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Review Article

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Blood Res 2023; 58(S1):

Published online April 30, 2023

https://doi.org/10.5045/br.2023.2023038

© The Korean Society of Hematology

Prognostication in myeloproliferative neoplasms, including mutational abnormalities

Junshik Hong

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Division of Hematology and Medical Oncology, Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea

Correspondence to : Junshik Hong, M.D., Ph.D.
Division of Hematology and Medical Oncology, Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea
E-mail: hongjblood@snu.ac.kr

Received: February 15, 2023; Revised: March 4, 2023; Accepted: March 6, 2023

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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Increasing knowledge of the molecular features of myeloproliferative neoplasms (MPNs) is being combined with existing prognostic models based on clinical, laboratory, and cytogenetic information. Mutation-enhanced international prognostic systems (MIPSS) for polycythemia vera (PV) and essential thrombocythemia (ET) have improved prognostic assessments. In the case of overt primary myelofibrosis (PMF), the MIPSS70 and its later revisions (MIPSS70+ and MIPSS70+ version 2.0) effectively predicted the overall survival (OS) of patients. Because post-PV and post-ET myelofibrosis have different biological and clinical courses compared to overt PMF, the myelofibrosis secondary to PV and ET-prognostic model was developed. Although these molecular-inspired prognostic models need to be further validated in future studies, they are expected to improve the prognostic power in patients with MPNs in the molecular era. Efforts are being made to predict survival after the use of specific drugs or allogeneic hematopoietic stem cell transplantation. These treatment outcome prediction models enable the establishment of personalized treatment strategies, thereby improving the OS of patients with MPNs.

Keywords Myeloproliferative neoplasms, Prognosis, Prognostic models, Myelofibrosis, Mutations

Article

Review Article

Blood Res 2023; 58(S1): S37-S45

Published online April 30, 2023 https://doi.org/10.5045/br.2023.2023038

Copyright © The Korean Society of Hematology.

Prognostication in myeloproliferative neoplasms, including mutational abnormalities

Junshik Hong

Division of Hematology and Medical Oncology, Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea

Correspondence to:Junshik Hong, M.D., Ph.D.
Division of Hematology and Medical Oncology, Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea
E-mail: hongjblood@snu.ac.kr

Received: February 15, 2023; Revised: March 4, 2023; Accepted: March 6, 2023

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

Increasing knowledge of the molecular features of myeloproliferative neoplasms (MPNs) is being combined with existing prognostic models based on clinical, laboratory, and cytogenetic information. Mutation-enhanced international prognostic systems (MIPSS) for polycythemia vera (PV) and essential thrombocythemia (ET) have improved prognostic assessments. In the case of overt primary myelofibrosis (PMF), the MIPSS70 and its later revisions (MIPSS70+ and MIPSS70+ version 2.0) effectively predicted the overall survival (OS) of patients. Because post-PV and post-ET myelofibrosis have different biological and clinical courses compared to overt PMF, the myelofibrosis secondary to PV and ET-prognostic model was developed. Although these molecular-inspired prognostic models need to be further validated in future studies, they are expected to improve the prognostic power in patients with MPNs in the molecular era. Efforts are being made to predict survival after the use of specific drugs or allogeneic hematopoietic stem cell transplantation. These treatment outcome prediction models enable the establishment of personalized treatment strategies, thereby improving the OS of patients with MPNs.

Keywords: Myeloproliferative neoplasms, Prognosis, Prognostic models, Myelofibrosis, Mutations

Fig 1.

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Figure 1.Prognostic system for myelofibrosis. a)Unfavorable karyotype: complex karyotype or one or two abnormalities that include trisomy 8, 7/7q-, i(17q), 5/5q-, 12p-, inv(3), or 11q23 rearrangements. b)HMR; Presence of a mutation in any of the following genes: ASXL1, EZH2, SRSF2, or IDH1/2. c)HMR; Presence of a mutation in any of the following genes: ASXL1, EZH2, SRSF2, U2AF1 Q157, or IDH1/2. d)VHR karyotype: single/multiple abnormalities of -7, i(17q), inv(3)/3q21, 12p -/12p11.2, 11q -/11q23, or other autosomal trisomies not including +8/+9 (e.g., +21, +19).
Online calculator for MIPSS-70+ Version 2.0 can be found at: http://www.mipss70score.it/
Abbreviations: Hb, hemoglobin; HMR, high molecular risk; mOS, median overall survival; PB, peripheral blood; WBC, white blood cell count.
Blood Research 2023; 58: S37-S45https://doi.org/10.5045/br.2023.2023038

Table 1 . Risk stratification of polycythemia vera: the classic risk model and the Molecular International Prognostic Scoring System for polycythemia vera (MIPSS-PV)..

Classical risk stratification for PVMIPSS-PV
Age ≥60 yrThrombosis history1 point
Thrombosis historyWBC ≥15×109/L1 point
Age >672 points
Mutated SRSF23 points
Stratification and treatmentSum of the points and interpretation
Low riskNone of them; no cytoreductionLow risk0–1; mOS 24 yr
High riskAny of them; cytoreduction neededIntermediate risk2–3; mOS 13.1 yr
High risk≥4; mOS 3.2 yr

Abbreviations: MIPSS-PV, Molecular International Prognostic Scoring System for polycythemia vera; mOS, median overall survival; PV, polycythemia vera; WBC, white blood cell count..

Table 2 . Risk stratification of essential thrombocythemia: the revised IPSET-thrombosis and the Molecular International Prognostic Scoring System for essential thrombocythemia (MIPSS-ET)..

Revised IPSET-thrombosis for ETMIPSS-ET
Thrombosis historyMale sex1 point
Age >60 yrWBC ≥11×109/L1 point
JAK2 V617F mutationAdverse mutationsb)2 points
Age >604 points
Stratification and treatmentSum of the points and interpretation
Very low riskNone of them; observationa)Low risk0–1; mOS 34.4 yr
Low riskJAK2 mutation only; aspirinIntermediate risk2–5; mOS 14.1 yr
Intermediate riskAge >60 yr only; aspirinHigh risk≥6; mOS 7.9 yr
High riskAny others; cytoreduction

a)Aspirin, if any cardiovascular risk factors are present. b)Mutations in SRSF2, SF3B1, U2AF1, or TP53..

Abbreviations: ET, essential thrombocythemia; IPSET, International Prognostic Score for Essential Thrombocythemia; MIPSS-ET, Molecular International Prognostic Scoring System for essential thrombocythemia; mOS, median overall survival; WBC, white blood cell count..

Table 3 . Risk stratification of post-polycythemia vera or post-essential thrombocythemia myelofibrosis: the Myelofibrosis Secondary to PV and ET-Prognostic Model (MYSEC-PM)..

Risk variables and points
Age at diagnosis0.15 points per yr
Hemoglobin <11 g/dL2 points
Circulating blast ≥3%2 points
Absence of CALR type 1/like mutation2 points
Platelet count <150×109/L1 point
Constitutional symptoms1 point
Risk group and interpretation
Low risk<11 point; mOS not reached
Intermediate-1 risk≥11 and <14 points; mOS 9.3 yr
Intermediate-2 risk≥14 and <16 points; mOS 4.4 yr
High risk≥16 points; mOS 2.0 yr

Abbreviation: mOS, median overall survival..

Table 4 . Prognostication in myeloproliferative neoplasms according to mutational abnormalities..

GenesPolycythemia veraEssential thrombocythemiaMyelofibrosis
Driver mutationsJAK2JAK2 exon 12 mutation

-. Associated with younger age, higher hemoglobin, lower leukocytes and platelet counts, but no difference in LFS, MFFS, and OS, compared to JAK2 V617F mutation [48].

-. Risk of thrombosis [31, 32].

: JAK2 V617F>CALR.

-. MMFS, LFS, OS [31, 32].

: JAK2=CALR.

-. Risk of thrombosis [49].

: JAK2 V617F>a)CALR.

: MPL W515L/K>CALR.

-. LFS [49-51].

: JAK2 V617F and CALR>triple negativity.

-. OS [51].

: CALR>JAK2 V617F.

CALR>triple negativity.

CALR type 1 >CALR type 2.

CALR-
MPL--
Triple negativityb)--
Non-driver mutationsASXL“Adverse variants/mutations” [24, 25]

-. All: inferior OS.

-. ASXL: inferior MFFS.

-. IDH2 and RUNX1: inferior LFS.

-Inferior LFS, OS [52]
Inferior PFS after HSCT [53]
IDH1-Inferior LFS [52, 53]
IDH2“Adverse variants/mutations” [24, 25]

-. All: inferior OS.

-. U2AF1 and SF3B1: inferior MMFS.

-. EZH2 and RUNX1: inferior LFS.

-. TP53: inferior LFS.

Inferior PFS after HSCT [52, 53]
RUNX1-
SRSF2Inferior LFS and OS [52]
TP53-Inferior LFS [54]
U2AF1-U2AF1 Q157 [55]
: Inferior OS compared to U2AF1 unmutated or U2AF1 S34 (Evident in younger patients)
U2AF1 or DNMT3A or CBL [56]
: inferior OS post allogeneic HSCT
EZH2-Inferior OS [52]
SF3B1--
SH2B3--
RAS-Inferior OS [57]

a)A>B: A has a higher thrombosis rate (or superior survival) than B. b)Triple negativity: no mutation in JAK2, CALR, and MPL..

Abbreviations: HSCT, hematopoietic stem cell transplantation; LFS, leukemia-free survival; MFFS, myelofibrosis-free survival; OS, overall survival..
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