Pulmonary hypertension on right heart catheterization is associated with worse progression-free survival in patients with myeloproliferative neoplasms

Abstract Introduction: Pulmonary hypertension (PH) is associated with Philadelphia-chromosome negative myeloproliferative neoplasms (MPNs. In prior studies utilizing transthoracic echocardiography (TTE) to screen for PH, PH was associated with increased risk of hematologic progression among patients with MPN. However, PH is a heterogenous disease that requires right heart catheterization (RHC) for diagnosis and hemodynamic profiling. Despite studies of PH noted on TTE, data on RHC-proven PH is sparse and the impact of the different hemodynamic phenotypes on MPN outcomes remains unclear. Methods: Using a multicenter registry of patients with MPN who underwent TTE after MPN diagnosis, we identified patients who also underwent RHC. PH was defined as a mean pulmonary artery pressure (mPAP) > 20 mmHg and was hemodynamically categorized as isolated pre-capillary (pre-cap), isolated post-capillary (post-cap), and combined pre-and post-capillary (Cpc-PH) per cardiology guidelines. Outcomes were progression-free survival (PFS), which was defined as survival free from MPN progression to secondary myelofibrosis (MF), acute leukemia, and/or death. Patients with PH as a whole and by hemodynamic category were compared with patients without PH. A secondary analysis was performed by stratifying patients by MPN type (essential thrombocythemia (ET) or polycythemia vera (PV) vs. MF [primary or secondary]) at time of RHC. Multivariable Cox proportional hazards modeling was performed to estimate hazard ratios (HR) and 95% confidence intervals (CI). Models were adjusted for age, sex, driver mutation, MPN type, non-phenotypic driver mutations (mutations other than JAK2, CALR, and MPL), high molecular risk (HMR) mutations, and MPN treatment. For analysis of MF patients, models were adjusted for age and Mutation-Enhanced International Prognostic Score System (MIPSS) 70 score given the low number of patients. Results: 86 patients were included, 70 (81.4%) had PH, 38 (44.2%) were female, and 68 (79.1%) were non-Hispanic White. The median age at time of RHC was 75 years (interquartile range [IQR] 69 – 79), the median time from MPN diagnosis to RHC was 75.8 months (IQR 39.8 – 116.8). There was no difference in age at RHC, sex, and race between PH and no PH patients. There was no difference in MPN phenotypes between PH and no PH patients. Patients with PH had similar rates of driver mutations (JAK2, CALR, MPL), non-phenotypic driver mutation, and HMR mutations. Among patients with PH, 30 (42.9%) had pre-cap PH, 12 (17.1%) post-cap PH, and 28 (40.0%) had Cpc-PH. In patients with a TTE within 12 months of RHC, patients with PH had higher TTE pulmonary artery systolic pressures compared with no PH (median 56 mmHg vs 47). There was no significant difference in cardiovascular disease between the two groups. After median follow-up time of 30.4 months, 58 (67.4%) had MPN progression or death (71.4% PH vs 50.0% no PH, p = 0.099). There were 0 patients with MPN progression to MF or leukemia in the no PH group compared with 14 (20.0%) patients in the PH group (p = 0.051). Patients with PH had shorter median PFS (27.6 months, CI 18.4 – 52.1) versus those without PH (median PFS 82.1 months, 95% CI 5.4 – no reached). After multivariable Cox proportional hazards regression, PH was associated with increased risk of worse PFS compared with no PH among all MPN patients (HR 2.48, 95% CI 1.03 – 6.00). After stratifying PH by hemodynamic categorization, post-cap (HR 3.53, 95% CI 1.14 – 10.93) and Cpc-PH (HR 3.08, 95% CI 1.21 – 7.85) but not pre-cap (HR 1.84, 95% CI 0.70 – 4.83) were associated with worse PFS compared with no PH. After stratifying by MPN type, PH was associated with worse PF in ET or PV patients (HR 2.85, 95% CI 1.05 – 7.72) but not MF patients (HR 3.31, 95% CI 0.42 – 25.85). Conclusions: PH was associated with worse PFS among patients with MPN, particularly those with ET or PV, who underwent RHC. PH is a heterogenous entity within MPN and our study suggests that those with post-capillary or Cpc-PH are at higher risk of worse PFS. Prospective studies to evaluate the utility of screening for PH in patients MPN and further studies to better characterize the pathogenesis of PH in MPN are needed.