Lasho, Terra L.

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.

AbstractTherapy related myeloid neoplasms (t‐MN) including therapy related myelodysplastic syndromes (t‐MDS) and acute myeloid leukemia (t‐AML) are associated with aggressive disease biologies and poor outcomes. In this large (n = 497) and informative (inclusive of molecular and cytogenetic information) chronic myelomonocytic leukemia (CMML) patient cohort, we demonstrate key biological insights and an independent prognostic impact for t‐CMML. T‐CMML was diagnosed in 9% of patients and occurred approximately 7 years after exposure to prior chemotherapy and/or radiation therapy. In comparison to de novo CMML, t‐CMML patients had higher LDH levels, higher frequency of karyotypic abnormalities and had higher risk cytogenetic stratification. There were no differences in the distribution of gene mutations and unlike t‐MDS/AML, balanced chromosomal translocations, abnormalities of chromosome 11q23 (1%) and Tp53 mutations (<2%) were uncommon. Molecularly integrated CMML prognostic models were not effective in risk stratifying t‐CMML patients and responses to hypomethylating agents were dismal with no complete responses. Median overall (OS) and leukemia free survival (LFS) was shorter for t‐CMML in comparison to d‐CMML (Median OS 10.9 vs 26 months and median LFS 50 vs 127 months) and t‐CMML independently and adversely impacted OS (P = .0001 HR 2.1 95% CI 1.4‐3.0). This prognostic impact was retained in the context of the Mayo Molecular Model (P = .001, HR 2.4, 95% CI 1.5‐3.7) and the GFM prognostic model (P < .0001, HR 2.15, 95% CI 1.5‐3.7). In summary, we highlight the unique genetics and independent prognostic impact of t‐CMML, warranting its inclusion as a separate entity in the classification schema for both CMML and t‐MN.

AbstractA 27‐gene panel was used for next‐generation sequencing (NGS) in 179 patients (median age 73 years) with primary myelodysplastic syndromes (MDS); risk distribution according to the revised International Prognostic Scoring System (IPSS‐R) was 11% very high, 18% high, 17% intermediate, 38% low and 16% very low. At least one mutation/variant was detected in 147 (82%) patients; 23% harbored three or more mutations/variants. The most frequent mutations/variants included ASXL1 (30%), TET2 (25%), SF3B1 (20%), U2AF1 (16%), SRSF2 (16%), TP53 (13%), RUNX1 (11%), and DNMT3A (10%). At a median follow up of 30 months, 148 (83%) deaths and 26 (15%) leukemic transformations were recorded. Multivariable analysis of mutations/variants identified ASXL1 (HR 1.7, 95% CI 1.2‐2.5), SETBP1 (HR 4.1, 95% CI 1.6‐10.2) and TP53 (HR 2.2, 95% CI 1.3‐3.4) as risk factors for overall and SRSF2 (HR 3.9, 95% CI 1.5‐10.2), IDH2 (HR 3.7, 95% CI 1.2‐11.4), and CSF3R (HR 6.0, 95% CI 1.6‐22.6) for leukemia‐free survival. Addition of age to the multivariable model did not affect these results while accounting for IPSS‐R weakened the significance of TP53 mutations/variants (P = .1). An apparently favorable survival impact of SF3B1 mutations was no longer evident after adjustment for IPSS‐R. Approximately 41% and 20% of patients harbored at least one adverse mutation/variant for overall and leukemia‐free survival, respectively. Number of mutations/variants did not provide additional prognostic value. The survival impact of adverse mutations was most evident in IPSS‐R very low/low risk patients. These observations suggest that targeted NGS might assist in treatment decision‐making in lower risk MDS.