Ph-Negative MPNs With Pulmonary Hypertension Associated With Poor Outcomes

June 22, 2020

These data suggest that screening for pulmonary hypertension is warranted in patients with a Philadelphia chromosome-negative myeloproliferative neoplasm, both at the time of diagnosis and during follow-up.

Patients with Philadelphia (Ph) chromosome-negative myeloproliferative neoplasms (MPN), including essential thrombocytopenia (ET), polycythemia vera (PV), and primary myelofibrosis (MF), were commonly diagnosed with pulmonary hypertension, and patients with PV specifically had poorer survival outcomes when they had pulmonary hypertension, according to a retrospective analysis presented at the 2020 European Hematology Association (EHA) Annual Congress.

These data suggest that screening for pulmonary hypertension is warranted in patients with a PH-negative MPN, both at the time of diagnosis and during follow-up. The purpose of this study was to review the prevalence of pulmonary hypertension and the clinical implications of it in Korean patients with Ph-negative MPNs. The study included retrospectively analyzed data from patients with ET, PV, or primary MF who were admitted to the Chungnam National University Hospital between January 1993 and June 2019.

The 10-year overall survival (OS) rate in patients with MPNs overall in this study was 82% for those with pulmonary hypertension compared with 91% for those without (P =.410). The 10-year OS rate in the ET arm was 90% for those with pulmonary hypertension versus 86% for those without (P =.510). In the PV arm, the 10-year OS rate was 53% for those with pulmonary hypertension versus 94% for those without (P =.001), and the 10-year OS rate for primary MF was 100% versus 75% (P =.410), respectively.

Among 121 patients with ET, 15.7% had primary pulmonary hypertension compared with 10.8% in patients with PV (n = 83) and 28.6% in patients with primary MF (n = 21). Primary pulmonary hypertension was observed in 15.1% of patients with MPNs overall (n = 225). Overall, heart failure-associated pulmonary hypertension was observed in 5.8% of the patients with MPNs, 5.8% in those with ET, 6.0% in those with PV, and 4.8% in those with primary MF.

According to a multivariate Cox regression analysis for OS in the PV cohort, old age (HR, 1.4; 95% CI, 1.1-1.8; P =.002), being female (HR, 0.7; 95% CI, 0.1-9.9; P =.977), having high LDH (HR, 11.3; 95% CI, 1.1-119.6; P =.045), diabetes mellitus (HR, 1.8; 95% CI, 0.1-31.0; P =.906), hypertension (HR, 0.5; 95% CI, 0.1-5.7; P =.784), chronic kidney disease (HR, 1.1; 95% CI, 0.1-12.0; P =.976), thrombotic event (HR, 1.8; 95% CI, 0.2-19.0; P =.794), and pulmonary hypertension (HR, 12.4; 95% CI, 18.86.6; P =.011).

MPNs have been identified as the cause of the fifth type of pulmonary hypertension, according to early case reports and small case series that have shown highly variable prevalence rates ranging from 5% to 50%. Recent studies have indicated patients with MPNs have higher prevalence of pulmonary hypertension, but the prevalence of this varied among studies. No studies have evaluated the prevalence of pulmonary hypertension in Asian patients with MPNs.

These patients had undergone a transthoracic echocardiographic examination to be enrolled in the study. The results were reviewed by 2 cardiologists for this analysis, and a diagnosis of pulmonary hypertension was made when the probability of this event was considered high to the European Society of Cardiology/European Respiratory Society guidelines. High probability was defined as when the tricuspid regurgitation velocity was > 3.4 m/sec or when the tricuspid regurgitation velocity was between 2.9 and 3.4 m/sec. If pulmonary hypertension was associated with left heart failure or chronic obstructive lung disease, those patients were excluded from the analysis.

In the ET cohort, a total of 19 patients with pulmonary hypertension and 102 patients without were included in the analysis, and the median age among these 2 groups was 65 years (range, 22-79) and 66 years (range, 29-88), respectively (P =.536). The group with pulmonary hypertension included 6 men and 13 women versus 56 men and 46 women in those without (P =.062). In the group with pulmonary hypertension, 1 (5.3%) had a low International prognostic score for ET, 9 (47.4%) had intermediate, and 9 (47.4%) had high versus 26 (25.5%) had low, 27 (26.5%) had intermediate, and 49 (48.0%) had high in the group without pulmonary hypertension.

Nine of 14 patients (64.3%) had a JAK3V617F mutation and 4 of 14 (28.6%) had a CALR mutation in the group with pulmonary hypertension compared with 67 of 84 (79.8%) who had a JAK2V617F mutation and 6 of 84 (7.1%) had a CALR mutation in the group without. The median duration of follow-up in the ET cohort was 7.1 years (range, 1.1-18.1) in those with pulmonary hypertension versus 3.7 years (range, 0.1-21.4) in those without (P =.032).

In the PV cohort, a total of 9 patients with pulmonary hypertension and 74 patients without were included in the analysis, and the median age was 71 years (range, 42-85) and 61.5 years (range, 26-91), respectively (P =.049). The group with pulmonary hypertension included 2 men and 7 women compared with 49 men and 25 women in those without (P =.010). In the group with pulmonary hypertension, 8 patients (88.9%) had a JAK3V617F mutation and 0 (0.0%) had a CALR mutation compared with 59 (79.7%) who had a JAK2V617Fmutation and 3 (4.1%) who had a CALR mutation in the group without. The median follow-up duration was 2.5 years (range, 0.1-20.4) for those with pulmonary hypertension versus 6.3 years (range, 0.1-25.5) in those without.

Among patients with primary MF, 6 had pulmonary hypertension and 15 did not, and the median age among the 2 groups was 77 years (range, 69-82) and 69 years (range, 36-86), respectively (P =.067). The group with pulmonary hypertension included 3 men and 3 women versus 9 men and 6 women in those without (P=1.000). In the group with pulmonary hypertension, 1 (16.7%) had prefibrotic or early-stage disease and 5 (83.3%) had overt MF compared with 4 (33.3%) who had prefibrotic or early stage disease in the group without pulmonary hypertension and 10 (66.6%) had overt MF.

According to the International prognostic scoring system, none of the patients with pulmonary hypertension had a low score versus 4 patients (26.7%) without, 3 (50.0%) had intermediate-1 versus 8 (53.3%), 1 (16.7%) had intermediate-2 versus 1 (6.7%), and 2 (33.3%) had high versus 2 (13.3%), respectively. Among 6 patients with driver mutations in the pulmonary hypertension group versus 13 without, 4 (66.7%) versus 10 (76.9%) had a JAK2V617F mutation and 2 (33.3%) versus 3 (23.1%), had a CALR mutation. The median duration of follow-up was 2.4 years (range, 0.4-4.1) among those with pulmonary hypertension and 2.8 years (range, 0.2-7.0) among those without (P =.529).

Reference

Jo DY, Lee MW, Ryu H, et al. Pulmonary Hypertension in Patients With Philadelphia-negative myeloproliferative neoplasm: a single center retrospective analysis of 225 patients. EHA Library. Jo D. 06/12/20; 293599; EP1110.