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Dose-sparing schedule may prolong response with IV romidepsin for cutaneous T-cell lymphoma
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Switching from a standard-dosing schedule to a reduced-dose schedule may prolong response in select patients with cutaneous T-cell lymphoma treated with romidepsin, according to the results of a retrospective review.
“Romidepsin [Istodax, Celgene] is a histone deacetylase inhibitor approved by the FDA for the treatment of relapsed/refractory cutaneous T-cell lymphoma (CTCL), based on the results of two large phase 2 clinical trials,” Joan Guitart, MD, professor of dermatology and pathology at Northwestern University’s Feinberg School of Medicine, and colleagues wrote. “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 six cycles has not been investigated and the long-term use of romidepsin using a dose-sparing regimen has not yet been reported.”
Joan Guitart
Guitart and colleagues performed a retrospective review of medical records for 47 patients (median age, 64 years; range, 18-87; 53% men) who responded to a dose-sparing romidepsin regimen. Twenty-three patients had mycosis fungoides, 15 patients had Sézary syndrome and nine patients had other forms of CTCL.
The researchers examined the doses and regimens administered, with duration of treatment the primary measure.
Overall, the median duration of treatment among patients with mycosis fungoides or Sézary syndrome was 5 months (range, 1-32).
None of the nine patients with unspecified CTCL achieved a durable response.
The overall response rate among the remaining patients was 61% (n = 23), with seven patients achieving complete remissions and 16 achieving partial remissions.
The researchers considered 17 patients who remained on treatment for more than 6 months to be long-term responders. Of these patients, nine received dose-sparing regimens (dosing every other week, n = 6; dosing monthly, n = 3)
The median duration of treatment in this cohort was 15 months (range, 7-34). Three patients achieved complete remission and six achieved partial remission.
A greater proportion of patients with Sézary syndrome were long-term responders (n = 10 of 15) than patients with mycosis fungoides (n = 7 of 23; P = .046). However, once long-term response was achieved, overall response rate, time to treatment response and incidence of adverse events appeared comparable between these two patient subgroups.
Sixty-nine percent of patients with available safety data (n = 29) experienced an adverse event. Seventeen patients experienced malaise and fatigue, causing six to discontinue treatment. Other frequent adverse events included nausea (n = 14) and dysgeusia (n = 5).
However, the researchers did not observe a significant difference in adverse events among patients on long-term treatment (12 of 21), compared with short-term treatment (12 of 17).
“This well-tolerated novel approach may offer a new option to prolong response in a disease notorious for short responses,” Guitart and colleagues wrote. “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.”
The dosing approach supported by these study outcomes presents a practical treatment strategy for patients and physicians, Susan E. Bates, MD, faculty member in drug development and epigenetic therapies at Columbia University Medical Center, and Larisa J. Geskin, MD, associate professor of dermatology and director of the Comprehensive Skin Cancer Center at Columbia University Medical Center, wrote in an accompanying editorial.
“Given the complexity of the weekly 4-hour IV infusions, the uptake of romidepsin in the oncology community after its approval by the FDA remained uncertain,” Bates and Geskin wrote. “A novel drug class, its use also requires a learning curve for treating physicians — infusions in patients without adequate skin barrier function, transient thrombocytopenia and the need for electrolyte monitoring and replacement. Here in the work of Martinez-Escala and colleagues, we see successful translation of clinical trial results to real-world experience.” – by Cameron Kelsall
Disclosure: Guitart reports a consultant role with Celgene. Other researchers report consultant or speakers bureau roles with Celgene. Bates reports research funding and other compensation from Celgene. Geskin reports no relevant financial disclosures.
Perspective
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Pamela B. Allen
Barbara Pro
Martinez-Escala and colleagues reported on the safety and efficacy of romidepsin (Istodax, Celgene) maintenance in a cohort of patients with cutaneous T-cell lymphoma (CTCL) treated in a real-world setting. Their findings are notable for several reasons.
Primarily, they demonstrated that utilizing a maintenance strategy with systematic adjustments in dosing frequency was well tolerated and resulted in unprecedented response rates in a population with advanced and heavily pretreated disease. The response rates reported in their manuscript were far superior to those achieved in phase 2 romidepsin trials, and exceed the best estimates of response for advanced CTCL in general. Martinez-Escala and colleagues’ results demonstrated a whopping 61% overall response rate in the Sézary syndrome and mycosis fungoides population, with a complete response rate of 18%. For reference, the median response rates to systemic therapy in CTCL are as high as 30% to 50%. The two pivotal phase 2 studies assessing romidepsin in CTCL achieved composite response rates of 34%, with complete response rates at 6%.
Given the rarity of disease, chronic and relapsing course, and limited efficacious treatment options, a maintenance approach based on this preliminary data is certainly reasonable. Although this is the first study to assess romidepsin maintenance in CTCL, the approach is not novel. Romidepsin maintenance also was studied in patients with peripheral T-cell lymphoma, with a similar dosing schema demonstrating improved duration of response and tolerability. Further, long-term maintenance data from patients with CTCL treated with another HDAC inhibitor, vorinostat (Zolinza, Merck), have been reported. They demonstrated an acceptable safety profile, although response rates were inferior to those seen in this retrospective analysis.
Although the small sample size and heterogeneous population limits interpretability, their ability to recruit 47 patients in a single institution in the face of the rarity of this disease is certainly noteworthy. CTCL constitutes only 4% of all non-Hodgkin lymphomas and recruitment to clinical trials is a monumental task, significantly limiting research in this disease and, subsequently, the availability of new therapies. To illustrate, the pivotal phase 2 romidepsin study required 33 sites and eight countries to complete accrual. Sézary syndrome and mycosis fungoides constituted the majority of patients in this study and also seized the majority of responses. As such, we would consider a maintenance strategy in those patients with mycosis fungoides and Sézary syndrome with at least stable disease following six cycles of therapy.
Other questions that remain include the duration of maintenance; whether treatment improves disease-associated quality of life, specifically in regard to pruritus; and whether response rates translate to an OS benefit. It also is important to clearly define what is meant by “response.” In the original phase 2 romidepsin study, responses were defined as a composite response in all disease compartments. Additionally, the optimal time to initiate dose reduction remains unknown. Nevertheless, this study provides evidence for the long-term safety and clinical activity of romidepsin in heavily pretreated patients with CTCL.
References:
Duvic M, et al. Clin Lymphoma Myeloma. 2009;doi:10.3816/CLM.2009.n.082.
Foss F, et al. J Hematol Oncol. 2016;doi:10.1186/s13045-016-0243-8.
Kim YH, et al. Arch Dermatol. 2003;139:857-866.
Piekarz RL, et al. J Clin Oncol. 2009;doi:10.1200/JCO.2008.21.6150.
Whittaker SJ, et al. J Clin Oncol. 2010;doi:10.1200/JCO.2010.28.9066.
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