Final Results of the Phase I Study of Lenalidomide In Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL-001 Study)

Patients who relapse after fludarabine-based treatments have poor prognosis. These patients have deteriorating immune functions with high infection rates resulting from progressing disease complicated further by ineffective and often immunosuppressive therapies. Two phase II studies in patients with relapsed or refractory (rel/ref) CLL at starting doses of 10 mg or 25 mg daily of lenalidomide (Len) demonstrated promising responses. A phase II/III study was initiated to assess Len 10 mg/d vs 25 mg/d given continuously for 21 days of a 28-day cycle. Four cases of serious tumor lysis syndrome (TLS) prompted an independent data monitoring committee to amend the protocol into a phase I trial (de Parseval et al., JCO 2007) Here we present results from this amended study.

Eligible patients had rel/ref CLL, received prior treatment with an alkylating agent and fludarabine, and progressed during or ≤ 12 months after completing fludarabine-based treatment. Primary objective was to determine whether Len 2.5 mg was a safe starting dose and the maximum tolerated dose escalation level (MTDEL). Prophylaxis with allopurinol and hydration were employed as part of an aggressive monitoring plan for TLS prevention. All patients initiated Len at 2.5 mg/d with subsequent dose escalation to 5 mg/d after 28 days with further dose escalations in 5 mg increments performed every 28 days until MTDEL was defined, or the maximum targeted 20 mg/d dose level attained. The first 6 patients at 10, 15 and 20 mg/d dose levels were considered a cohort and could not escalate beyond that dose level for the duration of treatment. Treatment continued until disease progression or unacceptable toxicity.

The redesigned phase I study enrolled 52 patients with a median age of 65 years (range, 37–80) and bulky disease (> 5 cm) in 70%. Cytogenetic data was available for 46 patients, of whom 22 (48%) had high-risk disease: 8 (17%) had del(17p), 12 (26%) had del(11q), 2 had both. Patients were heavily pretreated with a median of 4 prior therapies (range, 1–14); 54% were fludarabine refractory (no-response/relapse ≤ 6 mo), 42% had prior FCR or PCR and 21% had prior alemtuzumab. The TLS prevention strategy resulted in only 2 (3.8%) cases of TLS, both observed at 2.5 mg/d (1 patient with Gr.2 and another with lab TLS). Gr.3/4 tumor flare occurred in 5 (9.6%) patients and was managed with NSAIDs or low-dose steroids. The most common Gr.3/4 adverse events (AEs) included neutropenia (65%) and thrombocytopenia (33%). Febrile neutropenia occurred in 4 (8%) patients. Gr.3/4 infections were observed in 21 (40%) patients; 10 (19%) patients developed pneumonia and 3 developed sepsis; 2 cases of sepsis-related death at day 37 and 94 of therapy were also noted but deemed unrelated to study drug by the investigators. Reasons for study discontinuation included disease progression (37%), AEs (29%), consent withdrawal (15%), death (4%), and other reasons (10%). For 16 (31%) patients, 2.5 mg/d was the maximum dose reached and 22 (42%) patients were unable to escalate beyond 5 mg/d. Gr.4 neutropenia was the primary reason for delay in dose escalation. By intent-to-treat (ITT) analysis, 6 patients (12%) had a partial response (NCI-WG 1996), 30 patients (58%) had stable disease and 13 patients (25%) progressed; 3 patients were non-evaluable. Median duration of treatment was 3.1 months (range, 0.07–18.4) and the median time to response was 4.3 months (range, 2.8–7.4). Responses were observed at 10 mg/d (n=3), at 15 mg/d (n=1), and at 20 mg/d (n=2); Median PFS (ITT) was 5.5 months and median PFS for responders was 12 months. Three patients still remain on therapy.

We conclude that a Len starting dose of 2.5 mg/d appears safe, feasible and can be safely titrated to 20 mg/d (maximum intended dose). The MTDEL was not reached at 20 mg/d. Based on the response rate reported in this study, a higher starting dose, such as previously reported by Chanan-Khan et al (JCO 2006) and Ferrajoli et al (Blood 2008), may be needed to achieve clinical efficacy, particularly for patients with high-risk disease. Adequate TLS prophylaxis and monitoring allows for higher starting doses to be investigated. To identify a safe and clinically active starting dose, the CLL-009 study is evaluating Len at starting doses of 5 mg/d, 10 mg/d, and 15 mg/d in the setting of rel/ref CLL.

Wendtner:Celgene, BayerSchering, Roche, Mundipharma: Consultancy, Honoraria. Off Label Use: off-label use of lenalidomide. Hillmen:Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alexion Pharmaceuticals: Consultancy; Bayer Schering: Consultancy. Mahadevan:Pfizer, millenium, Amgen: Honoraria. Stilgenbauer:Roche, Bayer, Celgene, GSK, Amgen, Mundipharma: Consultancy, Honoraria, Research Funding. Frankfurt:Bayer, Celgene: Research Funding, Speakers Bureau. Kimby:Roche, Bayer-Schering, Mundipharma: Membership on an entity's Board of Directors or advisory committees, lecturer. Gobbi:Novartis, Jansen Cilag, Roche, Celgene, Amgen: Consultancy, Research Funding, Speakers Bureau. Hurd:Celgene: Research Funding. Sekeres:Celgene: Research Funding, Speakers Bureau. Ferrajoli:Celgene: Honoraria, Research Funding. Shah:Celgene: Employment, Equity Ownership. Zhang:Celgene: Employment. Moutouh de Parseval:Celgene: Employment, Equity Ownership.