). 56 As a result, pralatrexate was formally evaluated in patients with CTCL. Horwitz et al evaluated the anti-tumor activity of pralatrexate (administered in various dose-schedules) in 31 patients with relapsed/refractory MF, SS, and primary cutaneous ALCL. 57 Using modern response criteria (ie, Modified Severity Weighted Assessment Tool [SWAT] score), clinical activity was observed in 43% of patients. Toxicities were mild and consisted or grade 1 or 2 fatigue, nausea, mucositis, pyrexia, anemia, and epistaxis. 57 Ongoing studies are evaluating pralatrexate in combination with other biological agents (ie, bexarotene) in CTCL patients.


For advanced-stage or relapsed/refractory CTCL patients, several agents with proven clinical activity are emerging from previous or ongoing clinical trials (ie, HDAC inhibitors, brentuximab-vedotin, etc). Despite initial responses, the majority of these agents fail to produce long-lasting remissions or limit their clinical use due to the occurrence of adverse events. Ongoing molecular studies aimed to understand the biology of each subtype of CTCL will provide insightful information that may result in the optimization of current available agents or the discovery of new pathways suitable for targeting therapy.


  • 1 R. Willemze, E.S. Jaffe, G. Burg, et al. WHO-EORTC classification for cutaneous lymphomas. Blood. 2005;105:3768-3785 Crossref.
  • 2 Y.H. Kim, H.L. Liu, S. Mraz-G, et al. Long-term outcome of 525 patients with mycosis fungoides and Sezary syndrome: clinical prognostic factors and risk for disease progression. Arch Dermatol. 2003;139:857-866
  • 3 E.A. Olsen, S. Whittaker, Y.H. Kim, et al. Clinical end points and response criteria in mycosis fungoides and Sezary syndrome: a consensus statement of the International Society for Cutaneous Lymphomas, the United States Cutaneous Lymphoma Consortium, and the Cutaneous Lymphoma Task Force of the European Organisation for Research and Treatment of Cancer. J Clin Oncol. 2011;29:2598-2607 Crossref.
  • 4 R. Niebecker, C. Kloft. Safety of therapeutic monoclonal antibodies. Curr Drug Saf. 2010;5:275-286 Crossref.
  • 5 M. Duvic, R. Talpur. Optimizing denileukin diftitox (Ontak) therapy. Future Oncol. 2008;4:457-469 Crossref.
  • 6 J. Nichols, F. Foss, T.M. Kuzel, et al. Interleukin-2 fusion protein: an investigational therapy for interleukin-2 receptor expressing malignancies. Eur J Cancer. 1997;33(Suppl 1):S34-S36 Crossref.
  • 7 G.G. Re, C. Waters. Poisson L, et al. Interleukin 2 (IL-2) receptor expression and sensitivity to diphteria fusion toxin DAB389IL-2 in cultured hematopoietic cells. Cancer Res. 1996;56:2590-2595
  • 8 S. McCann, O.E. Akilov, L. Geskin. Adverse effects of denileukin diftitox and their management in patients with cutaneous T-cell lymphoma. Clin J Oncol Nurs. 2012;16:E164-E172 Crossref.
  • 9 C.F. LeMaistre, M.N. Saleh, T.M. Kuzel, et al. Phase I trial of a ligand fusion-protein (DAB389IL-2) in lymphomas expressing the receptor for interleukin-2. Blood. 1998;91:399-405
  • 10 E. Olsen, M. Duvic, A. Frankel, et al. Pivotal phase III trial of two dose levels of denileukin diftitox for the treatment of cutaneous T-cell lymphoma. J Clin Oncol. 2001;19:376-388
  • 11 H.M. Prince, M. Duvic, A. Martin, et al. Phase III placebo-controlled trial of denileukin diftitox for patients with cutaneous T-cell lymphoma. J Clin Oncol. 2010;28:1870-1877 Crossref.
  • 12 F. Foss, M. Duvic, E.A. Olsen. Predictors of complete responses with denileukin diftitox in cutaneous T-cell lymphoma. Am J Hematol. 2011;86:627-630 Crossref.
  • 13 R.J. Kreitman, P. Bailon, V.K. Chaudhary, et al. Recombinant immunotoxins containing anti-Tac(Fv) and derivatives of Pseudomonas exotoxin produce complete regression in mice of an interleukin-2 receptor-expressing human carcinoma. Blood. 1994;83:426-434
  • 14 J. Lundin, H. Hagberg, R. Repp, et al. Phase 2 study of alemtuzumab (anti-CD52 monoclonal antibody) in patients with advanced mycosis fungoides/Sezary syndrome. Blood. 2003;101:4267-4272 Crossref.
  • 15 M.G. Bernengo, P. Quaglino, A. Comessatti, et al. Low-dose intermittent alemtuzumab in the treatment of Sezary syndrome: clinical and immunologic findings in 14 patients. Haematologica. 2007;92:784-794 Crossref.
  • 16 O. Gautschi, N. Blumenthal, M. Streit, et al. Successful treatment of chemotherapy-refractory Sezary syndrome with alemtuzumab (Campath-1H). Eur J Haematol. 2004;72:61-63 Crossref.
  • 17 H. Wu, G.H. Telang, S.R. Lessin, et al. Mycosis fungoides with CD30-positive cells in the epidermis. Am J Dermatopathol. 2000;22:212-216 Crossref.
  • 18 A. Nikoo. The expression of CXCR3 and CD30 in mycosis fungoides. Arch Iran Med. 2012;15:146-150
  • 19 J.T. Edinger, B.Z. Clark, B.E. Pucevich, et al. CD30 expression and proliferative fraction in nontransformed mycosis fungoides. Am J Surg Pathol. 2009;33:1860-1868 Crossref.
  • 20 M. Paulli, E. Berti. Cutaneous T-cell lymphomas (including rare subtypes). Current concepts. II. Haematologica. 2004;89:1372-1388
  • 21 M. Krathen, U. Sundram, S. Bashey, et al. Brentuximab vedotin demonstrates significant clinical activity in relapsed or refractory mycosis fungoides with variable CD30 expression. Blood Am Soc Hematol Annual Meeting Procc. 2012;120:797
  • 22 J.M. Subramaniam, G. Whiteside, K. McKeage, et al. Mogamulizumab: first global approval. Drugs. 2012;72:1293-1298 Crossref.
  • 23 D.K. Chang, J. Sui, S. Geng, et al. Humanization of an anti-CCR4 antibody that kills cutaneous T-cell lymphoma cells and abrogates suppression by T-regulatory cells. Mol Cancer Ther. 2012;11:2451-2461 Crossref.
  • 24 K. Tobinai, T. Takahashi, S. Akinaga. Targeting chemokine receptor CCR4 in adult T-cell leukemia-lymphoma and other T-cell lymphomas. Curr Hematol Malig Rep. 2012;7:235-240 Crossref.
  • 25 S.M. Campbell, S.B. Peters, M.J. Zirwas, et al. Immunophenotypic diagnosis of primary cutaneous lymphomas: a review for the practicing dermatologist. J Clin Aesthet Dermatol. 2010;3:21-25
  • 26 J.H. Woo, Y.J. Lee, D.M. Neville, et al. Pharmacology of anti-CD3 diphtheria immunotoxin in CD3 positive T-cell lymphoma trials. Methods Mol Biol. 2010;651:157-175 Crossref.
  • 27 A. Frankel. Anti-CD3 immunotoxin to induce remissions in cutaneous T-cell lymphoma patients. J Clin Oncol ASCO Proc. 2012; (abstract 2505)
  • 28 JM. Reichert. Antibody-based therapeutics to watch in 2011. MAbs. 2011;3:76-99 Crossref.
  • 29 Y.H. Kim, M. Duvic, E. Obitz, et al. Clinical efficacy of zanolimumab (HuMax-CD4): two phase 2 studies in refractory cutaneous T-cell lymphoma. Blood. 2007;109:4655-4662 Crossref.
  • 30 Z. Zhang, M. Zhang, J.V. Ravetch, et al. Effective therapy for a murine model of adult T-cell leukemia with the humanized anti-CD2 monoclonal antibody, MEDI-507. Blood. 2003;102:284-288 Crossref.
  • 31 D. O'Mahony, J.C. Morris, M. Stetler-Stevenson, et al. EBV-related lymphoproliferative disease complicating therapy with the anti-CD2 monoclonal antibody, siplizumab, in patients with T-cell malignancies. Clin Cancer Res. 2009;15:2514-2522 Crossref.
  • 32 M.H. Glickman, A. Ciechanover. The ubiquitin-proteasome proteolytic pathway: destruction for the sake of construction. Physiol Rev. 2002;82:373-428
  • 33 A. Hershko, H. Heller, S. Elias, et al. Components of ubiquitin-protein ligase system. Resolution, affinity purification, and role in protein breakdown. J Biol Chem. 1983;258:8206-8214
  • 34 M. Scheffner, U. Nuber, J.M. Huibregtse. Protein ubiquitination involving an E1-E2-E3 enzyme ubiquitin thioester cascade. Nature. 1995;373:81-83 Crossref.
  • 35 C. Schauber, L. Chen, P. Tongaonkar, et al. Rad23 links DNA repair to the ubiquitin/proteasome pathway. Nature. 1998;391:715-718
  • 36 M.H. Kubbutat, S.N. Jones, K.H. Vousden. Regulation of p53 stability by Mdm2. Nature. 1997;387:299-303 Crossref.
  • 37 M.V. Blagosklonny, G.S. Wu, S. Omura, et al. Proteasome-dependent regulation of p21WAF1/CIP1 expression. Biochem Biophys Res Commun. 1996;227:564-569 Crossref.
  • 38 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;25:4293-4297 Crossref.
  • 39 O. Witt, H.E. Deubzer, T. Milde, et al. HDAC family: what are the cancer relevant targets?. Cancer Lett. 2009;277:8-21 Crossref.
  • 40 H. Ueda, T. Manda, S. Matsumoto, et al. FR901228, a novel antitumor bicyclic depsipeptide produced by Chromobacterium violaceum No. 968. III. Antitumor activities on experimental tumors in mice. J Antibiot (Tokyo). 1994;47:315-323 Crossref.
  • 41 R.L. Piekarz, R.W. Robey, Z. Zhan, et al. T-cell lymphoma as a model for the use of histone deacetylase inhibitors in cancer therapy: impact of depsipeptide on molecular markers, therapeutic targets, and mechanisms of resistance. Blood. 2004;103:4636-4643 Crossref.
  • 42 R.L. Piekarz, R. Frye, M. Turner, et al. Phase II multi-institutional trial of the histone deacetylase inhibitor romidepsin as monotherapy for patients with cutaneous T-cell lymphoma. J Clin Oncol. 2009;27:5410-5417 Crossref.
  • 43 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;28:4485-4491 Crossref.
  • 44 E.M. Bertino, G.A. Otterson. Romidepsin: a novel histone deacetylase inhibitor for cancer. Expert Opin Investig Drugs. 2011;20:1151-1158 Crossref.
  • 45 R.L. Piekarz, A.R. Frye, J.J. Wright, et al. Cardiac studies in patients treated with depsipeptide, FK228, in a phase II trial for T-cell lymphoma. Clin Cancer Res. 2006;12:3762-3773 Crossref.
  • 46 O. Moradei, C.R. Maroun, I. Paquin, et al. Histone deacetylase inhibitors: latest developments, trends and prospects. Curr Med Chem Anticancer Agents. 2005;5:529-560 Crossref.
  • 47 M. Duvic, J. Vu. Vorinostat: a new oral histone deacetylase inhibitor approved for cutaneous T-cell lymphoma. Expert Opin Investig Drugs. 2007;16:1111-1120 Crossref.
  • 48 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;25:3109-3115 Crossref.
  • 49 M. Duvic, R. Talpur, X. Ni, et al. Phase 2 trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) for refractory cutaneous T-cell lymphoma (CTCL). Blood. 2007;109:31-39 Crossref.
  • 50 B.S. Mann, J.R. Johnson, K. He, et al. Vorinostat for treatment of cutaneous manifestations of advanced primary cutaneous T-cell lymphoma. Clin Cancer Res. 2007;13:2318-2322 Crossref.
  • 51 M. Duvic, E.A. Olsen, D. Breneman, et al. Evaluation of the long-term tolerability and clinical benefit of vorinostat in patients with advanced cutaneous T-cell lymphoma. Clin Lymphoma Myeloma. 2009;9:412-416 Crossref.
  • 52 P. George, P. Bali, S. Annavarapu, et al. Combination of the histone deacetylase inhibitor LBH589 and the hsp90 inhibitor 17-AAG is highly active against human CML-BC cells and AML cells with activating mutation of FLT-3. Blood. 2005;105:1768-1776 Crossref.
  • 53 M. Duvic, R. Dummer, J.C. Becker, et al. Panobinostat activity in both bexarotene-exposed and -naive patients with refractory cutaneous T-cell lymphoma: results of a phase II trial. Eur J Cancer. 2013;49:386-394 Crossref.
  • 54 F.M. Sirotnak, J.I. DeGraw, D.M. Moccio, et al. New folate analogs of the 10-deaza-aminopterin series. Basis for structural design and biochemical and pharmacologic properties. Cancer Chemother Pharmacol. 1984;12:18-25
  • 55 E.S. Wang, O. O'Connor, Y. She, et al. Activity of a novel anti-folate (PDX, 10-propargyl 10-deazaaminopterin) against human lymphoma is superior to methotrexate and correlates with tumor RFC-1 gene expression. Leuk Lymphoma. 2003;44:1027-1035 Crossref.
  • 56 F. Foss, S.M. Horwitz, B. Coiffier, et al. Pralatrexate is an effective treatment for relapsed or refractory transformed mycosis fungoides: a subgroup efficacy analysis from the PROPEL study. Clin Lymphoma Myeloma Leuk. 2012;12:238-243 Crossref.
  • 57 S. Horwitz, Y. Kim, F. Foss, et al. Identification of an active, well-tolerated dose of pralatrexate in patients with relapsed or refractory cutaneous T-cell lymphoma (CTCL): final results of a multicenter dose-finding study. Blood Am Soc Hematol Annual Meeting Proc. 2010;116:2800


a Department of Medical Oncology, Roswell Park Cancer Institute, Buffalo, NY

b Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY

c Division of Hematology/Oncology, Vanderbilt-Ingram Cancer Center, Nashville, TN

lowast Address correspondence to: Nishitha M. Reddy, MD, Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232

Conflicts of interest: none.