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

Myeong-Won Lee; Hyewon Ryu; Yoon-Seok Choi; Ik-Chan Song; Hyo-Jin Lee; Hwan-Jung Yun; Byung Joo Sun; Jin-Ok Jeong; Deog-Yeon Jo

doi:10.5045/br.2020.2020001

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Blood Res 2020; 55(2):

Published online June 30, 2020

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

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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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

Article

Original Article

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

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

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

Abstract

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

Abstract

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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 diagnosis	Overall
Essential thrombocythemia	2/57 (3.5)	19/121 (15.7)	7/121 (5.8)
Polycythemia vera	1/38 (2.6)	9/83 (10.8)	5/83 (6.0)
Primary myelofibrosis	5/13 (38.5)	6/21 (28.6)	1/21 (4.8)
Total	8/108 (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:female	6:13	56:46	0.062
IPSET, N (%)			0.071
Low	1 (5.3)	26 (25.5)
Intermediate	9 (47.4)	27 (26.5)
High	9 (47.4)	49 (48.0)
Laboratory findings, mean±SD
WBC (×10⁹/L)	11.4±4.6	12.9±6.2	0.398
Monocyte (×10⁹/L)	0.6±0.2	0.8±0.6	0.429
Hemoglobin (g/dL)	13.1±2.6	13.9±2.1	0.176
Platelet (×10⁹/L)	1,152.2±572.0	968.8±377.6	0.107
LDH (×UNL)	1.4±0.4	1.2±0.5	0.094
Driver gene mutations, N (%)			0.080
JAK2V617F	9/14 (64.3)	67/84 (79.8)
CALR mutation	4/14 (28.6)	6/84 (7.1)
Comorbidity, N (%)
Diabetes mellitus	3 (15.8)	14 (13.7)	0.812
Hypertension	12 (63.2)	41 (40.2)	0.064
Chronic kidney disease	4 (21.1)	20 (19.6)	0.885
Smoking	2 (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:female	2:7	49:25	0.010
Laboratory findings, mean±SD
WBC (×10⁹/L)	17.2±7.5	14.5±7.4	0.330
Monocyte (×10⁹/L)	0.9±0.3	0.7±0.4	0.200
Hemoglobin (g/dL)	15.9±2.6	18.4±2.6	0.010
Platelet (×10⁹/L)	616.6±284.2	437.7±191.7	0.020
LDH (×UNL)	1.3±0.3	1.3±0.5	0.973
Driver gene mutations, N (%)
JAK2V617F	8 (88.9)	59 (79.7)	0.396
JAK2 exon12 mutation	0 (0)	3 (4.1)	-
Comorbidity, N (%)
Diabetes mellitus	2 (22.2)	20 (27.0)	0.556
Hypertension	6 (66.7)	44 (59.5)	0.486
Chronic kidney disease	4 (44.4)	24 (32.4)	0.355
Smoking	2 (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..

Variable	Hazard ratio (95% CI)	P
Old age	1.4 (1.1–1.8)	0.002
Gender, female	0.7 (0.1–9.9)	0.977
High LDH (>2 UNL)	11.3 (1.1–119.6)	0.045
Diabetes mellitus	1.8 (0.1–31.0)	0.906
Hypertension	0.5 (0.1–5.7)	0.784
Chronic kidney disease	1.1 (0.1–12.0)	0.976
Thrombotic events	1.8 (0.2–19.0)	0.794
Pulmonary hypertension	12.4 (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:female	3:3	9:6	1.000
Stage, N (%)			0.445
Prefibrotic/early	1 (16.7)	4 (33.3)
Overt myelofibrosis	5 (83.3)	10 (66.6)
IPSS, N (%)			0.398
Low	0 (0)	4 (26.7)
Intermediate-1	3 (50.0)	8 (53.3)
Intermediate-2	1 (16.7)	1 (6.7)
High	2 (33.3)	2 (13.3)
Laboratory findings, mean±SD
WBC (×10⁹/L)	22.0±16.7	13.8±8.0	0.141
Monocyte (×10⁹/L)	1.3±0.5	0.8±0.4	0.031
Hemoglobin (g/dL)	10.8±1.2	11.6±3.5	0.590
Platelet (×10⁹/L)	965.0±615.0	586.3±437.8	0.126
LDH (×UNL)	2.6±1.6	2.4±1.6	0.755
Driver gene mutation, N (%)
JAK2V617F	4/6 (66.7)	10/13 (76.9)	0.571
CALR mutation	2/6 (33.3)	3/13 (23.1)	0.811
Comorbidities, N (%)
Diabetes mellitus	1 (16.7)	4 (26.7)	0.627
Hypertension	3 (50.0)	9 (60.0)	0.676
Chronic kidney disease	2 (33.3)	5 (33.3)	1.000
Smoking	1 (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)/gender	Diagnosis	Prognostication	Driver gene mutations	WBC (×10⁹/L)	Hb (g/dL)	Platelet (×10⁹/L)	LDH (×UNL)	Thrombotic events^a)	Comorbidities	TRV (m/sec)	RVSP (mmHg)	Late thrombotic events^b)	Follow-up duration (yr)	Alive/dead
1	75/F	ET	R-IPSET-T high	JAK2V617F	16.5	11.1	2,299	1.2	None	None	3.0	41	No	4.3	Alive
2	79/F	ET	R-IPSET-T high	JAK2V617F	10.5	14.2	896	1.0	CI, IHD	HT, DL	3.7	60	No	1.2	Alive
3	80/F	PV	-	JAK2V617F	20.7	16.3	492	1.3	DVT	DM, HT	3.4	51	No	1.0	Alive
4	56/M	PMF	IPSS low	JAK2V617F	17.7	14.7	1,273	1.0	None	CKD	3.0	41	No	4.0	Alive
5	69/M	PMF	IPSS high	JAK2V617F	31.1	11.0	570	1.6	None	CKD	3.0	41	No	2.4	Alive
6	71/F	PMF	IPSS high	JAK2V617F	51.2	10.2	786	4.7	None	DM	4.1	72	No	4.1	Alive
7	79/M	PMF	IPSS intermediate-2	CALR	9.3	9.2	579	1.5	None	CKD	2.9	40	No	2.4	Alive
8	82/F	PMF	IPSS intermediate-1	JAK2V617F	19.7	12.2	2,178	1.6	None	None	3.1	43	No	0.6	Alive

^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..