Effect of lenalidomide treatment on clonal architecture of myelodysplastic syndromes without 5q deletion

Abstract

Key Points• Lenalidomide treatment has variable transient effects on the clonal architecture of myelodysplastic syndromes without 5q deletion.• Lenalidomide is unlikely to eradicate myelodysplastic clones characterized by combinations of SF3B1, TET2, DNMT3A, and ASXL1 mutations.Non-del(5q) transfusion-dependent low/intermediate-1 myelodysplastic syndrome (MDS) patients achieve an erythroid response with lenalidomide in 25% of cases. Addition of an erythropoiesis-stimulating agent could improve response rate. The impact of recurrent somatic mutations identified in the diseased clone in response to lenalidomide and the drug's effects on clonal evolution remain unknown. We investigated recurrent mutations by next-generation sequencing in 94 non-del(5q) MDS patients randomized in the GFMLen-Epo-08 clinical trial to lenalidomide or lenalidomide plus epoetin b. Clonal evolution was analyzed after 4 cycles of treatment in 42 cases and reanalyzed at later time points in 18 cases. The fate of clonal architecture of single CD34 1 CD38 2 hematopoietic stem cells was also determined in 5 cases. Mutation frequency was >10%: SF3B1 (74.5%), TET2 (45.7%), DNMT3A (20.2%), and ASXL1 (19.1%). Analysis of variant allele frequencies indicated a decrease of major mutations in 15 of 20 responders compared with 10 of 22 nonresponders after 4 cycles. The decrease in the variant allele frequency of major mutations was more significant in responders than in nonresponders (P < .001). Genotyping of single CD341 CD38 2 cell-derived colonies showed that the decrease in the size of dominant subclones could be associated with the rise of founding clones or of hematopoietic stem cells devoid of recurrent mutations. These effects remained transient, and disease escape was associated with the re-emergence of the dominant subclones. In conclusion, we show that, although the drug initially modulates the distribution of subclones, loss of treatment efficacy coincides with the re-expansion of the dominant subclone. This trial was registered at www.clinicaltrials.gov as #NCT01718379. (Blood. 2016; 127(6):749-760)

Mutational hierarchies in myelodysplastic syndromes dynamically adapt and evolve upon therapy response and failure

“…Our data confirmed the existence of a linear path of clonal evolution, but importantly, also uncovered previously unrecognized branching evolution leading to the emergence of genetically advanced MDS subclones during disease progression that are capable of mediating drug resistance. Although recently reported in the context of single MDS/CMML cases and other tumor entities, 32,39,[43][44][45][46][47][48][49] the observed frequency of this phenomenon was largely unrecognized in MDS so far. Moreover, we observed that treatment with drugs such as LEN, 5-aza, or temsirolimus was immediately followed by significantly elevated fluctuations in both the oligoclonal BM composition and clinical parameters.…”

“…[37][38][39] Our exhaustive analysis of a large cohort of 31 MDS patients in combination with our detection of mutated B cells in long-term xenoengrafted MDS hematopoiesis now provides definitive proof that genetically defined MDS HSC clones frequently contribute to lymphopoiesis. These findings raise important questions about the potential influence of intrinsically aberrant lymphopoiesis on the pathogenesis of MDS.…”

“…In recent years, our understanding of mutational landscapes in MDS greatly improved 6,7,[39][40][41] with studies suggesting linear subclonal evolution accompanied by continuous acquisition of molecular lesions as the putative main driver of disease progression. 41,42 However, the influence of drug treatment on the molecular plasticity of oligoclonal hierarchies remained poorly understood.…”

Efficacy and Safety of Lenalidomide for Treatment of Low-/Intermediate-1-Risk Myelodysplastic Syndromes with or without 5q Deletion: A Systematic Review and Meta-Analysis

“…The presence of a DNMT3A mutation could be predictive of better responses of lower-risk MDS patients without 5q deletion to the lenalidomide treatment. Especially, it was independently related to HI-E [36]. Further prospective studies are mandatory to predict which MDS patients may respond to lenalidomide.…”

Splicing factor mutations in MDS RARS and MDS/MPN-RS-T

“…However, an analysis of clonal architecture of non-del(5q) MDS patients who were treated with lenalidomide alone or lenalidomide plus epoetin-β showed that lenalidomide is unlikely to eradicate MDS clones bearing SF3B1 mutations [68]. The telomerase inhibitor imetelstat is another class of drug that is suggested to show preferential effects against myelofibrosis patients with SF3B1 or U2AF1 mutations versus patients without these mutations (complete response rate, 38 versus 4%, p = 0.04) [69].…”