Gender Is a Core Modifier of Disease Outcomes and Survival in the MPN

Introduction: Host modifiers contribute to variation in disease pathogenesis and clinical features in the myeloproliferative neoplasms (MPN), essentialthrombocytosis (ET), polycythemia vera (PV), and myelofibrosis (MF).Gender modifies the JAK2 V617F allele burden (women had lower levels and lower annual increases), influences PV gene expression (men had twice as many differentially-regulated genes as women) and influences thrombotic events (a predominance of abdominal vein thrombosis in women). The MPN symptom burden also appears to differ by gender. In this analysis, we describe gender differences in disease presentation and outcome in relation tomutational status.

Methods: We analyzed a prospective cohort of 612 PV, ET and MF patients enrolled between 2005 and 2013 to study genomic modifiers of the MPN and disease outcomes. We stratified disease evolution and survival by both gender and mutational status.

Results: In this cohort, 26% were newly diagnosed, and 61% were female. The current median follow-up is 8 years (> 4800 patient-years) and 110 have died.

Prevalence of Molecular lesions

JAK2 V617F was identified in 468/612 MPN patients (76%; 61% female), and comprised the majority of ET (62%; 70% female), PV (99.5%; 59% female), MF (62%; 39% female) and post MPN AML (80.7%; 38% female) patients. CALR mutations were identified in 81/612 MPN patients (13%; 58% female), representing 23% of all ET (59% female), and 21 % of all MF (52% female) and 3.8% of post MPN AML. MPL mutations were identified in 9 MPN patients (1.5%): 7 females with ET, and 2 males with MF.

Disease presentation

Among JAK2 V617F positive patients, more females presented with ET compared to males (43% vs 29%; p=0.002) and more males presented with MF (21% vs 9%; p=0.001). Gender differences in presentation were less apparent in those with CALR -mutated ET (59% women) and MF (53% women).

Disease transformation

By gender, among 197 women with an original diagnosis of ET, 62% retained their phenotype, whereas 20%, 17%, and 1.5% evolved to PV, MF, and AML, respectively. Among men with ET, 63% retained their phenotype, while 16%, 20%, and 1.1% evolved to PV, MF, and AML. Among MF patients, regardless of mutational status, 1 (3%) women and 5 (10%) men evolved to AML (p=0.39). With regard to transformations by gender, rates of MF (16% in both) and AML (2.6% and 5.5%p=0.083) were similar between women and men.

Among 123 JAK2V617F- positive ET women, during the follow-up period, 66 (54%) retained an ET phenotype, while 32%, 14%, and 0.8% evolved to PV, MF, and AML, respectively. Among 53 JAK2V617F-positive ET men, 54% retained an ET phenotype; 25%, 17%, and 4% evolved to PV, MF, and AML, respectively.

Among 141 JAK2V617F-positive PV females, 109 (77%) retained PV, 26 (18%) evolved to MF, and 6 (4%) evolved to AML (1 via MF, 5 PV to AML); among 100 JAK2V617F-positive males, 73% retained a PV phenotype, 20% evolved to MF, and 7% to AML (3 PV to AML, 4 via MF phase).

Among JAK2V617F -positive patients with an original MF diagnosis, 1/20 (5%) and 3/31 (10%) women and men evolved to AML (p=NS); 22% vs. 18% of JAK2V617F -positive men versus women evolved to MF or AML (p=0.28).

No CALR -mutated ET patient evolved to PV. Of 38 CALR- ET women, 27 (71%) retained their phenotype, 10 evolved to MF (26%), and 1 to AML (3%). Among the 26 CALR -mutated ET men, 81% retained their phenotype, while 19% evolved to MF (no AML transformations).

Survival

The proportion of deaths differed by gender; of the 612 patients, despite the predominance of females in the cohort, at the time of last follow-up, there were 110 deaths (18%): 50/375 women died, compared to 60/237 men (13% vs. 25%; p value=0.0002). A larger proportion of male deaths were due to MF and MF to AML, but this was not statistically different (male deaths in MF/AML phase: 54/60; (90%); women 38/50 (75%); p=0.0692)).

Conclusion:

We identified a gender influence on disease distribution at presentation, particularly in the JAK2V617F-positive subset with females presenting more commonly with ET and males more commonly with MF. Despite the predominance of females in this MPN cohort, the distribution of females at presentation and evolution into more indolent phenotypes compared to males and a trend toward lower rates of AML evolution may have accounted for longer disease duration and fewer deaths in females compared to males. This trend in MPN evolution complements a theme of gender differences in symptom burden, clinical consequences, and genomic changes.