Males With MPN Have More Aggressive Disease Biology, Independent of Other Factors

Males with myeloproliferative neoplasms have worse survival compared with females with MPN, even when adjusted for age at presentation, presenting phenotype, and molecular characteristics.

Males with myeloproliferative neoplasms (MPN) have worse survival compared with females with MPN, even when adjusted for age at presentation, presenting phenotype, and molecular characteristics. In addition, males present more frequently with primary myelofibrosis (PMF), whereas females present more frequently with essential thrombosis (ET), according to a recent study by Theodoros Karantanos, MD, PhD, and colleagues. Their findings were presented at the 60th American Society of Hematology (ASH) annual meeting and exposition in San Diego, CA, on December 1, 2018.

Chronic MPNs—ET, polycythermia vera (PV), or PMF—share mutations of JAK2, MPL, and CALR but vary widely with respect to sex distribution, age at diagnosis, disease evolution, and outcomes. Although it is known that age at diagnosis influences presenting phenotype, disease progression, and clinical outcome, the impact of sex was previously undefined, and Dr. Karantanos and his team of researchers set out to clarify that factor.

A total of 630 individuals (246 males, 384 females) with ET, PV, or PMF were enrolled in an observational cohort between 2005 and 2015. Median disease duration at the time of evaluation was 7.23 years; 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 mutations, CALR, or MPL mutations.

Multivariable logistic regression was used to evaluate associations of sex, age, and molecular characteristics with presenting phenotype; multivariable Cox regression was used to evaluate associations of sex, age, presenting phenotype, and molecular characteristics with mortality; survival curves were generated using the Kaplan-Meier method.

Over a median follow-up of 9 years, 185 study participants died, and the following trends were reported:

  • Males were more likely to present with PMF than PV or ET (P <.001) than females were, a sex difference that remained statistically significant across JAK2 V617F-positive and -negative groups, and across age groups (≤40, >40, and ≤60, and >60 years).
  • Male sex was significantly associated with PMF as presenting phenotype (P <.001) after adjusting for age at diagnosis (P = .4), and neutrophil and peripheral blood CD34+ JAK2 V617F VAF (P = .729 and P = .064, respectively).
  • Females had a higher rate of venous thromboembolism (15.7% vs 6.9%, P <.001), whereas males had 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).
  • Male sex was significantly associated with increased mortality (hazard ratio [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 [95% CI, 0.49-1.40], P = .064; MPL HR 0.74 [95% CI, 0.23-2.35], P = .493; triple negative: HR, 2.72 [95% CI, 1.30-5.69], P = .008), and hydroxyurea therapy (HR, 1.00 [95% CI, 0.73-1.36], P = .992).
  • The association of male sex with higher mortality was also seen in subgroup analyses of the JAK2 V617F-positive and JAK2 V617F-negative groups.

“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,” the researchers conclude. In addition, they recommend that sex stratification be considered in MPN prognostic risk algorithms and when designing and interpreting results from clinical trials.

Reference

Karantanos T, Chaturvedi S, Spivak JL, et al. Independent association of male sex with presentation and clinical outcomes in myeloproliferative neoplasms. Presented December 1, 2018, at the American Society of Hematology annual meeting, San Diego, CA. Blood. 2018 132. Abstract 1768. https://doi.org/10.1182/blood-2018-99-112683?rel=0" .