Frequency and prognostic impact of KIT and other genetic variants in indolent systemic mastocytosis

Javier I Muñoz-González, Iván Álvarez-Twose, María Jara-Acevedo, Ana Henriques, Esther Viñas, Carlos Prieto, Laura Sánchez-Muñoz, Carolina Caldas, Andrea Mayado, Almudena Matito, Noelia Dasilva-Freire, Alberto Orfao and Andrés C. García-Montero

Key Points

  • D816V KIT allele frequency in BM, higher sβ2M levels and ASXL1/RUNX1/DNMT3A pathogenic mutations identify ISM cases at risk of progression.

  • Pathogenic mutations in the ASXL1/RUNX1/DNMT3A genes identify ISM cases with multilineal KIT and poorer prognosis.


Indolent systemic mastocytosis (ISM) patients have a normal life-expectancy, except for 5-10% cases that progress to more advanced SM (advSM) with a significantly poorer outcome. Mutations in genes other than KIT frequently found in myeloid neoplasms have been associated with a poorer outcome among advSM, while limited information exists about their frequency and prognostic impact in ISM. Here we investigated the frequency and prognostic impact of variants in 18 genes previously found to be altered in advSM, in 322 ISM patients (median follow-up of 5.7y) divided into a discovery (n=200) and a validation (n=122) cohort. Overall, 71 genetic variants were detected in 55/322 (17%) patients. Mutated ISM cases, particularly those carrying ASXL1, RUNX1 and/or DNMT3A pathogenic variant allele frequencies (VAF) {greater than or equal to}30%, displayed significantly shortened (p<.001) progression-free (PFS) and overall survival (OS) rates. Multivariate analysis showed that serum β2-microglobulin levels >2.5µg/mL (hazard ratio -HR-: 9.8; p=.001) together with a KIT D816V VAF {greater than or equal to}1% in bone marrow (HR: 10.1; p=.02) and pathogenic variants of ASXL1, RUNX1 and/or DNMT3A (A/R/D) VAF {greater than or equal to}30% (HR: 4.2; p=.02) were the best combination of independent predictors for PFS; In turn, A/R/D gene pathogenic VAF {greater than or equal to}30% was the only independent predictor for OS (HR: 51.8; p<.001). Based on these variables two scoring systems were built for risk-stratification of ISM at diagnosis with significantly different 10y PFS (100%, 91% and 0% for scores of 0, 1 and {greater than or equal to}2, respectively) and OS (100% vs 50% for scores of 0 and 1) rates.

  • Submitted November 19, 2018.
  • Revision received May 24, 2019.
  • Accepted May 23, 2019.