The 2020 revision of the guidelines for the management of myeloproliferative neoplasms

Sung-Yong Kim; Sung Hwa Bae; Soo-Mee Bang; Ki-Seong Eom; Junshik Hong; Seongsoo Jang; Chul Won Jung; Hee-Jin Kim; Ho Young Kim; Min Kyoung Kim; Soo-Jeong Kim; Yeung-Chul Mun; Seung-Hyun Nam; Jinny Park; Jong-Ho Won; Chul Won Choi

doi:10.3904/kjim.2020.319

Kim, Bae, Bang, Eom, Hong, Jang, Jung, Kim, Kim, Kim, Kim, Mun, Nam, Park, Won, and Choi: The 2020 revision of the guidelines for the management of myeloproliferative neoplasms

Review

The Korean Journal of Internal Medicine 2021;36(1):45-62.

Published online: December 04, 2020

DOI: https://doi.org/10.3904/kjim.2020.319

The 2020 revision of the guidelines for the management of myeloproliferative neoplasms

Sung-Yong Kim¹, Sung Hwa Bae², Soo-Mee Bang³, Ki-Seong Eom⁴, Junshik Hong⁵, Seongsoo Jang⁶, Chul Won Jung⁷, Hee-Jin Kim⁸, Ho Young Kim⁹, Min Kyoung Kim¹⁰, Soo-Jeong Kim¹¹, Yeung-Chul Mun¹², Seung-Hyun Nam¹³, Jinny Park¹⁴, Jong-Ho Won¹⁵, Chul Won Choi¹⁶

¹Division of Hematology, Department of Internal Medicine, Konkuk University Medical Center, Seoul, Korea

²Department of Internal Medicine, Daegu Catholic University School of Medicine, Daegu, Korea

³Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea

⁴Department of Hematology, Seoul St. Mary’s Hematology Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea

⁵Division of Hematology and Medical Oncology, Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea

⁶Department of Laboratory Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea

⁷Division of Hematology/Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

⁸Department of Laboratory Medicine & Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

⁹Department of Internal Medicine, Hallym University Medical Center, Anyang, Korea

¹⁰Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Korea

¹¹Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea

¹²Department of Internal Medicine, Ewha Womans University School of Medicine, Seoul, Korea

¹³Department of Internal Medicine, Veterans Health Service Medical Center, Seoul, Korea

¹⁴Division of Hematology, Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Korea

¹⁵Division of Hematology-Oncology, Department of Internal Medicine, Soonchunhyang University College of Medicine, Seoul, Korea

¹⁶Division of Hematology-Oncology, Department of Internal Medicine, Korea University Guro Hospital, Seoul, Korea

Correspondence to: Chul Won Choi, M.D., Division of Hematology and Oncology, Department of Internal Medicine, Korea University Guro Hospital, 148 Gurodong-ro, Guro-gu, Seoul 08308, Korea, Tel: +82-2-2626-3058, Fax: +82-2-862-6453, E-mail: bonnie@korea.ac.kr

Received June 24, 2020 Accepted November 07, 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 noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited4

Abstract

In 2016, the World Health Organization revised the diagnostic criteria for myeloproliferative neoplasms (MPNs) based on the discovery of disease-driving genetic aberrations and extensive analysis of the clinical characteristics of patients with MPNs. Recent studies have suggested that additional somatic mutations have a clinical impact on the prognosis of patients harboring these genetic abnormalities. Treatment strategies have also advanced with the introduction of JAK inhibitors, one of which has been approved for the treatment of patients with myelofibrosis and those with hydroxyurea-resistant or intolerant polycythemia vera. Recently developed drugs aim to elicit hematologic responses, as well as symptomatic and molecular responses, and the response criteria were refined accordingly. Based on these changes, we have revised the guidelines and present the diagnosis, treatment, and risk stratification of MPNs encountered in Korea.

Keywords: Polycythemia vera; Thrombocythemia, essential; Primary myelofibrosis; Practice guideline

INTRODUCTION

Myeloproliferative neoplasms (MPNs) are clonal hematopoietic disorders characterized by the overproduction of terminally differentiated myeloid cells and an increased risk of thrombosis, bleeding, and leukemic transformation. The latest MPN classification of the World Health Organization (WHO), released in 2016, refined this disease category to include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) as “Philadelphia-negative classical MPNs” [1].

The discovery in 2005 of JAK2V617F mutations in patients with this disease entity represented an extraordinary advancement in our understanding of the disease [2,3]. It is now well-known that both acquired and constitutive genetic alterations contribute to the pathogenesis of Philadelphia-negative MPNs. Both the annual incidence and prevalence of MPNs in Korea have increased over the years [4,5]. Given that the expected survival of the general population is increasing, MPNs are an important disease entity in Korea.

In 2015, we published the diagnostic and therapeutic guidelines for Korean patients with MPNs [6]. The revised WHO diagnostic criteria for MPNs were published in 2016 [7]. Hence, revisions of the Korean MPN guidelines are necessary to keep pace with changes in the diagnosis and treatment of the disease. Here, we have updated the epidemiology, diagnostic criteria, risk stratification, response criteria, genetic mutations, and standard treatment strategies for patients with MPNs in Korea.

EPIDEMIOLOGY

Although there are limitations to clarifying the epidemiology of MPNs because of the their indolent nature, the complexity of the diagnostic process, and partial overlap with myeloid malignancies, several studies have attempted to define the epidemiologic features of MPNs [4,5,8–10]. According to data from the Cancer Registry of Norway [10], the incidence rates of PV, ET, and PMF approximately doubled from 1995–1997 (0.4, 0.3, and 0.2 per 10⁵ person-years, respectively) to 2010–2012 (0.7, 1.0, and 0.5 per 10⁵ person-years, respectively). Patients with PV and ET have similar relative survival rates, whereas patients with myelofibrosis (MF) have lower relative survival, compared with the normal population [10].

In a Korean study using nationwide population-based data from the Korean National Cancer Incidence Database and the Healthcare Insurance Reimbursement and Assessment, which covers approximately 90% of the total population of Korea [4], the age-standardized incidence rates of PV, ET, and PMF in 2011 were 0.31, 0.64, and 0.11 per 10⁵ person-years, respectively, while the respective prevalence rates were 3.28, 5.33, and 1.83 per 10⁵ person-years. Unlike the results reported by Western studies [8,10], the incidence and prevalence of MPN in Korea increased between 2004 and 2011. The 5-year relative survival rate for all patients with MPNs during the study period was 89.3%, with the lowest rate seen in patients with MF (53.1%). Another Korean study reported similar overall outcomes [5].

In another recent big-data study in Korea [11], which evaluated 7,454 patients with MPNs who were newly diagnosed with PV, ET, or PMF from 2008 to 2016, the transformation to secondary MF or secondary acute myeloid leukemia was rare in patients with PV and ET. However, in patients with PMF, the 8-year cumulative incidence of secondary acute myeloid leukemia was 21.4%. Patients with PV or ET had an approximately 14% 8-year cumulative incidence of second primary solid tumors [11]. Consistent with the results of Western studies [12,13], Korean patients with MPNs had a twofold greater risk of developing second primary solid tumors than the general population, highlighting the importance of regular medical check-ups for malignancies in patients with MPNs.

POLYCYTHEMIA VERA

In comparing the 2016 WHO criteria [7] with the 2008 WHO criteria [14], the hemoglobin level needed for a diagnosis of PV was lowered to 16.5 g/dL in men and 16.0 g/dL in women, based on the underdiagnosis of patients with PV who had JAK2 mutations, as well as the typical clinical course of PV [15]. In addition, bone marrow examinations were more heavily emphasized and morphologic criteria were clearly described for the reproducible diagnosis of PV.

More than 90% of patients with PV harbor JAK2V617F mutations in JAK2 exon 14, while 2% to 3% of patients with PV harbor JAK2 exon 12 mutations [3,16,17]. Thus, analysis of JAK2 mutations is the most valuable laboratory test to diagnose PV. The clinical outcomes did not significantly differ between patients with JAK2V617F mutations and those with JAK2 exon 12 mutations [18]. In patients with JAK2V617F-mutated PV, a persistently high or progressive increase in the JAK2V617F allele burden was the strongest predictor of MF transformation [19].

RISK STRATIFICATION AND TREATMENT FOR PV

Although PV is classified as a neoplasm, recent studies have shown that the life expectancy of patients with PV does not differed from that of the general population [20,21]. However, symptoms and complications (e.g., pruritus, erythromelalgia, splenomegaly, thrombosis, and transformation into MF or acute myeloid leukemia) cause patients with PV to have a poor quality of life and significant morbidity. Accordingly, symptom relief and the prevention of complications and hematologic transformation are the main goals of therapy. Because of the toxicity of therapeutics, especially cytoreductive cytotoxic agents, treatment decisions should be based on a balance between side effects and risk reduction.

Unlike other MPNs, the risk stratification of PV has not changed. Age older than 60 years and a history of thrombosis have been identified as major predictors of vascular complications [22,23]. Thus, patients who had either of those two factors were defined as high-risk patients, while those who had neither were defined as low-risk patients (Table 1).

All patients with PV require appropriate management of cardiovascular risk factors and phlebotomy to maintain a hematocrit level of < 45% in men and < 42% in women [24,25]. The effect of phlebotomy was demonstrated in an uncontrolled study [26]. A prior randomized study, “The Intensity of CYTOreductive Therapy to Prevent Cardiovascular Events in Patients with Polycythemia Vera (CYTO-PV)”, showed that patients with a hematocrit target of < 45% had a significantly lower rate of cardiovascular death and major thrombosis than did those with a hematocrit target of 45% to 50% [27].

The efficacy and safety of low-dose aspirin (100 mg daily) in PV was verified by the European Collaboration on Low-dose Aspirin in Polycythemia Vera (ECLAP) study [28]. At the 3-year follow-up, patients receiving 100 mg aspirin showed a significant reduction in vascular events. Major bleeding was not significantly increased by aspirin. Therefore, low-dose aspirin is recommended for all patients with PV, unless contraindicated.

CYTOREDUCTIVE THERAPY FOR PV

Cytoreductive therapy using hydroxyurea or interferon-alpha (IFN-α) is indicated for high-risk patients with PV. In low-risk patients, cytoreductive therapy is recommended in the event of a progressive increase in the leukocyte and/or platelet count, severe disease-related symptoms, symptomatic splenomegaly, or phlebotomy intolerance.

Hydroxyurea is recommended as the first-line cytoreductive therapy in Korea, because IFN-α has significant toxicity and pegylated-IFN (peg-IFN) is not currently covered by the National Health Insurance system of Korea. The starting dose of hydroxyurea is 15 to 20 mg/kg/day and the dose should be adjusted for optimal count control [24,25]. Supplemental phlebotomy should be performed to maintain hematocrit at the target level.

RESISTANCE OR INTOLERANCE TO HYDROXYUREA

In 2011, European LeukemiaNet (ELN) defined the criteria for the response of patients with PV to conventional cytoreductive therapy, as well as the criteria for hydroxyurea intolerance or resistance (Table 2) [29]. In 2013, ELN and the International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) revised the response criteria to incorporate clinical, hematological, and histological assessments, and to consider disease progression and vascular events (Table 3) [30], because the previous complete response criteria were not correlated with lower thrombosis incidence or improved survival [31,32]. The revised criteria were intended to evaluate the results of clinical trials measuring the activities of drugs expected to modify the biology and natural history of PV and ET.

Resistance and intolerance to hydroxyurea were observed in 5% to 10% of the patients with PV [32]. Of note, resistance to hydroxyurea was associated with a greater risk of death (hazard ratio, 5.6) and disease transformation (hazard ratio, 6.8) [32]. Therefore, we recommend bone marrow biopsy for hydroxyurea-resistant patients. Because leukocytosis and additional phlebotomy requirements, despite the use of hydroxyurea, are major thrombotic risk factors in patients with PV [33,34], a second-line drug for hydroxyurea-resistant or intolerant patients seems to be necessary.

A randomized controlled trial revealed that ruxolitinib, a JAK inhibitor, was superior to standard therapy in terms of controlling hematocrit levels, reducing spleen volume, and improving disease-related symptoms in patients with PV who had an inadequate response to or unacceptable side effects from hydroxyurea [35,36]. Peg-IFN also demonstrated efficacy in the treatment of hydroxyurea-resistant or intolerant patients with PV in a phase 2 trial, in which the overall response rate (complete or partial response) at 12 months was 60% [37]. Peg-IFN treatment was associated with a significant rate of adverse events, but most were manageable. Peg-IFN discontinuation related to adverse events occurred in only 13.9% of the patients.

In Korea, the currently available second-line therapeutics are IFN-α, peg-IFN, and ruxolitinib [35,37–39], all of which are approved by the Ministry of Food and Drug Safety. However, peg-IFN and ruxolitinib are not currently covered by the National Health Insurance system of Korea.

ESSENTIAL THROMBOCYTHEMIA

According to the 2016 WHO classification [7], bone marrow biopsy is mandatory for differentiating ET from other MPNs, especially prefibrotic PMF. Approximately 60% of patients with ET harbor JAK2V617F mutations [3,40,41]. Calreticulin (CALR) gene mutations are present in 20% to 35% of patients with ET [42,43], and a thrombopoietin receptor (MPL) gene mutation is found in 1% to 4% of patients with ET [44–46]. In the absence of any of the three major clonal mutations, testing for the most frequent accompanying mutations (e.g., ASXL1, EZH2, TET2, IDH1/IDH2, SRSF2, and SF3B1) is useful for determining the clonal nature of the disease. Although the CALR mutation is associated with a higher platelet count, lower hemoglobin level, lower leukocyte count, and lower risk of thrombosis [47–49], a large-scale study did not demonstrate that it had a significant impact on the International Prognostic Score of Thrombosis for Essential Thrombocythemia (IPSET-thrombosis) in predicting the risk of thrombosis in multivariate analysis [50]. Next-generation sequencing identified SH2B3, SF3B1, U2AF1, TP53, IDH2, and EZH2 mutations as significant risk factors for inferior overall survival (OS) and MF-free survival [51]. TP53 mutation was a predictor of inferior leukemia-free survival.

RISK STRATIFICATION AND TREATMENT OF ET

The risk stratification of ET is based on the assessment of the risk of thrombosis or bleeding complications, as in PV. However, mutational status was recently incorporated into the stratification system. In 2012, the IPSET-thrombosis was proposed, based on important factors used in assessing the risk of thrombotic complications. These factors included a prior history of venous or arterial thrombosis, age > 60 years, JAK2V617F mutation, and cardiovascular risk factors (e.g., hypertension, diabetes mellitus, and current smoking) [52]. The IPSET-thrombosis model was revised for clinical application in 2015 [53].

Table 4 describes the general therapeutic principles according to the revised IPSET-thrombosis model [54]. We recommend observation in lower (very low and low)-risk patients without cytoreductive therapy [55,56]. Low-dose aspirin in lower-risk patients is recommended in the presence of vasomotor symptoms, JAK2V617F mutation, or general indications for aspirin (e.g., cardiovascular risk factors).

Extreme thrombocytosis (i.e., platelets > 1 million/μL) may promote a hemostatic defect due to excessive adsorption of large von Willebrand factor multimers [56]. Therefore, aspirin should be avoided in patients with ristocetin cofactor activity < 30% due to the increased risk of hemorrhage [57,58]. Low-dose aspirin is acceptable if the ristocetin cofactor level is ≥ 30% [59]. Cytoreductive therapies are suggested to reduce the platelet count to 100,000 to 400,000/μL for lower-risk patients with extreme thrombocytosis [59].

In 2005, 809 patients with ET were randomly assigned to receive either hydroxyurea or anagrelide, both in combination with aspirin. Although equivalent long-term control of platelet counts was achieved in both groups, hydroxyurea plus aspirin was superior in terms of preventing both thrombosis and transformation into MF [60]. A meta-analysis also supported a favorable effect of hydroxyurea on the risk of thrombosis, major bleeding, and death (relative risk, 0.78; 95% confidence interval, 0.63 to 0.97) [61]. However, anagrelide was not inferior to hydroxyurea in preventing thrombotic complications in a subsequent trial, the ANAHYDRET Study [62]. Therefore, we recommend hydroxyurea and aspirin as first-line therapy in high-risk patients with ET, and anagrelide as second-line therapy in selected patients, including hydroxyurea-intolerant patients. We do not recommend standard IFN-α in patients with ET as a first-line treatment because of its toxicity profile, except for patients who exhibit treatment failure with hydroxyurea or who are/become pregnant during treatment.

RESISTANCE AND INTOLERANCE TO HYDROXYUREA IN PATIENTS WITH ET

Tables 5 [63] and 6 [29] depict the revised response criteria and definition of resistance and intolerance to hydroxyurea in patients with ET. A prior study revealed that approximately 10% of patients with ET became hydroxyurea-intolerant or were resistant [63]. Peg-IFN demonstrated excellent efficacy in terms of cytoreduction and the molecular response in patients with ET, without the high drug discontinuation rate observed in conventional IFN-α treatment [64–66]. This finding suggested that peg-IFN could be used in hydroxyurea-resistant or intolerant patients with ET as second-line therapy. A recent trial demonstrated the activity of peg-IFN in hydroxyurea-resistant or intolerant patients with ET [37].

In contrast to a prospective trial of patients with PV [35,39], ruxolitinib did not demonstrate superior efficacy to the conventional, best-available therapy in hydroxyurea-resistant or intolerant patients with ET [67]. Therefore, we currently do not recommend ruxolitinib over other available drugs for those patients.

PREGNANT WOMEN AND THOSE WHO DESIRE TO BECOME PREGNANT

ET is the most common MPN in women of childbearing age [68,69], and is associated with an increased risk of both maternal and fetomaternal thrombotic complications, especially when patients have JAK2 mutations [68]. Currently, no standard approach for managing the platelet count has been established for pregnant patients with ET.

We recommend observation in lower-risk patients without a previous history of complications during pregnancy without specific therapy. The use of a platelet-lowering agent may be necessary for high-risk women with a previous history of thrombotic complications during pregnancy. Currently, both hydroxyurea and anagrelide are contraindicated for use during pregnancy. The only drug with proven safety and cytoreduction effects in pregnant patients is standard IFN-α [70–73].

A recent meta-analysis reported that the live birth rate was higher in pregnant women with MPNs who received low-dose aspirin during pregnancy than in those managed with observation alone (odds ratio, 9.48; 95% confidence interval, 4.41 to 20.41) [74]. Low-molecular-weight heparin may reduce the risk of venous thromboembolism in the antepartum and postpartum periods without increasing the risk of bleeding, although the venous thromboembolism risk was not significantly different between pregnant patients with ET who used low-molecular-weight heparin and those who did not [75].

PREFIBROTIC (EARLY STAGE) PRIMARY MYELOFIBROSIS

The 2016 WHO classification defined prefibrotic/early stage PMF (pre-PMF) [7]. Previously, PMF had been diagnosed as ET according to the 2008 WHO diagnostic criteria for MPNs, because it shares characteristics with overt PMF, such as atypical megakaryocytes, reduced erythropoiesis, high lactate dehydrogenase level, and anemia. A prior study showed that 16% of patients with ET diagnosed based on the 2006 WHO criteria had prefibrotic PMF [76]. The prognosis of patients with pre-PMF is worse than that of patients with ET in terms of OS, leukemia transformation risk, and fibrotic progression risk [76]. Therefore, differentiation between the two diseases is important. A bone marrow aspirate and biopsy with trichrome and reticulin staining are critical for differentiating ET from prefibrotic PMF [7].

The main diagnostic difference between prefibrotic and overt PMF is the grade of reticulin fibrosis in the bone marrow. Compared with overt PMF, pre-PMF causes a higher hemoglobin level and platelet count, a lower circulating blast percentage, and a lower incidence of splenomegaly. Patients with pre-PMF have a lower Dynamic International Prognostic Scoring System-plus (DIPSS-plus) risk categorization [77–79]. Differences in the distributions of ASXL1, SRSF2, U2AF1, SF3B1, EZH2, and IDH1/2 mutations, and in the incidence of unfavorable karyotypes, between the two categories of disease vary among published studies [77,79]. The OS rate was significantly higher in patients with pre-PMF than in those with overt PMF, independent of the DIPSS-plus score (p = 0.03), driver mutation status (p = 0.001), ASXL1 mutation status (p = 0.008), and SRSF2 mutation status (p = 0.02). However, no significant difference in leukemia-free survival was noted between the two categories of disease (p = 0.25) [77].

No treatment guidelines have been established for patients with pre-PMF because of the absence of long-term observations and treatment validation for this disease entity. Because this disease shares the characteristics of both ET and lower-risk overt PMF, we suggest that the treatment strategy should follow the general treatment guidelines for patients with ET or PMF, depending upon the thrombosis risk and symptom burden of the individual patient, until sufficient data have accumulated concerning this entity.

PRIMARY MYELOFIBROSIS

Patients with PV or ET show near-normal life expectancies, but the median survival of patients with PMF ranges from 4 to 5.5 years. The majority of patients experience at least one of the symptoms caused by cytopenia, splenomegaly, and increased proinflammatory cytokine levels [80,81]. The Myeloproliferative Neoplasm Symptom Assessment Form total symptom score is a simple assessment tool for checking a patient’s constitutional symptoms, splenomegaly related symptoms, and quality of life at diagnosis and during the course of treatment [82,83].

The majority of patients with PMF harbor one of three driver mutations: JAK2 (58% to 66%), CALR (23% to 35%), or MPL (7% to 8%). Patients with PMF harboring CALR type1/type1-like mutations show improved median OS (8.2 to 10.3 years) compared with those harboring CALR type 2/type 2-like (3.1 years), JAK2 (4.3 years), or MPL (4.1 years) mutations [84,85]. Approximately 10% of patients with PMF are triple-negative, which is associated with worse OS and leukemia-free survival [48,86,87].

RISK STRATIFICATION AND TREATMENT OF PMF

Prognostic scoring evolved from the International Prognostic Scoring System in 2009 [88] to the DIPSS in 2010 [89], and the DIPSS-plus in 2011 [90]. The median OS is 15.4, 6.5, 2.9, and 1.3 years for low, intermediate-1, intermediate-2, and high risk patients, respectively, according to the DIPSS-plus. Recent molecular and cytogenetic studies found mutated genes in high-molecular risk (ASXL1, EZH2, SRSF2, IDH1, and IDH2) [87,91] and high-risk karyotypes (−7/7q−, −5/5q, i(17q), +8, inv(3), 12p−, 11q23, and monosomal karyotype). Therefore, the newly developed Mutation and Karyotype-Enhanced International Prognostic Scoring System 70 (MIPSS70) and MIPSS70+ version 2.0 (integrating clinical, cytogenetic, and mutation data [92,93]), and the Genetically Inspired Prognostic Scoring System (GIPSS) model (exclusively based on genetic markers [94]), were developed in 2018 (Table 7) [95]. Because next-generation sequencing has not been popular in Korea until recently, DIPSS and DIPSS-plus remain important for risk stratification in patients with PMF. The current treatment algorithm using the risk stratification in Korea is depicted in Fig. 1.

TREATMENT OF SPLENOMEGALY AND CONSTITUTIONAL SYMPTOMS

Hydroxyurea can improve splenomegaly, bone pain, constitutional symptoms, and pruritus [95,96]. However, these improvements are temporary and the myelosuppressive toxicity of this agent hampers continued therapy [97,98].

Ruxolitinib was the first JAK inhibitor approved for patients with intermediate- to high-risk MF, in 2011. In two pivotal randomized trials (COMFORT-I and COMFORT-II), approximately half of the patients experienced spleen volume reductions and showed significant improvement in symptoms [99,100]. Ruxolitinib treatment also led to a significant mortality reduction (p = 0.04) and survival improvement [101]. Because grade 3–4 anemia and thrombocytopenia occurred in 45.2% and 12.9% of the patients, respectively, supportive care and dose reduction should be considered. Fedratinib [102,103], pacritinib [104], and momelotinib [105] are new JAK inhibitors that have recently shown potential for patients resistant to or intolerant to ruxolitinib.

RESPONSE EVALUATION

No drug modifying the disease activity of PMF is available. Thus, current treatment is aimed at improving anemia, reducing splenomegaly, and relieving disease-related symptoms [106]. However, recent trials using JAK inhibitors, IFNs, and other emerging drugs have attempted to demonstrate effects on molecular and cytogenetic responses, and marrow fibrosis [107–109]. Therefore, the response criteria were revised to evaluate hematologic, clinical, molecular, and cytogenetic responses (Table 8) [110].

TREATMENT OF ANEMIA

Erythropoiesis-stimulating agents have been shown to improve anemia in 45% to 60% of MF patients. Plasma erythropoietin levels < 125 U/L have been associated with a higher probability of a response [111–113]. Androgenic steroids, such as danazol, may stimulate bone marrow function and improve hemoglobin concentrations in 30% to 40% of patients with MF [114,115]. Thalidomide [116] or lenalidomide [117], in combination with low-dose prednisone, can increase hemoglobin levels and decrease spleen size.

HEMATOPOIETIC CELL TRANSPLANTATION IN PMF

Despite the advent of JAK inhibitors, allogeneic hematopoietic cell transplantation remains the only curative treatment for PMF. Given that the median survival time of transplanted patients with PMF exceeded that of patients with PMF who did not receive transplantation in the high and intermediate-2 risk categories [118–120], allogeneic hematopoietic cell transplantation is recommended in patients with an intermediate-2 or high-risk classification, according to the DIPSS or DIPSS-plus at diagnosis or during follow-up [29,121–124]. For patients with intermediate-1 risk classification, individual counseling is necessary and we recommend MIPSS70 or GIPSS be used to assess the need for transplantation.

The Myelofibrosis Transplant Scoring System (MTSS) was suggested as a prognostic score for predicting the outcome of MF patients undergoing allogeneic hematopoietic cell transplantation based on clinical, molecular, and transplant-specific information [125]. The MTSS stratifies patients into four 5-year OS risk categories: low (85%), intermediate (64%), high (37%), or very high (22%).

The pre-transplant use of ruxolitinib may improve transplant outcomes by improving splenomegaly and performance status. Several recent trials have demonstrated the potential benefit of this strategy [126–128].

CONCLUSIONS

During the past decade, extensive knowledge concerning BCR-ABL-negative MPN has been accumulated through the detection of molecular abnormalities and many clinical analyses of affected patients. These advances led to the revision of the diagnostic criteria for MPNs by the WHO in 2016. The main change in the diagnosis was the separation of pre-PMF from the disease previously categorized as ET. This new disease classification can be differentiated using standardized bone marrow morphology and peripheral blood laboratory analysis. The hemoglobin and platelet count thresholds for the diagnosis of PV and ET were lowered in the new criteria due to the underdiagnosis of these disease entities in retrospective studies.

Because of the chronicity of MPN, risk stratification for treatment decisions is necessary to avoid unnecessary adverse effects of treatment. An in-depth understanding of the molecular abnormalities of underlying MPNs, and the clinical outcomes according to mutational status, facilitated refinement of the risk stratification. Data regarding molecular abnormalities also guided the development of targeted drugs such as JAK inhibitors, which improve the survival and quality of life of selected patients with PMF, and allow for hematologic control in hydroxyurea-resistant or intolerant patients with PV. However, newly developed drugs for the treatment of BCR/ABL-negative MPNs have not yet demonstrated efficacy in terms of improving the disease course and therapy remains supportive. A newly developed IFN agent has recently been introduced. Because immunotherapy using IFN has the potential to improve the disease course, long-term clinical data are critical.

Gene expression profiling and next-generation sequencing, which are now widely available laboratory methods, can identify various additional non-driver mutations. Additional clinical data of patients harboring these additional mutations may allow the prognosis to be better defined, and could also guide the development of agents that could change the natural course of these indolent but evolving diseases.

Conflict of Interest

No potential conflict of interest relevant to this article was reported.

Figure 1

Recommended algorithm for the treatment of primary myelofibrosis. IPSS, International Prognostic Scoring System; DIPSS, Dynamic International Prognostic Scoring System. ^aRuxolitinib for low or intermediate-1 risk patients is approved by the Ministry of Food and Drug Safety but not currently covered by National Health Insurance system of Korea, ^bRuxolitinib treatment before transplantation to alleviate symptoms and splenomegaly can be considered.

Table 1

General therapeutic principles for risk stratification of patients with polycythemia vera

Risk	Attributes	Management
Low	Age ≤ 60 years and no prior thrombosis history	Low-dose aspirin AND Phlebotomy (to keep hematocrit < 45% in males and < 42% in females)
High	Age > 60 years or prior thrombosis history regardless of other factors	Low-dose aspirin AND Phlebotomy (to keep hematocrit < 45% in males and < 42% in females) AND Cytoreductive therapy (first line: hydroxyurea, second line: ruxolitinib or peg-interferon)

Table 2

European LeukaemiaNet criteria for hydroxycarbamide intolerance and resistance in patients with polycythemia vera

1. Need for phlebotomy to keep hematocrit < 45% after 3 months of at least 2 g/day of hydroxyurea, OR

2. Uncontrolled myeloproliferation (i.e., platelet count > 400 × 10⁹/L and WBC count > 10 × 10⁹/L) after 3 months of at least 2 g/day of hydroxyurea, OR

3. Failure to reduce massivea splenomegaly by > 50% as measured by palpation OR failure to completely relieve symptoms related to splenomegaly after 3 months of at least 2 g/day of hydroxyurea, OR

4. Absolute neutrophil count < 1.0 × 10⁹/L OR platelet count < 100 × 10⁹/L OR hemoglobin < 10 g/dL at the lowest dose of hydroxyurea required to achieve a completeb or partialc clinicohematologic response, OR

5. Presence of leg ulcers or other unacceptable hydroxyurea-related nonhematologic toxicities, such as mucocutaneous manifestations, GI symptoms, pneumonitis, or fever at any dose of hydroxyurea

WBC, white blood cell; GI, gastrointestinal.

^a Organ extending by > 10 cm from the costal margin.

^b Complete response is defined as hematocrit less than 45% without phlebotomy, platelet count < 400 × 10⁹/L, WBC count < 10 × 10⁹/L, and no disease-related symptoms.

^c Partial response is defined as hematocrit less than 45% without phlebotomy or response in three or more of the other criteria.

Table 3

Revised (2013) European LeukemiaNet and IWG-MRT response criteria for polycythemia vera

	Criteria
Complete remission
A	Durablea resolution of disease-related signs including palpable hepatosplenomegaly, large symptoms improvementb, AND
B	Durablea peripheral blood count remission, defined as Ht lower than 45% without phlebotomies; platelet count ≤ 400 × 10⁹/L, WBC count < 10 × 10⁹/L, AND
C	Without progressive disease, and absence of any hemorrhagic or thrombotic event, AND
D	Bone marrow histological remission defined as the presence of age-adjusted normocellularity and disappearance of trilinear hyperplasia, and absence of > grade 1 reticulin fibrosis
Partial remission
A	Durablea resolution of disease-related signs including palpable hepatosplenomegaly, and large symptoms improvementb, AND
B	Durablea peripheral blood count remission, defined as Ht lower than 45% without phlebotomies; platelet count < 400 × 10⁹/L, WBC count < 10 × 10⁹/L, AND
C	Without progressive disease, and absence of any hemorrhagic or thrombotic event, AND
D	Without bone marrow histological remission defined as persistence of trilinear hyperplasia.
No response
	Any response that does not satisfy partial remission
Progressive disease
	Transformation into post-PV myelofibrosis, myelodysplastic syndrome or acute leukemiac

Molecular response is not required for assignment as complete response or partial response. Molecular response evaluation requires analysis in peripheral blood granulocytes. Complete response is defined as eradication of a preexisting abnormality. Partial response applies only to patients with at least 20% mutant allele burden at baseline. Partial response is defined as ≥ 50% decrease in allele burden.

IWG-MRT, International Working Group-Myeloproliferative Neoplasms Research and Treatment; WBC, white blood cell; PV, polycythemia vera.

^a Lasting at least 12 weeks.

^b Large symptom improvement (≥ 10-point decrease) in the MPN Symptom Assessment Form Total Symptom Score (MPN-SAF TSS).

^c For the diagnosis of post-PV myelofibrosis, see the IWG-MRT criteria; for the diagnosis of myelodysplastic syndrome and acute leukemia, see World Health Organization criteria.

Table 4

General therapeutic principles established by the 2015 revised IPSET model for thrombotic risk stratification in patients with essential thrombocythemia

Risk	Attributes	Management
Very low	Age ≤ 60 years, JAK2 wild type, no prior thrombosis	Observation or low-dose aspirin if vasomotor symptoms present
Low	Age ≤ 60 years, JAK2 V617F⁺, no prior thrombosis	Low-dose aspirin, unless contraindicated.a Twice-daily aspirin if cardiovascular risk factors present
Intermediate	Age > 60 years, JAK2 wild type, no prior thrombosis	Cytoreductive therapy plus low-dose aspirin, unless contraindicateda, or twice-daily aspirin without cytoreductive therapy if no cardiovascular risk factors present
High	Age > 60 years and JAK2 V617F⁺, or prior thrombosis history regardless of other factors	Cytoreductive therapy plus low-dose aspirin, unless contraindicateda

IPSET, International Prognostic Score of Thrombosis for Essential.

^a Aspirin is generally contraindicated in the presence of acquired von Willebrand’s disease caused by extreme thrombocytosis.

Table 5

Revised (2013) European LeukemiaNet and IWG-MRT revised response criteria for essential thrombocythemia

	Criteria
Complete remission
A	Durablea resolution of disease-related signs including palpable hepatosplenomegaly, large symptoms improvementb, AND
B	Durablea peripheral blood count remission, defined as: platelet count ≤ 400 × 10⁹/L, WBC count < 10 × 10⁹/L, absence of leukoerythroblastosis, AND
C	Without signs of progressive disease, and absence of any hemorrhagic or thrombotic events, AND
D	Bone marrow histological remission defined as disappearance of megakaryocyte hyperplasia and absence of > grade 1 reticulin fibrosis.
Partial remission
A	Durablea resolution of disease-related signs including palpable hepatosplenomegaly, and large symptoms improvement, AND
B	Durablea peripheral blood count remission, defined as: platelet count ≤ 400 × 10⁹/L, WBC count < 10 × 10⁹/L, absence of leukoerythroblastosis, AND
C	Without signs of progressive disease, and absence of any hemorrhagic or thrombotic events, AND
D	Without bone marrow histological remission, defined as the persistence of megakaryocyte hyperplasia.
No response	Any response that does not satisfy partial remission
Progressive disease	Transformation into PV, post-ET myelofibrosis, myelodysplastic syndrome or acute leukemia

IWG-MRT, International Working Group-Myeloproliferative Neoplasms Research and Treatment; WBC, white blood cell; PV, polycythemia vera; ET, essential thrombocythemia.

^a Lasting at least 12 weeks.

^b Large symptom improvement (≥ 10-point decrease) in MPN Symptom Assessment Form Total Symptom Score (MNP-SAF TSS).

Table 6

European LeukaemiaNet criteria for hydroxyurea intolerance and resistance in patients with essential thrombocythemia

1. Platelet count > 600 × 10⁹/L after 3 months of at least 2 g/day of hydroxyurea (2.5 g/day in patients with a body weight > 80 kg), OR

2. Platelet count > 400 × 10⁹/L and WBC count < 2.5 × 10⁹/L at any dose of hydroxyurea, OR

3. Platelet count > 400 × 10⁹/L and hemoglobin < 10 g/dL at any dose of hydroxyurea, OR

4. Presence of leg ulcers or other unacceptable mucocutaneous manifestations at any dose of hydroxyurea, OR

5. Hydroxyurea-related fever

Table 7

MIPSS, MIPSS-plus, and GIPSS models for primary myelofibrosis

Prognostic model and risk factors (weight)		Risk groups and median survival
MIPSS70
Genetic variables	• Clinical variables
One HMR mutation (1 point)	Hemoglobin < 10 g/dL (1 point)	Low risk: 0–1 point (not reached)
≥ 2 HMR mutations (2 points)	Leukocytes > 25 × 10⁹/L (2 points)	Intermediate risk: 2–4 (6.3 yr)
Type 1/like CALR absent (1 point)	Platelet < 100 × 10⁹/L (2 points)	High risk: ≥ 5 (3.1 yr)
	Circulating blast ≥ 2% (1 point)
	Constitutional symptom (1 point)
	Marrow fibrosis grade ≥ 2 (1 point)
MIPSS70+ version 2.0
• Genetic variables	• Clinical variables
VHR karyotype (4 points)	Severe anemiaa (2 points)	Very low risk: 0 point (not reached)
Unfavorable karyotype (3 points)	Moderate anemiab (1 point)	Low risk: 1–2 (16.4 yr)
≥ 2 HMR mutations (3 points)	Circulating blasts ≥ 2% (1 point)	Intermediate-1 risk: 3–4 (7.7 yr)
One HMR mutation (2 points)	Constitutional symptoms (2 points)	High risk: 5–8 (4.1 yr)
Type 1/like CALR absent (2 points)		Very high risk: ≥ 9 (1.8 yr)
GIPSS
• Genetic variables
VHR karyotype (2 points)		Low risk: 0 point (26.4 yr)
Unfavorable karyotype (1 point)		Intermediate-1 risk: 1 point (8 yr)
Type 1/like CALR absent (1 point)		Intermediate-2 risk: 2 points (4.2 yr)
ASXL1 mutation (1 point)		High risk: ≥ 3 points (2 yr)
SRSF2 mutation (1 point)
U2AF1Q157 mutation (1 point)

MIPSS70 for transplant-age patients (age ≤ 70 years); MIPSS70+ version 2.0: mutation and karyotype enhanced international prognostic system. Survival quotes are for age ≤ 70 years. Survival quotes are for all age groups; HMR mutations include ASXL1, SRSF2, EZH2, IDH1, IDH2, and in addition, for GIPSS and MIPSS70+ version 2.0, U2AF1Q157.

MIPSS, mutation-enhanced international prognostic scoring system; GIPSS, genetically inspired prognostic scoring system; HMR, high molecular risk; CALR, calreticulin; VHR, very high risk.

^a Severe anemia: Hemoglobin < 8 g/dL in women and < 9 g/dL in men.

^b Moderate anemia: Hemoglobin 8 to 9.9 in women and 9 to 10.9 in men.

Table 8

Revised (2013) IWG-MRT and European LeukaemiaNet response criteria for myelofibrosis

Response categories	Required criteria (for all response categories, benefit must last for ≥ 12 weeks to qualify as a response)
CR	Bone marrowa: Age-adjusted normocellularity; < 5% blasts; ≤ grade 1 MFb and Peripheral blood: Hemoglobin ≥ 10.0 g/dL and < UNL; neutrophil count ≥ 1 × 10⁹/L and < UNL; Platelet count ≥ 100 × 10⁹/L and < UNL; < 2% immature myeloid cellsc and Clinical: Resolution of disease symptoms; spleen and liver not palpable; no evidence of EMH
PR	Peripheral blood: Hemoglobin ≥10.0 g/dL and < UNL; neutrophil count ≥ 1 × 10⁹/L and <UNL; platelet count > 100 × 10⁹/L and < UNL; < 2% immature myeloid cellsc and Clinical: Resolution of disease symptoms; spleen and liver not palpable; no evidence of EMH or Bone marrowa: Age-adjusted normocellularity; < 5% blasts; ≤ grade 1 MFb, and Peripheral blood: Hemoglobin ≥ 8.5 but < 10.0 g/dL and < UNL; neutrophil count ≥ 1 × 10⁹/L and < UNL; platelet count ≥ 50, but < 100 × 10⁹/L and < UNL; < 2% immature myeloid cellsc and Clinical: Resolution of disease symptoms; spleen and liver not palpable; no evidence of EMH
Clinical improvement (CI)	The achievement of anemia, spleen or symptoms response without progressive disease or increase in severity of anemia, thrombocytopenia, or neutropeniad
Anemia response	Transfusion-independent patients: a ≥ 2.0 g/dL increase in hemoglobin levele Transfusion-dependent patients: becoming transfusion-independentf
Spleen responseg	A baseline splenomegaly that is palpable at 5–10 cm, below the LCM, becomes not palpableh or A baseline splenomegaly that is palpable at > 10 cm, below the LCM, decreases by ≥ 50%h A baseline splenomegaly that is palpable at < 5 cm, below the LCM, is not eligible for spleen response A spleen response requires confirmation by MRI or CT showing ≥ 35% spleen volume reduction
Symptoms response	A ≥ 50% reduction in the MPN-SAF TSSi
Progressive diseasej	Appearance of a new splenomegaly that is palpable at least 5 cm below the LCM or A ≥ 100% increase in palpable distance, below LCM, for baseline splenomegaly of 5–10 cm or A 50% increase in palpable distance, below LCM, for baseline splenomegaly of > 10 cm or Leukemic transformation confirmed by a bone marrow blast count of ≥ 20% or A peripheral blood blast content of ≥ 20% associated with an absolute blast count of ≥ 1 × 10(9)/L that lasts for at least 2 weeks
Stable disease	Belonging to none of the above listed response categories
Relapse	No longer meeting criteria for at least CI after achieving CR, PR, or CI, or Loss of anemia response persisting for at least 1 month or Loss of spleen response persisting for at least 1 month Recommendations for assessing treatment-induced cytogenetic and molecular changes
Cytogenetic remission	At least 10 metaphases must be analyzed for cytogenetic response evaluation and requires confirmation by repeat testing within 6 months window CR: eradication of a preexisting abnormality PR: ≥ 50% reduction in abnormal metaphases (partial response applies only to patients with at least 10 abnormal metaphases at baseline)
Molecular remission	Molecular response evaluation must be analyzed in peripheral blood granulocytes and requires confirmation by repeat testing within 6 months window CR: Eradication of a pre-existing abnormality PR: ≥ 50% decrease in allele burden (partial response applies only to patients with at least 20% mutant allele burden at baseline)
Cytogenetic/molecular relapse	Re-emergence of a pre-existing cytogenetic or molecular abnormality that is confirmed by repeat testing

IWG-MRT, International Working Group-Myeloproliferative Neoplasms Research and Treatment; CR, complete response; MF, myelofibrosis; UNL, upper normal limit; EMH, extramedullary hematopoiesis; PR, partial response; LCM, left costal margin; MRI, magnetic resonance imaging; CT, computed tomography; MPN-SAF TSS, MPN Symptom Assessment Form Total Symptom Score.

^a Baseline and posttreatment bone marrow slides are to be interpreted at one sitting by a central review process. Cytogenetic and molecular responses are not required for CR assignment.

^b Grading of MF is according to the European classification. It is underscored that the consensus definition of a CR bone marrow is to be used only in those patients in which all other criteria are met, including resolution of leukoerythroblastosis. It should also be noted that it was a particularly difficult task for the working group to reach a consensus regarding what represents a complete histologic remission.

^c Immature myeloid cells constitute blasts + promyelocytes + myelocytes + metamyelocytes + nucleated red blood cells. In splenectomized patients, < 5% immature myeloid cells is allowed.

^d See above for definitions of anemia response, spleen response, and progressive disease. Increase in severity of anemia constitutes the occurrence of new transfusion dependency or a ≥ 2.0 g/dL decrease in hemoglobin level from pretreatment baseline that lasts for at least 12 weeks. Increase in severity of thrombocytopenia or neutropenia is defined as a 2-grade decline, from pretreatment baseline, in platelet count or absolute neutrophil count, according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. In addition, assignment to CI requires a minimum platelet count of ≥ 25,000 × 10⁹/L and absolute neutrophil count of ≥ 0.5 × 10⁹/L.

^e Applicable only to patients with baseline hemoglobin of < 10.0 g/dL. In patients not meeting the strict criteria for transfusion dependency at the time of study enrollment (see as follows), but have received transfusions within the previous month, the pretransfusion hemoglobin level should be used as the baseline.

^f Transfusion dependency before study enrollment is defined as transfusions of at least 6 units of packed red blood cells (PRBC), in the 12 weeks prior to study enrollment, for a hemoglobin level of < 8.5 g/dL, in the absence of bleeding or treatment-induced anemia. In addition, the most recent transfusion episode must have occurred in the 28 days prior to study enrollment. Response in transfusion-dependent patients requires absence of any PRBC transfusions during any consecutive “rolling” 12-week interval during the treatment phase, capped by a hemoglobin level of ≥ 8.5 g/dL.

^g In splenectomized patients, palpable hepatomegaly is substituted with the same measurement strategy.

^h Spleen or liver responses must be confirmed by imaging studies where a ≥ 35% reduction in spleen volume, as assessed by MRI or CT, is required. Furthermore, a ≥ 35% volume reduction in the spleen or liver, by MRI or CT, constitutes a response regardless of what is reported with physical examination.

ⁱ Symptoms are evaluated by the MPN-SAF TSS. The MPN-SAF TSS is the summation of all the individual scores (0–100 scale). Symptoms response requires ≥ 50% reduction in the MPN-SAF TSS.

^j Progressive disease assignment for splenomegaly requires confirmation my MRI or computed tomography showing a ≥ 25% increase in spleen volume from baseline. Baseline values for both physical examination and imaging studies refer to pretreatment baseline and not to posttreatment measurements.

REFERENCES

1. Swerdlow SH. WHO classification of tumours of haematopoietic and lymphoid tissues Lyon: International Agency for Research on Cancer, 2017. [cited 2020 Nov 18]. Available from: https://archive.org/details/whoclassificatio00swer .

2. James C, Ugo V, Le Couedic JP, et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 2005;434:1144–1148.

3. Baxter EJ, Scott LM, Campbell PJ, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 2005;365:1054–1061.

4. Lim Y, Lee JO, Bang SM. Incidence, survival and prevalence statistics of classical myeloproliferative neoplasm in Korea. J Korean Med Sci 2016;31:1579–1585.

5. Byun JM, Kim YJ, Youk T, Yang JJ, Yoo J, Park TS. Real world epidemiology of myeloproliferative neoplasms: a population based study in Korea 2004–2013. Ann Hematol 2017;96:373–381.

6. Choi CW, Bang SM, Jang S, et al. Guidelines for the management of myeloproliferative neoplasms. Korean J Intern Med 2015;30:771–788.

7. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 2016;127:2391–2405.

8. Titmarsh GJ, Duncombe AS, McMullin MF, et al. How common are myeloproliferative neoplasms? A systematic review and meta-analysis. Am J Hematol 2014;89:581–587.

9. Mehta J, Wang H, Iqbal SU, Mesa R. Epidemiology of myeloproliferative neoplasms in the United States. Leuk Lymphoma 2014;55:595–600.

10. Roaldsnes C, Holst R, Frederiksen H, Ghanima W. Myeloproliferative neoplasms: trends in incidence, prevalence and survival in Norway. Eur J Haematol 2017;98:85–93.

11. Hong J, Lee JH, Byun JM, et al. Risk of disease transformation and second primary solid tumors in patients with myeloproliferative neoplasms. Blood Adv 2019;3:3700–3708.

12. Brunner AM, Hobbs G, Jalbut MM, Neuberg DS, Fathi AT. A population-based analysis of second malignancies among patients with myeloproliferative neoplasms in the SEER database. Leuk Lymphoma 2016;57:1197–1200.

13. Landtblom AR, Bower H, Andersson TM, et al. Second malignancies in patients with myeloproliferative neoplasms: a population-based cohort study of 9379 patients. Leukemia 2018;32:2203–2210.

14. Tefferi A, Thiele J, Vardiman JW. The 2008 World Health Organization classification system for myeloproliferative neoplasms: order out of chaos. Cancer 2009;115:3842–3847.

15. Barbui T, Thiele J, Gisslinger H, et al. Masked polycythemia vera (mPV): results of an international study. Am J Hematol 2014;89:52–54.

16. Scott LM, Tong W, Levine RL, et al. JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. N Engl J Med 2007;356:459–468.

17. Pietra D, Li S, Brisci A, et al. Somatic mutations of JAK2 exon 12 in patients with JAK2 (V617F)-negative myeloproliferative disorders. Blood 2008;111:1686–1689.

18. Passamonti F, Elena C, Schnittger S, et al. Molecular and clinical features of the myeloproliferative neoplasm associated with JAK2 exon 12 mutations. Blood 2011;117:2813–2816.

19. Senin A, Fernandez-Rodriguez C, Bellosillo B, et al. Non-driver mutations in patients with JAK2V617F-mutated polycythemia vera or essential thrombocythemia with long-term molecular follow-up. Ann Hematol 2018;97:443–451.

20. Crisa E, Venturino E, Passera R, et al. A retrospective study on 226 polycythemia vera patients: impact of median hematocrit value on clinical outcomes and survival improvement with anti-thrombotic prophylaxis and non-alkylating drugs. Ann Hematol 2010;89:691–699.

21. Passamonti F, Rumi E, Pietra D, et al. A prospective study of 338 patients with polycythemia vera: the impact of JAK2 (V617F) allele burden and leukocytosis on fibrotic or leukemic disease transformation and vascular complications. Leukemia 2010;24:1574–1579.

22. Marchioli R, Finazzi G, Landolfi R, et al. Vascular and neoplastic risk in a large cohort of patients with polycythemia vera. J Clin Oncol 2005;23:2224–2232.

23. Cervantes F, Passamonti F, Barosi G. Life expectancy and prognostic factors in the classic BCR/ABL-negative myeloproliferative disorders. Leukemia 2008;22:905–914.

24. Barbui T, Finazzi MC, Finazzi G. Front-line therapy in polycythemia vera and essential thrombocythemia. Blood Rev 2012;26:205–211.

25. Barbui T, Tefferi A, Vannucchi AM, et al. Philadelphia chromosome-negative classical myeloproliferative neoplasms: revised management recommendations from European LeukemiaNet. Leukemia 2018;32:1057–1069.

26. Pearson TC, Wetherley-Mein G. Vascular occlusive episodes and venous haematocrit in primary proliferative polycythaemia. Lancet 1978;2:1219–1222.

27. Marchioli R, Finazzi G, Specchia G, et al. Cardiovascular events and intensity of treatment in polycythemia vera. N Engl J Med 2013;368:22–33.

28. Landolfi R, Marchioli R, Kutti J, et al. Efficacy and safety of low-dose aspirin in polycythemia vera. N Engl J Med 2004;350:114–124.

29. Barbui T, Barosi G, Birgegard G, et al. Philadelphia-negative classical myeloproliferative neoplasms: critical concepts and management recommendations from European LeukemiaNet. J Clin Oncol 2011;29:761–770.

30. Barosi G, Mesa R, Finazzi G, et al. Revised response criteria for polycythemia vera and essential thrombocythemia: an ELN and IWG-MRT consensus project. Blood 2013;121:4778–4781.

31. Carobbio A, Finazzi G, Antonioli E, et al. Hydroxyurea in essential thrombocythemia: rate and clinical relevance of responses by European LeukemiaNet criteria. Blood 2010;116:1051–1055.

32. Alvarez-Larran A, Pereira A, Cervantes F, et al. Assessment and prognostic value of the European LeukemiaNet criteria for clinicohematologic response, resistance, and intolerance to hydroxyurea in polycythemia vera. Blood 2012;119:1363–1369.

33. Landolfi R, Di Gennaro L, Barbui T, et al. Leukocytosis as a major thrombotic risk factor in patients with polycythemia vera. Blood 2007;109:2446–2452.

34. Barbui T, Masciulli A, Marfisi MR, et al. White blood cell counts and thrombosis in polycythemia vera: a subanalysis of the CYTO-PV study. Blood 2015;126:560–561.

35. Vannucchi AM, Kiladjian JJ, Griesshammer M, et al. Ruxolitinib versus standard therapy for the treatment of polycythemia vera. N Engl J Med 2015;372:426–435.

36. Kiladjian JJ, Zachee P, Hino M, et al. Long-term efficacy and safety of ruxolitinib versus best available therapy in polycythaemia vera (RESPONSE): 5-year follow up of a phase 3 study. Lancet Haematol 2020;7:e226–e237.

37. Yacoub A, Mascarenhas J, Kosiorek H, et al. Pegylated interferon alfa-2a for polycythemia vera or essential thrombocythemia resistant or intolerant to hydroxyurea. Blood 2019;134:1498–1509.

38. Silver RT. Long-term effects of the treatment of polycythemia vera with recombinant interferon-alpha. Cancer 2006;107:451–458.

39. Passamonti F, Griesshammer M, Palandri F, et al. Ruxolitinib for the treatment of inadequately controlled polycythaemia vera without splenomegaly (RESPONSE-2): a randomised, open-label, phase 3b study. Lancet Oncol 2017;18:88–99.

40. Kralovics R, Passamonti F, Buser AS, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med 2005;352:1779–1790.

41. Levine RL, Wadleigh M, Cools J, et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell 2005;7:387–397.

42. Klampfl T, Gisslinger H, Harutyunyan AS, et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med 2013;369:2379–2390.

43. Nangalia J, Massie CE, Baxter EJ, et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med 2013;369:2391–2405.

44. Pardanani AD, Levine RL, Lasho T, et al. MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients. Blood 2006;108:3472–3476.

45. Pikman Y, Lee BH, Mercher T, et al. MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. PLoS Med 2006;3:e270.

46. Beer PA, Campbell PJ, Scott LM, et al. MPL mutations in myeloproliferative disorders: analysis of the PT-1 cohort. Blood 2008;112:141–149.

47. Rotunno G, Mannarelli C, Guglielmelli P, et al. Impact of calreticulin mutations on clinical and hematological phenotype and outcome in essential thrombocythemia. Blood 2014;123:1552–1555.

48. Rumi E, Pietra D, Ferretti V, et al. JAK2 or CALR mutation status defines subtypes of essential thrombocythemia with substantially different clinical course and outcomes. Blood 2014;123:1544–1551.

49. Elala YC, Lasho TL, Gangat N, et al. Calreticulin variant stratified driver mutational status and prognosis in essential thrombocythemia. Am J Hematol 2016;91:503–506.

50. Finazzi G, Carobbio A, Guglielmelli P, et al. Calreticulin mutation does not modify the IPSET score for predicting the risk of thrombosis among 1150 patients with essential thrombocythemia. Blood 2014;124:2611–2612.

51. Tefferi A, Lasho TL, Guglielmelli P, et al. Targeted deep sequencing in polycythemia vera and essential thrombocythemia. Blood Adv 2016;1:21–30.

52. Barbui T, Finazzi G, Carobbio A, et al. Development and validation of an International Prognostic Score of thrombosis in World Health Organization-essential thrombocythemia (IPSET-thrombosis). Blood 2012;120:5128–5133.

53. Barbui T, Vannucchi AM, Buxhofer-Ausch V, et al. Practice-relevant revision of IPSET-thrombosis based on 1019 patients with WHO-defined essential thrombocythemia. Blood Cancer J 2015;5:e369.

54. Bose P, Verstovsek S. Updates in the management of polycythemia vera and essential thrombocythemia. Ther Adv Hematol 2019;10:2040620719870052.

55. Ruggeri M, Finazzi G, Tosetto A, Riva S, Rodeghiero F, Barbui T. No treatment for low-risk thrombocythaemia: results from a prospective study. Br J Haematol 1998;103:772–777.

56. Tefferi A, Gangat N, Wolanskyj AP. Management of extreme thrombocytosis in otherwise low-risk essential thrombocythemia; does number matter? Blood 2006;108:2493–2494.

57. Fenaux P, Simon M, Caulier MT, Lai JL, Goudemand J, Bauters F. Clinical course of essential thrombocythemia in 147 cases. Cancer 1990;66:549–556.

58. Bellucci S, Janvier M, Tobelem G, et al. Essential thrombocythemias. Clinical evolutionary and biological data. Cancer 1986;58:2440–2447.

59. Budde U, Schaefer G, Mueller N, et al. Acquired von Willebrand’s disease in the myeloproliferative syndrome. Blood 1984;64:981–985.

60. Harrison CN, Campbell PJ, Buck G, et al. Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia. N Engl J Med 2005;353:33–45.

61. Samuelson B, Chai-Adisaksopha C, Garcia D. Anagrelide compared with hydroxyurea in essential thrombocythemia: a meta-analysis. J Thromb Thrombolysis 2015;40:474–479.

62. Gisslinger H, Gotic M, Holowiecki J, et al. Anagrelide compared with hydroxyurea in WHO-classified essential thrombocythemia: the ANAHYDRET Study, a randomized controlled trial. Blood 2013;121:1720–1728.

63. Hernandez-Boluda JC, Alvarez-Larran A, Gomez M, et al. Clinical evaluation of the European LeukaemiaNet criteria for clinicohaematological response and resistance/intolerance to hydroxycarbamide in essential thrombocythaemia. Br J Haematol 2011;152:81–88.

64. Quintas-Cardama A, Abdel-Wahab O, Manshouri T, et al. Molecular analysis of patients with polycythemia vera or essential thrombocythemia receiving pegylated interferon α-2a. Blood 2013;122:893–901.

65. Masarova L, Patel KP, Newberry KJ, et al. Pegylated interferon alfa-2a in patients with essential thrombocythaemia or polycythaemia vera: a post-hoc, median 83 month follow-up of an open-label, phase 2 trial. Lancet Haematol 2017;4:e165–e175.

66. Langer C, Lengfelder E, Thiele J, et al. Pegylated interferon for the treatment of high risk essential thrombocythemia: results of a phase II study. Haematologica 2005;90:1333–1338.

67. Harrison CN, Mead AJ, Panchal A, et al. Ruxolitinib vs best available therapy for ET intolerant or resistant to hydroxycarbamide. Blood 2017;130:1889–1897.

68. Passamonti F, Randi ML, Rumi E, et al. Increased risk of pregnancy complications in patients with essential thrombocythemia carrying the JAK2 (617V>F) mutation. Blood 2007;110:485–489.

69. Alimam S, Bewley S, Chappell LC, et al. Pregnancy outcomes in myeloproliferative neoplasms: UK prospective cohort study. Br J Haematol 2016;175:31–36.

70. Griesshammer M, Heimpel H, Pearson TC. Essential thrombocythemia and pregnancy. Leuk Lymphoma 1996;22(Suppl 1):57–63.

71. Martinelli P, Martinelli V, Agangi A, et al. Interferon alfa treatment for pregnant women affected by essential thrombocythemia: case reports and a review. Am J Obstet Gynecol 2004;191:2016–2020.

72. Delage R, Demers C, Cantin G, Roy J. Treatment of essential thrombocythemia during pregnancy with interferon-alpha. Obstet Gynecol 1996;87(5 Pt 2):814–817.

73. Milano V, Gabrielli S, Rizzo N, et al. Successful treatment of essential thrombocythemia in a pregnancy with recombinant interferon-alpha 2a. J Matern Fetal Med 1996;5:74–78.

74. Maze D, Kazi S, Gupta V, et al. Association of treatments for myeloproliferative neoplasms during pregnancy with birth rates and maternal outcomes: a systematic review and meta-analysis. JAMA Netw Open 2019;2:e1912666.

75. Skeith L, Carrier M, Robinson SE, Alimam S, Rodger MA. Risk of venous thromboembolism in pregnant women with essential thrombocythemia: a systematic review and meta-analysis. Blood 2017;129:934–939.

76. Barbui T, Thiele J, Passamonti F, et al. Survival and disease progression in essential thrombocythemia are significantly influenced by accurate morphologic diagnosis: an international study. J Clin Oncol 2011;29:3179–3184.

77. Mudireddy M, Shah S, Lasho T, et al. Prefibrotic versus overtly fibrotic primary myelofibrosis: clinical, cytogenetic, molecular and prognostic comparisons. Br J Haematol 2018;182:594–597.

78. Guglielmelli P, Rotunno G, Pacilli A, et al. Prognostic impact of bone marrow fibrosis in primary myelofibrosis. A study of the AGIMM group on 490 patients. Am J Hematol 2016;91:918–922.

79. Guglielmelli P, Pacilli A, Rotunno G, et al. Presentation and outcome of patients with 2016 WHO diagnosis of prefibrotic and overt primary myelofibrosis. Blood 2017;129:3227–3236.

80. Mesa RA, Niblack J, Wadleigh M, et al. The burden of fatigue and quality of life in myeloproliferative disorders (MPDs): an international Internet-based survey of 1179 MPD patients. Cancer 2007;109:68–76.

81. Scherber RM, Geyer H, Dueck AC, et al. Symptom burden as primary driver for therapy in patients with myelofibrosis: an analysis by MPN international quality of life study group. Blood 2016;128:3117.

82. Mesa RA, Schwager S, Radia D, et al. The Myelofibrosis Symptom Assessment Form (MFSAF): an evidence-based brief inventory to measure quality of life and symptomatic response to treatment in myelofibrosis. Leuk Res 2009;33:1199–1203.

83. Emanuel RM, Dueck AC, Geyer HL, et al. Myeloproliferative neoplasm (MPN) symptom assessment form total symptom score: prospective international assessment of an abbreviated symptom burden scoring system among patients with MPNs. J Clin Oncol 2012;30:4098–4103.

84. Tefferi A, Lasho TL, Finke C, et al. Type 1 vs type 2 calreticulin mutations in primary myelofibrosis: differences in phenotype and prognostic impact. Leukemia 2014;28:1568–1570.

85. Spivak JL. Myeloproliferative neoplasms. N Engl J Med 2017;376:2168–2181.

86. Tefferi A, Lasho TL, Finke CM, et al. CALR vs JAK2 vs MPL-mutated or triple-negative myelofibrosis: clinical, cytogenetic and molecular comparisons. Leukemia 2014;28:1472–1477.

87. Vannucchi AM, Lasho TL, Guglielmelli P, et al. Mutations and prognosis in primary myelofibrosis. Leukemia 2013;27:1861–1869.

88. Cervantes F, Dupriez B, Pereira A, et al. New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment. Blood 2009;113:2895–2901.

89. Passamonti F, Cervantes F, Vannucchi AM, et al. Dynamic International Prognostic Scoring System (DIPSS) predicts progression to acute myeloid leukemia in primary myelofibrosis. Blood 2010;116:2857–2858.

90. Gangat N, Caramazza D, Vaidya R, et al. DIPSS plus: a refined Dynamic International Prognostic Scoring System for primary myelofibrosis that incorporates prognostic information from karyotype, platelet count, and transfusion status. J Clin Oncol 2011;29:392–397.

91. Guglielmelli P, Lasho TL, Rotunno G, et al. The number of prognostically detrimental mutations and prognosis in primary myelofibrosis: an international study of 797 patients. Leukemia 2014;28:1804–1810.

92. Guglielmelli P, Lasho TL, Rotunno G, et al. MIPSS70: mutation-enhanced international prognostic score system for transplantation-age patients with primary myelofibrosis. J Clin Oncol 2018;36:310–318.

93. Tefferi A, Guglielmelli P, Lasho TL, et al. MIPSS70+ version 2.0: mutation and karyotype-enhanced international prognostic scoring system for primary myelofibrosis. J Clin Oncol 2018;36:1769–1770.

94. Tefferi A, Guglielmelli P, Nicolosi M, et al. GIPSS: genetically inspired prognostic scoring system for primary myelofibrosis. Leukemia 2018;32:1631–1642.

95. Odenike O, Tefferi A. Conventional and new treatment options for myelofibrosis with myeloid metaplasia. Semin Oncol 2005;32:422–431.

96. Martinez-Trillos A, Gaya A, Maffioli M, et al. Efficacy and tolerability of hydroxyurea in the treatment of the hyperproliferative manifestations of myelofibrosis: results in 40 patients. Ann Hematol 2010;89:1233–1237.

97. Abelsson J, Merup M, Birgegard G, et al. The outcome of allo-HSCT for 92 patients with myelofibrosis in the Nordic countries. Bone Marrow Transplant 2012;47:380–386.

98. Mesa RA. The evolving treatment paradigm in myelofibrosis. Leuk Lymphoma 2013;54:242–251.

99. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med 2012;366:799–807.

100. Harrison C, Kiladjian JJ, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med 2012;366:787–798.

101. Cervantes F, Vannucchi AM, Kiladjian JJ, et al. Three-year efficacy, safety, and survival findings from COMFORT-II, a phase 3 study comparing ruxolitinib with best available therapy for myelofibrosis. Blood 2013;122:4047–4053.

102. Pardanani A, Harrison C, Cortes JE, et al. Safety and efficacy of fedratinib in patients with primary or secondary myelofibrosis: a randomized clinical trial. JAMA Oncol 2015;1:643–651.

103. Harrison CN, Schaap N, Vannucchi AM, et al. Janus kinase-2 inhibitor fedratinib in patients with myelofibrosis previously treated with ruxolitinib (JAKARTA-2): a single-arm, open-label, non-randomised, phase 2, multicentre study. Lancet Haematol 2017;4:e317–e324.

104. Mascarenhas J, Hoffman R, Talpaz M, et al. Pacritinib vs best available therapy, including ruxolitinib, in patients with myelofibrosis: a randomized clinical trial. JAMA Oncol 2018;4:652–659.

105. Harrison CN, Vannucchi AM, Platzbecker U, et al. Momelotinib versus best available therapy in patients with myelofibrosis previously treated with ruxolitinib (SIMPLIFY 2): a randomised, open-label, phase 3 trial. Lancet Haematol 2018;5:e73–e81.

106. Cervantes F. How I treat myelofibrosis. Blood 2014;124:2635–2642.

107. Deininger M, Radich J, Burn TC, Huber R, Paranagama D, Verstovsek S. The effect of long-term ruxolitinib treatment on JAK2p.V617F allele burden in patients with myelofibrosis. Blood 2015;126:1551–1554.

108. Ianotto JC, Chauveau A, Boyer-Perrard F, et al. Benefits and pitfalls of pegylated interferon-α2a therapy in patients with myeloproliferative neoplasm-associated myelofibrosis: a French Intergroup of Myeloproliferative neoplasms (FIM) study. Haematologica 2018;103:438–446.

109. Sorensen AL, Mikkelsen SU, Knudsen TA, et al. Ruxolitinib and interferon-α2 combination therapy for patients with polycythemia vera or myelofibrosis: a phase II study. Haematologica 2019;105:235648.

110. Tefferi A, Cervantes F, Mesa R, et al. Revised response criteria for myelofibrosis: International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European LeukemiaNet (ELN) consensus report. Blood 2013;122:1395–1398.

111. Huang J, Tefferi A. Erythropoiesis stimulating agents have limited therapeutic activity in transfusion-dependent patients with primary myelofibrosis regardless of serum erythropoietin level. Eur J Haematol 2009;83:154–155.

112. Cervantes F, Alvarez-Larran A, Hernandez-Boluda JC, Sureda A, Torrebadell M, Montserrat E. Erythropoietin treatment of the anaemia of myelofibrosis with myeloid metaplasia: results in 20 patients and review of the literature. Br J Haematol 2004;127:399–403.

113. Cervantes F, Alvarez-Larran A, Hernandez-Boluda JC, et al. Darbepoetin-alpha for the anaemia of myelofibrosis with myeloid metaplasia. Br J Haematol 2006;134:184–186.

114. Cervantes F, Alvarez-Larran A, Domingo A, Arellano-Rodrigo E, Montserrat E. Efficacy and tolerability of danazol as a treatment for the anaemia of myelofibrosis with myeloid metaplasia: long-term results in 30 patients. Br J Haematol 2005;129:771–775.

115. Cervantes F, Isola IM, Alvarez-Larran A, Hernandez-Boluda JC, Correa JG, Pereira A. Danazol therapy for the anemia of myelofibrosis: assessment of efficacy with current criteria of response and long-term results. Ann Hematol 2015;94:1791–1796.

116. Mesa RA, Steensma DP, Pardanani A, et al. A phase 2 trial of combination low-dose thalidomide and prednisone for the treatment of myelofibrosis with myeloid metaplasia. Blood 2003;101:2534–2541.

117. Mesa RA, Yao X, Cripe LD, et al. Lenalidomide and prednisone for myelofibrosis: Eastern Cooperative Oncology Group (ECOG) phase 2 trial E4903. Blood 2010;116:4436–4438.

118. Ballen KK, Shrestha S, Sobocinski KA, et al. Outcome of transplantation for myelofibrosis. Biol Blood Marrow Transplant 2010;16:358–367.

119. Passamonti F, Cervantes F, Vannucchi AM, et al. A dynamic prognostic model to predict survival in primary myelofibrosis: a study by the IWG-MRT (International Working Group for Myeloproliferative Neoplasms Research and Treatment). Blood 2010;115:1703–1708.

120. Kroger N, Giorgino T, Scott BL, et al. Impact of allogeneic stem cell transplantation on survival of patients less than 65 years of age with primary myelofibrosis. Blood 2015;125:3347–3350.

121. Gupta V, Hari P, Hoffman R. Allogeneic hematopoietic cell transplantation for myelofibrosis in the era of JAK inhibitors. Blood 2012;120:1367–1379.

122. McLornan DP, Mead AJ, Jackson G, Harrison CN. Allogeneic stem cell transplantation for myelofibrosis in 2012. Br J Haematol 2012;157:413–425.

123. Reilly JT, McMullin MF, Beer PA, et al. Guideline for the diagnosis and management of myelofibrosis. Br J Haematol 2012;158:453–471.

124. Tefferi A. Primary myelofibrosis: 2013 update on diagnosis, risk-stratification, and management. Am J Hematol 2013;88:141–150.

125. Gagelmann N, Ditschkowski M, Bogdanov R, et al. Comprehensive clinical-molecular transplant scoring system for myelofibrosis undergoing stem cell transplantation. Blood 2019;133:2233–2242.

126. Shanavas M, Popat U, Michaelis LC, et al. Outcomes of allogeneic hematopoietic cell transplantation in patients with myelofibrosis with prior exposure to Janus kinase 1/2 inhibitors. Biol Blood Marrow Transplant 2016;22:432–440.

127. Hanif A, Hari PN, Atallah E, Carlson KS, Pasquini MC, Michaelis LC. Safety of ruxolitinib therapy prior to allogeneic hematopoietic stem-cell transplantation for myeloproliferative neoplasms. Bone Marrow Transplant 2016;51:617–618.

128. Salit RB, Scott BL, Stevens EA, Baker KK, Gooley TA, Deeg HJ. Pre-hematopoietic cell transplant Ruxolitinib in patients with primary and secondary myelofibrosis. Bone Marrow Transplant 2020;55:70–76.