Targeting the CLL microenvironment with immunomodulatory agents like lenalidomide results in antileukemic activity. Addition of lenalidomide to an effective regimen such as fludarabine and cyclophosphamide (FC) could further increase therapeutic activity. On this basis, we designed a study aimed at evaluating the activity and safety profile of FC combined with lenalidomide (FCL) in previously treated CLL patients.
Treatment consists of 6 monthly courses of FC (F, fudarabine: 30 mg/m2 iv and C, cyclophosphamide: 250 mg/m2, days 1–3) combined with 14 consecutive days of lenalidomide administration (days1-14). The first phase of this study was focused on defining the maximum tolerated dose (MTD) of lenalidomide given in combination with FC. In all patients, lenalidomide was given at the starting dose of 2.5 mg daily during the first course. For the subsequent courses the dose of lenalidomide was progressively escalated to reach a maximum daily dose of 5 mg, 10 mg and 15 mg, respectively, in each 3 cohorts of 3 patients, unless a dose limiting toxicity (DLT) was experienced. DLT was defined as persistent and severe hematologic toxicity, grade ≥2 tumor lysis syndrome (TLS), grade ≥3 tumor flare reaction (TFR) or other grade ≥3 toxicities. Supportive treatment included primary prophylaxis of granulocytopenia (G-CSF, days 6–11), PC and HVZ prophylaxis, thromboembolic prophylaxis with low molecular weight heparin (enoxaparin, 4000 units/sc/day) and TLS prophylaxis (oral hydration, allopurinol 300 mg/day, days -3 - 90). Strict contraceptive measures were required for all males and females with childbearing potential. At present, 9 relapsed CLL patients with advanced disease have been included in the first phase of the study focused on identifying the MTD for lenalidomide given in combination with FC. The median age was 63 years (range: 50–68); the median number of prior treatments was 2 (range: 1–2). All patients but 1 had been previously treated with the FC/FCR regimens; the majority showed a considerably high white blood count (range: 33–216 × 109/L) and 2 had a bulky nodal disease. Adverse cytogenetic abnormalities were detected by FISH in 5 cases (17p-, 2 cases; 6q-, 3 cases). While no DLT was observed in 3 patients who reached the 5 mg dose of lenalidomide given in combination with FC, a DLT was recorded in 2 of 3 patients who received 10 mg of lenalidomide (pneumonia; grade 3 hepatic toxicity). The 5 mg dose of lenalidomide was tested in 3 further patients with no DLT. Thus, 5 mg of lenalidomide was defined as the MTD of lenalidomide given in combination with FC. A marked reduction of white blood count was observed within the first 2 weeks of treatment in all cases but 1. A response was observed in 6 patients (67%; CR, 3; PR, 3), while a treatment-failure was recorded in 3 cases (SD, 2; Richter's syndrome,1). Despite G-CSF prophylaxis, the majority of patients experienced transient grade 3–4 neutropenia. Grade 1 fatigue and constipation were frequently observed during the first course of treatment. A transient grade 1 TFR was documented, while no episodes of TLS and thrombosis were recorded. Our findings indicate that 5 mg daily is the MTD of lenalidomide given in combination with FC. Initial responses suggest that FCL is a promising investigational regimen for patients with CLL who have failed prior treatment with fludarabine-based combinations. In the ongoing phase 2 of this study 32 patients are planned to receive 5 mg of lenalidomide in combination with FC.
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