David P. Steensma, MD
Study Title: A Study of Lenalidomide Versus Placebo in Subjects With Transfusion Dependent Anemia in Low Risk Myelodysplastic Syndrome (MDS) Without Del 5Q (MDS-005)
Coordinator: The study is sponsored by Celgene, the manufacturer of lenalidomide.
Clinical Trials.gov Identifier: NCT01029262
Participating Centers: This international trial is being conducted at more than 70 medical centers in 14 countries, including nine centers in the United States and Canada.
Accrual Goal: 375 patients.
Study Design: The study is a phase III, double-blind, randomized, placebo-controlled trial of lenalidomide in patients with International Prognostic Scoring System (IPSS) low- or intermediate-1-risk MDS who do not have del(5q), have not responded to erythropoiesis-stimulating agent therapy and require regular red blood cell transfusions. Patients with severe neutropenia or thrombocytopenia are excluded. Enrolled patients are being randomized (2:1) to receive either 10 mg of lenalidomide daily or placebo for up to four years. The primary endpoint of the study is transfusion independence; secondary endpoints include safety and health-related quality of life. An ancillary study is assessing the capacity of an erythroid differentiation gene expression signature (based on microarray analysis) to predict treatment response.
Rationale: Lenalidomide was approved in December 2005 by the Food and Drug Administration for the treatment of patients with transfusion-dependent anemia due to IPSS low- or intermediate-1-risk MDS associated with a deletion 5q cytogenetic abnormality, with or without additional cytogenetic abnormalities. Approximately two-thirds of such patients will become transfusion-independent during lenalidomide therapy. Some patients with MDS lacking del(5q) also respond to lenalidomide, but transfusion independence in this group is uncommon and rarely durable (e.g., 26 percent transfusion independence rate and 41-week median response duration in the MDS-002 phase II study). The characteristics of responding non-del(5q) patients are poorly understood. In 2008, the European Medicines Agency refused marketing authorization for lenalidomide for the treatment of MDS-associated anemia, citing lack of randomized data and limited safety information. The MDS-005 randomized study, like the similarly designed and recently completed MDS-004 study in del(5q) patients, will provide additional safety and efficacy data, including controlled information on disease progression.
Comment: Lenalidomide is an expensive drug, and most MDS patients without del(5q) do not benefit from it. This study may give additional insight into which patients without del(5q) are most likely to respond favorably to lenalidomide, allowing for more cost-effective drug use. In addition, some investigators are concerned that lenalidomide may, in some cases, selectively suppress a slow-growing, indolent clone in the marrow of patients with lower-risk disease, thereby allowing a more aggressive clone (e.g., with a p53 mutation) to expand, precipitating clinically apparent disease progression. While this placebo-controlled study would be difficult to accrue to in the United States, where lenalidomide is widely used off-label in the non-del(5q) population, most of the study sites are located in countries where lenalidomide is not available.