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Figure.  Plot of the 17 Patients Who Received Romidepsin for More Than 6 Months
Plot of the 17 Patients Who Received Romidepsin for More Than 6 Months

Nine of the 17 patients received a dose-sparing regimen. All patients received 14 mg/m2 per dose administered. Type and time course of coadjuvant treatment is specified with the turquoise line in qualifying patients. Type of response is specified after each patient with ongoing treatment; the remaining patients had progressive disease. Further details are provided in eTable 2 in the Supplement. CR indicates complete remission; MF, mycosis fungoides; NB UV-B, narrow-band UV-B; PR, partial response; RT, radiation therapy; SS, Sézary syndrome.

Table 1.  Demographic and Clinical Data
Demographic and Clinical Data
Table 2.  Response and Duration of Response to Romidepsin of the 47 Patients
Response and Duration of Response to Romidepsin of the 47 Patients
1.
Piekarz  RL, Frye  R, Turner  M,  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(32):5410-5417.PubMedGoogle ScholarCrossref
2.
Whittaker  SJ, Demierre  MF, Kim  EJ,  et al.  Final results from a multicenter, international, pivotal study of romidepsin in refractory cutaneous T-cell lymphoma.  J Clin Oncol. 2010;28(29):4485-4491.PubMedGoogle ScholarCrossref
3.
Coiffier  B, Pro  B, Prince  HM,  et al.  Romidepsin for the treatment of relapsed/refractory peripheral T-cell lymphoma: pivotal study update demonstrates durable responses.  J Hematol Oncol. 2014;7:11.PubMedGoogle ScholarCrossref
4.
Bates  SE, Eisch  R, Ling  A,  et al.  Romidepsin in peripheral and cutaneous T-cell lymphoma: mechanistic implications from clinical and correlative data.  Br J Haematol. 2015;170(1):96-109.PubMedGoogle ScholarCrossref
5.
Olsen  EA, Whittaker  S, Kim  YH,  et al; International Society for Cutaneous Lymphomas; United States Cutaneous Lymphoma Consortium; Cutaneous Lymphoma Task Force of the European Organisation for Research and Treatment of Cancer.  Clinical end points and response criteria in mycosis fungoides and Sézary 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(18):2598-2607.PubMedGoogle ScholarCrossref
6.
Salles  G, Seymour  JF, Offner  F,  et al.  Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial.  Lancet. 2011;377(9759):42-51.PubMedGoogle ScholarCrossref
7.
Palumbo  A, Gay  F, Cavallo  F,  et al.  Continuous therapy versus fixed duration of therapy in patients with newly diagnosed multiple myeloma.  J Clin Oncol. 2015;33(30):3459-3466.PubMedGoogle ScholarCrossref
8.
Hughes  CF, Khot  A, McCormack  C,  et al.  Lack of durable disease control with chemotherapy for mycosis fungoides and Sézary syndrome: a comparative study of systemic therapy.  Blood. 2015;125(1):71-81.PubMedGoogle ScholarCrossref
Brief Report
June 2016

Durable Responses With Maintenance Dose-Sparing Regimens of Romidepsin in Cutaneous T-Cell Lymphoma

Author Affiliations
  • 1Department of Dermatology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois
  • 2Division of Hematology/Oncology, Department of Medicine, Northwestern University, Feinberg School of Medicine, Chicago, Illinois
  • 3Northwestern Medicine Developmental Therapeutics Institute, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Feinberg School of Medicine, Chicago, Illinois
  • 4Comprehensive Cancer Center and Beckman Research Institute, City of Hope, Duarte, California
JAMA Oncol. 2016;2(6):790-793. doi:10.1001/jamaoncol.2016.0004
Abstract

Importance  Romidepsin is a histone deacetylase inhibitor approved for the treatment of cutaneous T-cell lymphoma (CTCL). Durable responses have been published without establishing a standard recommendation about duration of treatment.

Objective  To review the long-term use of romidepsin in responders who received a dose-sparing regimen.

Design, Setting, and Participants  Retrospective review of medical records of patients with a diagnosis of CTCL, including mycosis fungoides (MF), Sézary syndrome (SS), or CTCL not otherwise specified seen at a multidisciplinary clinic at Northwestern University from 2009 until December 2014.

Exposures  Doses administered and different regimens of romidepsin were reviewed.

Main Outcomes and Measures  Duration of treatment, participants receiving dose-sparing regimen.

Results  Of 47 patients identified, 23 had MF, 15 had SS, and 9 had other types of CTCL. None of these 9 (mostly cytotoxic lymphomas) achieved a durable response. Of the remaining 38 patients, 17 were considered long-term responders (>6 months of treatment). Nine of these patients received a dose-sparing regimen. The median (range) duration of treatment was 15 (7-34) months; the frequency of patients with SS (10 of 15) in the long-term group was significantly higher than that of patients with MF (7 of 23; P = .046). Adverse events were reported in 29 (69%) of 42 patients for whom data were available. There was no significant difference in the incidence of AEs between the short-term and long-term groups (12 of 21 vs 12 of 17; P = .50).

Conclusions and Relevance  Decreasing the frequency of infusions in patients with MF or SS who achieve a response with romidepsin therapy may provide a practical strategy to prolong response.

Introduction

Romidepsin is a histone deacetylase inhibitor approved by the US Food and Drug Administration for the treatment of relapsed/refractory cutaneous T-cell lymphoma (CTCL) based on results of 2 large phase 2 clinical trials.1,2 The standard romidepsin schedule for CTCL includes infusions on days 1, 8, and 15 of a 28-day cycle, but to our knowledge, treatment beyond 6 cycles has not been investigated and the long-term use of romidepsin using a dose-sparing regimen has not yet been reported.3,4 The objective of this study was to describe our real-world experience with the long-term use of a dose-sparing romidepsin regimen for the treatment of CTCL.

Box Section Ref ID

Key Points

  • Question What are the potential benefits of long-term use of romidepsin in a dose-sparing regimen in patients with cutaneous T-cell lymphoma (CTCL)?

  • Findings In this case series of 47 patients with CTCL, 23 (49%) achieved response with romidepsin. Nine patients who reached more than 6 months of treatment received a dose-sparing regimen as maintenance treatment.

  • Meaning This reduced-dosing approach may be a practical strategy to prolong response.

Methods

This retrospective review project was approved by the Northwestern University institutional review board, which granted a waiver of consent because of the retrospective nature of the study (NCT02296398). Medical records of patients with CTCL who received at least 1 dose of romidepsin and were seen in our center were reviewed for the following: demographic features, histologic diagnosis, stage at diagnosis, and at romidepsin initiation, prior treatments received, romidepsin duration of treatment (DOT), dosing schedule, time to response (TTR), adverse events (AEs), and reasons for treatment withdrawal. Response was assessed by body surface area, lymph nodes, and peripheral blood Sézary cell count. End points included overall response rate (ORR), TTR, duration of response, time to treatment failure (TTF), disease-free survival, progression-free survival (PFS), and current survival status.5 Cytopenias were graded in accordance with National Comprehensive Cancer Network guidelines. Frequencies between groups were assessed with the Fisher exact test, whereas the nonparametric Mann-Whitney U test was performed for continuous variables.

The study population was divided into 3 groups based on diagnosis: (1) mycosis fungoides (MF), (2) Sézary syndrome (SS), and (3) other rare CTCL subtypes; and romidepsin DOT into 2 groups: (1) short-term cohort (treated ≤6 months) and (2) long-term cohort (treated >6 months). Romidepsin was initially administered using the standard dose (14 mg/m2) and aforementioned regimen. Once a response (either partial or complete) was achieved, the dosing schedule was gradually reduced, at the discretion of the physician, to once every other week and eventually monthly. Those patients receiving dose reductions or omissions solely for AEs were not included in the analysis of the dose-sparing regimen.

Results

Forty-seven patients with advanced CTCL received romidepsin from June 1, 2010, until May 31, 2015. Demographic and clinical data are presented in Table 1. The CTCL subtype distribution was 23 with MF, 15 with SS, and 9 with the following other CTCL subtypes: 1 CD30-positive anaplastic large-cell lymphoma, 1 primary cutaneous γδ T-cell lymphoma, 1 primary cutaneous aggressive epidermotropic CD8-positive T-cell lymphoma, 1 subcutaneous panniculitis-like T-cell lymphoma, 1 natural killer cell/T-cell lymphoma, and 4 CTCL not otherwise specified. Treatment regimens administered prior to romidepsin included methotrexate (n = 19), interferon (n = 19), bexarotene (n = 19), psoralen-UV-A light therapy (n = 19), narrow-band UV-B (n = 19), gemcitabine (n = 15), systemic steroids (n = 11), extracorporeal photophoresis (n = 11), radiation therapy (n = 7), polychemotherapy (n = 7), alemtuzumab (n = 6), acitretin (n = 5), and allogenic hematopoietic stem cell transplantation (n = 4).

Adverse events were reported in 29 (69%) of the 42 patients for whom data were available. Malaise and fatigue (n = 17) ranged from mild to severe and caused treatment discontinuation in 6 patients. Nausea and dysgeusia were noted in 14 and 5 patients, respectively. Seven patients experienced electrolyte abnormalities and 15 developed cytopenias, including grade 1/2 anemia (n = 11), grade 1 thrombocytopenia (n = 5), grade 2/3 thrombocytopenia (n = 2), and unknown grade in other cytopenia (n = 4). Dose reductions or omissions were needed in 4 patients with thrombocytopenia. Two of 25 experienced asymptomatic drug-related QT interval prolongation (eTable 1 in the Supplement).

Responses were noted primarily in patients with MF or SS (Table 2). The non-MF/SS patients experienced progressive disease (7 of 9) or withdrew due to toxic effects (2 of 9); therefore, none were included in the dose-sparing component of the analysis.

The median (range) DOT among the patients with MF or SS (n = 38) was 5 (1-32) months. The ORR was 61% (n = 23) and included 7 complete remissions (18%) and 16 partial remissions (PRs) (42%). The median (range) TTR and duration of response were 2 (1-10) and 13 (1-31) months, respectively. The median (range) TTF was 4 (1-30) months among the 20 patients whose treatment was discontinued or abandoned. Median (range) disease-free survival for the MF and SS patients was 12.6 (3-28) months, and PFS was 4 (1-30) months. Seventeen of the 25 patients who responded received treatment for more than 6 months. The clinical course of the remaining 8 patients evolved as follows: 2 patients experienced disease progression after more than 4 months; 2 discontinued treatment as a result of toxic effects (fatigue); 2 were still receiving romidepsin by the end of the study; and the other 2 patients had PRs but were lost to follow-up.

Seventeen of the 38 (45%; 7 MF, 10 SS) patients received romidepsin for more than 6 months, making up the long-term cohort (Figure and eTable 2 in the Supplement). The median (range) duration of treatment exposure was 15 (7-34) months. The frequency of patients with SS (10 of 15) in the long-term group was significantly higher than that of patients with MF (7 of 23; P = .046). Once long-term treatment was achieved, statistically significant differences were not found for ORR (2.6 [95% CI, 0.67-10.0]; P = .19), TTR (1.8 [IQR, 0.94-334]; P = .41), and AEs (71% in patients with MF vs 70% in patients with SS; P = .95). There was no significant difference in the incidence of AEs between the short-term and long-term groups (12 of 21 vs 12 of 17; P = .50). Nine (53%) of the 17 patients received a dose-sparing regimen, 6 of whom were switched from the standard regimen to dosing every other week (eventually 3 were changed to monthly dosing). Three of the 9 patients were switched directly to monthly dosing, 1 of whom was subsequently switched from monthly to every-6-weeks dosing. The median (range) time to first reduction of dosing frequency was 7.4 (3-15) months, whereas the median (range) time to first response was 2.7 (1-4) months. Median (range) DOT was 21 (12-34) months. Three patients achieved complete remissions, and 6 achieved PR. Adverse events experienced by these 9 patients are specified in eTable 1 in the Supplement.

Discussion

Results obtained from this case series suggest that patients initially benefiting from a standard dosing schedule of romidepsin may benefit by transitioning to a reduced dose-sparing regimen, which allows for maintaining response, tolerability, and convenience. One could argue in favor of discontinuing romidepsin therapy after achievement of a robust response, with the plan to re-treat on progression during the active surveillance period, as compared with continuing therapy with the dose reduction (ie, maintenance) strategy. A randomized trial comparing these approaches could be conducted. Maintenance strategies have already made their way into routine clinical practice for the treatment of other hematologic malignant neoplasms, including rituximab maintenance in indolent non-Hodgkin lymphomas (improving PFS) and lenalidomide or bortezomib in multiple myeloma (improving PFS and possibly overall survival in certain populations).6,7

The median TTF of chemotherapies for CTCL is only 3 months.8 Our novel approach presents an alternative to the standard regimens, offering the possibility of prolonged responses with an improvement in quality of life for patients with MF and SS. As mentioned, these preliminary results need to be confirmed with prospective clinical trials.

Conclusions

Our data suggest that reduced long-term treatment with romidepsin may benefit patients with advanced CTCL. This well-tolerated novel approach may offer a new option to prolong response in a disease notorious for short responses. Because this study was retrospective, uncontrolled, and relatively small, the results cannot be compared with the published studies that led to romidepsin’s approval, but they may serve as the basis for future efforts to compare dose-sparing regimens to standard therapy.

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Article Information

Accepted for Publication: January 7, 2016.

Corresponding Author: Joan Guitart, MD, Department of Dermatology, Northwestern University, Feinberg School of Medicine, 676 N St Clair St, Ste 1765, Chicago, IL 60611 (j-guitart@northwestern.edu).

Published Online: April 7, 2016. doi:10.1001/jamaoncol.2016.0004.

Author Contributions: Drs Martinez-Escala and Guitart had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Kuzel, Rosen, Guitart.

Acquisition, analysis, or interpretation of data: Martinez-Escala, Kuzel, Kaplan, Petrich, Nardone, Rosen, Guitart.

Drafting of the manuscript: Martinez-Escala, Kaplan, Petrich, Rosen, Guitart.

Critical revision of the manuscript for important intellectual content: Kuzel, Kaplan, Petrich, Nardone, Rosen, Guitart.

Statistical analysis: Nardone.

Administrative, technical, or material support: Martinez-Escala, Guitart.

Study supervision: Kuzel, Kaplan, Guitart.

Conflict of Interest Disclosures: Drs Martinez-Escala, Rosen, and Guitart have served as compensated consultant for Celgene. Drs Kuzel and Rosen have served as compensated speaker for Celgene. No other disclosures are reported.

References
1.
Piekarz  RL, Frye  R, Turner  M,  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(32):5410-5417.PubMedGoogle ScholarCrossref
2.
Whittaker  SJ, Demierre  MF, Kim  EJ,  et al.  Final results from a multicenter, international, pivotal study of romidepsin in refractory cutaneous T-cell lymphoma.  J Clin Oncol. 2010;28(29):4485-4491.PubMedGoogle ScholarCrossref
3.
Coiffier  B, Pro  B, Prince  HM,  et al.  Romidepsin for the treatment of relapsed/refractory peripheral T-cell lymphoma: pivotal study update demonstrates durable responses.  J Hematol Oncol. 2014;7:11.PubMedGoogle ScholarCrossref
4.
Bates  SE, Eisch  R, Ling  A,  et al.  Romidepsin in peripheral and cutaneous T-cell lymphoma: mechanistic implications from clinical and correlative data.  Br J Haematol. 2015;170(1):96-109.PubMedGoogle ScholarCrossref
5.
Olsen  EA, Whittaker  S, Kim  YH,  et al; International Society for Cutaneous Lymphomas; United States Cutaneous Lymphoma Consortium; Cutaneous Lymphoma Task Force of the European Organisation for Research and Treatment of Cancer.  Clinical end points and response criteria in mycosis fungoides and Sézary 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(18):2598-2607.PubMedGoogle ScholarCrossref
6.
Salles  G, Seymour  JF, Offner  F,  et al.  Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial.  Lancet. 2011;377(9759):42-51.PubMedGoogle ScholarCrossref
7.
Palumbo  A, Gay  F, Cavallo  F,  et al.  Continuous therapy versus fixed duration of therapy in patients with newly diagnosed multiple myeloma.  J Clin Oncol. 2015;33(30):3459-3466.PubMedGoogle ScholarCrossref
8.
Hughes  CF, Khot  A, McCormack  C,  et al.  Lack of durable disease control with chemotherapy for mycosis fungoides and Sézary syndrome: a comparative study of systemic therapy.  Blood. 2015;125(1):71-81.PubMedGoogle ScholarCrossref
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