Citations

Key Points Mutation patterns in blast phase MPN, including paired sample analysis, point to specific mutations with potential pathogenetic relevance. RUNX1 mutations predict inferior survival in blast phase MPN, independent of specific treatment strategies.

AbstractTo develop a genetic risk model for primary myelodysplastic syndromes (MDS), we queried the prognostic significance of next‐generation sequencing (NGS)‐derived mutations, in the context of the Mayo cytogenetic risk stratification, which includes high‐risk (monosomal karyotype; MK), intermediate‐risk (non‐MK, classified as intermediate/poor/very poor, per the revised international prognostic scoring system; IPSS‐R), and low‐risk (classified as good/very good, per IPSS‐R). Univariate analysis in 300 consecutive patients with primary MDS identified TP53, RUNX1, U2AF1, ASXL1, EZH2, and SRSF2 mutations as “unfavorable” and SF3B1 as “favorable” risk factors for survival; for the purposes of the current study, the absence of SF3B1 mutation was accordingly dubbed as an “adverse” mutation. Analysis adjusted for age and MK, based on our previous observation of significant clustering between MK and TP53 mutations, confirmed independent prognostic contribution from RUNX1, ASXL1, and SF3B1 mutations. Multivariable analysis that included age, the Mayo cytogenetics risk model and the number of adverse mutations resulted in HRs (95% CI) of 5.3 (2.5‐10.3) for presence of three adverse mutations, 2.4 (1.6‐3.7) for presence of two adverse mutations, 1.5 (1.02‐2.2) for presence of one adverse mutation, 5.6 (3.4‐9.1) for high‐risk karyotype, 1.5 (1.1‐2.2) for intermediate‐risk karyotype and 2.4 (1.8‐3.3) for age >70 years; HR‐weighted risk point assignment generated a three‐tiered genetic risk model: high (N = 65; 5‐year survival 2%), intermediate (N = 100; 5‐year survival 18%), and low (N = 135; 5‐year survival 56%). The current study provides a practically simple risk model in MDS that is based on age, karyotype, and mutations only.

Abstract The 2013 discovery of calreticulin ( CALR ) mutations in myeloproliferative neoplasms was attended by their association with longer survival in primary myelofibrosis (PMF). Subsequent studies have suggested prognostic distinction between type 1/like and type 2/like CALR mutations and detrimental effect from triple‐negative mutational status. Among 709 Mayo Clinic patients with PMF, 467 (66%) harbored JAK2 , 112 (16%) CALR type 1/like, 24 (3.4%) CALR type 2/like, 38 (5.4%) MPL mutations and 68 (10%) were triple‐negative. Survival was longer with type 1/like CALR , compared to JAK2 (HR 2.6, 95% CI 1.9‐3.5), type 2/like CALR (HR 2.5, 95% CI 1.4‐4.5), MPL (HR 1.8, 95% CI 1.1‐2.9) and triple‐negative mutational status (HR 2.4, 95% CI 1.6‐3.6), but otherwise similar between the non‐type 1/like CALR mutational states ( P = .41). In multivariable analysis, the absence of type 1/like CALR ( P < .001; HR 2, 95% CI 1.4‐2.7), presence of ASXL1 / SRSF2 mutations ( P < .001; HR 1.9, 95% CI 1.5‐2.4) and DIPSS‐plus ( P < .001) were each predictive of inferior survival. Furthermore, among 210 patients with ASXL1 / SRSF2 mutations, survival was significantly longer in the presence vs. absence of type 1/like CALR mutations (median 5.8 vs. 2.9 years; P < .001). Triple‐negative status did not disclose additional prognostic information for overall or leukemia‐free survival. The observations regarding the prognostic distinction between CALR mutation variants were validated in an external cohort of 386 patients from the University of Florence Careggi hospital. We conclude that type 1/like CALR mutations in PMF not only predict superior survival, but also partially amend the detrimental effect of high molecular risk mutations.