Blood Res 2023; 58(S1):
Published online April 30, 2023
https://doi.org/10.5045/br.2023.2023038
© The Korean Society of Hematology
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
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.
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
The BCR-ABL1-negative myeloproliferative neoplasms (MPNs) are a heterogeneous group of clonal hematopoietic neoplasms that include polycythemia vera (PV), essential thrombocythemia (ET), and overt primary or post-ET/post-PV myelofibrosis. Hyperactivation of signal transduction pathways, such as JAK/STAT, is a pathological hallmark of MPNs, resulting in increased numbers of myeloid lineage blood cells and systemic proinflammatory conditions. Myelocytosis and inflammation significantly increase the risk of vascular events of both arterial and venous origins. In addition, PV and ET can progress to secondary acute myeloid leukemia either directly or via transformation to myelofibrosis. In addition, some patients with overt primary myelofibrosis (PMF) eventually develop secondary acute myeloid leukemia (AML), which has a poor prognosis. MPNs are most common in patients in their 50s or above, although they can affect all age groups. PV and ET have indolent clinical courses, and the prevention of vascular events is a short-term treatment goal. In cases of overt myelofibrosis, patients experience systemic constitutional symptoms and splenomegaly as the disease progresses, and ruxolitinib and other JAK inhibitors are the current treatment standards. Some selected patients with a higher risk of myelofibrosis can be cured through allogeneic hematopoietic stem cell transplantation (allo-HSCT).
Similar to other areas of oncology, knowledge regarding the diagnosis and treatment of MPNs is rapidly evolving. In particular, by analyzing the genetic information of patients with MPN and associating this information with clinical variables, the survival and treatment outcomes of individual patients with MPN can be predicted much better than before. Here, we review several currently established and suggested prognostic systems and recommendations for patients with MPN, focusing on the integration of molecular data obtained by next-generation sequencing (NGS) testing.
The European Collaboration on Low-Dose Aspirin in Polycythemia Vera study showed that cardiovascular event-free survival of the 1,638 patients with PV can be stratified into three groups according to age ≥65 years and a previous history of thrombosis: low-risk (neither of them), intermediate-risk (either of them), and high-risk (both of them) [1]. Based on the results of subsequent studies [2, 3], age ≥60 years (rather than ≥65 yr) and previous thrombosis have been considered as two factors predicting thrombotic events in patients with PV, consisting of the conventional risk model (Table 1) [4, 5]. Guidelines recommend that patients with low-risk PV according to the conventional risk model (age <60 yr and no prior history of thrombosis) do not need cytoreductive therapy [6, 7] unless in specific clinical subgroups, including poor tolerance to phlebotomy, symptomatic progressive splenomegaly, and persistent leukocytosis [7].
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 PV | MIPSS-PV | |
---|---|---|
Age ≥60 yr | Thrombosis history | 1 point |
Thrombosis history | WBC ≥15×109/L | 1 point |
Age >67 | 2 points | |
Mutated | 3 points |
Stratification and treatment | Sum of the points and interpretation | ||
---|---|---|---|
Low risk | None of them; no cytoreduction | Low risk | 0–1; mOS 24 yr |
High risk | Any of them; cytoreduction needed | Intermediate risk | 2–3; 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.
Other factors have been reported to affect the development of vascular events in patients with PV, including the presence of leukocytosis in patients aged <60 years [8-10], arterial hypertension in lower-risk patients according to the conventional risk model [11], higher intensity of phlebotomy [12], and higher
Mortality in patients with MPNs results not only from thrombotic events, but also from disease progression (to MF or secondary AML) and disease-associated infections. Thus, to predict the overall survival (OS), disease-related biological risk factors should be incorporated into the thrombotic risk factors in patients with MPN. Cytogenetic abnormalities are associated with OS [20-22]. Barraco
With the introduction of the NGS technology, interests in the effect of MPN driver mutations and other myeloid neoplasm-relevant genetic mutations on the OS of patients with MPNs increased. Tefferi
The International Prognostic Score for Essential Thrombocythemia-Thrombosis (IPSET-thrombosis) [26] is a modified version of the original IPSET [27], which aims to prognosticate OS of ET. Because IPSET was also able to predict thrombosis, an effort was made to develop a thrombosis-specific prognostic model, and IPSET thrombosis was introduced from the analyses of 891 patients with ET. IPSET thrombosis suggested that age >60 years, history of thrombosis, presence of cardiovascular risk factors, and mutated
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 ET | MIPSS-ET | |
---|---|---|
Thrombosis history | Male sex | 1 point |
Age >60 yr | WBC ≥11×109/L | 1 point |
Adverse mutationsb) | 2 points | |
Age >60 | 4 points |
Stratification and treatment | Sum of the points and interpretation | ||
---|---|---|---|
Very low risk | None of them; observationa) | Low risk | 0–1; mOS 34.4 yr |
Low risk | Intermediate risk | 2–5; mOS 14.1 yr | |
Intermediate risk | Age >60 yr only; aspirin | High risk | ≥6; mOS 7.9 yr |
High risk | Any others; cytoreduction |
a)Aspirin, if any cardiovascular risk factors are present. b)Mutations in
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.
Previous studies showed that the incidence of thrombosis is lower in patients with
The IPSET was developed for 867 patients with ET with a median follow-up period of 6.2 years (range, 0–27) (27 yr). It includes age ≥60 years (2 points), leukocyte count ≥11×109/L (1 point), and prior thrombosis (1 point) as risk factors for inferior OS and stratified the patients into three risk categories: low-risk [0 points; median OS not reached (NR)], intermediate-risk [1–2 points; median OS, 24.5 yr; 95% confidence interval (CI), 22.3–NR], and high-risk (3–4 points; median OS, 14.7 yr; 95% CI, 11.9–18), respectively [27].
In the study, which developed MIPSS-ET (Table 2), clinical and molecular information from 451 patients with ET were analyzed [25]: age >60 years (4 points); the presence of adverse mutations
Multiple risk stratification tools have been proposed for patients with overt PMF, with or without the integration of genetic information (Fig. 1).
Mutational information not included: DIPSS and DIPSS-Plus: The International Prognostic Scoring System (IPSS) [33] is a classical prognostic scoring system for patients with overt PMF only at the time of initial diagnosis. As a dynamic risk stratification system applicable at any point over the course of overt PMF treatment is required, the impact of each adverse variable on OS during follow-up after treatment was investigated, and the DIPSS was developed [34]. The same adverse variables in the IPSS were used in the DIPSS. The only difference was that two points were assigned for a hemoglobin level of <10 g/dL, considering its stronger impact on OS [34]. The DIPSS stratifies patients into four risk groups: low-risk (0 points), intermediate-1 risk (1–2 points), intermediate-2 risk (3–4 points), and high-risk (5–6 points) with a median OS of NR, 14.2 years, 4 years, and 1.5 years, respectively [34].
Even after the suggestion of DIPSS, several DIPSS-independent risk factors have been suggested, including red blood cell (RBC) transfusion dependency, thrombocytopenia, and the presence of an unfavorable karyotype [35-37]. Therefore, it is necessary to evaluate these factors. For example, the median OS of low-risk DIPSS patients with thrombocytopenia or an unfavorable karyotype was 6.5 years compared to >15 years in the absence of these two variables [38]. Thus, DIPSS-Plus was introduced by incorporating the need for RBC transfusion, a platelet count of <100×109/L, and the presence of unfavorable karyotypes into the existing DIPSS [38]. After calculating DIPSS risk, DIPSS-Plus was calculated by adding one point each for the need for RBC transfusion, platelet count <100×109/L, and the presence of an unfavorable karyotype. The DIPSS-Plus also stratified patients into four risk groups: low-risk (0 points), intermediate-1 risk (1 point), intermediate-2 risk (2–3 points), and high-risk (≥4 points) with a median OS of 15.4, 6.5, 2.9, and 1.3 years, respectively [38]. DIPSS-Plus is particularly useful and currently recommended when karyotyping information is available; however, molecular testing is not.
Mutational information included: MIPSS70, MIPSS70-Plus, MIPSS70-Plus V2.0, and GIPSS: As genetic information acquired using NGS technology has gained popularity, mutational information-integrating risk stratification models for overt PMF have been investigated and proposed. The Mutation- Enhanced International Prognostic Score System for transplantation eligible-aged (i.e., age ≤70 yr) patients with overt PMF (MIPSS70) [39] includes hemoglobin <10 g/dL (1 point), leukocyte count >25×109/L (2 points), platelet count <100×109/L (2 points), circulating blasts ≥2% (1 point), MF-2 or higher bone marrow fibrosis grades (1 point), presence of constitutional symptoms (1 point), absence of
The MIPSS70-Plus version 2.0 was introduced to 406 patients with overt PMF with fully informative cytogenetic and molecular data. It subdivided anemia into severe anemia (hemoglobin <8 g/dL in women and <9 g/dL in men) and moderate anemia (hemoglobin 8–9.9 g/dL in women and 9–10.9 g/dL in men). Additionally, it added a VHR karyotype as a separate risk factor and included
The genetically inspired prognostic scoring system for PMF (GIPSS) [41] is a prognostic system for overt PMF, which comprises solely genetic information: among 641 patients with overt PMF with a complete set of both cytogenetic and mutational profile, multivariate analysis showed that VHR karyotype (2 points), unfavorable karyotype (1 point), absence of type 1
Currently, DIPSS-Plus is preferred for prognostication if a patient has cytogenetic information but lacks mutational information. If a patient with overt PMF has mutational data but cytogenetic information is not available and is 70 years old or younger, the MIPSS70 can be used. If a patient with overt PMF has both cytogenetic and mutational data, the MIPSS70-Plus version 2.0 is recommended. The MIPSS70 and MIPSS70-Plus versions were calculated online (http://www.mipss70score.it/).
Although patients with post-PV or post-ET MF have different disease characteristics and natural courses from those with overt PMF [42], DIPSS and its variants have developed only in patients with overt PMF. The Myelofibrosis Secondary to PV and ET-Prognostic Model (MYSEC-PM) [43] effectively stratifies patients with post-PV or post-ET MF into four risk groups: low-risk (<11 points), intermediate-1 (≥11 and <14 points), intermediate-2 (≥14 and <16 points), and high-risk (≥16 points) according to age (0.15 points per a yr), hemoglobin <11 g/dL (2 points), circulating blasts ≥3% (2 points),
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 diagnosis | 0.15 points per yr |
Hemoglobin <11 g/dL | 2 points |
Circulating blast ≥3% | 2 points |
Absence of | 2 points |
Platelet count <150×109/L | 1 point |
Constitutional symptoms | 1 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.
Prognostication for patients with myelofibrosis treated with ruxolitinib: As ruxolitinib has become the standard of care for patients with a higher risk of myelofibrosis, the development of a treatment-specific prognostic model has been sought. The response to Ruxolitinib after 6 months (RR6) [45] classifies patients with myelofibrosis treated with ruxolitinib according to OS. Risk variables were as follows: receiving ruxolitinib <20 mg twice daily at all three time points (i.e., at baseline and months 3 and 6; 1 point), requirement of RBC transfusion not at baseline but at months 3 and/or 6 (1 point), achievement of <30% spleen length reduction at months 3 and 6 compared to baseline (1.5 points), and RBC transfusion requirement at all three time points (1.5 points). The median OS for patients with low (0 points), intermediate (1–2 points), and high (2.5–4 points) risk was NR, 61 months, and 33 months, respectively [45]. The investigators commented that RR6 could be a useful tool for selecting a population that needs an early shift to second-line therapy, although it needs further validation. As JAK inhibitors and other targeted agents have been investigated and introduced, a more refined treatment-specific prognostic system would contribute to improving treatment outcomes.
Prognostication for patients with myelofibrosis treated with ruxolitinib who underwent allo-HSCT: Allo-HSCT is the only curative treatment for myelofibrosis for curative intent [6]. Owing to the complexity and significant risk of non-relapse mortality after allo-HSCT, risk stratification models that can predict the outcomes of allo-HSCT in patients with myelofibrosis would be particularly useful. The myelofibrosis Transplant Scoring System (MTSS) aims to predict treatment outcomes at the time of referral for allo-HSCT in patients with overt primary or post-ET/post-PV myelofibrosis [46]. The risk variables included human leukocyte antigen-mismatched unrelated donors (2 points), non-
Table 4 summarizes the results of the analyses of certain mutations and the prognosis reported for patients with MPN. Currently, the results should be used as a component within a comprehensive clinico-hematological-genetic context rather than solely focusing on the prognostic value of individual variants/mutations [24, 25, 31, 32, 48-57].
Table 4 Prognostication in myeloproliferative neoplasms according to mutational abnormalities.
Genes | Polycythemia vera | Essential thrombocythemia | Myelofibrosis | |
---|---|---|---|---|
Driver mutations | - Associated with younger age, higher hemoglobin, lower leukocytes and platelet counts, but no difference in LFS, MFFS, and OS, compared to | |||
- | ||||
- | - | |||
Triple negativityb) | - | - | ||
Non-driver mutations | “Adverse variants/mutations” [24, 25] - All: inferior OS - - | - | Inferior LFS, OS [52] | |
Inferior PFS after HSCT [53] | ||||
- | Inferior LFS [52, 53] | |||
“Adverse variants/mutations” [24, 25] - All: inferior OS - - - | Inferior PFS after HSCT [52, 53] | |||
- | ||||
Inferior LFS and OS [52] | ||||
- | Inferior LFS [54] | |||
- | : Inferior OS compared to | |||
: inferior OS post allogeneic HSCT | ||||
- | Inferior OS [52] | |||
- | - | |||
- | - | |||
- | Inferior OS [57] |
a)A>B: A has a higher thrombosis rate (or superior survival) than B. b)Triple negativity: no mutation in
Abbreviations: HSCT, hematopoietic stem cell transplantation; LFS, leukemia-free survival; MFFS, myelofibrosis-free survival; OS, overall survival.
In addition to the existing clinical understanding, a deeper understanding of the molecular aspect of the diseases enabled the development of a more accurate prognostic system in MPNs. In PV, mutations in
No potential conflicts of interest relevant to this article were reported.
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.
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
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.
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
The BCR-ABL1-negative myeloproliferative neoplasms (MPNs) are a heterogeneous group of clonal hematopoietic neoplasms that include polycythemia vera (PV), essential thrombocythemia (ET), and overt primary or post-ET/post-PV myelofibrosis. Hyperactivation of signal transduction pathways, such as JAK/STAT, is a pathological hallmark of MPNs, resulting in increased numbers of myeloid lineage blood cells and systemic proinflammatory conditions. Myelocytosis and inflammation significantly increase the risk of vascular events of both arterial and venous origins. In addition, PV and ET can progress to secondary acute myeloid leukemia either directly or via transformation to myelofibrosis. In addition, some patients with overt primary myelofibrosis (PMF) eventually develop secondary acute myeloid leukemia (AML), which has a poor prognosis. MPNs are most common in patients in their 50s or above, although they can affect all age groups. PV and ET have indolent clinical courses, and the prevention of vascular events is a short-term treatment goal. In cases of overt myelofibrosis, patients experience systemic constitutional symptoms and splenomegaly as the disease progresses, and ruxolitinib and other JAK inhibitors are the current treatment standards. Some selected patients with a higher risk of myelofibrosis can be cured through allogeneic hematopoietic stem cell transplantation (allo-HSCT).
Similar to other areas of oncology, knowledge regarding the diagnosis and treatment of MPNs is rapidly evolving. In particular, by analyzing the genetic information of patients with MPN and associating this information with clinical variables, the survival and treatment outcomes of individual patients with MPN can be predicted much better than before. Here, we review several currently established and suggested prognostic systems and recommendations for patients with MPN, focusing on the integration of molecular data obtained by next-generation sequencing (NGS) testing.
The European Collaboration on Low-Dose Aspirin in Polycythemia Vera study showed that cardiovascular event-free survival of the 1,638 patients with PV can be stratified into three groups according to age ≥65 years and a previous history of thrombosis: low-risk (neither of them), intermediate-risk (either of them), and high-risk (both of them) [1]. Based on the results of subsequent studies [2, 3], age ≥60 years (rather than ≥65 yr) and previous thrombosis have been considered as two factors predicting thrombotic events in patients with PV, consisting of the conventional risk model (Table 1) [4, 5]. Guidelines recommend that patients with low-risk PV according to the conventional risk model (age <60 yr and no prior history of thrombosis) do not need cytoreductive therapy [6, 7] unless in specific clinical subgroups, including poor tolerance to phlebotomy, symptomatic progressive splenomegaly, and persistent leukocytosis [7].
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 PV | MIPSS-PV | |
---|---|---|
Age ≥60 yr | Thrombosis history | 1 point |
Thrombosis history | WBC ≥15×109/L | 1 point |
Age >67 | 2 points | |
Mutated | 3 points |
Stratification and treatment | Sum of the points and interpretation | ||
---|---|---|---|
Low risk | None of them; no cytoreduction | Low risk | 0–1; mOS 24 yr |
High risk | Any of them; cytoreduction needed | Intermediate risk | 2–3; 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..
Other factors have been reported to affect the development of vascular events in patients with PV, including the presence of leukocytosis in patients aged <60 years [8-10], arterial hypertension in lower-risk patients according to the conventional risk model [11], higher intensity of phlebotomy [12], and higher
Mortality in patients with MPNs results not only from thrombotic events, but also from disease progression (to MF or secondary AML) and disease-associated infections. Thus, to predict the overall survival (OS), disease-related biological risk factors should be incorporated into the thrombotic risk factors in patients with MPN. Cytogenetic abnormalities are associated with OS [20-22]. Barraco
With the introduction of the NGS technology, interests in the effect of MPN driver mutations and other myeloid neoplasm-relevant genetic mutations on the OS of patients with MPNs increased. Tefferi
The International Prognostic Score for Essential Thrombocythemia-Thrombosis (IPSET-thrombosis) [26] is a modified version of the original IPSET [27], which aims to prognosticate OS of ET. Because IPSET was also able to predict thrombosis, an effort was made to develop a thrombosis-specific prognostic model, and IPSET thrombosis was introduced from the analyses of 891 patients with ET. IPSET thrombosis suggested that age >60 years, history of thrombosis, presence of cardiovascular risk factors, and mutated
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 ET | MIPSS-ET | |
---|---|---|
Thrombosis history | Male sex | 1 point |
Age >60 yr | WBC ≥11×109/L | 1 point |
Adverse mutationsb) | 2 points | |
Age >60 | 4 points |
Stratification and treatment | Sum of the points and interpretation | ||
---|---|---|---|
Very low risk | None of them; observationa) | Low risk | 0–1; mOS 34.4 yr |
Low risk | Intermediate risk | 2–5; mOS 14.1 yr | |
Intermediate risk | Age >60 yr only; aspirin | High risk | ≥6; mOS 7.9 yr |
High risk | Any others; cytoreduction |
a)Aspirin, if any cardiovascular risk factors are present. b)Mutations in
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..
Previous studies showed that the incidence of thrombosis is lower in patients with
The IPSET was developed for 867 patients with ET with a median follow-up period of 6.2 years (range, 0–27) (27 yr). It includes age ≥60 years (2 points), leukocyte count ≥11×109/L (1 point), and prior thrombosis (1 point) as risk factors for inferior OS and stratified the patients into three risk categories: low-risk [0 points; median OS not reached (NR)], intermediate-risk [1–2 points; median OS, 24.5 yr; 95% confidence interval (CI), 22.3–NR], and high-risk (3–4 points; median OS, 14.7 yr; 95% CI, 11.9–18), respectively [27].
In the study, which developed MIPSS-ET (Table 2), clinical and molecular information from 451 patients with ET were analyzed [25]: age >60 years (4 points); the presence of adverse mutations
Multiple risk stratification tools have been proposed for patients with overt PMF, with or without the integration of genetic information (Fig. 1).
Mutational information not included: DIPSS and DIPSS-Plus: The International Prognostic Scoring System (IPSS) [33] is a classical prognostic scoring system for patients with overt PMF only at the time of initial diagnosis. As a dynamic risk stratification system applicable at any point over the course of overt PMF treatment is required, the impact of each adverse variable on OS during follow-up after treatment was investigated, and the DIPSS was developed [34]. The same adverse variables in the IPSS were used in the DIPSS. The only difference was that two points were assigned for a hemoglobin level of <10 g/dL, considering its stronger impact on OS [34]. The DIPSS stratifies patients into four risk groups: low-risk (0 points), intermediate-1 risk (1–2 points), intermediate-2 risk (3–4 points), and high-risk (5–6 points) with a median OS of NR, 14.2 years, 4 years, and 1.5 years, respectively [34].
Even after the suggestion of DIPSS, several DIPSS-independent risk factors have been suggested, including red blood cell (RBC) transfusion dependency, thrombocytopenia, and the presence of an unfavorable karyotype [35-37]. Therefore, it is necessary to evaluate these factors. For example, the median OS of low-risk DIPSS patients with thrombocytopenia or an unfavorable karyotype was 6.5 years compared to >15 years in the absence of these two variables [38]. Thus, DIPSS-Plus was introduced by incorporating the need for RBC transfusion, a platelet count of <100×109/L, and the presence of unfavorable karyotypes into the existing DIPSS [38]. After calculating DIPSS risk, DIPSS-Plus was calculated by adding one point each for the need for RBC transfusion, platelet count <100×109/L, and the presence of an unfavorable karyotype. The DIPSS-Plus also stratified patients into four risk groups: low-risk (0 points), intermediate-1 risk (1 point), intermediate-2 risk (2–3 points), and high-risk (≥4 points) with a median OS of 15.4, 6.5, 2.9, and 1.3 years, respectively [38]. DIPSS-Plus is particularly useful and currently recommended when karyotyping information is available; however, molecular testing is not.
Mutational information included: MIPSS70, MIPSS70-Plus, MIPSS70-Plus V2.0, and GIPSS: As genetic information acquired using NGS technology has gained popularity, mutational information-integrating risk stratification models for overt PMF have been investigated and proposed. The Mutation- Enhanced International Prognostic Score System for transplantation eligible-aged (i.e., age ≤70 yr) patients with overt PMF (MIPSS70) [39] includes hemoglobin <10 g/dL (1 point), leukocyte count >25×109/L (2 points), platelet count <100×109/L (2 points), circulating blasts ≥2% (1 point), MF-2 or higher bone marrow fibrosis grades (1 point), presence of constitutional symptoms (1 point), absence of
The MIPSS70-Plus version 2.0 was introduced to 406 patients with overt PMF with fully informative cytogenetic and molecular data. It subdivided anemia into severe anemia (hemoglobin <8 g/dL in women and <9 g/dL in men) and moderate anemia (hemoglobin 8–9.9 g/dL in women and 9–10.9 g/dL in men). Additionally, it added a VHR karyotype as a separate risk factor and included
The genetically inspired prognostic scoring system for PMF (GIPSS) [41] is a prognostic system for overt PMF, which comprises solely genetic information: among 641 patients with overt PMF with a complete set of both cytogenetic and mutational profile, multivariate analysis showed that VHR karyotype (2 points), unfavorable karyotype (1 point), absence of type 1
Currently, DIPSS-Plus is preferred for prognostication if a patient has cytogenetic information but lacks mutational information. If a patient with overt PMF has mutational data but cytogenetic information is not available and is 70 years old or younger, the MIPSS70 can be used. If a patient with overt PMF has both cytogenetic and mutational data, the MIPSS70-Plus version 2.0 is recommended. The MIPSS70 and MIPSS70-Plus versions were calculated online (http://www.mipss70score.it/).
Although patients with post-PV or post-ET MF have different disease characteristics and natural courses from those with overt PMF [42], DIPSS and its variants have developed only in patients with overt PMF. The Myelofibrosis Secondary to PV and ET-Prognostic Model (MYSEC-PM) [43] effectively stratifies patients with post-PV or post-ET MF into four risk groups: low-risk (<11 points), intermediate-1 (≥11 and <14 points), intermediate-2 (≥14 and <16 points), and high-risk (≥16 points) according to age (0.15 points per a yr), hemoglobin <11 g/dL (2 points), circulating blasts ≥3% (2 points),
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 diagnosis | 0.15 points per yr |
Hemoglobin <11 g/dL | 2 points |
Circulating blast ≥3% | 2 points |
Absence of | 2 points |
Platelet count <150×109/L | 1 point |
Constitutional symptoms | 1 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..
Prognostication for patients with myelofibrosis treated with ruxolitinib: As ruxolitinib has become the standard of care for patients with a higher risk of myelofibrosis, the development of a treatment-specific prognostic model has been sought. The response to Ruxolitinib after 6 months (RR6) [45] classifies patients with myelofibrosis treated with ruxolitinib according to OS. Risk variables were as follows: receiving ruxolitinib <20 mg twice daily at all three time points (i.e., at baseline and months 3 and 6; 1 point), requirement of RBC transfusion not at baseline but at months 3 and/or 6 (1 point), achievement of <30% spleen length reduction at months 3 and 6 compared to baseline (1.5 points), and RBC transfusion requirement at all three time points (1.5 points). The median OS for patients with low (0 points), intermediate (1–2 points), and high (2.5–4 points) risk was NR, 61 months, and 33 months, respectively [45]. The investigators commented that RR6 could be a useful tool for selecting a population that needs an early shift to second-line therapy, although it needs further validation. As JAK inhibitors and other targeted agents have been investigated and introduced, a more refined treatment-specific prognostic system would contribute to improving treatment outcomes.
Prognostication for patients with myelofibrosis treated with ruxolitinib who underwent allo-HSCT: Allo-HSCT is the only curative treatment for myelofibrosis for curative intent [6]. Owing to the complexity and significant risk of non-relapse mortality after allo-HSCT, risk stratification models that can predict the outcomes of allo-HSCT in patients with myelofibrosis would be particularly useful. The myelofibrosis Transplant Scoring System (MTSS) aims to predict treatment outcomes at the time of referral for allo-HSCT in patients with overt primary or post-ET/post-PV myelofibrosis [46]. The risk variables included human leukocyte antigen-mismatched unrelated donors (2 points), non-
Table 4 summarizes the results of the analyses of certain mutations and the prognosis reported for patients with MPN. Currently, the results should be used as a component within a comprehensive clinico-hematological-genetic context rather than solely focusing on the prognostic value of individual variants/mutations [24, 25, 31, 32, 48-57].
Table 4 . Prognostication in myeloproliferative neoplasms according to mutational abnormalities..
Genes | Polycythemia vera | Essential thrombocythemia | Myelofibrosis | |
---|---|---|---|---|
Driver mutations | -. Associated with younger age, higher hemoglobin, lower leukocytes and platelet counts, but no difference in LFS, MFFS, and OS, compared to | |||
- | ||||
- | - | |||
Triple negativityb) | - | - | ||
Non-driver mutations | “Adverse variants/mutations” [24, 25] -. All: inferior OS. -. -. | - | Inferior LFS, OS [52] | |
Inferior PFS after HSCT [53] | ||||
- | Inferior LFS [52, 53] | |||
“Adverse variants/mutations” [24, 25] -. All: inferior OS. -. -. -. | Inferior PFS after HSCT [52, 53] | |||
- | ||||
Inferior LFS and OS [52] | ||||
- | Inferior LFS [54] | |||
- | : Inferior OS compared to | |||
: inferior OS post allogeneic HSCT | ||||
- | Inferior OS [52] | |||
- | - | |||
- | - | |||
- | Inferior OS [57] |
a)A>B: A has a higher thrombosis rate (or superior survival) than B. b)Triple negativity: no mutation in
Abbreviations: HSCT, hematopoietic stem cell transplantation; LFS, leukemia-free survival; MFFS, myelofibrosis-free survival; OS, overall survival..
In addition to the existing clinical understanding, a deeper understanding of the molecular aspect of the diseases enabled the development of a more accurate prognostic system in MPNs. In PV, mutations in
No potential conflicts of interest relevant to this article were reported.
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 PV | MIPSS-PV | |
---|---|---|
Age ≥60 yr | Thrombosis history | 1 point |
Thrombosis history | WBC ≥15×109/L | 1 point |
Age >67 | 2 points | |
Mutated | 3 points |
Stratification and treatment | Sum of the points and interpretation | ||
---|---|---|---|
Low risk | None of them; no cytoreduction | Low risk | 0–1; mOS 24 yr |
High risk | Any of them; cytoreduction needed | Intermediate risk | 2–3; 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 ET | MIPSS-ET | |
---|---|---|
Thrombosis history | Male sex | 1 point |
Age >60 yr | WBC ≥11×109/L | 1 point |
Adverse mutationsb) | 2 points | |
Age >60 | 4 points |
Stratification and treatment | Sum of the points and interpretation | ||
---|---|---|---|
Very low risk | None of them; observationa) | Low risk | 0–1; mOS 34.4 yr |
Low risk | Intermediate risk | 2–5; mOS 14.1 yr | |
Intermediate risk | Age >60 yr only; aspirin | High risk | ≥6; mOS 7.9 yr |
High risk | Any others; cytoreduction |
a)Aspirin, if any cardiovascular risk factors are present. b)Mutations in
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 diagnosis | 0.15 points per yr |
Hemoglobin <11 g/dL | 2 points |
Circulating blast ≥3% | 2 points |
Absence of | 2 points |
Platelet count <150×109/L | 1 point |
Constitutional symptoms | 1 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..
Genes | Polycythemia vera | Essential thrombocythemia | Myelofibrosis | |
---|---|---|---|---|
Driver mutations | -. Associated with younger age, higher hemoglobin, lower leukocytes and platelet counts, but no difference in LFS, MFFS, and OS, compared to | |||
- | ||||
- | - | |||
Triple negativityb) | - | - | ||
Non-driver mutations | “Adverse variants/mutations” [24, 25] -. All: inferior OS. -. -. | - | Inferior LFS, OS [52] | |
Inferior PFS after HSCT [53] | ||||
- | Inferior LFS [52, 53] | |||
“Adverse variants/mutations” [24, 25] -. All: inferior OS. -. -. -. | Inferior PFS after HSCT [52, 53] | |||
- | ||||
Inferior LFS and OS [52] | ||||
- | Inferior LFS [54] | |||
- | : Inferior OS compared to | |||
: inferior OS post allogeneic HSCT | ||||
- | Inferior OS [52] | |||
- | - | |||
- | - | |||
- | Inferior OS [57] |
a)A>B: A has a higher thrombosis rate (or superior survival) than B. b)Triple negativity: no mutation in
Abbreviations: HSCT, hematopoietic stem cell transplantation; LFS, leukemia-free survival; MFFS, myelofibrosis-free survival; OS, overall survival..
Sung-Eun Lee
Blood Res 2021; 56(S1): S26-S33Young‑Uk Cho
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