Ketterling, Rhett P.

AbstractThis study examines the long‐term OS of relapsed AML patients who were enrolled to 9 successive ECOG‐ACRIN trials for newly diagnosed AML, during 1984‐2008. The objectives were to examine whether there is a trend of improvement in the survival of relapsed AML patients in the more recent studies and to search for prognostic factors that are associated with long‐term OS after relapse. A total of 3012 patients were enrolled, 1779 (59.1%) achieved CR1 and of these, 58.9% relapsed. The median follow‐up was 9.7 years. The median OS from relapse was 0.5 years and the 5‐year OS was 10 (±1)%. These results were similar even for the most recent studies. A multivariate model showed that age, cytogenetics at diagnosis, duration of CR1 and undergoing allogeneic transplantation were significantly associated with OS from relapse. Even among patients who relapsed with better prognostic factors; age < 40 and CR1 > 12 months, there was no significant OS difference between the studies. In conclusion, this large cohort appears to confirm that the survival of AML patients postrelapse continues to be dismal and has not improved during the past quarter of a century.

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.

AbstractThe prognostic importance of genetic information in primary myelofibrosis (PMF) was recently highlighted in a study of over 1000 cytogenetically‐annotated patients; 5‐year survival rates were 8% for very high risk (VHR), 27% “unfavorable” and 45% “favorable” karyotype. The current study addresses the practice‐relevant question of whether or not allogeneic hematopoietic stem cell transplant (HCT) can overcome the detrimental survival effect of VHR or unfavorable karyotype. The study included 67 patients with PMF or secondary MF who received HCT at the Mayo Clinic and in whom pretransplant cytogenetic information was available. Dynamic international prognostic scoring system (DIPSS) risk distribution was 13% high, 66% intermediate‐2 and 21% intermediate‐1. Cytogenetic risk distribution was 11% VHR, 34% unfavorable and 55% favorable. At median post‐HCT follow‐up of 60 months for living patients (range 34‐170), 28 (42%) deaths were recorded. Five‐year survival was 62% and was not affected by VHR or unfavorable karyotype (P = .68). The salutary effect of HCT in patients with VHR or unfavorable karyotype was also apparent during analysis of a combined dataset that included a nontransplant cohort of 383 patients with PMF; multivariable analysis of the combined dataset (n = 450) resulted in HRs (95% CI) of 2.4 (1.6‐3.6) for absence of transplant, 3.3 (2.2‐4.8) for VHR karyotype, 1.6 (1.2‐2.1) for unfavorable karyotype, 2.9 (2.0‐4.2) for DIPSS high and 1.7 (1.4‐2.2) for DIPSS intermediate‐2. These observations were further confirmed by analysis of more stringently matched case‐control subset cohorts and provide the evidence for the therapeutic preference of HCT in cytogenetically high risk patients with MF.