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.

Biological drivers of clinical phenotype in myelofibrosis

“…However, allelic burden is not universally found to correlate with advanced MF and cytopenias, suggesting that the underlying causality is likely more complex. In a cohort of 594 WHO-defined MF patients from Florence, a cytopenic phenotype, defined by ≥1 cytopenia without accompanying cytosis (leukocytes > 15 × 10 9 /L, hemoglobin >16.5 g/dL for male and >16 g/dL for female, platelets >450 × 10 9 /L) was identified in 166 patients [ 54 ]. Differences between PMF and sMF were also explored.…”

Towards a Personalized Definition of Prognosis in Philadelphia-Negative Myeloproliferative Neoplasms

“…RAS/ MAPK pathway genes do not seem to play a role in SMF course [70]. A "myelodepletive" phenotype in PPV/PET-MF was found to be associated with U2AF1 mutations (as in PMF) but also distinctively with TP53 and SETBP1 alterations [71]. This subgroup of patients had a significantly shorter OS compared to the counterpart (44 vs 105 months) [71].…”

“…The association of some molecular alterations with the outcome of certain MF subtypes has been recently noted [70,71]. RAS/MAPK pathway genes have an unfavorable role on survival only in overt-PMF, even in a multivariate analysis that considered conventional prognostic parameters [70].…”

“…RAS/MAPK pathway genes have an unfavorable role on survival only in overt-PMF, even in a multivariate analysis that considered conventional prognostic parameters [70]. In an abstract presented at the 2021 American Society of Hematology (ASH) meeting, patients with "myelodepletive" phenotype (at least one among leukocytes < 4 × 10 9 /L, Hb < 11 g/dL for males and < 10 g/dL for females, PLT < 100 × 10 9 /L) presented more frequently TN signature and ASXL1, IDH1/2, N/KRAS, U2AF1, and CUX1 mutations [71]. On univariate analysis, OS was significantly shorter in this subgroup [71].…”

Impact of molecular profiling on the management of patients with myelofibrosis

“…They have limited treatment options, as use of JAK inhibitors or cytoreductive agents can exacerbate cytopenias. It has recently been shown that this phenotype is enriched with mutations in U2AF1 gene in both PMF and SMF [36,37].…”