Romidepsin in combination with low‐dose methotrexate in advanced‐stage mycosis fungoides and Sézary syndrome

Abstract

Dear Editor Mycosis fungoides (MF) is the most common subtype of cutaneous T cell lymphoma (CTCL), accounting for 55% of cases. Sézary syndrome (SS) is a rare leukemic variant of CTCL. Skin-directed therapies are appropriate for early-stage MF (IA-IIA). However, patients with advanced-stage disease (IIB-IVB) and SS frequently require systemic treatment, and allogenic cell transplantation remains the only treatment with curative intent. Romidepsin is a histone deacetylase inhibitor approved by the Food and Drug Administration for treatment of CTCL following at least one prior systemic therapy. Approval was based on two pivotal phase II trials in which romidepsin demonstrated an overall response rate (ORR) of 34% and a complete response (CR) rate of 6% with a duration of response of 13.7 to 15 months in CTCL. In Spain, romidepsin is available only through an expanded access program. Oral or subcutaneous, weekly low-dose methotrexate (≤50 mg weekly) is recommended for the treatment of MF/SS. When used in combination with bexarotene and interferon-α, it has been shown to be safe but not superior to monotherapy. To the best of our knowledge, there are no previously published cases of romidepsin and weekly low-dose methotrexate combination therapy. We report our experience using this approach in two patients with advanced-stage MF (IIB) and two patients with SS. All patients had received more than one prior systemic therapy, which had failed to control their disease, including subcutaneous methotrexate (20-50 mg/wk) for more than 6 months in combination with other systemic therapies. We therefore decided to start intravenous romidepsin at the standard dose of 14 mg/m on days 1, 8, and 15 of each 28-day cycle. The clinical characteristics and clinical response of the patient, treatments administered, and side effects are detailed in Table 1. Our first patient, a 49-year-old female with tumor-stage MF, began receiving romidepsin as monotherapy. We withdrew all previous systemic treatments, including methotrexate. After the first cycle, we only observed improvement of the patches and no infiltrated plaques; the tumors not only failed to improve, but also increased in size. This is the reason why we added a chemotherapeutic agent such as methotrexate to the regimen again. Therefore, methotrexate (20 mg/wk) was added, resulting in CR after 5 months without additional toxicity (Figure 1). The remaining three patients were already also receiving weekly low-dose methotrexate; the drug was not withdrawn when romidepsin was introduced due to the favorable response observed in case 1. Our second patient, a 40-year-old male with tumor-stage MF, required localized radiotherapy to treat three tumors that were 5 cm in diameter. The combined therapy was well tolerated with no severe side effects. In contrast, methotrexate was discontinued or reduced in the two patients with SS: in one case due to severe pancytopenia, while the other was tapered from 30 to 10 mg/wk due to moderate hematological toxicity. There are few real-life studies of romidepsin in CTCL and variable results compared to the pivotal phase II trials are reported (ORR of 25%-61% and CR of 0%-18%). Currently, there are some phase I studies assessing the combination of romidepsin with other treatments in peripheral T cell lymphomas in order to achieve better response rates with fewer side effects. Romidepsin in combination with liposomal doxorubicin demonstrated an acceptable safety profile and effectiveness in relapsed/refractory CTCL in a phase I study. Combined therapy is probably the future of treatment for advanced-stage MF and SS. To date, two case series have shown that the combination of romidepsin and local or total electron beam therapy is safe and causes no unexpected toxicity in advanced-stage MF and SS. We report four cases of refractory CTCL treated with romidepsin in combination with weekly low-dose methotrexate. This series is too small to draw conclusions regarding the efficacy and safety of this combined therapy, although our findings do suggest that it can help control MF patches and plaques and, to a lesser extent, tumors. This combined therapy also seems to be safe in patients with tumor-stage MF and it was an option while romidepsin takes effect or to enhance its effect. Although it increases hematological toxicity in patients with SS. Received: 13 November 2020 Revised: 15 February 2021 Accepted: 11 March 2021