Refractory Cutaneous T-cell Lymphoma Research Articles

Final Results From a Multicenter, International, Pivotal Study of Romidepsin in Refractory Cutaneous T-Cell Lymphoma

The primary objective of this study was to confirm the efficacy of romidepsin in patients with treatment refractory cutaneous T-cell lymphoma (CTCL). This international, pivotal, single-arm, open-label, phase II study was conducted in patients with stage IB to IVA CTCL who had received one or more prior systemic therapies. Patients received romidepsin as an intravenous infusion at a dose of 14 mg/m(2) on days 1, 8, and 15 every 28 days. Response was determined by a composite assessment of total tumor burden including cutaneous disease, lymph node involvement, and blood (Sézary cells). Ninety-six patients were enrolled and received one or more doses of romidepsin. Most patients (71%) had advanced stage disease (≥ IIB). The response rate was 34% (primary end point), including six patients with complete response (CR). Twenty-six of 68 patients (38%) with advanced disease achieved a response, including five CRs. The median time to response was 2 months, and the median duration of response was 15 months. A clinically meaningful improvement in pruritus was observed in 28 (43%) of 65 patients, including patients who did not achieve an objective response. Median duration of reduction in pruritus was 6 months. Drug-related adverse events were generally mild and consisted mainly of GI disturbances and asthenic conditions. Nonspecific, reversible ECG changes were noted in some patients. Romidepsin has significant and sustainable single-agent activity (including improvement in pruritus) and an acceptable safety profile, making it an important therapeutic option for treatment refractory CTCL.

Vorinostat for the treatment of cutaneous T-cell lymphoma

Vorinostat (suberoylanilide hydroxamic acid) is the first US FDA-approved histone deacetylase inhibitor for the treatment of cutaneous manifestations in patients with cutaneous T-cell lymphomas (CTCLs). In two Phase II trials, vorinostat was safe and effective at an oral dose of 400 mg/day, with an overall response rate of 24–30% in refractory advanced CTCL patients, including large-cell transformed mycosis fungoides and Sezary syndrome. Most patients with CTCL also experience significant itching relief with vorinostat therapy. Moreover, a recent follow-up study reported long-term safety and clinical benefits of vorinostat in heavily pretreated patients with CTCL, regardless of previous treatment failures. The most frequent side effects of vorinostat include gastrointestinal symptoms, fatigue and thrombocytopenia. These side effects are dose-related and reversible upon cessation of therapy. Translational studies have shown that vorinostat has in vitro and in vivo anti-tumor activities against CTCL, includ...

Histone deacetylase inhibitors: clinical implications for hematological malignancies

Histone modifications have widely been implicated in cancer development and progression and are potentially reversible by drug treatments. The N-terminal tails of each histone extend outward through the DNA strand containing amino acid residues modified by posttranslational acetylation, methylation, and phosphorylation. These modifications change the secondary structure of the histone protein tails in relation to the DNA strands, increasing the distance between DNA and histones, and thus allowing accessibility of transcription factors to gene promoter regions. A large number of HDAC inhibitors have been synthesized in the last few years, most being effective in vitro, inducing cancer cells differentiation or cell death. The majority of the inhibitors are in clinical trials, unlike the suberoylanilide hydroxamic acid, a pan-HDACi, and Romidepsin (FK 228), a class I-selective HDACi, which are only approved in the second line treatment of refractory, persistent or relapsed cutaneous T-cell lymphoma, and active in approximately 150 clinical trials, in monotherapy or in association. Preclinical studies investigated the use of these drugs in clinical practice, as single agents and in combination with chemotherapy, hypomethylating agents, proteasome inhibitors, and MTOR inhibitors, showing a significant effect mostly in hematological malignancies. The aim of this review is to focus on the biological features of these drugs, analyzing the possible mechanism(s) of action and outline an overview on the current use in the clinical practice.

Low-Dose Bexarotene Alone or in Combination for the Treatment of Relapsed or Refractory Cutaneous T-Cell Lymphoma.

Abstract 4790 IntroductionSelective ligands of retinoid X receptor (i.e. bexarotene) are used in the treatment of early and advanced stages of cutaneous T-cell lymphoma (CTCL). The objective of this study is to report a Peruvian single-institution experience on 13 cases of relapsed or refractory CTCL who were treated with low-dose bexarotene alone or in combination with phototherapy or interferon alfa-2a. MethodsFrom 2002 to 2008, thirteen patients with relapsed or refractory CTCL were treated with bexarotene at low dose (75-300 mg/day) as monotherapy (BEX; 3 cases) or in combination with interferon alfa-2a (INF) at 3-9 million units subcutaneously three times a week (5 cases) or phototherapy (PT; 4 cases). Therapy was continuously administered until progression of disease or unacceptable toxicity. Eight patients with mycosis fungoides (MF), two patients with aggressive epidermotropic CD8+ cytotoxic lymphoma (AECL), two patients with Sezary Syndrome (SS) and one with smoldering adult T-cell leukemia/lymphoma (ATLL) were included in this study. ResultsMean age was 57 years (range 26 to 74 years). In average, patients were exposed to three prior lines of therapy (range 1 to 5). From the 8 cases of MF, 3 cases were treated with BEX monotherapy, achieving 1 complete response (CR), 1 partial response (PR) and 1 progressive disease (PD); 3 cases were treated with BEX and PT, obtaining 1 CR and 2 PR; and 2 cases were treated with BEX and IFN, both showing PD. From the 2 cases with AECL, 1 case received BEX/PT achieving a PR and 1 case received BEX/IFN showing PD. From the 2 cases with SS, both were treated with BEX/IFN achieving a PR. The case of ATLL achieved a PR with BEX/PT. The overall response for the entire group was 69.2% (9/13) with a mean duration of response of 15 months (range 2 to 67 months). From the therapy point of view, BEX alone achieved a 66% overall response rate (ORR), BEX/IFN showed a 40% ORR and BEX/PT showed a 100% ORR with a 20% CR. Most common adverse events were mild, seven patients experienced grade 1–2 hypercholesterolemia, and hypertriglyceridemia grade 1–2 was seen in seven patients and grade 3 in two cases. Four patients developed grade 1–2 hypothyroidism. ConclusionsLow-dose BEX alone or in combination with INF or PT is effective in the treatment of patients with relapsed or refractory CTCL and is associated with mild toxicity. Prospective studies, if possible, are needed to further investigate novel therapeutic approaches in these hard-to-treat patients. Disclosures:No relevant conflicts of interest to declare.

Pralatrexate Is Active in Cutaneous T-Cell Lymphoma (CTCL): Results of a Multicenter, Dose-Finding Trial.

Abstract 919 Background:Pralatrexate enters cancer cells via the reduced folate carrier-1 (RFC-1) and is efficiently polyglutamated by folylpolyglutamyl synthetase (FPGS), leading to high intracellular retention. In a Phase 1/2 study of patients with hematologic malignancies, pralatrexate demonstrated activity in aggressive T-cell lymphoma with a maximum tolerated dose (MTD) of 30 mg/m2 once weekly for 6 of 7 weeks. The generally indolent course of CTCL may be better treated at lower doses in a maintenance fashion if a lower incidence and severity of adverse events can be achieved while preserving activity. PDX-010 is an open-label, single-agent, multicenter, Phase 1 dose-reduction trial in patients with relapsed or refractory CTCL. The primary objective is to identify an optimal dose and schedule of pralatrexate for these patients. Methods:Eligibility included mycosis fungoides (MF), Sézary syndrome (SS), and primary cutaneous anaplastic large cell lymphoma (ALCL); with disease progression after at least 1 prior systemic therapy. The pralatrexate dose and schedule started at 30 mg/m2 by IV push on 3 of 4 weeks and subsequent cohorts received reduced doses (20, 15, 10 mg/m2) and/or schedules (3/4 or 2/3 weeks) of pralatrexate based on tolerability. All patients received supplementation with vitamin B12 1 mg intramuscularly every 8-10 weeks and folic acid 1 mg orally once daily. As we sought a well tolerated regimen the definition of DLTs to trigger dose reduction included toxicities such as grade ≥ 3 neutropenia, grade ≥ 2 thrombocytopenia, febrile neutropenia, grade ≥ 2 mucositis/stomatitis, and any toxicity leading to dose omission or reduction in cycle 1. If DLT occurred and a response was seen, the following cohort was opened at the next lower dose or next less frequent schedule. Response was evaluated by modified severity-weighted adjustment tool (SWAT) every 2 cycles for 6 months and then every 4 cycles. For patients with lymph node involvement, scans were completed at baseline and upon clinical response or end of treatment, whichever occurred first. Results:Thirty-one patients received pralatrexate, with 18 (58%) men and median age of 57 yrs (range, 30-81). Patients had received a median of 6 prior therapies (range, 1-25). Cohorts at the following doses/schedules were enrolled: 30 mg/m2 x 3/4 weeks (n=2), 20 mg/m2 x 3/4 weeks (n=3), 20 mg/m2 x 2/3 weeks (n=7), 15 mg/m2 x 3/4 weeks (n=6), 15 mg/m2 x 2/3 weeks (n=3), and 10 mg/m2 x 3/4 weeks (n=10). Patients received pralatrexate for a median of 72 days (range, 7-491+); 4 patients received >10 cycles of treatment. The most common treatment-related adverse events (all grades) were mucositis (18 patients [58%]), nausea (14 patients [45%]), fatigue (14 patients [45%]), pyrexia (7 patients [23%]), vomiting (6 patients [19%]), anemia (6 patients [19%]), and edema (5 patients [16%]). Grade 3-4 treatment-related toxicities in >1 patient each were mucositis (4 patients [13%]) and anemia (2 patients [6%]). Mucositis was dose limiting (≥ grade 2) in 8 patients (26%). A total of 11 responses were observed, including 2 complete responses and 9 partial responses. In the 18 patients who received pralatrexate at a dose intensity of 15 mg/m2 x 3/4 weeks or greater, the objective response rate was 56% (10/18 patients). This appeared to be the threshold dose for substantial activity in CTCL, below which the incidence of responses decreased in this dose de-escalation trial. Conclusion:Pralatrexate shows impressive activity in the treatment of relapsed CTCL. The optimal dose and schedule that provided activity with tolerability for CTCL was determined to be pralatrexate 15 mg/m2 weekly on 3 of 4 weeks. This cohort is being expanded to better assess efficacy and durability. Disclosures:Horwitz:Allos Therapeutics, Inc: Consultancy, Research Funding. Duvic:Allos Therapeutics, Inc.: Research Funding. Lechowicz:Allos Therapeutics, Inc.: Consultancy. Fruchtman:Allos Therapeutics, Inc.: Employment.

Final Results of a Phase II Trial of Belinostat (PXD101) in Patients with Recurrent or Refractory Peripheral or Cutaneous T-Cell Lymphoma.

Abstract 920 Background:Belinostat is a pan-HDAC inhibitor of the hydroxamate chemical class that is well-tolerated and has shown clinical activity. Methods:Open label, multicenter trial enrolling patients (pts) with peripheral T-cell lymphoma (PTCL) or cutaneous T-cell lymphoma (CTCL) who failed ≥ 1 prior systemic therapy. Pts received 1000 mg/m2 IV belinostat over 30 min on days 1 to 5 of a 3-wk cycle. Primary endpoint was objective response (OR) assessed by IWG criteria for PTCL and by SWAT (cutaneous lesions) and IWG criteria (non-cutaneous lesions) for CTCL. Pruritus in pts with CTCL was assessed using a 10-point scale; relief defined as reduction of pruritus score of ≥ 3 points in pts with baseline score ≥ 3. ECGs were monitored and reviewed centrally (pre-/ post-infusion ECGs on all treatment days in cycle 1, and pre-/ post-infusion ECGs on day 1 of subsequent cycles) to evaluate potential cardiac toxicity. Results:The study enrolled a total of 53 treated pts, including 20 and 29 evaluable pts with a diagnosis of PTCL and CTCL, respectively. The 20 pts with PTCL [10 PTCL-unspecified (PTCL-U), 3 anaplastic large cell lymphoma (ALCL), 3 angioimmunoblastic TCL (AITL), 3 NK/T-cell lymphoma, and 1 subcutaneous panniculitis-like TCL (SPTCL)] had received a median of 3 prior systemic therapies (range 1 – 10), and 40 % of them had stage IV disease. 5/20 (25%) PTCL pts responded with 2 CR (both in patients with PTCL-U) and 3 PR (PTCL-U, AITL, ALCL). The 5 responding pts had a median duration of response of 159+ days (range 1 – 504+). Additionally, SD was observed in 5 pts (2 PTCL-U, 2 NK/T-cell, and 1 ALCL) with median duration of SD of 109+ days (range 80 -185+).The 29 pts with CTCL [15 mycosis fungoides (MF), 7 Sezary syndrome (SS), 5 non MF/SS, 2 unclassified] had received a median of 1 prior skin directed therapies (range 0 – 4) and 3 prior systemic therapies (range 1 – 9), and 55 % of them had stage IV disease. 4/29 (14%) CTCL pts responded with 2 CR (ALCL, MF) and 2 PR (MF, SS). The 4 responding pts had a median duration of response of 273 days (range 48 - 469+). Importantly, time to response was short with a median of 16 days (range 14-35). In addition, SD was observed in 17 pts (10 MF, 3 SS, 2 non MF/SS, 2 unclassified) with current duration of up to 127 days. Pruritus relief (score reduction ≥ 3) was seen in 7 of 14 pts with significant baseline pruritis. Median time to pruritus relief was also short, 16 days (range 7-45).Hematological toxicity was minimal without any grade 4 events (shift from baseline) and only one pt each experiencing grade 3 neutropenia and grade 3 thrombocytopenia, respectively. No grade 3 QTcF prolongation was detected in more than 700 ECGs. Four grade 3/4 drug-related AEs were reported: pruritis, rash/erythema, edema, and adynamic ileus. Conclusions:Belinostat monotherapy is safe, well tolerated, and efficacious in pts with recurrent/refractory T-cell lymphoma with durable remissions in both CTCL and PTCL. These results are the basis for a pivotal study with belinostat monotherapy in pts with PTCL. Disclosures:Advani:Seattle Genetics, Inc.: Research Funding. Duvic:Topotarget: research support for conduct of clinical trial. Fagerberg:TopoTarget A/S: Employment, Equity Ownership. Foss:Eisai : Speakers Bureau.

Alemtuzumab for relapsed and refractory erythrodermic cutaneous T-cell lymphoma: a single institution experience from the Robert H. Lurie Comprehensive Cancer Center

We present the results of an open-label clinical trial and the clinical use of alemtuzumab in 19 heavily pretreated patients with advanced erythrodermic cutaneous T-cell lymphomas (CTCL) (erythrodermic mycosis fungoides and Sézary syndrome). Ten patients received alemtuzumab intravenously using an escalating dose regimen with a final dose of 30 mg three times weekly for 4 weeks followed by subcutaneous administration for 8 weeks. Nine patients were treated with only the SQ or IV dosing. The overall response rate was 84%, with 9 (47%) complete and 7 (37%) partial remissions. The median follow-up was 24 months (range, 6 to 62+ months). Median overall survival was 41 months whereas median progression free survival was 6 months. Minimal residual disease by T-cell gene rearrangement studies was detected in 11 patients who achieved complete response and partial response. Toxicities included myelosuppression and infections; however, the majority of side effects were of Grade 2 in severity and transient. One patient was diagnosed with a concurrent lymphoma (mantle cell lymphoma) 6 months after completing alemtuzumab therapy. Alemtuzumab is particularly effective in patients with erythrodermic CTCL with acceptable toxicities. Combined strategies with alemtuzumab may achieve molecular remissions with longer response durations.

Vorinostat for the Treatment of Bullous Pemphigoid in the Setting of Advanced, Refractory Cutaneous T-Cell Lymphoma

Histone deacetylase (HDAC) inhibitors represent a novel class of medication that is being targeted for use in the treatment of cancer. A member of this class, vorinostat, has recently been approved for the therapy of cutaneous T-cell lymphoma. Importantly, emerging data from animal studies have indicated that HDAC inhibitors may have the capacity to potently suppress the development of autoimmune disease. In this report, we describe a patient with advanced cutaneous T-cell lymphoma who developed refractory bullous pemphigoid (BP) and then experienced the rapid resolution of the BP following initiation of treatment with vorinostat. This observation may be broadly applicable to the treatment of other autoimmune skin diseases.

7025 Prognostic value of hypermethylation for retinoic acid receptor beta (RARB) and p-16 genes in patients with prostate cancer

Panobinostat is a potent, oral pan-deacetylase inhibitor (pan-DACi) that increases the acetylation of proteins involved in multiple oncogenic pathways. Here, panobinostat is studied in bexarotene-exposed and -naïve patients with refractory cutaneous T-cell lymphoma (CTCL).Patients with CTCL subtypes mycosis fungoides and Sézary syndrome who received ⩾2 prior systemic therapy regimens received panobinostat (20 mg) three times every week. The primary objective was overall response rate (ORR) as determined by a combined evaluation of skin disease and involvement of lymph node and viscera. Disease progression was defined as an unconfirmed, ⩾25% increase in modified Severity Weighted Assessment Tool (mSWAT) compared with nadir.Seventy-nine bexarotene-exposed and 60 bexarotene-naïve patients were enrolled. Reductions in baseline mSWAT scores were observed in 103 patients (74.1%). The ORR was 17.3% in all patients in the primary analysis (15.2% and 20.0% in the bexarotene-exposed and -naïve groups, respectively). The median progression-free survival was 4.2 and 3.7 months in the bexarotene-exposed and -naïve groups, respectively. The median duration of response was 5.6 months in the bexarotene-exposed patients and was not reached at data cutoff in the bexarotene-naïve patients. Additional responses were observed when less-stringent progression criteria were used. The most common adverse events were thrombocytopenia, diarrhoea, fatigue and nausea. Thrombocytopenia and neutropenia were the only grade 3/4 adverse events in >5% of patients and were manageable.Despite a very conservative definition of disease progression, panobinostat demonstrated activity with a manageable safety profile in bexarotene-exposed and -naïve CTCL patients. ClinicalTrials.gov Identifier: NCT00425555.

Gemcitabine treatment in cutaneous T-cell lymphoma: a multicentre study of 23 cases

Primary cutaneous T-cell lymphomas (CTCLs) are malignancies characterized by a clonal T-cell infiltrate involving the skin. CTCLs often show resistance to conventional antineoplastic chemotherapy. Gemcitabine is a pyrimidine analogue which has shown efficacy and a favourable safety profile in solid tumours and haematological malignancies. We report a multicentre retrospective study of 23 patients who received gemcitabine for advanced-stage CTCL and emphasize the high incidence of serious unusual adverse events. We collected data from 23 patients with refractory CTCL (14 mycosis fungoides, six Sézary syndrome and three other CTCL). Gemcitabine was given weekly within a 21- or 28-day schedule. Response was evaluated after three and six cycles of chemotherapy. For each patient, all adverse events were recorded. Of the 16 patients who received at least three cycles of gemcitabine, 10 achieved a response (62.5%). Only five patients reached the sixth cycle of treatment and four still had a favourable response. Haematological toxicity was recorded in 15 cases with severe grade 3 or 4 neutropenia in seven patients (30%) and six serious infections (26%). Other serious adverse events were observed in six cases (26%): one haemolytic-uraemic syndrome, one severe capillary leak syndrome, one acute heart failure related to cardiac arrhythmia, two bullous and erosive dermatitis, and one recurrent influenza-like syndrome with altered general condition. Our study confirms the early efficacy of gemcitabine in advanced-stage CTCL. However, our results contradict the safety profile of gemcitabine previously reported and underline the high incidence of severe complications including visceral and cutaneous involvement.

Bexarotene therapy for mycosis fungoides and Sézary syndrome

Bexarotene (Targretin) is a synthetic retinoid which is licensed for the treatment of advanced refractory cutaneous T-cell lymphoma (CTCL). To summarize our experience with bexarotene for patients with CTCL with the aim of assessing efficacy and safety. A retrospective study of 66 patients (44 male, 22 female) with mycosis fungoides (40 patients) or Sézary syndrome (26 patients) who were commenced on bexarotene prior to August 2007 was carried out. Nineteen patients had early-stage (IB-IIA) refractory mycosis fungoides and 47 patients had advanced-stage CTCL (IIB-IVB). Fifty-two out of 66 (79%) patients completed over 1 month of therapy with an intention-to-treat response rate of 44% (29/66). Of the patients, six (9%) had a complete response, 23 (35%) had a partial response, 15 (23%) had stable disease and eight (12%) had progressive disease. Median time to maximal response was 3 months (1-9 months). Median response duration was 8 months (1 to > 48 months). Median time to progression was 9 months (3-44 months). Fourteen patients (21%) did not complete a month of bexarotene therapy. Adverse effects of the whole group included central hypothyroidism in 100% (all grade II and managed with thyroid replacement) and hyperlipidaemia in 100% (all managed with lipid-lowering therapy +/- dose reduction). Responses were seen in all stages and were higher in advanced stages: 26% (five of 19) with early-stage and 51% (24/47) of advanced-stage disease. Responses were seen in skin, blood and lymph nodes. Twenty-eight out of 66 patients were treated with bexarotene monotherapy and the remainder were on one or more additional anti-CTCL therapies. Our data demonstrate that bexarotene is well tolerated in most patients and responses are seen in almost half of patients with all disease stages. However partial responses were not graded and would include any improvement seen in the skin, blood and lymph node.

Evaluation of the efficacy of the combination of oral bexarotene and methotrexate for the treatment of early stage treatment-refractory cutaneous T-cell lymphoma

Background: Various combination therapies are used in refractory cutaneous T-cell lymphoma (CTCL). Although bexarotene has been studied in combination with psoralen photochemotherapy (PUVA), IFN-α and denileukin difitox, there have been no published data assessing the efficacy of the combination of bexarotene and methotrexate. Objective: To evaluate the efficacy and safety of an oral bexarotene and methotrexate combination for the treatment of refractory CTCL. Method: A retrospective study was carried out of 12 patients with refractory stage CTCL treated with an oral combination of bexarotene and methotrexate from 2000 to 2007. Results: Twelve patients with CTCL stage IA–IIB disease who received a combination of bexarotene and methotrexate were identified. The median dose of bexarotene was 150 mg/day (range 75–300 mg/day) and methotrexate 15 mg/week (range 5–30 mg/week). The duration of time to achieve an overall response was 6.5 months (range 3–11 months). The overall response occurred in 66% (8/12). One patient had complete response (CR = 8%) and seven had partial response (PR = 58%). Six of 12 patients progressed at some point during treatment and needed additional intervention. Tolerance to the treatment was good and commonly observed side effects were hyperlipidemia, elevated liver transaminases and a decreased white blood cell count. Limitations of the study included a restricted number of patients, relatively short evaluation times and retrospective analysis. Conclusion: An oral bexarotene and methotrexate combination may be a promising future alternative to monotherapy for the treatment of CTCL, but further studies are required.

Low-Dose Bexarotene and Phototherapy or Interferon Alfa-2a in the Treatment of Patients with Relapsed or Refractory Cutaneous T-Cell Lymphoma

Background: Selective ligands of retinoid X receptor (i.e. bexarotene) are used in the treatment of early and advanced stages of cutaneous T-cell lymphoma (CTCL). Relapsed or refractory cases of CTCL have poor prognosis and are in need of safe and more effective therapies. Synergy between bexarotene and interferon or phototherapy has been previously described.Objective: Report a Peruvian single-institution experience on eight cases of relapsed or refractory CTCL who were treated with low-dose bexarotene in combination with phototherapy or interferon alfa-2a.Methods: From 2002 to 2007, eight patients with relapsed or refractory CTCL were treated with bexarotene 300 mg by mouth daily in combination with interferon alfa-2a 9 million units subcutaneously three times a week (five patients) or phototherapy (two patients received PUVA therapy and one patient received narrow-wave UVB therapy). Bexarotene, interferon and phototherapy were continuously administered until progression of disease or unacceptable toxicity. Five patients were diagnosed with mycosis fungoides (MF), two patients had aggressive epidermotropic CD8+ cytotoxic lymphoma (AECL) and one patient had Sezary Syndrome (SS).Results: Mean age was 58 years (range 36 to 70). Patients were exposed to three prior lines of therapy in average (range 2 to 5). One patient had complete response, four patients had partial response and three patients experienced progressive disease. The overall response for the entire group was 62.5% with a mean duration of response of 20 months (range 7 to 67 months). Forty percent (2/5) of patients had partial response to the bexarotene and interferon combination; no complete responses were observed. The two responders, one patient with SS and one patient with MF, are alive 67 and 17 months, respectively. On the other hand, 100% (3/3) of patients responded to the bexarotene and phototherapy combination. A patient with stage I MF experienced a complete response and two patients had a partial response, one patient with MF and one with AECL. Of note, the patient who achieved a complete response was treated with bexarotene and narrow-wave UVB. Most commonly side effects observed were mild, five patients experienced grade 1–2 hypercholesterolemia, hypertriglyceridemia grade 1–2 was seen in four patients and grade 3 in one case. Two patients developed grade 1–2 hypothyroidism. Our patient with SS developed cardiomyopathy related to interferon after 17 months of therapy and continues on single-agent bexarotene. The use of bexarotene in the treatment of AECL has seldom been reported. We are also reporting one of the longest lasting responses described in a patient with SS treated with bexarotene.Conclusions: Low-dose bexarotene in combination with phototherapy or interferon alfa-2a in the treatment of relapsed and refractory CTCL seems safe and effective. Further research is necessary to develop improved, more effective therapies.Table 1. Characteristics of reported patientsAgeSexHistologyStageNumber previous treatmentsTreatmentResponseDuration response (months)Bexarotene/interferonBexarotene/phototherapy69FSS-2XPR6761MMFIII2XPR1736FAECLIB4XPD-70FMFIIB2XPD-57MMFIIB5XPD-44MMFIB2XCR1759MMFIIB2XPR767MAECLIIB3XPR12F: female; M: male; SS: Sezary syndrome; AECL: aggressive epidermotropic CD8+ cytotoxic lymphoma; MF: mycosis fungoides; PR: partial response; CR: complete response; PD: progressive disease

Phase II Trial of Oral Panobinostat (LBH589) in Patients with Refractory Cutaneous T-Cell Lymphoma (CTCL).

Background: Panobinostat is a histone deacetylase inhibitor that has shown promising results in cutaneous T-cell lymphoma (CTCL).Objectives: An open-label, multicenter, Phase II study is being conducted with a primary objective of establishing the efficacy and safety of the pan-deacetylase inhibitor, panobinostat (LBH589), for patients (pts) with relapsed/refractory CTCL with Stage IB–IVA mycosis fungoides (MF) or Sézary syndrome (SS).Methods: Inclusion criteria include adequate organ function, no clinically significant cardiovascular abnormalities (QTcF ≤ 450 ms, ECOG PS ≤2), failure of ≥2 prior systemic therapies, and no prior HDAC inhibitor treatment. Pts were grouped as having bexarotene therapy (Group [Gr] 1) or bexarotene naïve (Gr 2). Panobinostat was administered at a dose of 20 mg orally on Days 1, 3, 5, weekly, every 28 days until progression or unacceptable toxicity. Response was based on a composite score, including skin assessment with the modified Severity-Weighted Assessment Tool (mSWAT) and systemic disease assessed by CT scan.Results: To date, 95 pts (Gr 1=62; Gr 2=33) have enrolled with median age of 58 yrs [range 25–88]: 58 male, 37 female; 70 MF, 25 SS. Median prior treatment regimens are 4 and 3 for Gr 1 and 2, respectively. Most pts were ≥Stage IIB at study entry (Gr 1=42; Gr 2=26) and received 1–17+ (median=3) treatment cycles of panobinostat. In Gr 1, 11/62 pts have had confirmed skin responses by SWAT, including 2 complete skin responses. Confirmatory CT scans are pending for 2 patients. In Gr 2, 4/33 pts had confirmed skin and CT scan responses. Common AEs (>20%; all grades, regardless of causality) included diarrhea, thrombocytopenia, nausea, pruritus, fatigue, and asthenia, and Grade 3/4 AEs (>2%, regardless of causality) included thrombocytopenia, neutropenia, pruritus, diarrhea, and hypophosphatemia. Of 4,542 ECGs analyzed, 2 pts have had QTcF >480 ms; 4 had QTcF >60 ms increase from baseline.Conclusions: Panobinostat continues to demonstrate encouraging clinical activity with a manageable safety profile in pts with CTCL. Per predefined criteria, Group 2 enrollment to Stage 2 is open. Updated efficacy and safety data will be presented.

A Retrospective Comparison of Autologous Vs. Allogeneic Transplantation for Peripheral T-Cell Lymphoma: A Single Institution Experience

Peripheral T-cell Lymphomas (PTCL) are a heterogenous group of malignanices that represent 10–15% of non-Hodgkin lymphoma (NHL). This group has a worse prognosis with conventional chemotherapy compared to B-cell lymphomas. Both autologous (AutoSCT) and allogeneic stem cell transplantation (AlloSCT) have been used as consolidation in first remission and at relapse, but the role of transplantation has not been clearly defined.We report a retrospective analysis of 42 patients with PTCL who underwent AutoSCT (24) or AlloSCT (18) between 8/1997 and 12/2007. The AlloSCT group consisted of 4 PTCL unspecified (PTCLu), 3 angioimmunoblastic T-cell lymphomas (AITL), 2 panniculitic T-cell lymphomas, 2 cutaneous T-cell lymphomas (CTCL) with large cell transformation, 2 NK-cell lymphomas, 2 anaplastic large cell lymphomas (ALCL, 1 Alk+, 1 Alk unknown), 1 hepatosplenic T-cell lymphoma, 1 enteropathic T-cell lymphoma, and 1 refractory CTCL. The AutoSCT group consisted of 6 PTCLu, 12 ALCL (5 Alk+, 5 Alk−, 2 Alk unknown), 4 AITL, 1 CTCL with transformation, and 1 T-lymphoblastic lymphoma. The median age of the AlloSCT and AutoSCT groups was 51 (range 29–72) and 52 years (range 19–67), respectively.The median number of prior treatments of the AlloSCT and AutoSCT groups were 3 (range 1 to 5) and 1 (range 1 to 5), respectively. Within the AlloSCT group there were 14 matched-related donor transplants, and 4 matched-unrelated donor transplants; 7 were ablative and 11 were reduced-intensity transplants; the AlloSCT conditioning regimens varied. The AutoSCT group predominantly received BEAM as their conditioning regimen. Median time from diagnosis to AlloSCT or AutoSCT was 18.4 (range 6.9 to 109) and 7.5 (range 3.9 to 25) months, respectively. Median follow-up times for the AlloSCT and AutoSCT groups were 28.6 and 23.5 months, respectively.The day 100 transplant-related mortality rates in the AlloSCT and AutoSCT groups were 11% and 0%, respectively. Within the AlloSCT group the relapse and non-relapse mortalities were 11% and 33%, respectively. In the AutoSCT group, the relapse mortality was 33%. The 1- and 2-year overall survival (OS) rates were similar within the AlloSCT and AutoSCT groups (78% vs 74%, and 67% vs 60%, respectively). The 1- and 2-year progression-free survival (PFS) rates for the AlloSCT vs AutoSCT groups were 68% vs 52%, and 53% vs 45%, respectively (p = 0.28). Within the AutoSCT group, 14 patients (58%) were transplanted in first complete remission (CR1), and 10 (42%) in second complete remission (CR2), beyond CR2, or partial remission (PR). Patients in CR1 had significantly better PFS (57 vs 17 months, p=0.007) and OS (76 vs 29 months, p=0.004) than those in CR2, PR2, or beyond. Within the AlloSCT group, there was a trend toward poorer OS in 6 patients (33%) who had prior AutoSCT (32 vs 60 months, p=0.15). One patient (6%) was transplanted in CR1, and is still alive.We conclude that outcomes for AutoSCT are best in CR1. For patients with resistant or relapsed disease, AlloSCT should be strongly considered rather than AutoSCT. Prior AutoSCT may affect the outcome of AlloSCT. These results suggest that a prospective randomized trial comparing AutoSCT and AlloSCT for aggressive PTCL in first remission is warranted.

Prospective Multicenter Study of Pegylated Liposomal Doxorubicin Treatment in Patients With Advanced or Refractory Mycosis Fungoides or Sézary Syndrome

To assess the rate of objective response to pegylated liposomal doxorubicin hydrochloride (Caelyx) in patients with advanced or refractory cutaneous T-cell lymphoma (CTCL). Prospective, open, multicenter study. Thirteen dermatology departments in France. Twenty-five patients with either (1) stage II to stage IV CTCL previously unsuccessfully treated with at least 2 lines of treatments or (2) histologically transformed epidermotropic CTCL requiring chemotherapy. Administration of Caelyx intravenously once every 4 weeks at a dose of 40 mg/m(2). The response to treatment was evaluated by clinical evaluation. At the end of treatment, we observed an objective response (primary end point) in 56% of the patients (14 of 25): 5 complete responses and 9 partial responses. The median overall survival time was 43.7 months. For the 14 patients who experienced an objective response, the median progression-free survival time after the end of treatment was 5 months. This prospective study demonstrates the effectiveness of Caelyx in treating CTCL, with an overall response rate of 56% in spite of the high proportion of patients with advanced-stage disease. Responses were observed in 2 subpopulations of patients in which the prognosis is known to be poorer: Sézary syndrome (overall response rate, 60%) and transformed CTCL (overall response rate, 50%). Moreover, this study shows that dose escalation to 40 mg/m(2) does not seem to improve the effectiveness but increases toxic effects (especially hematologic toxic effects) compared with the dose previously tested of 20 mg/m(2).

Phase II study of oral panobinostat (LBH589), a potent pan-deacetylase inhibitor, in patients with refractory Cutaneous T-cell Lymphoma (CTCL)

8555 Background: Panobinostat (LBH589) is a potent pan-deacetylase inhibitor (DACi) which has demonstrated activity in patients (pts) with CTCL in a phase I study (Prince et al, ASCO 2007). This phase II study aims to confirm that activity. Methods: This open-label study enrolled pts with CTCL (stage IB-IVA), including Mycosis fungoides (MF) and Sezary syndrome (SS), who have failed ≥2 prior systemic therapies, have adequate organ function and ECOG PS ≤2. Pts with significant cardiovascular abnormalities or QTcF >450 msec on screening ECG were excluded. Pts were accrued to Group 1 (Grp 1, previously treated with oral bexarotene) or Group 2 (Grp 2, bexarotene naive); both following a Simon 2-stage design. Panobinostat (20 mg) was administered orally on days 1, 3, and 5 weekly until disease progression or intolerance. Primary endpoint is the response rate measured using a composite score derived from assessment of skin disease using modified Severity-Weighted Assessment Tool [mSWAT], evaluation of visceral ...

Phase II trial of oral vorinostat (suberoylanilide hydroxamic acid) in relapsed diffuse large-B-cell lymphoma

BackgroundVorinostat has demonstrated activity in refractory cutaneous T-cell lymphoma. In a phase I trial, an encouraging activity in diffuse large-B-cell lymphoma (DLBCL) was noted. Patients and methodsWe carried out a phase II trial (NCT00097929) of oral vorinostat 300 mg b.i.d. (14 days/3 weeks or 3 days/week) in patients with measurable, relapsed DLBCL who had received two or more systemic therapies. Response rate and duration (DOR), time to progression (TTP) and safety were assessed. ResultsEighteen patients were enrolled (median age: 66 years; median prior therapies: 2). Seven received 300 mg b.i.d. 14 days/3 weeks, but four had grade 3 or 4 toxicity (dose-limiting toxicity, DLT). The schedule was amended to 300 mg b.i.d. 3 days/week), and none had DLT. One achieved a complete response (TtR = 85 days; DOR = >468 days) and one had stable disease (301 days). Sixteen discontinued for progressive disease; median TTP was 44 days. Median number of cycles was 2 (1 to >19). Common drug-related adverse experiences (AEs; mostly grade 1/2) were diarrhea, fatigue, nausea, anemia and vomiting. Three patients had dose reduction; none discontinued for drug-related AEs. Drug-related AE ≥grade 3 included thrombocytopenia (16.7%) and asthenia (11.1%). ConclusionVorinostat was well tolerated at 300 mg b.i.d. 3 days/week or 200 mg b.i.d. 14 days/3 weeks but had limited activity against relapsed DLBCL.

Mycosis Fungoides: Pathophysiology and Emerging Therapies

Primary cutaneous T-cell lymphomas (CTCLs) are a heterogeneous group of non-Hodgkin's lymphomas characterized by skin infiltration of neoplastic T lymphocytes. Mycosis fungoides and its leukemic variant Sézary syndrome represent the most common CTCL subtypes. Current treatment for patients with mycosis fungoides involves topical and systemic therapies for the cutaneous manifestations. However, no therapy is curative and patients often progress to advanced extracutaneous CTCL with visceral organ complications or relapsed disease that is frequently refractory to most topical and aggressive systemic regimens. The emergence of novel targeted therapies such as biologic agents, histone deacetylase inhibitors, and purine nucleoside phosphorylase inhibitors offers promise for more effective and safer treatment strategies for refractory CTCLs.

Response to Oral Forodesine in Refractory Cutaneous T-Cell Lymphoma: Interim Results of a Phase I/II Study.

Background: Forodesine is a rationally designed, potent inhibitor of purine nucleoside phosphorylase (PNP) that leads to intracellular accumulation of dGTP and then apoptosis. Intravenous forodesine has demonstrated activity in treatment of cutaneous T-cell lymphoma (CTCL) and served as the basis for the design of an oral forodesine Phase I/II trialMethods: An open label dose escalation study of oral forodesine (40 mg/m2 to 320 mg/m2 QD) for 4 weeks was performed to determine the maximum tolerated dose (MTD) and/or the optimal biologic dose (OBD) based on PK, and PNP inhibition as evidenced by elevation of plasma deoxyguanosine (dGuo) levels. Additional subjects were accrued at the optimal dose (80 mg/m2) to further assess clinical safety and efficacy. Patients with previously treated, refractory CTCL with stage IB disease or higher were eligible. The primary efficacy endpoint (objective response rate [ORR]) for this analysis was defined as at least a 50% decrease in modified severity-weighted assessment tool (mSWAT) from baseline maintained for at least 28 days. Only subjects who had at least 6 months follow-up as of March 1, 2007 were included in this analysis.Results: Although an MTD was not reached, based on plateau of the AUC versus dose plot at and above 80 mg/m2, and the same observation for plasma dGuo versus dose, 80 mg/m2 was judged as an OBD. The 36 subjects treated at 80 mg/m2 are the main subject of this report. Median age was 61.6 years (range 28.4–81.1) and 67% were males and were exposed to a median of 3 prior systemic therapies (range 0, 8). The ORR using mSWAT was 39% (14/36) with a median duration of response of 127 days (25%–75%, 71 - NA). Response by stage was: IB 3/9, IIA 1/1, IIB 3/5, III 4/12, IVA 2/5, IVB 1/4. Median time to response was 42 days (25%–75%, 29–58). The median time on treatment was 131 days (range 1, 479) with 6 subjects remaining on treatment. For subjects with Sezary Syndrome (n=20, defined by ISCL B2 classification), the ORR by mSWAT was 40%, and 65% by erythroderma score. More than a 50% reduction in Sezary cells (detected by flow cytometry) was observed in 9/20 (45%) subjects with SS. For all 56 forodesine-treated subjects, the only grade 3 or higher non-laboratory adverse events (without regard to attribution and observed in at least 2 subjects) were diarrhea, acute renal failure (not related), cellulitis, and rash (2 subjects each). The only grade 3 or higher related non-laboratory AEs were vertigo, diarrhea, generalized edema, and pneumonia (1 each). For laboratory events, a single grade 3 elevation for each of the following liver-related parameters was noted: AST, ALT, bilirubin, and alkaline phosphatase. There were no grade 3 or higher elevations of creatinine. Grade 3 or higher lymphopenia and low CD4 counts were observed in 71% and 31% of subjects and these rates were similar across dose groups. Median baseline, nadir, and last visit lymphocytes counts (1000/mm3) were 0.8 (95%CI: 0.0, 6.0), 0.2 (95% CI: 0.0, 0.8), and 0.6 (95% CI: 0.0, 2.9) respectively. Hematopoietic toxicity was limited to 1 episode of grade 3 neutropenia, and 1 episode of grade 3 anemia.Conclusion: Oral forodesine demonstrates clinical activity in subjects with refractory CTCL, including those with SS, with minimal toxicity to date.