Myelodysplastic syndromes with 20q deletion: incidence, prognostic value and impact on response to azacitidine of ASXL1 chromosomal deletion and genetic mutations

Summary In myelodysplastic syndromes (MDS), the 20q deletion [del(20q)] may cause deletion of the ASXL1 gene. We studied 153 patients with MDS and del(20q) to assess the incidence, prognostic value and impact on response to azacitidine (AZA) of ASXL1 chromosomal alterations and genetic mutations. Additionally, in vitro assay of the response to AZA in HAP1 (HAP1 WT ) and HAP1 ASXL1 knockout (HAP1 KN ) cells was performed. ASXL1 chromosomal alterations were detected in 44 patients (28·5%): 34 patients (22%) with a gene deletion ( ASXL1 DEL ) and 10 patients (6·5%) with additional gene copies. ASXL1 DEL was associated with a lower platelet count. The most frequently mutated genes were U2AF1 (16%), ASXL1 (14%), SF3B1 (11%), TP53 (7%) and SRSF2 (6%). ASXL1 alteration due to chromosomal deletion or genetic mutation ( ASXL1 DEL / ASXL1 MUT ) was linked by multivariable analysis with shorter overall survival [hazard ratio, (HR) 1·84; 95% confidence interval, (CI): 1·11–3·04; P = 0·018] and a higher rate for acute myeloid leukaemia progression (HR 2·47; 95% CI: 1·07–5·70, P = 0·034). ASXL1 DEL / ASXL1 MUT patients were correlated by univariable analysis with a worse response to AZA. HAP1 KN cells showed more resistance to AZA compared to HAP1 WT cells. In conclusion, ASXL1 alteration exerts a negative impact on MDS with del(20q) and could become useful for prognostic risk stratification and treatment decisions.