Inclusion of RBC-Transfusion Dependency Improves the Prognostic Value of Revised-IPSS (R-IPSS) in MDS Patients

Abstract

S44 Context: The clinical implementation of next-generation sequencing has allowed for the quantitative detection of clinically significant somatic mutations in myelodysplastic syndromes (MDS). However, the clinical relevance of variant allele frequency (VAF) for the majority of mutations is unknown. Objective: To determine the importance of VAF in highly recurrent gene mutations for which genotype-phenotype relationships have been characterized in MDS and the impact of TP53 VAF on survival. Design: We profiled TP53 and up to 20 additional genes in our training set of 219 patients with MDS or secondary AML. Clinical variables and outcomes of these patients were characterized at the time of sample procurement. VAF was evaluated for genes with well described genotype-phenotype relationships with findings confirmed in a validation cohort. Fisher’s exact and Mann-Whitney’s tests were used for comparative analyses. Kaplan-Meier estimates were used to estimate overall survival and analyzed from the date of mutation identification. Results: When parsed by VAF, TP53 VAF strongly predicted for complex cytogenetics in both the training (P 1⁄4 .001) and validation set (P 40% had a median overall survival (OS) of 124 days versus an OS that was not reached in patients with VAF 40% was an independent covariate (HR, 1.61; P < .0001). For validation, TP53 VAF predicted survival in an independent cohort (HR, 4.94, P 1⁄4.01). Additionally, SRSF2 VAF predicted the presence (P 1⁄4 .003) and magnitude (P 1⁄4.004) of monocytosis, RUNX1 VAF with thrombocytopenia (P1⁄4.01), and SF3B1 with ringed sideroblasts (P < .0001). Conclusions: Allele burden influences phenotype penetrance across multiple genes. Notably, TP53 VAF improves prognostic precision compared to binary mutational analysis alone. Our study indicates that VAF should be incorporated in patient management and risk stratification in MDS.