Phase 1 Study of Lenalidomide and Decitabine for High and Intermediate 2 Risk MDS

Myelodysplasticsyndromes (MDS) are a heterogeneous group of hematopoietic diseases characterized by peripheral blood cytopenias and increased apoptosis of precursor cells in the marrow. Current therapies are focused on disease control, with no cure other than allogeneic stem cell transplantation. Decitabine is known to act as a hypomethylator while lenalidomide has multiple affects, including actions on the stromal marrow cell interaction. It is hypothesized that the combination of decitabine with lenalidomide may show synergistic results. Thus we performed a phase 1 study to estimate the maximally tolerated dose of lenalidomide in combination with decitabine in patients with high risk MDS.

Adults with primary or secondary MDS, including all subcategories and IPSS risk categories of INTERM-2 or High were eligible, including those who had prior therapy even if they progressed with prior exposure to hypomethylators. Patients also must have had CrCl ³ 60ml/min, and liver function test ² 3 × ULN. Following a standard phase 1 3+3 design, patients received decitabine 20mg/m2 over one hour intravenously daily for 5 days, with cycles repeated every 28 days. Lenalidomide was given in cohorts at doses of 5mg, 10mg, or 15mg daily for days 1–21 of the 28 day cycle. Patients were analyzed during the first cycle for dose limiting toxicity and responders that did not have a DLT could continue until progression or toxicity required discontinuation. DLT was defined as any non-heme grade 3 toxicity (CTC v. 4) that was study related lasting ³ 7 days or grade 4 of any duration or Neutropenia or thrombocytopenia ³ grade 3 due to study agents >14 days.

Patients and disease characteristics are noted in the table below. Twelve evaluable patients were treated, 5 had prior therapy (all included a hypomethylator). The combination seems tolerable, though toxicities included the following: 4 patients had a grade 3 febrile neutropenia (2 in cohorts 1 and 3 each), 2 with grade 2 rash (1 cohorts 1 and 3 each), and 4 with grade 3 anorexia/fatigue (1 cohort 1, 2 cohort 2, 1 cohort 3).

With median duration of follow up for survivors of 6 months (2–38months) the median number of cycles of therapy was 4 (1–16) with 3 continuing on therapy at this time. Responses were noted at all dose levels, including those with prior hypomethylator exposure (see table 1): 3 (25%) complete responders, 1 partial responder (8%), and 3 (25%) with stable disease. The Median duration of response was 5 months (1–21) with 3 continuing in response.

In patients with high risk MDS, the combination of decitabine and lenalidomide is tolerable and provides encouraging response rates in this population. The MTD was determined as decitabine 20mg/m2 daily for 5 days with lenalidomide 10mg daily for days 1–21 of a 28 day cycle. Larger studies of this combination are warranted.

*MTD

Rizzieri:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Beaven:Celgene: Research Funding.