Men with chronic myeloproliferative neoplasms (MPNs) are more likely than women to have disease characterized by high-risk, non-MPN-related somatic mutations, according to findings of a study published in Blood Advances.

Although sex has been independently associated with prognosis in patients with chronic Philadelphia chromosome-negative MPNs, including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), with men having worse clinical outcomes compared with women, factors underlying this relationship are not well understood.

This prospective, observational cohort study included 815 patients with MPN who were referred to the Johns Hopkins Center for chronic MPNs between May 2005 and September 2019. The median time from initial diagnosis was 5 years with a median follow-up of 8 years.

The patients enrolled in this study were more likely to be male (469 women and 346 men), with women more likely to present with ET (53.7% vs 37.3%; P <.001) and men more likely to have PMF upon disease presentation (11.5% vs 26.3%; P <.001). This difference was also observed in the subgroup of patients with disease characterized by theJAK2 V617F mutation, with ET and PMF at presentation in respectively 44.9% and 8.2% of women and 38.1% and 24% of men (P <.001 for both comparisons across sexes).


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Furthermore, multivariable analyses of the overall cohort adjusted for potential confounding factors, such as age and type of MPN at diagnosis, MPN-specific mutation, and treatment with hydroxyurea, male sex was independently associated with worse overall survival (OS) in the overall cohort compared with female sex (hazard ratio [HR], 1.63; 95% CI, 1.22-2.17; P <.001). Similarly, male sex was also independently associated with shorter OS in subgroups with JAK2 V617F mutation-positive (P <.001) and JAK2 V617F mutation-negative disease (P =,011).

In addition, an independent association was observed between male sex and more aggressive disease, with men having a higher likelihood of progression to secondary myelofibrosis (HR, 1.55; 95% CI, 1.1-2.18; P = .013) and transformation to acute myeloid leukemia (HR, 3.67; 95% CI, 1.95-6.99; P >.001) compared with women.

A key study finding was that although men presented with more aggressive MPN and had worse OS compared with women, these differences were not significantly associated with neutrophil variant allele frequency (VAF) of JAK2 V617F or the change in neutrophil VAF of JAK2 V617F per year. In contrast, JAK2 V617F VAF (P =.024) and change in VAF per year (P =.040) were significantly associated with OS in women with MPN.

The study authors commented that this result “suggests that disease progression is more dependent on JAK2 mutation VAF in women, likely due to the fact that women with the JAK2 mutation commonly present with ET and PV, phenotypes in which increases in allele burden are associated with phenotype evolution.

“On the contrary and consistent with our results that disease progression and survival seem to be less dependent on the JAK2 mutation in men, men in the general population with a JAK2 V617F mutation have a higher risk of hematologic malignancies, cancer, and worse survival compared with women.”

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Furthermore, in the cohort of 227 patients with MPN characterized by next-generation sequencing, men were found to have a significantly higher somatic mutational burden with respect to high-risk, non-MPN-related genes, excluding JAK2, CALR, and MPL, such as KRAS, NRAS, EZH2, CBL, ASXL1, EZH2, SRSF2, and U2AF1, when compared with women (P =.012), and this finding was independent of age, specific type of MPN, and the presence of MPN-related mutations.

“Deeper understanding of the underlying mechanisms, and particularly further study of the hypothesis that these [sex] differences are mediated by higher-risk mutational burden, is warranted,” concluded the study authors.

Reference

Karantanos T, Chaturvedi S, Braunstein EM, et al. Sex determines the presentation and outcomes in MPN and is related to sex-specific differences in the mutational burden [published online June 15, 2020]. Blood Adv. doi: 10.1182/bloodadvances.2019001407