A Myelodepletive Phenotype Is Associated with Distinctive Molecular Features and Adverse Outcomes in Patients with Myelofibrosis

Abstract Introduction: Myelofibrosis -either primary (PMF) or post-polycythemia vera/essential thrombocythemia (collectively, secondary MF [SMF])- is characterized by biologic and clinical heterogeneity, with some patients (pts) presenting with features of myeloproliferation (MyP) and others exhibiting a myelodepletive (MyD) phenotype. Although not well defined, the latter is marked by cytopenias involving one or more hematopoietic lineages, in some respects mimicking a myelodysplastic or bone marrow (BM) failure syndrome. MyD features have been associated with poor prognosis in patients with MF, but cytopenias have been usually considered individually. In the current study, we aimed at investigating the phenotypic and prognostic correlates of a MyD phenotype in a large cohort of MF patients. Methods: After IRB approval, 704 consecutive patients with WHO-defined MF referring to CRIMM (Florence), were included in the study. There were 442 (63%) PMF and 262 (37%) SMF. Cytopenias at diagnosis were defined as follows: white blood cell (WBC) <4×10 9/L, hemoglobin (Hb) <11 g/dL for male and <10 g/dL for female, platelets (Plt) <100×10 9/L. A MyD phenotype was defined by the presence of at least one cytopenia in the absence of any increase of other blood cells (WBC >15×10 9/L, Hb >16.5 g/dL for male and >16 g/dL for female, Plt >450×10 9/L). Pts not included in the MyD group were considered as having a MyP phenotype. Mutational analysis by targeted NGS was available for 594/704 patients (PMF 368/442; SMF 226/262). Results: Overall, 166 pts were diagnosed as having a MyD MF, including 108 (24%) PMF and 58 (22%) SMF. Among PMF patients, leukopenia, sex-adjusted anemia and thrombocytopenia were present in 38%, 84% and 35%, respectively; in SMF, corresponding figures were 24%, 91% and 24%. Two or more cytopenias were found in 11% and 6% of PMF and SMF patients, respectively. In PMF, a MyD phenotype was associated with male gender (P=.0468), older age (P=.0002), lower peripheral blast count (P=.0006), higher prevalence of splenomegaly (P=0.0142), constitutional symptoms (P<.0001), and BM fibrosis grade ≥2 (P<.0001). The rates of thrombosis and bleeding were not different compared to MyP PMF. MyD pts were more likely to have very high risk (VHR) karyotype abnormalities (P=.0002) and to be triple negative (TN; P<.0001); there were no correlations with JAK2 mutation status and mutant burden, CALR and MPL mutations. Among non-driver mutations, a MyD phenotype was significantly enriched in ASXL1 (P=.0074), IDH1/2 (P=0.064), N/KRAS (P=.0014), U2AF1 (P<.0001), and CUX1 (P=.0002) mutations. Karyotype abnormalities (P=.0084), VHR cytogenetics (P=.0343), CBL (P=.0.171) and U2AF1 (P=.0148) mutations were significantly enriched in MyD pts with ≥2 cytopenias. On univariate analysis, OS was significantly shorter in pts with MyD vs MyP PMF (median, 55 vs 103 months, respectively; P<.0001), and not different between MyD pts with one (median, 65 months) and ≥2 (median, 44 months) cytopenias (Fig. 1A). After competing risk analysis, the cumulative incidence of leukemic transformation (LT) was not different between MyD and MyP phenotypes (16% vs 11% at 5 years, respectively). Phenotypic differences between MyD and MyP patients were less evident in SMF, a part for older age of the former (P=.0207). The molecular background was likewise different: a MyD feature was enriched in mutations in TP53 (P=.0024), U2AF1 (P<.0001), and SETBP1 (P=.0125). TP53 mutations were remarkably more frequent in MyD SMF pts with ≥2 cytopenias (19%). Pts with MyD SMF had a significantly shorter OS compared to the MyP counterpart (median, 44 vs 105 months; P<.0001). Median OS was significantly inferior in MyD patients with ≥2 cytopenias compared to one cytopenia (median, 27 vs 58 months, respectively; P<.0001) (Fig. 1B). The cumulative incidence of LT was not different: 16% vs 7% at 5 years, respectively, for SMF pts with MyD and MyP phenotype. Conclusion: The current study provides a comprehensive analysis of the MyD phenotype in pts with PMF and SMF, partly recapitulating findings of previous studies (Marcellino BK et al. Clin Lymphoma Myeloma Leuk 2020). We showed that the MyD phenotype is associated with high-risk clinical and molecular features, particularly in PMF, and correlates with inferior OS. Of interest, U2AF1 mutations emerged as a distinct molecular marker of MyD in both PMF and SMF, while mutations in TP53 appear prevalent in MyD SMF. Figure 1 Figure 1. Disclosures Vannucchi: Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees.