A Phase I Study of the Combination of Decitabine with Lenalidomide for Patients with High Risk (IPSS Int-2 or High) Myelodysplastic Syndrome

Decitabine and lenalidomide have demonstrated single agent activity in patients with myelodysplastic syndromes (MDS). The addition of lenalidomide to decitabine in patients with high risk MDS may improve responses through distinct mechanisms. A phase I study of azacytidine and lenalidomide has previously demonstrated the feasibility of the combination of a hypomethylating agent with lenalidomide and did suggest higher response rates. (Sekeres M, et al. JCO 2010)

We conducted a 3×3 cohort design. Patients with high risk MDS who had received prior hypomethylating agent were eligible for the study. Patients were treated with decitabine 20mg/m2 IV over 1 hour daily on days 1–5. Lenalidomide was escalated in each cohort using a dose of 5 mg po daily for 21 days in cohort 1 and 10 mg po daily for 21 days in cohort 2. Additional cohorts using 15 mg and 25 mg of lenalidomide are planned but have not yet been entered. Cycles were repeated every 28 days if count recovery was adequate. Toxicity was assessed by NCI CTCAE v3.0 criteria. Responses (a secondary objective) were assessed using IWSG criteria.

Seven patients have been entered into this study and are evaluable for toxicity and response. Median age is 74 years (69–77). Because of 1 death in cohort 1 (felt to be due to respiratory failure in a patient with severe COPD and not related to study drugs), the cohort was expanded to 6 patients. No other deaths occurred on study. One patient has been entered on cohort 2. No grade 3 or 4 toxicities were seen in the other 6 patients. Myelosuppression is common but does not appear to be worse than decitabine alone. In the 6 patients in which response could be assessed, there were 2 complete responses (CRs) and 3 partial responses (PRs). One patient progressed to AML after one cycle. Responses were seen in the 3 patients that had received prior treatment with hypomethylating agents (1 CR, 2 PR). Duration of responses ranged from 4 months to 16 months.

The combination of decitabine and lenalidomide has been well tolerated in patients with high-risk MDS. The maximum tolerate dose has not been reached, although myelosupression is common. Good responses have been seen even in patients with prior treatment with a hypomethylating agent.

Off Label Use: Decitabine in combination with lenalidomide for high risk myelodysplastic syndrome. Rizzieri:Celgene: Speakers Bureau.