Safety and efficacy of lenalidomide in combination with rituximab in recurrent indolent non-follicular lymphoma: final results of a phase II study conducted by the Fondazione Italiana Linfomi.

The efficacy of rituximab alone in the treatment of B-cell non-Hodgkin lymphoma (NHL) has been well estab-lished since 1999. Furthermore, the addition of rituximab to conventional chemotherapy improved survival outcome. Lenalidomide (Celgene Corp., Summit, NJ, USA) a potent immunomodulatory agent, has shown efficacy in patients with relapsed or refractory indolent NHL. The combination of these agents showed synergistic effects in vitro and in animal models. Thus, in 2009, we started a Phase II study to test the combination of rituximab and lenalidomide in patients with marginal zone lymphoma (MZL), lymphoplasmacytic lymphoma (LPL), and small lymphocytic lymphoma (SLL). The study started under the patronage of the Intergruppo Italiano Linfomi (IIL) and was completed after the merge of the IIL in the Fondazione Italiana Linfomi (FIL). This study was an investigator-initiated, open label, multicenter, phase II trial, conducted from 2009 to 2013 at 16 Italian institutions (INFL08/RV-LYM-PI 378, clinicaltrials.gov identifier 01830478, EudraCT number 2008-001591-80). Eligibility criteria were: age 18 years or older and biopsy-proven diagnosis of indolent non-follicular lymphoma, including MZL, LPL and SLL, according to the World Health Organization Classification of Tumors of Hematopoietic and Lymphoid Tissue. Patients with extranodal gastric MZL were excluded. The inclusion criteria were: relapsed after 2 or 3 prior lines of rituximab-containing immunotherapy with measurable disease; Eastern Cooperative Oncology Group performance status of 2 or under, and adequate organ function. All patients provided written informed consent The study protocol was approved by the ethics committee of each participating institution. The study was conducted according to the provisions of the Declaration of Hel-sinki, the International Conference on Harmonization, and the Guidelines for Good Clinical Practice. Patients received oral lenalidomide 20 mg/day; days 121. Rituximab (375 mg/m) was administered once on day 14 of every course. Treatment was repeated every 28 days for up to 6 courses. To avoid tumor flare, patients with SLL started lenalidomide at a dose of 10 mg/day, with a monthly 5 mg increase, up to 20 mg/day in the absence of toxicity. The primary end points were safety and efficacy. Efficacy was evaluated in terms of the overall response rate (ORR) and of tumor control rate (TCR). ORR was defined as the ratio between the number of patients that achieved complete response (CR), CR unconfirmed (CRu), and partial response (PR) over all eligible patients. TCR was defined as the ratio between the number of patients who achieved at least stable disease (SD) over all the eligible patients. Both ORR and TCR were evaluated at four weeks after the end of treatment. Tumor response was defined according to the 1999 Cheson criteria. Safety was based on laboratory parameters and adverse events. Toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE version 3.0, http://ctep.cancer.gov/reporting/ctc.html); toxicity was reported on an individual patient basis. Secondary end points were progression-free survival (PFS) duration of remission (DoR) and overall survival (OS).