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Original Article

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Blood Res 2020; 55(2):

Published online June 30, 2020

https://doi.org/10.5045/br.2020.2020001

© The Korean Society of Hematology

Pulmonary hypertension in patients with Philadelphia-negative myeloproliferative neoplasms: a single-center retrospective analysis of 225 patients

Myeong-Won Lee1, Hyewon Ryu1, Yoon-Seok Choi1, Ik-Chan Song1, Hyo-Jin Lee1, Hwan-Jung Yun1, Byung Joo Sun2, Jin-Ok Jeong2, Deog-Yeon Jo1

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1Division of Hematology/Oncology, 2Division of Cardiology, Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon, Korea

Correspondence to : Deog-Yeon Jo, M.D., Ph.D.
Division of Hematology/Oncology, Department of Internal Medicine, Chungnam National University Hospital, 282 Munwha-ro, Jung-gu, Daejeon 35015, Korea
E-mail: deogyeon@cnu.ac.kr

Received: January 1, 2020; Revised: March 16, 2020; Accepted: April 16, 2020

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

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Background
The prevalence of pulmonary hypertension (PH) in myeloproliferative neoplasms (MPNs) varies among studies. We analyzed the prevalence of PH in Korean patients with Philadelphia-negative (Ph-) MPNs.
Methods
Medical records of patients with Ph- MPNs [essential thrombocythemia (ET), polycythemia vera (PV), or primary myelofibrosis (PMF)] visiting a single hospital between 1993 and 2019 were reviewed retrospectively. Transthoracic echocardiographic examination (TTE) results were reviewed and PH was diagnosed according to established guidelines.
Results
Of the 320 MPN (179 ET, 107 PV, and 34 PMF) patients, 225 (121 ET, 83 PV, and 21 PMF) underwent TTE. Of these 225 MPN patients, 19 of 121 (15.7%) ET, 9 of 83 (10.8%) PV, and 6 of 21 (28.6%) PMF patients had PH. PV patients with PH were older [71 (42‒85) vs. 61.5 (26‒91) yr, respectively; P =0.049], predominantly female (male:female ratio, 0.29 vs. 1.96, respectively; P =0.010), had lower hemoglobin levels (15.9±2.6 g/dL vs. 18.4±2.6 g/dL, respectively; P =0.010), and higher platelet counts (616.6±284.2×109/L vs. 437.7±191.7×109/L, respectively; P =0.020) than PV patients without PH. PMF patients with PH had higher monocyte counts (1.3±0.5×109/L vs. 0.8±0.4×109/L, respectively; P =0.031) than those without PH. PH was a risk factor for poor survival in PV (HR, 12.4; 95% CI, 1.8‒86.6).
Conclusion
PH is common in patients with Ph- MPNs and hence, careful screening for PH is warranted.

Keywords Myeloproliferative neoplasm, Essential thrombocytopenia, Polycythemia vera, Primary myelofibrosis, Pulmonary hypertension

Article

Original Article

Blood Res 2020; 55(2): 77-84

Published online June 30, 2020 https://doi.org/10.5045/br.2020.2020001

Copyright © The Korean Society of Hematology.

Pulmonary hypertension in patients with Philadelphia-negative myeloproliferative neoplasms: a single-center retrospective analysis of 225 patients

Myeong-Won Lee1, Hyewon Ryu1, Yoon-Seok Choi1, Ik-Chan Song1, Hyo-Jin Lee1, Hwan-Jung Yun1, Byung Joo Sun2, Jin-Ok Jeong2, Deog-Yeon Jo1

1Division of Hematology/Oncology, 2Division of Cardiology, Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon, Korea

Correspondence to:Deog-Yeon Jo, M.D., Ph.D.
Division of Hematology/Oncology, Department of Internal Medicine, Chungnam National University Hospital, 282 Munwha-ro, Jung-gu, Daejeon 35015, Korea
E-mail: deogyeon@cnu.ac.kr

Received: January 1, 2020; Revised: March 16, 2020; Accepted: April 16, 2020

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background
The prevalence of pulmonary hypertension (PH) in myeloproliferative neoplasms (MPNs) varies among studies. We analyzed the prevalence of PH in Korean patients with Philadelphia-negative (Ph-) MPNs.
Methods
Medical records of patients with Ph- MPNs [essential thrombocythemia (ET), polycythemia vera (PV), or primary myelofibrosis (PMF)] visiting a single hospital between 1993 and 2019 were reviewed retrospectively. Transthoracic echocardiographic examination (TTE) results were reviewed and PH was diagnosed according to established guidelines.
Results
Of the 320 MPN (179 ET, 107 PV, and 34 PMF) patients, 225 (121 ET, 83 PV, and 21 PMF) underwent TTE. Of these 225 MPN patients, 19 of 121 (15.7%) ET, 9 of 83 (10.8%) PV, and 6 of 21 (28.6%) PMF patients had PH. PV patients with PH were older [71 (42‒85) vs. 61.5 (26‒91) yr, respectively; P =0.049], predominantly female (male:female ratio, 0.29 vs. 1.96, respectively; P =0.010), had lower hemoglobin levels (15.9±2.6 g/dL vs. 18.4±2.6 g/dL, respectively; P =0.010), and higher platelet counts (616.6±284.2×109/L vs. 437.7±191.7×109/L, respectively; P =0.020) than PV patients without PH. PMF patients with PH had higher monocyte counts (1.3±0.5×109/L vs. 0.8±0.4×109/L, respectively; P =0.031) than those without PH. PH was a risk factor for poor survival in PV (HR, 12.4; 95% CI, 1.8‒86.6).
Conclusion
PH is common in patients with Ph- MPNs and hence, careful screening for PH is warranted.

Keywords: Myeloproliferative neoplasm, Essential thrombocytopenia, Polycythemia vera, Primary myelofibrosis, Pulmonary hypertension

Fig 1.

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Figure 1.Overall survival of patients with MPNs according to pulmonary hypertension. Essential thrombocythemia (A). Polycythemia vera (B). Primary myelofibrosis (C). All MPN patients (D). Abbreviations: MPNs, myeloproliferative neoplasms; OS, overall survival; PH, pulmonary hypertension.
Blood Research 2020; 55: 77-84https://doi.org/10.5045/br.2020.2020001

Table 1 . Prevalence of pulmonary hypertension in myeloproliferative neoplasms..

MPN-associated PH, N (%)Heart failure-associated PH, N (%)
At diagnosisOverall
Essential thrombocythemia2/57 (3.5)19/121 (15.7)7/121 (5.8)
Polycythemia vera1/38 (2.6)9/83 (10.8)5/83 (6.0)
Primary myelofibrosis5/13 (38.5)6/21 (28.6)1/21 (4.8)
Total8/108 (7.4)34/225 (15.1)13/225 (5.8)

Abbreviations: MPN, myeloproliferative neoplasms; PH, pulmonary hypertension..

Table 2 . Characteristics and clinical features of essential thrombocythemia patients with and without pulmonary hypertension..

With PH (N=19)Without PH (N=102)P
Age (yr), median (range)65 (22–79)66 (29–88)0.536
Gender, male:female6:1356:460.062
IPSET, N (%)0.071
Low1 (5.3)26 (25.5)
Intermediate9 (47.4)27 (26.5)
High9 (47.4)49 (48.0)
Laboratory findings, mean±SD
WBC (×109/L)11.4±4.612.9±6.20.398
Monocyte (×109/L)0.6±0.20.8±0.60.429
Hemoglobin (g/dL)13.1±2.613.9±2.10.176
Platelet (×109/L)1,152.2±572.0968.8±377.60.107
LDH (×UNL)1.4±0.41.2±0.50.094
Driver gene mutations, N (%)0.080
JAK2V617F9/14 (64.3)67/84 (79.8)
CALR mutation4/14 (28.6)6/84 (7.1)
Comorbidity, N (%)
Diabetes mellitus3 (15.8)14 (13.7)0.812
Hypertension12 (63.2)41 (40.2)0.064
Chronic kidney disease4 (21.1)20 (19.6)0.885
Smoking2 (10.5)26 (25.5)0.363
Thrombotic eventsa)8 (42.1)37 (36.3)0.797
Follow-up duration (yr), median (range)7.1 (1.1–18.1)3.7 (0.1–21.4)0.032

a)Overall thrombotic events (before, at the time of, and after diagnosis)..

Abbreviations: CALR, calreticulin; IPSET, International Prognostic Score for Essential Thrombocythemia; LDH, lactate dehydrogenase; PH, pulmonary hypertension; UNL, upper normal limit..

Table 3 . Characteristics and clinical features of polycythemia vera patients with and without pulmonary hypertension..

With PH (N=9)Without PH (N=74)P
Age (yr), median (range)71 (42–85)61.5 (26–91)0.049
Gender, male:female2:749:250.010
Laboratory findings, mean±SD
WBC (×109/L)17.2±7.514.5±7.40.330
Monocyte (×109/L)0.9±0.30.7±0.40.200
Hemoglobin (g/dL)15.9±2.618.4±2.60.010
Platelet (×109/L)616.6±284.2437.7±191.70.020
LDH (×UNL)1.3±0.31.3±0.50.973
Driver gene mutations, N (%)
JAK2V617F8 (88.9)59 (79.7)0.396
JAK2 exon12 mutation0 (0)3 (4.1)-
Comorbidity, N (%)
Diabetes mellitus2 (22.2)20 (27.0)0.556
Hypertension6 (66.7)44 (59.5)0.486
Chronic kidney disease4 (44.4)24 (32.4)0.355
Smoking2 (22.2)42 (43.2)0.266
Thrombotic eventsa)2 (22.2)22 (29.7)0.723
Follow-up duration (yr), median (range)2.5 (0.1–20.4)6.3 (0.1–25.5)0.298

a)Overall thrombotic events (before, at the time of, and after diagnosis)..

Abbreviations: LDH, lactate dehydrogenase; PH, pulmonary hypertension; UNL, upper normal limit..

Table 4 . Multivariate Cox regression analysis for overall survival in patients with polycythemia vera..

VariableHazard ratio (95% CI)P
Old age1.4 (1.1–1.8)0.002
Gender, female0.7 (0.1–9.9)0.977
High LDH (>2 UNL)11.3 (1.1–119.6)0.045
Diabetes mellitus1.8 (0.1–31.0)0.906
Hypertension0.5 (0.1–5.7)0.784
Chronic kidney disease1.1 (0.1–12.0)0.976
Thrombotic events1.8 (0.2–19.0)0.794
Pulmonary hypertension12.4 (1.8–86.6)0.011

Abbreviations: LDH, lactate dehydrogenase; UNL, upper normal limit..

Table 5 . Characteristics and clinical features of primary myelofibrosis patients with and without pulmonary hypertension..

With PH (N=6)Without PH (N=15)P
Age (yr), median (range)77 (69–82)68 (36–86)0.067
Gender, male:female3:39:61.000
Stage, N (%)0.445
Prefibrotic/early1 (16.7)4 (33.3)
Overt myelofibrosis5 (83.3)10 (66.6)
IPSS, N (%)0.398
Low0 (0)4 (26.7)
Intermediate-13 (50.0)8 (53.3)
Intermediate-21 (16.7)1 (6.7)
High2 (33.3)2 (13.3)
Laboratory findings, mean±SD
WBC (×109/L)22.0±16.713.8±8.00.141
Monocyte (×109/L)1.3±0.50.8±0.40.031
Hemoglobin (g/dL)10.8±1.211.6±3.50.590
Platelet (×109/L)965.0±615.0586.3±437.80.126
LDH (×UNL)2.6±1.62.4±1.60.755
Driver gene mutation, N (%)
JAK2V617F4/6 (66.7)10/13 (76.9)0.571
CALR mutation2/6 (33.3)3/13 (23.1)0.811
Comorbidities, N (%)
Diabetes mellitus1 (16.7)4 (26.7)0.627
Hypertension3 (50.0)9 (60.0)0.676
Chronic kidney disease2 (33.3)5 (33.3)1.000
Smoking1 (16.7)2 (13.3)0.844
Thrombotic eventsa)1 (16.7)2 (13.3)0.844
Follow-up duration (yr), median (range)2.4 (0.4–4.1)2.8 (0.2–7.0)0.529

a)Overall thrombotic events (before, at the time of, and after diagnosis)..

Abbreviations: CALR, calreticulin; IPSS, International Prognostic Scoring System; LDH, lactate dehydrogenase; PH, pulmonary hypertension; UNL, upper normal limit..

Table 6 . Characteristics and clinical features of MPN patients who had pulmonary hypertension at the time of diagnosis..

No.Age (yr)/genderDiagnosisPrognosticationDriver gene mutationsWBC (×109/L)Hb (g/dL)Platelet (×109/L)LDH (×UNL)Thrombotic eventsa)ComorbiditiesTRV (m/sec)RVSP (mmHg)Late thrombotic eventsb)Follow-up duration (yr)Alive/dead
175/FETR-IPSET-T highJAK2V617F16.511.12,2991.2NoneNone3.041No4.3Alive
279/FETR-IPSET-T highJAK2V617F10.514.28961.0CI, IHDHT, DL3.760No1.2Alive
380/FPV-JAK2V617F20.716.34921.3DVTDM, HT3.451No1.0Alive
456/MPMFIPSS lowJAK2V617F17.714.71,2731.0NoneCKD3.041No4.0Alive
569/MPMFIPSS highJAK2V617F31.111.05701.6NoneCKD3.041No2.4Alive
671/FPMFIPSS highJAK2V617F51.210.27864.7NoneDM4.172No4.1Alive
779/MPMFIPSS intermediate-2CALR9.39.25791.5NoneCKD2.940No2.4Alive
882/FPMFIPSS intermediate-1JAK2V617F19.712.22,1781.6NoneNone3.143No0.6Alive

a)Thrombotic events prior to or at the time of diagnosis. b)Thrombotic events after diagnosis..

Abbreviations: CALR, calreticulin; CI, cerebral infarction; CKD, chronic kidney disease; DL, dyslipidemia; DM, diabetes mellitus; DVT, deep vein thrombosis; ET, essential thrombocythemia; F, female; HT, hypertension; IHD, ischemic heart disease; IPSS, International Prognostic Scoring System; LDH, lactate dehydrogenase; M, male; MPN, myeloproliferative neoplasm; PMF, primary myelofibrosis; PV, polycythemia vera; R-IPSET-T, revised International Prognostic Score for Essential Thrombocythemia-thrombosis; RVSP, right ventricle systolic pressure; TRV, tricuspid regurgitation velocity; UNL, upper normal limit..
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