Mutations and karyotype predict treatment response in myelodysplastic syndromes

Abstract

We examined the influence of mutations and karyotype on conventional treatment response, specifically hematological improvement in anemia, in primary myelodysplastic syndromes (MDS). Cytogenetic and next generation sequencing (NGS)-derived mutation information was available in 357 patients (median age 74 years; 70% males); the revised international prognostic scoring system risk distribution was very high in 11%, high 15%, intermediate 17%, low 40% and very low 16%. At least one mutation was detected in 81% of patients; most frequent were SF3B1 (32%), ASXL1 (27%), TET2 (24%) and U2AF1 (15%). At median follow-up of 24 months, treatment with hypomethylating agents (HMAs) was documented in 121 (34%) patients, lenalidomide (LEN) in 55 (15%), and erythropoiesis stimulating agents (ESAs) in 136 (38%). ASXL1 mutations adversely affected response to HMAs (27% vs 48%; P = 0.02) and LEN (9% vs 43%; P = 0.04), but not ESAs (P = 0.6). LEN response was also adversely affected by U2AF1 mutations (0% vs 42%; P = 0.02) and high risk karyotype (0% vs 41% in intermediate vs 47% in low risk; P = 0.01). Patients with SF3B1 mutations were more likely to respond to LEN (56% vs 27%; P = 0.04). Contrary to previous reports, we found no association between TET2 mutations and HMA treatment response (40% vs 41%; P = 0.9), even in the absence of ASXL1 mutations (P = 0.4).We conclude that ASXL1 mutations in MDS predict inferior response to treatment with both HMAs and LEN; response to LEN was also compromised by U2AF1 mutations and high risk karyotype; SF3B1 mutations identified patients likely to respond to LEN.

Integrating the “Immunome” in the Stratification of Myelodysplastic Syndromes and Future Clinical Trial Design

“…Although earlier studies reported a favorable effect of TET2 mutations on response rates, 102,103 this association was not confirmed in a different cohort. 104 Finding predictive biomarker(s) for response to therapy is of particular relevance for the elderly population, which often displays lower response and higher toxicity rates. However, finding a magic "fits all" predictive biomarker in MDS is an unlikely scenario, considering the complexity of the disease and the role of several genetic, immunologic, and environmental factors in its pathophysiology.…”

In MDS, is higher risk higher reward?

“…63 In contrast, the higher response rate to azacitidine reported in patients carrying TET2 mutations 64 has not been consistently confirmed. 62,65 Novel treatment approaches…”

Ten‐eleven translocation‐2 affects the fate of cells and has therapeutic potential in digestive tumors

“…Mutated TET2 showed a higher response rate to azacitidine in MDS and low blast count AMLs 66 . TET2 mutations occurred in early disease evolution in MDS 62 , 67 , 68 . TET2 mutations were also found in T cell lymphomas 69 , 70 and diffuse large B‐cell lymphoma 71 , 72 .…”