Lenalidomide as Initial Treatment of Elderly Patients with Chronic Lymphocytic Leukemia (CLL)

CLL is a disease of the elderly, 53% of the patients are older than 70 years at diagnosis. Despite elderly patients representing the largest proportion of patients living with CLL, they are underrepresented in clinical trials and the best frontline treatment strategy for this group of patients has not been defined. Lenalidomide (Revlimid) is an immunomodulatory drug used in the treatment of MDS and MM. Based on the clinical efficacy demonstrated in patients with relapsed or refractory CLL (Chanan-Khan et al. JCO 2006, Ferrajoli et al. Blood 2008) we designed a phase II study to evaluate the efficacy and tolerability of lenalidomide as initial therapy of older patients with CLL. Patients were eligible for this study if age 65 or older and met indications for treatment according to the 1996 NCI-WG guidelines. Standard inclusion criteria were required in terms of organ function and performance status; patients with any neutrophil or platelet count were eligible. Prior to study entry patients were evaluated for genomic aberrations by conventional cytogenetic and FISH analysis, IgV_H mutation status and ZAP-70 expression. All patients received lenalidomide orally, at the dose of 5mg daily for the first 56 days. Lenalidomide dose could then be titrated up by 5mg increments every 28 days to reach a maximum dose of 25mg daily. Allopurinol 300 mg daily was administered from day 1 to 14 as tumor lysis prophylaxis. Forty-three patients have been registered to date. Median age is 72 years (range 66–85), 18 patients (42%) had Rai stage III–IV disease. The median beta-2-microglobulin was 4.5 mg/dL (range 2–10.2) and 13 patients (30%) carried unfavorable genomic abnormalities (17p deletion in 3 patients, 11q deletion in 8 patients), 19 patients (44%) had unmutated IgV_H, and Zap-70 immunohistochemistry was positive in 19 patients (44%). Thirty-five patients are evaluable for response having received treatment for at least 3 months. Nineteen patients achieved a partial response according to the 1996 NCIWG criteria for an overall response rate of 54%, 14 patients (40%) had stable disease and 2 patients (6%) experienced disease progression after 4 and 5 months respectively. Treatment with lenalidomide rapidly reduced the number of circulating lymphocytes: 47% of the patients achieved a blood CR and 38% a blood PR. Bone marrow evaluation was performed in patients that achieved a blood CR and residual disease was detected. Thirty-nine patients are evaluable for toxicity having received treatment for at least 2 months: myelosuppression (grade 3–4 neutropenia and/or thrombocytopenia) occurred in 10 patients (26%). Infectious complications were observed in 3 patients: neutropenic fever in 2 and pneumonia in 1. Tumor flare reactions were observed in 17 patients (44%) and were limited to grade 1–2 and managed with oral steroids, tumor lysis syndrome was not observed. Thirty-seven patients (84%) continue on treatment, 2 patients discontinued after 6 and 8 months because of toxicity (rash and fatigue). All patients registered on this study are alive. In conclusion, our early results indicate that lenalidomide given as continuous therapy at a start dose of 5 mg followed by slow dose escalation is safe and well-tolerated as initial therapy by elderly patients with CLL. Accrual to this study is ongoing.