Daily Alternating of Immunomodulating Agents and Rituximab in Therapy for Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma, and Mantle Cell Lymphoma: The THRIL (Thalidomide [TH], Rituximab [RI], and Lenalidomide [L]) Regimen
Authors: Coleman Morton , Martin Peter , Ruan Jia , Niesvizky Ruben , Leonard John P. , Elstrom Rebecca , Furman Richard R. 
Published: April 2020

Abstract
Introduction: Immunomodulatory drugs thalidomide and lenalidomide, alone or in combination with other agents, have shown activity in treatment of chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and mantle cell lymphoma (MCL). Lenalidomide when used as part of the 21 day on, 7 day off schedule, may be limited by marrow toxicity, whereas continuous use of thalidomide is often limited by neurologic toxicity. Interestingly, lenalidomide is not associated with neurologic toxicity, and thalidomide is not associated with marrow toxicity. By alternating thalidomide and lenalidomide daily, adverse events seen with each drug may be attenuated, as total dosage of either drug is reduced. Preliminary data suggest that thalidomide and lenalidomide are not cross-resistant. The two agents may have synergistic activity, resulting in improved responses. This phase II study aims to assess efficacy and safety of THRIL (thalidomide [TH] rituximab [RI], and lenalidomide [L]) combination therapy in patients with CLL/SLL, or MCL.
Methods: Patients were treated with the THRIL regimen, which consists of a 50 mg/day thalidomide oral dose, alternated with oral lenalidomide 10 mg/day. Rituximab 375 mg/m2/week was given intravenously for 4 weeks, every 6 months, for up to 4 courses. Patients received 162 mg/day aspirin prophylaxis against venous thromboembolism.
Results: Of the 14 patients enrolled, 11 had CLL/SLL, and 3 had MCL; most had received at least 3 prior treatments. Median patient age was 71 years (range 58–9). Four patients had a complete response (CR) as seen by 4-color flow cytometry (n = 2) or bone marrow/computed tomography criteria (n = 2). Three patients had a partial response, and 3 had stable disease. With a median follow-up of 8 months (range 2–27), the median response duration was over 12 months (range 3–27+). The 2 patients with MCL who had a CR, relapsed after 6 and 9 months of therapy, respectively. Disease regressed with increased dosing to 100 mg/day thalidomide and 25 mg/day lenalidomide. Treatment was discontinued in 8 patients due to lack of response (n = 4), progressive disease (n = 2, including 1 patient who initially responded), and rash (n = 2). The THRIL regimen was associated with few adverse events; the only grade 3–4 adverse events were neutropenia and rash, each occurring in 2 patients. Four grade 2 tumor flare reactions were recorded, all in CLL patients, and each successfully treated with steroids. In each case the flares announced a response. No significant neurological adverse events or thromboembolic events were observed. Lenalidomide therapy was paused briefly due to cytopenias in 4 cases.
Conclusion: Alternating thalidomide and lenalidomide in the THRIL regimen may be an effective method of reducing adverse events, while achieving responses in patients by enabling longer continuous use of immunomodulating agents. Further investigation is needed to assess whether enhanced responsiveness results from combined sequential use of thalidomide and lenalidomide. Exploration of this regimen may be beneficial in other diseases that respond to lenalidomide and thalidomide, particularly myeloma and myelodysplasia.