Lenalidomide in Myelodysplastic Syndromes: An Erythropoiesis-Stimulating Agent or More?

Abstract

Anemia remains the most challenging clinical manifestation to treat in patients with lower-risk myelodysplastic syndromes (MDS). Erythropoiesis-stimulating agents are widely used to treat anemia in such patients, but less than one third respond to these agents, and the duration of response is often limited. Lenalidomide, a second-generation immunomodulatory drug (IMiD), is approved by the US Food and Drug Administration for treatment of transfusion-dependent anemia in lower-risk MDS patients with deletion 5q chromosomal abnormality. Lenalidomide also has meaningful clinical activity in lower-risk patients without deletion 5q. The experience with lenalidomide in MDS is a modern example of reciprocal translational research, in which bench work led to an approved drug for patients, and clinical observations led to better understanding of the mechanism of action of the drug itself and even more understanding of the biology of the underlying disease. This article reviews the clinical experience with lenalidomide, highlighting recent understanding of the dual karyotype-dependent mechanisms of action.

Establishing Rps6 hemizygous mice as a model for studying how ribosomal protein haploinsufficiency impairs erythropoiesis

“…As erythropoiesis improved in control mice, it is unclear if the improvement in Rps6 heterozygously-deleted mice is specific. The lack of understanding of the mode of action of lenalidomide in 5q-syndrome MDS, the suggestion that the erythroid response may be mediated in part by haploinsufficiency of two phosphatase genes located on 5q[23] independent of a ribosome biogenesis defect, and the drug’s clinical risk of causing neutropenia and thrombocytopenia underscore the importance of animal models for testing its therapeutic efficacy in DBA. Our studies establish Rps6 heterozygously-deleted mice as one available model.…”

Health care utilization and risk of infection and bleeding among patients with myelodysplastic syndromes with/without transfusions, and with/without active therapy

“…Moreover, these results suggest that active therapy may help to lower supportive care requirements, and may also help to reduce disease-specific resource utilization by lowering the risk of MDS-related adverse clinical events. Interestingly, recent data suggest that active therapy, and not supportive care [14,15], may in fact alter the natural history of these bone marrow failure malignancies [8,16,17]. It appears that both transfusion needs and active therapy may contribute to the utilization of disease-specific medical resources by this group of patients.…”

Targeted therapy in rare cancers—adopting the orphans

“…96 In patients with del(5q) MDS, lenalidomide suppresses abnormal clonal expansion by inhibiting M-phase inducer phosphatase 3 and protein phosphatase 2A, resulting in lenalidomide-specific apoptosis. 97,98 Lenalidomide regulates other critical pathways, including regulators of the cytoskeleton and tumoursuppressor genes, encoded for within the del(5q) region, which may account for some of its direct antitumour and immunomodulatory properties. 97,98 A randomized phase III study of lenalidomide versus placebo in red blood cell transfusion-dependent patients with low-risk or intermediate-risk MDS and del(5q) showed that more patients in the lenalidomide groups achieved transfusion independence (primary end point) compared with placebo (56.1% and 42.6%; P <0.001), while also attaining high cytogenetic response rates of 50.0% (lenalidomide 10 mg) versus 25.0% (lenalidomide 5 mg; P = 0.066).…”