Phase II Study of Lenalidomide Maintenance after Salvage Therapy for Relapsed or Refractory Peripheral T-Cell Lymphomas
Authors: Kim Seok Jin , Lee Myung-Won , Lim Sung-Nam , Kang Ka-Won , Yoon Sang Eun , Lee Yoo Jin , Kang Hye Jin , Lee Ho Sup , Kim Hyo Jung , Koo Hong Hoe , Shin Ho-Jin , Eom Hyeon-Seok , Won Jong-Ho , Kim Won Seog 
Published: December 2023

Introduction
Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of non-Hodgkin lymphomas. Their prognoses are still poor especially after they relapse or become refractory to the first-line treatment. Although salvage chemotherapy followed by autologous stem cell transplantation (ASCT) could be used for those relapsed or refractory patients, a substantial number of patients relapse even after ASCT. Furthermore, ASCT is not always possible because elderly or frail patients are not eligible for high-dose chemotherapy followed by ASCT. Thus, there are limited treatment option for patients who failed after ASCT or ineligible for ASCT because there is no established salvage treatment strategy and the impact of novel therapies in previous trials is unknown. Lenalidomide is widely used for the treatment of B-cell lymphomas as well as multiple myeloma, however, there are a few data about its efficacy in patients with PTCLs. Considering the mode of action is related with the immune modulatory effect on tumor microenvironment, lenalidomide might have a role in the management of relapsed or refractory PTCLs. Thus, we hypothesized that the use of lenalidomide as a maintenance therapy for patients who achieve response after salvage therapy might produce survival benefit comparable to that of ASCT after salvage therapy.
Methods
This is a prospective, open-labeled, single-arm, multi-center phase II study for relapsed or refractory PTCLs. The inclusion criteria are as follows: 1) Patients should have relapsed or refractory disease after at least one-line of prior chemotherapy; 2) Patients should not be eligible for ASCT; 3) Patients should have any subtypes of PTCLs including PTCL-not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), anaplastic lymphoma kinase (ALK)-positive or -negative anaplastic large-cell lymphoma (ALCL), extranodal NK/T-cell lymphoma (ENKTL), monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), hepatosplenic T-cell lymphoma (HSTL), and mycosis fungoides (MF). When patients eligible for the study achieve complete response (CR) or partial response (PR) after four cycles of any kinds of salvage chemotherapy, they can receive lenalidomide as a maintenance therapy. One cycle is 28 days consisting of lenalidomide 25 mg (day 1 - day 21). The treatment can be repeated until progression or the occurrence of intolerable toxicities (up to 2 years). The primary end point is 1-year progression-free survival, and the target rate is 35%.
Results
A total of 58 patients were enrolled between February 2019 and May 2023. The median age was 62 years (range: 20 - 83 years) and male was dominant (male: 35, female: 23). Patients who failed after ASCT or could not undergo ASCT due to their health status participated in the study. Patients with AITL (n = 23) and PTCL-NOS (15) accounted for 66% of patients whereas other subtypes included ENKTL (n = 4), ALK-negative ALCL (n = 3), MEITL (n = 3), HSTL (n = 2) and MF (n = 7). Prior to the maintenance therapy with lenalidomide, their disease status was CR (n = 22, 38%) and PR (n = 36, 62%). At the median follow-up of 20.7 months (95% CI: 17.7 - 23.7 months), seven patients completed the planned treatment of 2 years, and three patients withdrew their informed consents. Disease progression was documented in 21 patients during the maintenance and the other 20 patients discontinued the treatment due to their adverse events. At the time of analysis, seven patients were maintaining their treatments. Out of 36 patients with PR before maintenance, five patients achieved CR and 13 patients showed PR. However, 18 patients showed disease progression during maintenance. On the other hand, only three patients showed disease progression among 22 patients with CR prior to lenalidomide maintenance. Thus, 1-year PFS after enrollment was 49% and the median OS was (34.1 months, 95% CI: 7.9 - 18.6 months, Figure 1). The most common hematologic toxicities were neutropenia and thrombocytopenia; thus, dose-reduction should be done in patients with grade 4 hematologic toxicity. The most frequent non-hematologic toxicities included skin rash (40%), nausea (35%), and diarrhea (20%) however, they were manageable.
Conclusions
The lenalidomide maintenance might be a feasible and effective treatment approach for patients with relapsed or refractory PTCLs who are ineligible for ASCT or intensive consolidation chemotherapy.