Mutational dynamics in patients with del(5q) MDS treated with lenalidomide prior to transfusion dependency—Molecular results from the Sintrarev clinical trial

Abstract Lenalidomide (Len) is the standard of care for red blood cell transfusion‐dependent (TD) patients with myelodysplastic syndromes (MDS) and del(5q). A Phase III clinical trial (SintraRev) demonstrated better efficacy of early treatment with Len in anemic del(5q) MDS patients prior to TD, but clonal evolution with this approach remained unexplored. We evaluated changes in mutational profiles of non‐TD del(5q) MDS patients treated with Len to assess whether early administration of Len could reduce or worsen the mutational burden in those patients. The molecular profile of patients included in the SintraRev trial was analyzed by targeted sequencing. Median follow up of patients was 60.6 months (interquartile range [IQR] 32.3–73.9). Next‐generation sequencing (NGS) was available in a total of 51 patients. SF3B1 (25.5%) and TP53 (21.3%) were the most frequently mutated genes. Clonal evolution during treatment among patients receiving Len or placebo (Pcb) was markedly different, with a 41.2% reduction in predominating clones in the Len arm, while remaining stable/increase in 100% of Pcb patients after 2 years. Mutations in SF3B1 and TP53 decreased/remained stable in the Len cohort, while only DNMT3A mutations increased under cytogenetic response. Regarding disease progression, only 20% of Len patients carrying TP53 mutations developed acute myeloid leukemia (AML), similar to the Pcb group (20%). Treatment with low‐dose Len in transfusion‐independent del(5q) MDS reduced the mutational burden of most genes and did not promote the expansion of preexisting clones or AML progression, especially TP53 ‐mutated clones. Early administration of Len in del(5q) MDS patients without TD may be an effective therapeutic approach with a manageable safety profile regarding clonal evolution.