Clofarabine Followed by Lenalidomide for Treatment of High Risk Myelodysplastic Syndromes and Acute Myeloid Leukemia

High risk myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML) and acute myelogenous leukemia (AML) are hetereogeneous myeloid malignancies that are associated with a poor prognosis. Due to advanced age and medical comorbidities, the majority of MDS, CMML, and AML patients are not candidates for potentially curative standard treatments such as allogeneic stem cell transplantation (SCT) or intensive chemotherapy (ICT). New therapeutic approaches that improve response rates, have lesser toxicity, and extend survival are clearly needed for high risk MDS and AML patients.

Clofarabine is a myelosuppressive, second generation purine nucleoside analogue which has shown meaningful efficacy at variable dosing levels for high risk MDS and AML patients with a favorable toxicity profile compared to intensive chemotherapy. Lenalidomide is an oral structural analogue of thalidomide with a complex mechanism of action including immunomodulatory, anti-angiogenic, and direct cytotoxic effects which is a well-established treatment for MDS and has shown agent single efficacy at higher doses for AML. Lenalidomide s therapeutic benefit in AML has been the greatest in patients with low presenting total leukocyte and circulating blast counts. We hypothesize that the initial cytoreductive effects of clofarabine may augment the effectiveness of subsequent lenalidomide therapy and create a favorable immunologic milieu for patients eligible for lenalidomide maintenance therapy. This open-label, single institution phase I trial will evaluate a sequential combination of IV clofarabine with oral lenalidomide for the treatment of high risk MDS, CMML, and AML. Subjects will receive a single course of IV clofarabine (5 milligrams per metered square per day times 5) for cytoreduction. This will be followed by oral lenalidomide consolidation with dose escalation from 25 mg daily for 21/28 days for 1 cycle in the first cohort up to 50 mg daily for 28/28 days for 2 cycles in the fourth cohort. In the absence of dose limiting toxicity or disease progression, Subjects will receive lenalidomide maintenance, starting at a dose of 10 mg daily in 28 day cycles, with dose adjustments, for up to 12 cycles.

The overall objective is to determine the safety of sequential therapy with clofarabine and lenalidomide in subjects with high risk MDS, CMML, and AML. The primary study endpoint will be the toxicity profile of this novel treatment combination in each cohort. Secondary endpoints will include characterization of response and duration, overall survival, and the feasibility of maintenance lenalidomide therapy for responding subjects.