Sex determines the presentation and outcomes in MPN and is related to sex-specific differences in the mutational burden

Abstract

The factors underlying the variable presentation and clinical course of myeloproliferative neoplasms (MPNs) remain unclear. The aim of this study was to evaluate the independent effect of sex on MPN presentation and outcomes. A total of 815 patients with essential thrombocytosis, polycythemia vera, or primary myelofibrosis were evaluated between 2005 and 2019, and the association of sex with presenting phenotype, JAK2 V617F burden, progression, and survival was examined. Men presented more often with primary myelofibrosis vs essential thrombocytosis (relative risk, 3.2; P < .001) and polycythemia vera (relative risk, 2.1; P < .001), had higher rates of transformation to secondary myelofibrosis (hazard ratio [HR], 1.55; P = .013) and acute myeloid leukemia (HR, 3.67; P < .001), and worse survival (HR, 1.63; P = .001) independent of age, phenotype at diagnosis, and MPN-specific mutation. Men had higher JAK2 V617F allele burdens in their CD34+ cells (P = .001), acquired more somatic mutations (P = .012) apart from the MPN-specific mutations, and had an increased frequency of 1 (odds ratio, 2.35; P = .017) and 2 (odds ratio, 20.20; P = .011) high-risk mutations independent of age, phenotype, and driver mutation. Male sex is an independent predictor of poor outcomes in MPNs. This seems to be due to an increased risk of non–MPN-specific somatic mutations, particularly high-risk mutations, rather than MPN-specific mutation allele frequency. Conversely, disease progression in female subjects is more dependent on JAK2 mutation allele burden than on acquisition of other somatic mutations. Sex should be considered in prognostic models and when evaluating therapeutic strategies in MPNs.

Is there a gender effect in polycythemia vera?

“…The same incidence rate between genders was also found in a large cohort of MPNs prospectively evaluated at the Mayo Clinic, which included 711 PV patients [80]. [62]. They observed that arterial ischemic events were more common in males, independently from driver mutation status and MPN subtype [62].…”

“…[62]. They observed that arterial ischemic events were more common in males, independently from driver mutation status and MPN subtype [62].…”

“…Within 76 MPN patients sequenced at Johns Hopkins Hospital, females showed fewer additional somatic genetic alterations [62]. On the contrary, males present more frequently with non-driver mutations as ASXL1, SRSF2, U2AF1, EZH2, IDH1, and IDH2 [62]. A Mayo Clinic-Florence collaboration analyzed 906 molecularly annotated MPNs, including 404 PV [53].…”

“…In pregnant ET, the role of JAK2 has been debatable, with studies suggesting its correlation with late fetal loss, and others denying this evidence [57,115,116,118,119]. Even if PV is strictly associated with JAK2, no association has yet [62] been found between pregnancy complications and differential type of mutation (exon 12 vs exon 14) or mutation load (heterozygous vs homozygous). Indications on gestation management in MPNs are mainly derived from experts' consensus.…”

Next Generation Sequencing in MPNs. Lessons from the Past and Prospects for Use as Predictors of Prognosis and Treatment Responses

“…Moreover, an increase of >0.5% per year of the JAK2V617F allele burden compared with <0.5% per year was associated with shorter OS in females, which was not observed in men. The authors concluded that male sex in patients with MPNs is an independent prognostic risk factor for poor outcome caused by an increased number of non-driver mutations, especially HMR mutations including U2AF1 [181].…”