Fig. 3.

A model linking MoA of lenalidomide with clinical data. In patients with del(5q) MDS, lenalidomide has a direct cytotoxic effect on abnormal del(5q) clones, by targeting haploinsufficient genes and their pathways. The high probability of cytogenetic remission in patients given lenalidomide reflects this potent cytotoxic effect on del(5q) cells. Because of the clonal nature of the disease, lenalidomide often has a myeloablative effect during early cycles of treatment resulting in high frequencies of cytopenic AEs [9, 11]. These AEs are transient and usually manageable on-treatment by dose reductions, delays, or concomitant myeloid growth factors. Once the del(5q) clone has effectively been eliminated, the BM is repopulated with lineages derived from a small number of normal CD34+ that are not eliminated by lenalidomide. A rapid return to normal hematopoiesis is facilitated by pleiotropic beneficial effects of lenalidomide on BM function [11, 47, 49]. The replacement of del(5q) precursors with normal ones leads to high rates of durable RBC-TI, usually with 4–5 weeks [9, 11]. Achievement of RBC-TI is associated with significant benefits in terms of improved overall survival, reduced probability of non-leukemic death, and improved QoL [9, 11]. Cytogenetic response is associated with reduced progression to AML [14]. However, del(5q) MDS is a heterogeneous disease, and some patients, including those treated with lenalidomide, remain at risk of AML progression due to clonal evolution [3, 4]. Therefore, patients must be carefully assessed for their probability of disease progression prior to initiating treatment. Also, regular monitoring of cytogenetic response in patients treated with lenalidomide is essential [44]. MoA mechanism of action, del(5q) deletion of the long arm of chromosome 5, MDS myelodysplastic syndromes, AE adverse event, BM bone marrow, RBC-TI red blood cell transfusion independent, QoL quality of life, AML acute myeloid leukemia