Rare Disease Report

Males with MPN Have Inferior Survival Compared to Females

DECEMBER 01, 2018
Krista Rossi
While myeloproliferative neoplasms (MPN)—which include essential thrombocytosis (ET), polycythemia vera (PV) and primary myelofibrosis (PMF)—share JAK2MPL and CALR mutations, wide variations regarding sex distribution, age at diagnosis, disease evolution, and outcomes exist.

Additionally, presenting phenotype, disease progression, and clinical outcome are all known to be influenced by age at diagnosis; however, sex’s impact remains an undefined area.

In an effort to assess sex’s impact in presenting phenotype, disease progression, complications, and mortality, a team of investigators presented new data from a well-defined, prospective, observational cohort at the 60th ASH Annual Meeting & Exposition in San Diego, California.

Between 2005-2015, 630 patients (246 males and 384 females) with ET, PV or PMF were enrolled in an observational cohort. At the time of evaluation, patients had a median disease duration of 7.23 years; however, 152 were enrolled within 1 year of diagnosis.

All individuals were genotyped for neutrophil JAK V617F variant allele frequency (VAF), and JAK2 V617F-negative individuals were studied for other JAK2, CALR or MPL mutations.

Associations of sex, age, and molecular characteristics with presenting phenotype were evaluated with multivariable logistic regression, while associations of sex, age, presenting phenotype, and molecular characteristics with mortality were evaluated with multivariable cox regression. The Kaplan Meier method was used to generate survival curves.

From the 630 patients enrolled in the cohort, 6819 patient-years of follow up were included in the study. One hundred and eighty-five patients died over a median follow up of 9 (Q25-75% 6, 15) years.

A higher mean age of presentation (52.9 versus 48.8 years, P=.002) was presented in males. PMF, more so than PV or ET, was more likely to be presented in males (P <.001) compared to females. Across JAK2 V617F positive and negative groups and age groups (≤40 years, >40 and ≤60 years, and >60 years), this sex difference remained statistically significant.

After adjusting for age at diagnosis (P=.4), neutrophil and peripheral blood CD34+ JAK2 V617F VAF (P=.729 and P=.064 respectively) in a multivariable logistic regression model, PMF as a presenting phenotype was significantly associated with male sex (P<.001) in a multivariable logistic regression model.

A higher rate of venous thromboembolism (15.7% vs. 6.9%, P<.001) was present in females, while higher rates of progression to acute myeloid leukemia (6.5% vs. 2.9%, P=.028) and overall mortality (38.2% vs. 23.7% P<.001) were present in males.

“In a multivariable cox regression model, male sex was significantly associated with increased mortality (HR 1.63 [95% CI 1.20-2.22], P=.002) after adjusting for age at diagnosis (HR 1.10 [95% CI 1.08-1.12), P<.001), presenting phenotype (PV, HR 1.66 [95% CI 1.13-2.45], P=.010; PMF 3.70 [95% CI 2.46-5.57), P <.001), genotype (JAK2V617F+ reference category, CALR HR 0.83 [955 CI .49-1.40], P=.064; MPL HR .74 [95% CI .23-2.35], P =.493; triple negative HR 2.72 [95% CI 1.30-5.69], P=.008), and hydroxyurea therapy (HR 1.00 [95% CI .73-1.36], P=.992).”

In subgroup analyses of the JAK2 V617F-positive and JAK2 V617F-negative groups separately, an association between male sex and higher mortality was also observed.
 
From the collected data, investigators concluded that, even when adjusted for age at presentation, presenting phenotype, and molecular characteristics, men with MPN have inferior survival compared to females.

Additionally, PMF is more often presented in males, while ET is more often presented in females.

Overall, the team asserted that the male sex is associated with more aggressive disease biology independent of other factors

Looking forward, the authors noted that, “These striking sex-based differences in MPN presentation and outcomes demonstrate that male sex is associated with more aggressive disease biology independent of other factors, and further study to dissect the molecular mechanisms are warranted. Moreover, sex stratification should be considered in MPN prognostic risk algorithms and when designing and interpreting results from clinical trials.”

The study, titled “Independent Association of Male Sex with Presentation and Clinical Outcomes in Myeloproliferative Neoplasms,” was presented at the 60th ASH Annual Meeting & Exposition.

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