Preliminary Results of a Phase 1/2, Multi-Center, Open-Label Study (CLL- 001) Investigating a Stepwise Dose-Escalation Schedule of Lenalidomide in Relapsed or Refractory Chronic Lymphocytic Leukemia.

Lenalidomide is an immunomodulatory drug that has demonstrated therapeutic activity in 2 independent phase II trials in patients with relapsed or refractory chronic lymphocytic leukemia (CLL). Based on those data a new phase II trial (CC-5013-CLL-001) was designed to compare 25 mg versus 10 mg, the doses used in those completed phase 2 studies. Patients were randomized in the initial protocol design to treatment with either 25 mg of lenalidomide daily for 21 out of each 28-day cycle, or with 10 mg of lenalidomide daily for 28 out of each 28–day cycle. However, when 5 out of 18 patients enrolled developed tumor lysis syndrome (TLS) resulting in 2 fatalities the protocol was amended to a phase I/II trial to determine a safe dose and schedule (Moutouh-de Parseval et al. J Clin Oncol2007, 25: 5047). In this ongoing phase I dose escalation study the safety of several lenalidomide doses was investigated. Patients with prior treatment with an alkylating agent and who have failed fludarabine were started on 2.5 mg of lenalidomide daily, followed by slow intra-patient dose escalation to 5 mg after 28 days. Doses were then escalated as tolerated by 5 mg every 28 days by initial cohort of 6 patients, until the maximum tolerated dose escalation level (MTDEL) was defined or a maximum dose of 25 mg daily. Patients were treated until disease progression, and all patients received TLS prophylaxis with hydration starting 3 days prior to lenalidomide treatment and continuing for at least the first 3 cycles. Seventeen patients, with a median age of 66 years (range 50–76), have been enrolled on the amended protocol. Patients had a median of 4 prior therapies (range 2–14), 56.3% of patients were refractory to fludarabine and 31.3% had prior alemtuzumab therapy. Among these, 77% of patients had bulky lymphadenopathy. Treatment is continued in 13 patients, while 4 patients have discontinued treatment (2 lack of therapeutic effect, 1 grade 4 thrombocytopenia at 2.5 mg every other day in a patient with preexisting thrombocytopenia, and 1 withdrew consent). During therapy, common toxicities included ≥ grade 3 neutropenia [4/17 (23.5%) at 2.5 mg; 3/7 (42.9%) at 5 mg; 2/3 (66.7%) at 10 mg], ≥ grade 3 thrombocytopenia [2/17 (11.8%) at 2.5 mg daily], and tumor flare reaction [TFR; 4/17 (23.5%) at 2.5 mg; 1/7 (14.3%) at 5 mg]. TFR ≥ grade 3 occurred in 2 patients, in one patient at the 2.5 mg dose and in one at the 5 mg dose which was effectively managed with non-steroidal anti-inflammatory drugs, corticosteroids and/or temporary interruption of treatment. On the amended protocol, TLS has not been observed in any patient except 1 in whom laboratory findings consistent with TLS was observed at the 2.5 mg dose. The patient was able to continue treatment without TLS recurrence. To date, the MTDEL has not been reached. At the time of data collection patients were not yet evaluable for clinical response. Preliminary data presented here demonstrate the safety of lenalidomide therapy administered by a step-wise dose escalation with an initial 2.5 mg starting dose in patients with heavily treated CLL. We further observe that use of prophylaxis, as well as frequent monitoring of patients, was effective in decreasing the incidence of TLS. Further data are needed to confirm the optimal dose for lenalidomide in the treatment of CLL. Additional safety data observed in the patients treated on this study will be presented at the meeting.