Myeloproliferative Neoplasms, Version 3.2022, NCCN Clinical Practice Guidelines in Oncology

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  • 1 Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute;
  • | 2 Stanford Cancer Institute;
  • | 3 City of Hope National Medical Center;
  • | 4 The University of Texas MD Anderson Cancer Center;
  • | 5 Memorial Sloan Kettering Cancer Center;
  • | 6 Roswell Park Comprehensive Cancer Center;
  • | 7 Huntsman Cancer Institute at the University of Utah;
  • | 8 Fred & Pamela Buffett Cancer Center;
  • | 9 Abramson Cancer Center at the University of Pennsylvania;
  • | 10 Massachusetts General Hospital Cancer Center;
  • | 11 The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins;
  • | 12 UC San Diego Moores Cancer Center;
  • | 13 UC Davis Comprehensive Cancer Center;
  • | 14 Moffitt Cancer Center;
  • | 15 UT Southwestern Simmons Comprehensive Cancer Center;
  • | 16 University of Colorado Cancer Center;
  • | 17 Vanderbilt-Ingram Cancer Center;
  • | 18 University of Wisconsin Carbone Cancer Center;
  • | 19 Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine;
  • | 20 Mayo Clinic Cancer Center;
  • | 21 Yale Cancer Center/Smilow Cancer Hospital;
  • | 22 Duke Cancer Institute;
  • | 23 Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance;
  • | 24 Robert H. Lurie Comprehensive Cancer Center of Northwestern University;
  • | 25 University of Michigan Rogel Cancer Center;
  • | 26 O'Neal Comprehensive Cancer Center at UAB;
  • | 27 Dana-Farber/Brigham and Women’s Cancer Center;
  • | 28 The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute;
  • | 29 UCLA Jonsson Comprehensive Cancer Center; and
  • | 30 National Comprehensive Cancer Network.

The classic Philadelphia chromosome–negative myeloproliferative neoplasms (MPN) consist of myelofibrosis, polycythemia vera, and essential thrombocythemia and are a heterogeneous group of clonal blood disorders characterized by an overproduction of blood cells. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for MPN were developed as a result of meetings convened by a multidisciplinary panel with expertise in MPN, with the goal of providing recommendations for the management of MPN in adults. The Guidelines include recommendations for the diagnostic workup, risk stratification, treatment, and supportive care strategies for the management of myelofibrosis, polycythemia vera, and essential thrombocythemia. Assessment of symptoms at baseline and monitoring of symptom status during the course of treatment is recommended for all patients. This article focuses on the recommendations as outlined in the NCCN Guidelines for the diagnosis of MPN and the risk stratification, management, and supportive care relevant to MF.

Overview

Myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET) are a group of heterogeneous disorders of the hematopoietic system collectively known as Philadelphia chromosome–negative myeloproliferative neoplasms (MPN). The prevalence of MF, ET, and PV in the United States is estimated to be approximately 13,000, 134,000, and 148,000, respectively.1 In a survey that assessed the incidence rates (IRs) of different subtypes of MPN in the United States (2001–2012), the age-adjusted IRs per one million person-years were highest for PV (IR=11) and ET (IR=10).2

MPN are characterized by a complicated symptom profile; the symptom profile varies within and between each MPN subtype, but often includes fatigue, pruritus, weight loss, and symptoms from splenomegaly.36 Variable laboratory abnormalities are observed depending on the type of MPN, including erythrocytosis, thrombocytosis, and leukocytosis, and sometimes myeloid immaturity, especially in progressive myelofibrosis.6 A SEER-Medicare database analysis showed that patients with MPN have substantially inferior survival compared with matched controls, and the survival for patients with MF is worse than that of patients with ET or PV and significantly worse than matched controls.7 In addition, MPN also have the propensity for disease transformation into blast phase (MPN-BP), which is akin to acute myeloid leukemia (AML), which is associated with poor prognosis.8,9

The diagnosis and management of patients with MPN has evolved since the identification of JAK-STAT “driver” mutations (JAK2, CALR, and MPL mutations), and the development of targeted therapies has resulted in significant improvements in disease-related symptoms and quality of life.10 However, certain aspects of clinical management regarding the diagnosis, assessment of symptom burden, and selection of appropriate symptom-directed therapies continue to present challenges for hematologists and oncologists.11

Molecular Abnormalities in MPN

JAK2 V617F mutations account for the majority of patients with PV (more than 90%) and 60% of patients with ET or MF.1214 JAK2 V617F can be identified in hematopoietic stem and progenitor cells.15 The V617F mutation occurs in exon 14; however, rare insertions and deletions have been found in exon 12. JAK2 exon 12 mutations have been described in 2% to 3% of patients with PV.16,17

Activating mutations in the thrombopoietin receptor gene (MPL W515L/K) are reported in approximately 5%–8% of all patients with MF and 1%–4% of all patients with ET.1820

Frameshift mutations in exon 9 of the calreticulin gene (CALR) are reported in approximately 20%–35% of all patients with ET and MF (accounting for approximately 60%–80% of patients with JAK2/MPL-negative ET and MF).21,22 Type 1 (52 base pair deletions) and type 2 (5 base pair insertions) mutations are the most frequent CALR variants. CALR type 1 mutations are more frequent in patients with MF and CALR type 2 mutations are preferentially associated with ET.2325

Mutations in several other genes that are involved in signal transduction (CBL and LNK/SH2B3), chromatin modification (TET2, EZH2, IDH1/2, ASXL1, and DNM3TA), RNA splicing (SF3B1, SRSF2, and U2AF1), and tumor suppressor function (TP53) have also been reported in patients with MPN.26,27

Myelofibrosis

Mutations in CALR are associated with better overall survival (OS) than the JAK2 V617F or MPL W515 mutations, and the survival advantage is more pronounced in patients with a type 1/type 1-like mutation.9,24,28,29 In a study of 617 patients with primary MF (PMF), the median OS was 18 years for those with CALR mutations versus 9 years for those with JAK2 V617F mutation or MPL mutation and 3 years for patients with triple-negative MF.28 CALR mutations retained their prognostic significance for better OS compared with JAK2 V617F mutation (P=.019) or triple-negative status (P<.001) in a multivariate analysis corrected for age. The 10-year cumulative incidence of leukemic transformation was also lower (9%) for patients with CALR mutation compared with 19% for those with JAK2 V617F mutation, 17% for those with MPL mutation, and 34% for those with triple negative disease. In a study that evaluated the prognostic impact of the 2 different types of CALR mutations in 396 patients with PMF, the median survival was significantly higher for patients with type 1/type 1-like mutation than for those with type 2/type 2-like mutation or JAK2 V617F mutation (26 vs 7 years; P<.0001).29 The rate of leukemic transformation was also higher among patients with type 2/type 2-like mutation than for those with type 1/type 1-like and JAK2 V617F mutation.

MPL mutations are associated with lower hemoglobin levels at diagnosis and increased risk of transfusion dependence in patients with MF.30 The triple-negative mutation status (lack of all 3 “driver” mutations—JAK2, CALR, or MPL), which occurs in approximately 10% of patients, is associated with a worse prognosis in patients with MF.31,32

ASXL1, EZH2, SRSF2, TP53, IDH1, IDH2, or U2AF1 mutations are considered as high-molecular-risk (HMR) mutations and are associated with significantly shorter OS and leukemia-free survival (LFS) in patients with PMF.3338 ASXL1, EZH2, SRSF2, and RAS mutations are predictive of OS, while ASXL1, SRSF2, and IDH1 or IDH2 are predictive of leukemic transformation in patients with PMF.3336,39,40 TET2 or TP53 mutations have also been associated with a worsened overall prognosis and an increased rate of leukemic transformation.27,37 U2AF1 mutations have also been associated with inferior survival in patients with PMF.38

In a study that evaluated the prognostic significance of somatic mutations in 879 patients with PMF, the median survival was significantly shorter (81 vs 148 months; P<.0001) in patients with at least one mutation in the prognostically significant genes (ASXL1, EZH2, SRSF2, IDH1, or IDH2) compared with those with no mutation in any of these genes.35 However, only ASXL1 mutations retained prognostic significance after accounting for known prognostic factors. The results of a subsequent analysis that evaluated the additional prognostic value of the “number” of mutated genes in 797 patients with PMF confirmed that patients harboring ≥2 HMR mutations had significantly reduced OS and LFS compared not only to patients with no mutations but also to those presenting with only one HMR mutation.36 The median OS was 3 years for patients with ≥2 HMR mutations compared with 7 years and 12 years, respectively, for those with one HMR mutation and no mutations. The corresponding LFS was 7 years, 11 years, and 27 years, respectively.

An analysis that assessed the impact of both CALR and ASXL1 mutations on OS in 570 patients with PMF identified CALR(−)/ASXL1(+) mutational status as the most significant adverse risk factor for survival.41 CALR(+)/ASXL1(−) was associated with the longest median OS (10.4 years) and CALR(−)/ASXL1(+) was associated with shortest median OS (2.3 years); this prognostic significance was independent of the Dynamic International Prognostic Scoring System (DIPSS)-plus risk score.

The prognostic significance of these HMR mutations, perhaps with the exception of SRSF2 mutations, has not yet been established in patients with post-PV or post-ET MF.42

Diagnostic Classification

The WHO classification of myeloid neoplasms was first published in 2001 and was updated in 2008 to refine the diagnostic criteria for previously described neoplasms based on new scientific and clinical information and to introduce newly recognized disease entities.43,44 It was revised in 2017 and once again in 2022 to incorporate new clinical, prognostic, morphologic, immunophenotypic, and genetic data that have emerged since the publication of the 2008 WHO classification.4548

The 2017 WHO diagnostic criteria include molecular testing for JAK2, CALR, and MPL mutations for PMF and ET and molecular testing for JAK2 V617F or JAK2 exon 12 mutations for PV.46 In the absence of JAK2, CALR, and MPL mutations, the presence of another clonal marker is included as one of the major diagnostic criteria for PMF. Additional mutations in ASXL1, EZH2, TET2, IDH1, IDH2, SRSF2, and SF3B1 genes are noted to be of use in determining the clonal nature of the disease.35,36

MF can present as a de novo disorder (PMF) or it can develop from the progression of PV and ET (post-PV MF or post-ET MF).49 Prefibrotic/early-stage PMF is characterized by an increase in atypical megakaryocytes, reduced erythropoiesis, and increased age-matched bone marrow cellularity. However, overt bone marrow fibrosis might be absent in early-stage/prefibrotic PMF, leading to a diagnosis of ET.50 The revised 2017 WHO diagnostic criteria also include separate criteria for prefibrotic/early-stage PMF and overt fibrotic-stage PMF to differentiate true ET from prefibrotic/early PMF by the morphologic findings of the bone marrow biopsy, including the lack of reticulin fibrosis at onset.46 The revised diagnostic criteria for prefibrotic/early-stage PMF and overt fibrotic-stage PMF have also been validated in a large series of patients with pre-PMF and overt PMF.5153

In the International Working Group for MPN Research and Treatment (IWG-MRT) study that re-evaluated 1,104 patients with a diagnosis of ET, central pathology review revealed a diagnosis (as defined by the WHO criteria) of ET in 891 patients (81%) and early/prefibrotic PMF in 180 patients (16%). The remaining 33 patients (3%) were unevaluable.50 The frequency of grade 1 bone marrow fibrosis was greater in patients with early/prefibrotic PMF. In addition, leukocyte count, platelet count, serum lactate dehydrogenase, and the incidence of palpable splenomegaly were greater in patients with early/prefibrotic PMF, whereas hemoglobin level was greater in patients with ET. The long-term clinical outcomes were significantly worse for patients with early-stage/prefibrotic PMF. The 15-year rates of OS, leukemic transformation, and fibrotic progression were 59%, 12%, and 17%, respectively, for patients with early-stage/prefibrotic PMF. The corresponding rates were 80%, 2%, and 9%, respectively, for patients with ET. In a multivariate analysis, bone marrow histopathology remained prognostically significant for survival (P=.03), leukemic transformation (P=.007), and overt fibrotic progression (P=.019). Therefore, accurate evaluation of bone marrow morphology is essential to distinguish early-stage/prefibrotic PMF from ET, especially since the long-term clinical outcomes are significantly better for patients with ET than for those with prefibrotic MF.

The diagnosis of MPN should be based on the 2017 WHO diagnostic criteria and requires a combination of clinical, laboratory, cytogenetic, and molecular testing.46 The diagnosis of PMF requires meeting all 3 major criteria and at least one minor criterion as outlined in the revised 2017 WHO criteria.46 The diagnosis of PV requires meeting either all three major criteria or the first two major criteria and the minor criterion, whereas the diagnosis of ET requires meeting all four major criteria or the first three major criteria and the minor criterion as outlined in the revised 2017 WHO criteria.46 See “2017 WHO Diagnostic Criteria for Primary Myelofibrosis and 2017 WHO Diagnostic Criteria for PV and ET” in the algorithm (available at NCCN.org) for the lists of major and minor criteria. The diagnosis of post-PV MF or post-ET MF is based on the 2008 IWG-MRT diagnostic criteria, requiring the documentation of a previous diagnosis of PV or ET as defined by the WHO criteria and the development of European bone marrow fibrosis grade MF-2 to MF-3 (or 3–4+, depending on the scale) and at least 2 minor criteria.54

Workup of Suspected MPN

Initial evaluation of patients with suspected MPN should include a history and physical examination, palpation of spleen, evaluation of thrombotic and hemorrhagic events, cardiovascular risk factors, as well as transfusion and medication history. Laboratory evaluations should include CBC with differential, microscopic examination of the peripheral smear, comprehensive metabolic panel with serum uric acid, serum lactate dehydrogenase, liver function tests, serum erythropoietin (EPO) level, and serum iron studies. Human leukocyte antigen (HLA) typing should be performed for patients with MF for whom allogeneic hematopoietic cell transplant (HCT) would be considered.

Fluorescence in situ hybridization (FISH) or a multiplex reverse transcription polymerase chain reaction (RT-PCR), if available, on peripheral blood to detect BCR::ABL1 transcripts and exclude the diagnosis of CML is especially recommended for patients with left-shifted leukocytosis and/or thrombocytosis with basophilia.46 FISH may have better specificity than RT-PCR in the detection of unusual breakpoints. Some institutions prefer FISH to detect cryptic translocations whereas others prefer RT-PCR. The preferred method may vary based on institutional expertise. Molecular testing on blood or bone marrow for JAK2 V617F mutations is recommended as part of initial workup for all patients.46 If JAK2 V617F mutation testing is negative, molecular testing for CALR and MPL mutations should be performed for patients with suspected ET and MF; molecular testing for the JAK2 exon 12 mutation should be done for those with suspected PV and negative for the JAK2 V617F mutation.16,17 Alternatively, molecular testing using the multigene next generation sequencing (NGS) panel that includes JAK2, CALR, and MPL can be used as part of initial workup for all patients. Once an MPN diagnosis is confirmed, NGS is recommended for mutational prognostication. The application of an NGS-based 28-gene panel in patients with MPN identified significantly more mutated splicing genes (SF3B1, SRSF2, and U2AF1) in patients with PMF compared with those with ET, and no mutations in splicing genes were found in patients with PV.55 NGS may also be useful to establish the clonality in selected circumstances (eg, triple-negative MPN with nonmutated JAK2, MPL, and CALR). It can also identify second, third, and fourth mutations that may hold prognostic relevance.

Bone marrow aspirate with iron stain and biopsy with trichrome and reticulin stains and bone marrow cytogenetics (karyotype, with or without FISH; peripheral blood for FISH, if bone marrow is inaspirable) are necessary to accurately distinguish the bone marrow morphologic features between the disease subtypes (early or prefibrotic PMF, ET, and masked PV).46,50,56 Bone marrow histology shows hypercellularity and megakaryocytic proliferation. In the case of MF, bone marrow fibrosis is demonstrated on the reticulin stain and an additional trichrome stain is recommended to distinguish grade MF-1 from MF-2 or MF-3, as outlined in the 2017 WHO diagnostic criteria.46,57 Progression of PV or ET to MF can only be detected by performing a bone marrow biopsy; however, in patients with PV, bone marrow biopsy may not be required in patients with sustained absolute erythrocytosis (hemoglobin levels >18.5 g/dL in men [hematocrit, 55.5%] or >16.5 g/dL in women [hematocrit, 49.5%]), JAK2V617F or JAK2 exon 12 mutations, and subnormal EPO level.46 If there is evidence of mast cell aggregates, the diagnostic workup should be performed according to the NCCN Guidelines for Systemic Mastocytosis (available at NCCN.org).

MPN are associated with an increased risk of major bleeding and thrombosis compared with the general population, and these events contribute considerably to morbidity and mortality in patients with MPN.58,59 Acquired von Willebrand disease is associated with a variety of hematologic disorders, being particularly frequent in lymphoproliferative (48%) and myeloproliferative disorders (15%). Among MPN, the frequency of acquired von Willebrand disease is more common among patients with ET (11%–17%) but can also be seen in patients with PV.60 Coagulation tests to evaluate for acquired von Willebrand disease (plasma von Willebrand factor antigen measurement, ristocetin cofactor activity [also referred to as von Willebrand factor activity], von Willebrand multimer analysis, and Factor VIII level)61 or other coagulopathies (prothrombin time, partial thromboplastin time, and fibrinogen activity) are recommended for patients undergoing high-risk surgical procedures and those with elevated platelet count or splenomegaly or unexplained bleeding.

Assessment of Symptom Burden

MPN are characterized by a complicated symptom profile resulting in reductions in quality of life, functional status, and activities of daily living.35 Constitutional symptoms (fever, night sweats, and weight loss) are more frequently reported in patients with MF compared with those with PV or ET.3,5 In a landmark survey that evaluated the symptom burden experienced by patients with MPN, disease-related symptoms were reported 1 or more years before diagnosis in 49% of patients with MF, 61% of patients with PV, and 58% of patients with ET.4 In a recent online survey of 669 patients with MPN, fatigue was the most frequent symptom observed in 54% of patients with MF, 45% of patients with PV, and 64% of patients with ET.5 Abdominal discomfort, night sweats, difficulty sleeping, shortness of breath, pruritus, bruising, loss of concentration, and dizziness were the other common symptoms and the incidences varied by disease type.

Various tools have been developed and validated in a large cohort of patients with MPN for the assessment of symptom burden.6266

The Myelofibrosis Symptom Assessment Form (MF-SAF) is a 20-item tool used for the assessment of MF-associated symptoms, including fatigue, symptoms associated with splenomegaly (early satiety, abdominal pain or discomfort, inactivity, and cough), constitutional symptoms (night sweats, itching, bone pain, fever, and weight loss), and quality of life.62 MF-SAF was subsequently expanded to a 27-item tool, MPN Symptom Assessment Form (MPN-SAF), to include the assessment of additional symptoms that are relevant to ET and PV (insomnia, headaches, concentration, dizziness, vertigo, lightheadedness, numbness or tingling, depression, and sexual desire dysfunction).64

MPN-SAF was further simplified to a concise and abbreviated tool, MPN-SAF Total Symptom Score (MPN-SAF TSS; MPN 10), which is used for the assessment of the 10 most relevant symptoms in patients with MPN (fatigue, concentration, early satiety, inactivity, night sweats, itching, bone pain, abdominal discomfort, weight loss, and fever) in both clinical practice and clinical trial settings.65 The MPN-10 score is influenced by JAK2, CALR, and triple-negative mutation status, which can be helpful for predicting survival and disease progression in patients with MPN.67

All 3 symptom assessment tools are coadministered with the Brief Fatigue Inventory, and symptom severity is rated by patients on a scale of 1 to 10. Assessment of symptom burden at baseline and during the course of treatment with MPN-SAF TSS (MPN-10) is recommended for all patients.64,65

Symptom Management in Patients With MPN

Disease-related symptoms commonly contribute to decreased quality of life in patients with MPN.68 While JAK inhibitors have been shown to broadly improve disease-related symptoms,6975 their use is not indicated in all patients with symptomatic MPN, and the presence of specific symptoms often requires a targeted approach. Pruritus, bone pain, headaches, and tinnitus occur across all MPN, albeit with some disease preference, and greatly impact quality of life. The optimal management of these symptoms in the setting of MPN has not been established and recommendations for symptom management as outlined in the NCCN Guidelines (see “Supportive care for patients with MPN: Symptom management in patients with MPN,” in the algorithm, available at NCCN.org) are based on the subset analysis of large trials, small pilot studies, anecdotal evidence, extrapolation from other disease states, and expert opinion.

Management of Myelofibrosis

The treatment approach is currently identical for PMF and post-PV or post-ET MF. Referral to specialized centers with expertise in the management of MPN is strongly recommended for all patients diagnosed with MF.

Risk Stratification

Primary Myelofibrosis

The International Prognostic Scoring System (IPSS), DIPSS, and DIPSS-Plus are the 3 most common prognostic scoring systems used for the risk stratification of patients with MF.7678 Other prognostic models incorporating cytogenetic information and mutational status such as Mutation-Enhanced International Prognostic Scoring System 70 (MIPSS70), MIPSS70-Plus, and Genetically Inspired Prognostic Scoring System (GIPSS) have been developed to refine the risk stratification.79,80

IPSS is validated for risk stratification at the time of diagnosis only.76 DIPSS is a dynamic model and has been validated for use at any point over the course of disease.77 MIPSS70 or MIPSS70-Plus version 2.0 is preferred for the prognostic risk stratification of patients with PMF.79,81 Additionally, DIPSS-Plus is recommended for risk stratification at the time of treatment if molecular testing is not available78 and DIPSS can be used if recent karyotyping is not available.77 Myelofibrosis Secondary to PV and ET-Prognostic Model (MYSEC-PM) is recommended for the risk stratification of post-PV or post-ET MF.82,83

International Prognostic Scoring System

Age older than 65 years, presence of constitutional symptoms, hemoglobin level <10 g/dL, leukocyte count >25 × 109/L, and circulating blast cells ≥1% at diagnosis were identified as independent predictors of inferior survival.76 IPSS stratifies patients at diagnosis into 4 different risk groups based on the presence of 0, 1, 2, and 3 or more adverse factors: low risk, intermediate-1 risk, intermediate-2 risk, and high-risk with a median survival of 135 months, 95 months, 48 months, and 27 months, respectively (P<.001).

Dynamic International Prognostic Scoring System

In a subsequent analysis that evaluated the impact of each adverse factor on survival during follow-up after treatment, all variables retained statistical significance. However, the development of anemia over time significantly affected survival (hazard ratio [HR] was approximately double that of other adverse factors).77 Thus, a modified risk stratification system (DIPSS) was developed using the same prognostic variables as in IPSS (age >65 years, presence of constitutional symptoms, hemoglobin level <10 g/dL, leukocyte count >25 × 109/L, and circulating blast cells ≥1%), but 2 points were assigned for hemoglobin <10 g/dL. The DIPSS can be applied at any point during the disease course to stratify patients into 4 different risk groups: low risk (0 adverse points), intermediate-1 risk (1 or 2 points), intermediate-2 risk (3 or 4 points), and high-risk (5 or 6 points) with the median survival rates of not reached, 14 years, 4 years, and 1.5 years, respectively.77

DIPSS-Plus

In subsequent reports, the need for RBC transfusion, platelet count, and unfavorable karyotype have been identified as additional IPSS- and DIPSS-independent prognostic factors for inferior OS and LFS in patients with PMF.8487 The median survival of DIPSS low-risk patients with thrombocytopenia or unfavorable karyotype was 6.5 years compared with >15 years in the absence of these 2 additional risk factors.78 Similarly, the median survival was <1.5 years for patients with DIPSS high-risk disease with one or more of these additional prognostic factors compared with approximately 3 years for those patients without these prognostic factors.78

DIPSS was modified into DIPSS-Plus by the incorporation of platelet count <100 × 109/L, RBC transfusion need, and unfavorable karyotype [complex karyotype or one or two abnormalities that include trisomy 8, del 7/7q, i(17q), del5/5q, del12p, inv(3), or 11q23 rearrangement].78 DIPSS-Plus also stratifies patients into 4 risk groups based on the aforementioned 8 risk factors: low-risk (no risk factors), intermediate-1 risk (1 risk factor), intermediate-2 risk (2 or 3 risk factors), and high-risk (4 or more risk factors) with respective median survival rates of 15.4, 6.5, 2.9, and 1.3 years, respectively. To calculate the DIPSS-Plus score, clinicians must first calculate the DIPSS score. Points are assigned as follows: 0 for DIPSS low-risk, 1 for DIPSS intermediate-1 risk, 2 for DIPSS intermediate-2 risk, and 3 for DIPSS high-risk. One point each is then added for platelets <100 × 109/L, RBC transfusion need, and unfavorable karyotype.

MIPSS70 and MIPSS70-Plus

In a study of 805 patients with PMF (age ≤70 years), in a multivariate analysis, hemoglobin level <10 g/dL, leukocyte count >25 × 109/L, platelet count <100 × 109/L, circulating blast cells ≥2%, bone marrow fibrosis grade ≥MF-2, constitutional symptoms, absence of CALR type-1 mutation, and presence of ≥2 HMR mutations (ASXL1, EZH2, SRSF2, and IDH1/2) were identified as independent predictors of inferior OS.79 This mutation-informed (MIPSS70) prognostic model (without the cytogenetic information) stratified patients into 3 risk categories (low risk, intermediate risk, and high risk) with a median OS of 28 years, 7 years, and 2 years, respectively. The 5-year OS rates were 95%, 70%, and 29%, respectively. The MIPSS70-Plus prognostic model, which included cytogenetic information but omitted bone marrow fibrosis grade and leukocyte and platelet counts, stratified patients into 4 risk categories (low risk, intermediate risk, high risk, and very high risk) with 5-year OS rates of 91%, 66%, 42%, and 7%, respectively. The MIPSS70-Plus version 2.0 prognostic model accounted for very-high-risk karyotype, included U2AF1 Q157 as an HMR mutation, and specified new hemoglobin thresholds with adjustments for sex and severity.81 It stratified patients into 5 risk categories (very low risk, low risk, intermediate risk, high risk, and very high risk) with a median OS of not reached, 10.3 years, 7.0 years, 3.5 years, and 1.8 years, respectively, for patients of all ages. The 10-year survival rates were 86%, 50%, 30%, 10%, and less than 3%, respectively.

Genetically Inspired Prognostic Scoring System

In an analysis of 641 patients with PMF for whom both cytogenetic information and mutational status were available, in a multivariate analysis, very high risk karyotype, unfavorable karyotype, absence of type 1/like CALR mutation, and the presence of ASXL1, SRSF2, or U2AF1 Q157 mutations were identified as predictors of inferior survival.80 GIPSS stratified patients into four risk categories (low risk, intermediate-1, intermediate-2, and high risk) based exclusively on genetic factors described previously. The median 5-year survival rates were 94%, 73%, 40%, and 14%, respectively. However, the authors point out that this prognostic model should not be considered as a finished product but rather a template for incorporating additional genetic information, as it becomes available. The GIPSS was further validated in 266 patients diagnosed with PMF or post-ET/post-PV MF and appeared to be superior to DIPSS in instances where the two models were discordant.88

Post-PV MF and Post-ET MF

The prognostic scoring systems described previously have been studied and validated only in patients with PMF. Although these prognostic scoring systems have been clinically used for the risk stratification of patients with post-PV or post-ET MF, they are not effective for the risk stratification of patients with post-PV or post-ET MF.89 The MYSEC-PM is a prognostic model that stratifies patients with post-PV or post-ET MF into 4 risk groups, with distinct survival outcomes (low risk, intermediate-1, intermediate-2, and high risk) based on age, hemoglobin level (<11 g/dL), circulating blasts (≥3%), CALR mutation status, platelet count (<150 × 109/L), and constitutional symptoms.82 The median survival was not reached, 9 years, 4 years, and 2 years, respectively. Palandri et al83 validated the MYSEC-PM model in post-PV and post-ET MF. The model was successfully used to stratify patients into different risk categories, while the IPSS failed. Spleen responses and hematologic toxicities also differed based on the predicted risk. In a retrospective analysis of cytogenetic data from 376 patients with post-PV and post-ET MF, a significant association was uncovered between abnormal karyotypes and higher MYSEC-PM risk categories (P=.006).90 However, patients with a monosomal karyotype had a lower chance of survival that was independent of the MYSEC-PM stratification.

Treatment Options

Interferons

Interferons may demonstrate activity in low-risk MF9193 but they are generally not recommended for higher-risk disease.

In a retrospective study of 62 patients with early MF treated with peginterferon alfa-2a, improvement in constitutional symptoms and complete resolution of thrombocytosis and leukocytosis were observed in 82%, 83%, and 69% of patients, respectively, and a reduction of splenomegaly was seen in 47% of patients.91 Ianotto et al92 reported an improved OS compared with the reference cohorts used to determine DIPSS scores (intermediate-2: 6.9 vs 4 years and high-risk: 4.58 vs 1.5 years). A reduction of more than 50% in the JAK2 V617F allele burden was observed in 58.8% of patients. Having one or more additional mutation was associated with worse OS and LFS.

In a prospective trial of 30 patients (21 patients with PMF, 7 patients with post-PV MF, and 2 patients with post-ET MF), treatment with interferon alfa-2b or peginterferon alfa-2a resulted in an overall response rate (ORR) of 73% (7% complete response [CR], 30% partial response [PR], 13% clinical improvement, and 23% of patients had stable disease).93 The corresponding response rates were 3%, 27%, 6%, and 13%, respectively, for patients with low-risk disease. Among patients with marked splenomegaly, spleen response (≥50% reduction in spleen size) was observed in 40% of patients (4 of 10) and 60% of patients (6 of 10) had either a slight decrease in spleen size or stable spleen size. Among the 25 patients with evaluable bone marrow biopsies, reduction in bone marrow cellularity and reductions of reticulin fibrosis were observed in 12 patients and 5 patients, respectively, after a median treatment duration of 6 years. The presence of HMR mutations or ≥3 mutations was associated with inferior response rates, and the survival rates were better for patients without ASXL1 mutation; the 5-year progression-free survival (PFS) and OS rates were 88% and 92%, respectively.

The combination of interferons with JAK inhibitors is under investigation in clinical trials.94,95 The phase II COMBI study, which evaluated the efficacy of combined ruxolitinib and low-dose pegylated interferon alfa-2 in 32 patients with PV and 18 patients with primary or secondary MF, reported a remission rate of 31% in patients with PV and 44% in patients with primary or secondary MF at 2 years, as determined by the 2013 ELN and IWG-MRT response criteria.94 Forty-six patients previously had disease that was intolerant of, or refractory to pegylated interferon alfa-2. Reductions in symptom burden (22 to 15) as assessed by the MPN-SAF TSS and in the median JAK2 V617F allele burden (47%–12%) were also obtained. The main grade 3–4 hematologic adverse events reported were anemia (14.0%), thrombocytopenia (4.0%), and leukopenia (2.0%) and the main grade 3–4 nonhematologic adverse events were pneumonia (12.0%), hypertension (6%), and gastrointestinal bleeding (6%). Preliminary data from the phase I/II RUXOPEG trial demonstrated reductions in the spleen size and in the JAK2 V617F allele burden (mean of 75% at baseline to 46% at 6 months) in patients with MF treated with ruxolitinib and pegylated interferon alfa-2.95

Ruxolitinib

Ruxolitinib is a potent and selective JAK1 and JAK2 inhibitor FDA-approved for the treatment of intermediate-risk or high-risk MF as determined by IPSS, based on the results of phase III studies (COMFORT-I and COMFORT-II).69,96 The COMFORT studies did not include patients with low-risk or intermediate-1-risk MF, and the use of ruxolitinib in this patient population is based on the evidence from retrospective analysis and nonrandomized clinical studies as discussed below.97100

Lower-Risk MF

The efficacy of ruxolitinib in low-risk MF has not been evaluated in prospective clinical trials. The results from a retrospective analysis suggest that ruxolitinib may be an appropriate treatment option for symptomatic patients with low-risk MF.97 In this retrospective analysis of 108 patients (25 patients with low-risk MF and 83 patients with intermediate-1-risk MF) treated with ruxolitinib, patients with low-risk MF experienced a substantial improvement in splenomegaly and constitutional symptoms. The proportion of patients with moderate to severe splenomegaly reduced from 64% at the time of diagnosis to 16% at the time of best response to ruxolitinib. The proportion of patients with moderate or severe fatigue decreased from 90% at the time of diagnosis to 37% at the time of best response to ruxolitinib.

The safety and efficacy of ruxolitinib in patients with intermediate-1-risk MF has been demonstrated in a retrospective analysis97 and nonrandomized studies.98100

In the retrospective analysis (discussed previously), among the 83 patients with intermediate-1-risk MF, the proportion of patients with moderate or severe splenomegaly decreased from 53% at the time of diagnosis to 10% at the time of best response to ruxolitinib, and the proportion of patients with moderate or severe fatigue decreased from 76% at the time of diagnosis to 42% at the time of best response to ruxolitinib.97

The ROBUST trial is an open-label phase II trial that evaluated the efficacy of ruxolitinib in patients with intermediate-1-risk MF (48 patients; 14 patients with intermediate-1-risk MF along with 13 patients with intermediate-2-risk MF and 21 patients with high-risk MF).98 The primary composite endpoint was the achievement of treatment success at 48 weeks after ruxolitinib therapy (≥50% reduction in palpable spleen length and/or a ≥50% decrease in MF-SAF). At 48 weeks, 47% of the overall population experienced a reduction in mean palpable spleen length and the effect was seen across all risk groups (52% of patients with intermediate-1-risk, 37% of patients with intermediate-2-risk, and 49% of patients with high-risk disease). A ≥50% reduction in MF-SAF at 48 weeks was achieved in 20.8% of patients in the overall population and across all risk groups (intermediate-1 risk, 21%; intermediate-2 risk, 23%; high-risk, 19%). Improvements in MF-SAF were seen in 80%, 73%, and 72% of patients with intermediate-1-risk, intermediate-2-risk, and high-risk disease, respectively.

JUMP is an expanded-access phase III study designed to assess the safety and efficacy of ruxolitinib in patients with intermediate-2-risk or high-risk MF with or without splenomegaly or intermediate-1-risk MF with a palpable spleen (≥5 cm from the costal margin).101 The JUMP study comprised 2,087 patients with platelet count ≥100 × 109/L and 138 patients with platelet count <100 × 109/L. A primary analysis revealed that at 24, 48, and 96 weeks, 56.5%, 61.4%, and 66.5% of evaluable patients experienced a ≥50% reduction from baseline in palpable spleen length, respectively. At the same time points, 23.3%, 18.9%, and 14.3% of patients had a 25% to <50% reduction from baseline in palpable spleen length, respectively. Of evaluable patients with platelet count less than 100 × 109/L, 38.4% and 31.9% experienced a ≥50% reduction from baseline in palpable spleen length at 24 and 48 weeks, respectively. The most common grade 3 or 4 hematologic adverse events were anemia and thrombocytopenia in patients with platelet count ≥100 × 109/L (34.7% and 17.1%, respectively) and in patients with platelet count <100 × 109/L (35.5% and 54.3%, respectively).

The most common grade 3 or 4 nonhematologic adverse events were pneumonia (4.6%), pyrexia (2.3%), and asthenia (2.2%) in patients with platelet count ≥100 × 109/L and pneumonia (5.8%), pyrexia (3.6%), and dyspnea (3.6%) in patients with platelet count <100 × 109/L. At 96 weeks, the estimated OS and PFS (per IWG-MRT criteria) probabilities were 87% (95% CI, 85%–89%) and 81% (95% CI, 78%–83%), respectively. Treatment with ruxolitinib also led to the amelioration of symptoms. A multivariate analysis determined that IPSS low/intermediate-1 risk category (43.1% vs 30.6% for IPSS intermediate-2/high risk category; adjusted odds ratio [AOR], 0.65; 95% CI, 0.44–0.95), use of ruxolitinib in the first-line setting (40.2% vs 31.5% for use in subsequent-line setting; AOR, 0.53; 95% CI, 0.38–0.75), and a total daily dose of greater than 20 mg/day at 12 weeks (41.3% vs 30.4% for <20 mg/day; AOR, 0.47; 95% CI, 0.33–0.68) were associated with a higher spleen response rate.102 However, no association was found with symptom response rate.

In another study that evaluated efficacy and safety of ruxolitinib in 70 patients with intermediate-1-risk MF, the rates of spleen and symptom response at 6 months were 55% and 80%, respectively. The majority of patients (83%) were still on therapy after a median follow-up of 27 months.100

Higher-Risk MF

The results of COMFORT-I69,103,104 and COMFORT-II96,105,106 studies demonstrated that continuous ruxolitinib therapy was associated with significant clinical benefits in patients with MF in terms of reduction in spleen size, amelioration of disease-related symptoms, and improvement in quality of life and OS compared with either placebo or best available therapy for patients with intermediate-2-risk or high-risk MF (PMF, post-PV MF, or post-ET MF).

The COMFORT-I trial randomized 259 patients with intermediate-2-risk or high-risk MF to twice-daily ruxolitinib (n=155) or placebo (n=154).69 The starting dose of ruxolitinib was based on the baseline platelet count (15 mg twice daily for a platelet count 100 × 109/L to 200 x109/L and 20 mg twice daily for >200 × 109/L) and patients with protocol-defined worsening splenomegaly were permitted to cross over from placebo to ruxolitinib. The primary endpoint (≥35% reduction in spleen volume as assessed by MRI at 24 weeks) was reached in 42% of patients in the ruxolitinib group as compared with 0.7% in the placebo group (P<.001). An improvement of ≥50% in the MF-SAF at 24 weeks was seen in 46% of patients treated with ruxolitinib as compared with 5% of patients who received placebo (P<.001). Long-term follow-up results confirmed the safety and durable efficacy of ruxolitinib for the treatment of patients with intermediate-2-risk or high-risk MF.103,104 The 5-year follow-up data showed that patients treated with ruxolitinib had prolonged median OS compared with placebo (not reached compared with 200 weeks for patients randomized to placebo; HR, 0.69; 95% CI, 0.50–0.96; P = 0.025).104 Spleen response (≥35% reduction from baseline in spleen volume) was achieved in 59% of patients randomized to ruxolitinib and the median duration of spleen response was 168 weeks. At the time of this analysis, 111 patients from the placebo group had crossed over to ruxolitinib (median time to crossover was 40 weeks). The subgroup analyses showed that clinical benefit of ruxolitinib was seen across all patient subgroups including PMF, post-ET MF or post-PV MF, IPSS risk groups, and JAK mutation status (positive or negative), and there was also a nonsignificant trend toward longer OS for patients with IPSS intermediate-2-risk and high-risk MF treated with ruxolitinib. However, this study was not designed or powered to detect treatment efficacies between treatment arms within each subgroup.104,107

In the COMFORT-II study, 219 patients with intermediate-2-risk or high-risk MF were randomized to ruxolitinib (n=146) or best available therapy (n=73).96 The primary endpoint was at least a 35% reduction in spleen volume as assessed with MRI or CT scan at 48 weeks. The starting dose of ruxolitinib was based on the baseline platelet count (15 mg twice daily if the platelet count was ≤200 × 109/L and 20 mg twice daily if the platelet count was >200 × 109/L). A total of 28% of the patients in the ruxolitinib arm had a ≥35% reduction in spleen volume at 48 weeks compared with 0% in the group receiving the best available therapy (P<.001). The median duration of response among patients treated with ruxolitinib was not reached, with 80% of patients still having a response at a median follow-up of 12 months.96 Patients receiving ruxolitinib had improved quality of life and role functioning as well as significant reductions in disease-related symptoms compared with those receiving best available therapy. Long-term follow-up results confirmed that ruxolitinib is associated with durable efficacy and survival benefit compared with best available therapy for patients with intermediate-2-risk or high-risk MF.105,106 At the time of the 5-year final analysis, 53% of patients in the ruxolitinib arm experienced a ≥35% reduction in spleen volume at any time on treatment, and spleen volume reductions of ≥35% were sustained with long-term therapy (median duration, 3 years).106 The median OS was not reached for patients in the ruxolitinib arm, and it was 4 years for those in the best available therapy arm.

The pooled analysis of COMFORT-I and COMFORT-II studies showed that patients with intermediate-2-risk or high-risk MF treated with ruxolitinib had prolonged OS, and the OS of patients with high-risk disease in the ruxolitinib group was similar to that of patients with intermediate-2-risk MF in the control group.108 Larger spleen size at baseline was associated with shortened survival, whereas any spleen volume reductions (>10% reduction in spleen size) and a palpable spleen length reduction of ≥25% correlated with longer survival. Verstovsek et al109 also determined that compared with patients who had a decrease of <25% in spleen length, those with a ≥50% decrease had significantly improved survival (HR, 0.223; 95% CI, 0.097–0.512; P=.0001).

The European Registry for Myeloproliferative Neoplasms: Toward a Better Understanding of Epidemiology, Survival, and Treatment study enrolled patients with PMF or post-PV/ET MF.110 At enrollment, 10.7% of patients had received treatment with ruxolitinib and 48.2% of patients had received treatment with hydroxyurea only. Sixty four percent of patients treated with ruxolitinib had received treatment with hydroxyurea. Analysis of the real-world data revealed an improved median OS with ruxolitinib compared with those treated with hydroxyurea (6.7 vs 5.1 years; P=.001). A propensity score matching analysis also demonstrated an improved median OS in patients treated with ruxolitinib (7.7 years) as first-line therapy or second-line therapy after hydroxyurea compared with those treated with hydroxyurea only (3.4 years; P=.002).

Toxicity

Anemia and thrombocytopenia were the most common hematologic toxicities associated with ruxolitinib, consistent with its mechanism of action, and the incidences of grade 3/4 anemia or thrombocytopenia were higher during the first 8 to 12 weeks of treatment.69,96,99 In the COMFORT-I study, ecchymosis, dizziness, and headache were the most frequent nonhematologic toxicities associated with ruxolitinib, and diarrhea was the most frequent nonhematologic adverse event associated with ruxolitinib in the COMFORT-II study.69,96 In general, the incidences of nonhematologic toxicities decreased with long-term therapy.103,106 Anemia associated with ruxolitinib treatment may not share the inferior prognosis of disease-related anemia as ruxolitinib can overcome the inferior prognosis of disease-induced anemia.111 A study by Cervantes et al112 suggests that an alternative dosing strategy for ruxolitinib consisting of a dose of 10 mg twice daily for 12 weeks and titrating up to a dose of 25 mg twice daily was well-tolerated and effective in patients with PMF or post-PV/ET MF and anemia.

Ruxolitinib is associated with a potentially increased risk of opportunistic infections and viral reactivations.113,114 In particular, herpes simplex and zoster virus reactivations are common; tuberculosis, progressive multifocal leukoencephalopathy, and reactivation of hepatitis B, have also been reported in patients treated with ruxolitinib.104,115119 Patients should be monitored for signs and symptoms of infections and vaccinations against viral infections such as recombinant (killed) zoster vaccine may be considered when possible. Serious infections should be resolved prior to initiation of ruxolitinib. Ruxolitinib is contraindicated in patients with evidence of active or latent tuberculosis. Viral reactivations should be treated and monitored according to clinical guidelines.

Nonmelanoma skin cancers and precancerous lesions have been reported in patients treated with ruxolitinib120; annual skin examinations are recommended.120 Lymphoid neoplasms may be diagnosed concurrently with MPN or may develop during the natural history of MF, PV, or ET.121124 Although one report indicated that JAK inhibitor therapy may be associated with an increased risk of aggressive B-cell lymphomas in patients with MF,125 other studies found no evidence of increased lymphoma risk in patients treated with a JAK inhibitor.126129

Impact of Mutational Status and Response to Ruxolitinib

In the COMFORT-II study, ruxolitinib was associated with clinical efficacy and survival improvement across different molecular subsets of patients with MF.130 HMR mutations (ASXL1, EZH2, SRSF2, IDH1, or IDH2) were identified in 33%, 7%, 3%, less than 1%, and 0% of patients, respectively, and these frequencies were comparable in ruxolitinib and best available therapy arms. Responses in splenomegaly (>35% spleen volume reduction), symptomatic improvement, and the risk of ruxolitinib-associated anemia and thrombocytopenia were observed at similar frequencies across different mutation profiles. Ruxolitinib improved survival and reduced the risk of death in patients harboring HMR mutations (ASXL1, EZH2, SRSF2, IDH1, or IDH2) with an HR of 0.57.130 The use of ruxolitinib did not appreciably influence the acquisition of additional mutations during treatment compared with the use of hydroxyurea.131 A decrease in the JAK2 V617F variant allele frequency was associated with the duration of the spleen volume response. An increase in the variant allele frequency of any initial mutation or the acquisition of one or more nondriver mutations during treatment was associated with increased rates of treatment discontinuation.

The results of another analysis of 95 patients with MF treated with ruxolitinib in a single institution also showed that ASXL1, EZH2, and IDH1/2 mutations are associated with poor outcomes and patients with three or more mutations in ASXL1, EZH2, or IDH1/2 had shorter time to treatment discontinuation and OS.132 However, in contrast to the findings of the COMFORT-II study, patients with one or more mutations in ASXL1, EZH2, or IDH1/2 were significantly less likely to have a spleen response. Patients with 3 or more mutations had the worst outcomes, suggesting that multigene profiling may be useful for treatment planning in patients with MF.

Fedratinib

Fedratinib is a potent and selective JAK2 and FLT3 inhibitor approved by the FDA for the treatment of intermediate-2 or high-risk MF as determined by IPSS, based on the results of the randomized phase III JAKARTA trial, as well as the nonrandomized phase II JAKARTA-2 trial, which evaluated efficacy in patients with ruxolitinib-resistant or ruxolitinib-intolerant intermediate-1, intermediate-2, or high-risk MF.72,73

The phase III JAKARTA trial randomized 289 patients with intermediate-2-risk or high-risk MF (PMF, post-PV MF, or post-ET MF) to once-daily fedratinib 400 mg (n=96) or 500 mg (n=97), or placebo (n=96) for at least 6 consecutive 4-week cycles.72 Patients had palpable splenomegaly (≥5 cm below the left costal margin) and platelet count ≥50 × 103/μL. Patients with protocol-defined progressive disease (PD) were permitted to cross over from placebo to fedratinib. The proportion of patients achieving the primary endpoint (spleen response; ≥35% reduction in spleen volume as assessed by MRI or CT scan at 24 weeks and confirmed 4 weeks later) was significantly higher (P<.001) in the fedratinib group (36% for 400 mg and 40% for 500 mg) than in the placebo group (1%). The confirmed spleen response rates at 24 weeks were higher for patients randomized to fedratinib 400 mg and 500 mg regardless of baseline platelet count, disease type (PMF, post-ET MF, or post-PV MF), risk status, and JAK2 mutation status. The symptom response rates at 24 weeks (≥50% reduction in the MF-SAF-TSS from baseline) were 36%, 34%, and 7%, respectively, for fedratinib 400 mg, fedratinib 500 mg, and placebo groups. Seventy-four percent of patients initially in the placebo group crossed over to fedratinib during the study.133 The median OS was not reached in either group (HR, 0.57; 95% CI, 0.30–1.10; P=.094). The survival rates at 1 year and 18 months were 92% and 87%, respectively, for the fedratinib group, and 86% and 80%, respectively, for the placebo group. Patients treated with fedratinib had significantly longer median PFS (23.2 vs 17.5 months) (HR, 0.42; 95% CI, 0.23–0.76; P=.004). The PFS rates were 83% for the fedratinib group and 67% for the placebo group at 1 year. A subsequent analysis of the JAKARTA study showed that the baseline platelet count did not significantly impact the rate of spleen response (P=.37), which was 36% in patients with platelet count 50 to <100 × 109/L (n=14) and 49% in patients with platelet count ≥100 × 109/L (n=82) who were treated with 400 mg daily fedratinib at 24 weeks.134 Similar results were obtained for the rates of symptom response (33% in the first group and 42% in the second group; P=.57).

The phase II nonrandomized JAKARTA-2 trial (n=97) showed that fedratinib 400 mg was also effective in reducing splenomegaly and symptom burden in patients with ruxolitinib-resistant or ruxolitinib-intolerant intermediate-1-risk or intermediate-2-risk/high-risk MF (PMF, post-PV MF, or post-ET MF, palpable splenomegaly [≥5 cm below the left costal margin] and platelet count ≥50 × 109/L).73 Patients were assigned by treating investigators as resistant or intolerant to ruxolitinib. Spleen response (≥35% reduction in spleen volume as assessed by MRI or CT scan at 24 weeks; 83 evaluable patients) and symptom response (≥50% reduction in the MF-SAF-TSS at 24 weeks; 90 evaluable patients) were achieved in 55% (53% in the ruxolitinib-resistant group and 63% in the ruxolitinib-intolerant group) and 26% (21% in the ruxolitinib-resistant group and 32% in the ruxolitinib-intolerant group) of patients, respectively. Another analysis of the JAKARTA-2 study reported the efficacy data in 3 different cohorts of patients (intent-to-treat population, n=97; stringent criteria cohort, n=79; and sensitivity analysis cohort, 66 patients treated with 6 cycles of fedratinib or discontinued before cycle 6 for reasons other than study closure) by using updated criteria for ruxolitinib failure and intolerance.135 The spleen response rates were 31%, 30%, and 36%, respectively, for these 3 cohorts. The corresponding symptom response rates were 27%, 27%, and 32%, respectively. At the end of the study, 81% of patients were censored for survival.133 The median OS was not reached (95% CI, 17.1 months–not reached) and the survival rates at 1 year and 18 months were 84% and 67%, respectively. The median PFS was 13.3 months (95% CI, 8.4–17.1 months) and the PFS rate at 1 year was 59%. A subgroup analysis of the JAKARTA2 study showed the baseline platelet count did not significantly impact the rate of spleen response (P=.41), which was 36% in patients with platelet count 50 to <100 × 109/L (n=33) and 28% in patients with platelet count ≥100 × 109/L (n=64) at 24 weeks.134 The rate of symptom response was 39% in the former group and 20% in the latter group (P=.06). Post hoc analyses from the JAKARTA and JAKARTA2 trials determined that treatment with fedratinib (400 mg daily) was not associated with clinically significant weight gain or an increase in the body mass index.136

Toxicity

Anemia and thrombocytopenia were the most common hematologic toxicities associated with fedratinib.72,73 In the JAKARTA trial, grade 3 or 4 anemia and thrombocytopenia were reported in 43% and 17% of patients, respectively, in the fedratinib 400 mg group, and the corresponding rates were 60% and 27% in the fedratinib 500 mg group.72 In an analysis of the JAKARTA-2 trial, grade 3 or 4 anemia was reported in 46% of patients and thrombocytopenia in 24% of patients.73 A pooled analysis of the JAKARTA/JAKARTA2/ARD11936 cohorts revealed a higher percentage of grade 3–4 treatment-emergent thrombocytopenia (40% for platelet count 50 to <100 × 109/L [n=48] and 5% for platelet count ≥100 × 109/L [n=155]) in patients treated with 400 mg daily fedratinib.134

Diarrhea, vomiting, and nausea were the most common nonhematologic toxicities and usually abated after the first 28-day cycle.72,73 Fedratinib has demonstrated inhibition of FLT3, which has been implicated in the occurrence of these gastrointestinal toxicities.137,138 Elevation of liver enzymes or creatinine levels were more frequent with fedratinib than with placebo.72 Fedratinib was also associated with a higher rate of infections (42% and 39%, respectively, for fedratinib 400 mg and 500 mg compared with 27% in the placebo group).

The phase IIIb FREEDOM trial evaluated the efficacy and safety of fedratinib at a dose of 400 mg daily in patients with DIPSS intermediate-risk or high-risk PMF or post-PV/ET MF who were previously treated with ruxolitinib.139 Preliminary results showed that constipation, diarrhea, and nausea were the most common gastrointestinal adverse events and were reported in 47%, 35%, and 26% of patients, respectively. No grade 3/4 treatment-related gastrointestinal adverse occurrences were observed. Data also suggest that early treatment with gastrointestinal prophylactic agents (ondansetron or loperamide) may help to mitigate the rates of gastrointestinal adverse events. No cases of Wernicke encephalopathy (WE) were observed.

In August 2017, the FDA removed the clinical hold on the fedratinib development program, which was initially placed in 2013 because eight out of 670 patients in fedratinib clinical trials experienced symptoms suggestive of WE, which is a neurologic disorder that develops in the setting of thiamine deficiency.140 A subsequent report showed that fedratinib does not increase the risk of thiamine deficiency beyond its potential to worsen malnutrition, which could be due to poor management of preventable gastrointestinal adverse events.140 In the JAKARTA2 study, only one case of encephalopathy was reported, which was subsequently determined to be related to hepatic encephalopathy and inconsistent with WE.135 In 670 patients enrolled in clinical trials evaluating fedratinib in patients with MPN or solid tumors, the overall prevalence of WE was observed in less than 1% of treated patients,140 and thus was not found to be clearly different than the 1%–2% prevalence of WE in the general United States population.141

As a result of these updated analyses, the FDA approved fedratinib in 2019 for the treatment of patients with intermediate-2-risk or high-risk MF (PMF, post-PV MF, or post-ET MF). The prescribing information for fedratinib includes a boxed warning regarding the potential risk of encephalopathy, including WE. Thiamine (vitamin B1) levels, CBC with platelets, and nutritional status should be assessed in all patients prior to starting fedratinib, periodically during treatment, and as clinically indicated. Fedratinib should not be started in patients with thiamine deficiency. If low levels of thiamine are detected, thiamine should be repleted prior to treatment initiation. If WE is suspected, fedratinib should be discontinued immediately and parenteral thiamine should be initiated. Patients should be monitored until the resolution of symptoms or improvement and normalization of thiamine levels.

Pacritinib

Pacritinib, a JAK2, FLT3, and IRAK1 inhibitor, was evaluated in patients with intermediate-1, intermediate-2, and high-risk MF.74,75,142 Pacritinib is FDA-approved for the treatment of intermediate or high-risk MF with a platelet count <50 × 109/L.75,142

The phase II PAC203 trial reported that 200 mg pacritinib twice daily showed clinical activity and had a manageable safety profile in patients with ruxolitinib-resistant or ruxolitinib-intolerant intermediate-1, intermediate-2, or high-risk MF with platelet count <50 × 109/L.142 At 24 weeks, the spleen response rate (≥35% reduction in spleen volume) was 9.3% in the overall cohort versus 16.7% in those with platelet count <50 × 109/L and the total symptom score response rate (≥50% reduction in total symptom score based on the MPN-SAF TSS 2.0) was 7.4% in the overall cohort versus 8.3% in those with platelet count <50 × 109/L.

In the phase III PERSIST-1 trial, patients with intermediate-1, intermediate-2, or high-risk MF with palpable splenomegaly (≥5 cm below the left costal margin) were randomized 2:1 to receive pacritinib (n=220), 400 mg once daily, or best available therapy (n=107) (excluding JAK2 inhibitors).74 Patients were allowed to cross over to pacritinib at 24 weeks or if their disease progressed. In the best available therapy group, 84% of the patients crossed over to the pacritinib group at a median time point of 6.3 months. Nineteen percent of patients receiving pacritinib met the primary endpoint (≥35% spleen volume reduction, as determined by MRI or CT, in the intention-to-treat population) compared with 5% of patients receiving best available therapy (P=.0003) at 24 weeks. At the same time point, the percentage of patients with a total symptom score reduction of ≥50%, as determined using the MPN-SAF TSS 2.0, was similar in the pacritinib and best available therapy study arms (19% vs 10%; P=.24). At 48 weeks, a significantly higher percentage of patients in the pacritinib study arm achieved this reduction (15% vs 0%; P=.0027). Overall survival did not differ between the 2 groups (HR, 1.36; 95% CI, 0.89–2.09; P=.16) prior to week 24.

The phase III PERSIST-2 trial randomized patients with intermediate-1, intermediate-2, or high-risk MF with platelet count ≤100 × 109/L 1:1:1 to receive once-daily pacritinib 400 mg, twice-daily pacritinib 200 mg, or best available therapy.75 Patients had palpable splenomegaly (≥5 cm below the left costal margin) and platelet count ≤100 × 109/L. Forty-eight percent of patients were previously treated with ruxolitinib. Among the best available therapy group, 45% of patients received ruxolitinib. Patients were allowed to cross over to pacritinib at 24 weeks or if splenomegaly progressed. At 24 weeks, in the intention-to-treat population, the proportion of patients achieving the coprimary endpoint of ≥35% reduction in spleen volume, as assessed by MRI/CT, was significantly higher in the pacritinib groups (15% [95% CI, 7.6%–24.7%; P=.02] for 400 mg once daily and 22% [95% CI, 12.9%–32.7%; P=.001] for 200 mg twice daily) than in the best available therapy group (3% [95% CI, 0.3%–9.7%]). Seventeen percent (95% CI, 9.6%–27.8%; P=.65) of patients receiving once-daily 400 mg pacritinib and 32% (95% CI, 22.0%–44.3%; P=.01) of patients receiving twice-daily 200 mg pacritinib met the coprimary endpoint of ≥50% reduction in total symptom score (MPN-SAF TSS 2.0), as opposed to 14% (95% CI, 6.9%–24.1%) of patients receiving best available therapy. Overall survival was similar across all three groups (HR, 1.18; 95% CI, 0.57–2.44; and HR, 0.68; 95% CI, 0.30–1.53 for pacritinib 400 mg once daily and 200 mg twice daily, respectively, when compared with best available therapy).

Toxicity

The phase II PAC203 trial reported thrombocytopenia (33.3%), anemia (20.4%), and neutropenia (5.6%) as the most common grade 3 or 4 treatment-emergent hematologic events in patients with MF resistant to or intolerant of ruxolitinib who received twice-daily pacritinib 200 mg.142 Pneumonia (9.3%) as well as diarrhea, abdominal pain, and hyperuricemia (5.6% each) were the most common nonhematologic grade 3 or 4 treatment-emergent adverse events. Like fedratinib, pacritinib also exhibits FLT3 inhibition, which has been implicated in gastrointestinal toxicity.137,138

In the PERSIST-1 trial, the most frequent grade 3 or 4 adverse events in the pacritinib study arm were anemia (17%), thrombocytopenia (12%), and diarrhea (5%) and in the best available therapy arm, they were anemia (15%), thrombocytopenia (11%), dyspnea (3%), and hypotension (3%).74 One percent of patients in the pacritinib group had an infection compared with none in patients receiving best available therapy. In the PERSIST-2 trial, the most frequent grade 3 or 4 treatment-emergent adverse events in patients receiving once-daily pacritinib 400 mg, twice-daily pacritinib 200 mg, or best available therapy were thrombocytopenia (31%, 32%, and 18%, respectively) and anemia (27%, 22%, and 14%, respectively).75

In 2016, the FDA placed a clinical hold on the development of pacritinib while evaluating deaths related to intracerebral hemorrhage and cardiovascular events. In 2017, the FDA lifted the clinical hold and in 2022, the drug was approved for the treatment of intermediate- or high-risk myelofibrosis (PMF, post-PV MF, or post-ET MF) for patients with platelet count <50 × 109/L.

Allogeneic Hematopoietic Cell Transplant

Allogeneic HCT is the only potentially curative treatment option resulting in long-term remissions for patients with MF. Myeloablative conditioning and reduced-intensity conditioning (RIC) are relatively similar in terms of OS.143 The use of RIC is associated with a lower rate of nonrelapse mortality (NRM), but it is also associated with a higher risk of relapse compared with myeloablative conditioning.144151 Comparison studies of RIC also do not show a difference in OS,151,152 although one study reported a trend toward lower NRM (HR, 0.52; 95% CI, 0.26–1.05; P=.068) and a higher relapse rate (HR, 9.21; 95% CI, 1.81–46.9; P=.008) with regimens that use the combination of busulfan and fludarabine.151 Another study also determined a higher relapse rate but the difference was not statistically significant (P=.21).152 No statistically significant difference was obtained for NRM (P=.32). Patients with MPN are at particularly high risk for hepatobiliary toxicities related to transplant, including sinusoidal obstructive syndrome (SOS). Approaches to reduce SOS and NRM using specialized myeloablative conditioning have been used and may be helpful.153,154 The estimated OS and NRM rates for myeloablative conditioning at 3 to 5 years range from 30% to 61% and 35%–50%, respectively.155 In a retrospective registry analysis of 289 patients with MF, allogeneic HCT resulted in long-term OS in approximately one third of patients, but the probability of long-term survival and NRM was dependent on the source of stem cells.156 The 5-year posttransplant OS rates were 37%, 40%, and 30%, respectively, for HLA-matched sibling donor transplant, other related donor transplant, and unrelated donor (URD) transplant, respectively. The corresponding 5-year disease-free survival rates were 33%, 22%, and 27%, respectively. The NRM rate at 5 years was higher for URD transplant (50% compared with 35% and 38% for HLA-matched sibling donor transplant and other related donor transplant, respectively).

In a prospective, multicenter study that evaluated allogeneic HCT with RIC in 103 patients with MF, the cumulative incidence of NRM at 1 year was 16% and the cumulative incidence of relapse at 3 years was 22%.145 The estimated 5-year event-free survival and OS rates were 51% and 67%, respectively. The NRM was significantly lower for patients with a completely matched donor (12% vs 38%; P=.003). Other large retrospective registry analyses have also reported similar outcomes.148,149 In the Center for International Blood and Marrow Transplant Research analysis that included 233 patients who underwent allogeneic HCT using RIC for PMF, the probabilities of OS and PFS at 5 years were 47% and 27%, respectively.148 The cumulative incidence of NRM and relapse/progression at 5 years were 24% and 48%, respectively. In the European Bone Marrow Transplantation Registry analysis that included 193 patients who underwent transplantation for post-PV or post-ET MF, the 3-year OS rate, incidence of relapse, and NRM were 55%, 32%, and 28%, respectively.149 Another study that included 2,459 patients with MF who underwent allogeneic HCT reported an OS rate of 41% (95% CI, 39%–44%) and a disease-free survival rate of 32% (95% CI, 30%–35%) at 10 years.157 In 1055 patients that were disease-free at 2 years, the 10-year OS and disease-free survival rates were 74% (71%–78%) and 64% (60%–68%), respectively.

Age (>55 years) and donor type (HLA-identical sibling donor transplant vs HLA-well-matched URD transplant or partially/mismatched URD transplant) have been the most important prognostic factors of OS and NRM. Among patients who underwent allogeneic HCT with RIC for PMF, the 5-year survival rates following HLA-identical sibling donor transplant, HLA-well-matched URD transplant, and partially/mismatched URD transplant were 56%, 48%, and 34%, respectively (P=.002) and the relative risk of NRM was also the lowest for HLA-identical sibling donor transplant (1%) compared with 3% and 9% for HLA-well-matched URD transplant and partial/mismatched URD transplant, respectively.148 In patients who underwent allogeneic HCT with RIC for post-PV MF or post-ET MF, the overall 3-year cumulative incidence of NRM was significantly higher in patients older than 55 years (35% vs 20% for younger patients; P=.032) and in those who underwent URD transplant (34% vs 18% for those who had a related donor transplant; P=.034).149

The results of a retrospective study by the European Society for Blood and Marrow Transplantation with MF patients who underwent allogeneic HCT from an HLA-identical sibling or an unrelated donor identified age 60 years or older, Karnofsky performance status of <90% at the time of transplant, graft failure, acute graft versus host disease (GVHD) (grades III–IV), and disease progression or relapse as factors that were independently associated with a higher mortality rate.158 These factors, along with HCT-specific comorbidity index ≥3 and extensive chronic GVHD, were associated with higher NRM. The DIPSS risk score was not a prognostic factor.

Another retrospective multicenter study of 69 patients with chronic phase MF who were treated with allogeneic blood or marrow transplantation from a haploidentical donor and received cyclophosphamide posttransplantation reported an OS of 72% (95% CI, 59%– 81%), a relapse-free survival recurrence-free survival (RFS) of 44% (95% CI, 29%–59%), and a GVHD-free-RFS of 30% (95% CI, 17%–43%) at 3 years.159 A cumulative incidence of 10% was obtained for grade 3–4 acute GVHD and 8% for extensive chronic GVHD.

A few studies have shown that larger spleen size may be associated with inferior outcomes after transplant, possibly reflecting an aggressive disease biology.159161 A spleen size ≥22 cm or a prior splenectomy (HR, 6.37; 95% CI, 2.02–20.1; P=.002) and bone marrow grafts (HR, 4.92; 95% CI, 1.68–14.4; P=.004) were associated with a higher incidence of relapse.159 An univariate analysis determined that a spleen size ≥17 cm or a prior splenectomy was associated with worse RFS (HR, 3.50; 95% CI, 1.18–10.37; P=.02) and a higher relapse rate (subdistribution HR not calculable; P=.01).160 The results of a multivariate analysis by Polverelli et al161 demonstrated that splenectomy was associated with reduced NRM (HR, 0.64; 95% CI, 0.44–0.93; P=.018), a higher risk of relapse (HR, 1.43; 95% CI, 1.01–2.02; P=.042), but no effect on OS (HR, 0.86; 95% CI, 0.67–1.12; P=.274).

In another study, DIPSS risk score has been shown to predict outcome after transplant.148,162 In the aforementioned Center for International Blood and Marrow Transplant Research analysis, there was a trend toward lower mortality rates in patients with low or intermediate-1-risk disease, and higher NRM in patients with intermediate-2 or high-risk disease.148 In another retrospective analysis of 170 patients with MF who received HCT, DIPSS risk score significantly correlated with mortality risk and NRM (HR for posttransplant mortality was 4.11 for high-risk disease compared with 3.15, 1.97, and 1, respectively, for intermediate-2, intermediate-1, and low-risk disease; the corresponding HRs for NRM were 3.41, 3.19, 1.41, and 1, respectively).162 The association of DIPSS risk score with relapse was not significant, although patients with higher-risk disease experienced more relapses than those with lower-risk disease.

DIPSS risk scores prior to HCT have also been shown to correlate with OS following allogeneic HCT.148,163,164 However, in one retrospective analysis, the differences in OS between patients with intermediate-1 and intermediate-2-risk disease were not significantly different. In a multivariate analysis, only JAK2 wild-type, age 57 years or older, and the presence of constitutional symptoms were independent predictors of OS. The 5-year OS rates were 90%, 74%, and 50% for the presence of 0, 1, and 2 risk factors.163 In another retrospective analysis that evaluated the impact of allogeneic HCT on survival in patients younger than 65 years at the time of diagnosis of PMF (n=438; 190 patients received allogeneic HCT and 248 patients received conventional therapy), the relative risk of death after allogeneic HCT was 5.6 for patients with DIPSS low-risk disease, 1.6 for patients with intermediate-1-risk disease, 0.55 for patients with intermediate-2-risk disease, and 0.37 for patients with high-risk disease.164

These findings suggest that outcomes following allogeneic HCT are better for patients with low or intermediate-1-risk MF.148,162 However, since HCT is associated with a significant rate of transplant-related complications and morbidity that may not otherwise occur with nontransplant therapies in this group of patients, the overall benefit may be with nontransplant therapies.165 Allogeneic HCT is associated with a clear benefit in patients with intermediate-2 or high-risk MF. A retrospective study of 544 patients with MF investigated the different prognostic models (IPSS, DIPSS, and DIPSS-Plus) and determined that the IPSS and DIPSS-plus models were most able to differentiate between the intermediate-1 and intermediate-2 risk categories.166

The myelofibrosis transplant scoring system (MTSS) is a recently introduced model that takes into account clinical (age ≥57 years, Karnofsky performance status <90%, platelet count <150 × 109/L, leukocyte count >25 × 109/L), molecular (presence of ASXL1 mutation and absence of CALR and MPL mutations), and transplant-specific factors (HLA-mismatched unrelated donor), and is designed to assess prognosis after allogeneic transplant in patients with primary and post-ET/PV MF.167 It stratifies patients into 4 risk categories: low, intermediate, high, and very high. Validated in a cohort of 156 patients, the survival rates for these categories were 83% (95% CI, 71%–95%), 64% (95% CI, 53%–75%), 37% (95% CI, 17%–57%), and 22% (95% CI, 4%–39%), respectively (P<.001). Another study evaluating the performance of the MTSS model concluded that it may need to be refined as it did not distinctly stratify patients into 4 risk categories.168 However, the authors note that it still has clinical value. When the risk levels were combined to give 2 new categories, standard (low and intermediate) and high (high and very high), the MTSS was better able to distinguish risk (P<.001). The OS at 3 years for the standard- and high-risk levels were 62% (95% CI, 49%–72%) and 25% (95% CI, 9%–45%), respectively. Further validation studies are needed to confirm these findings.

Impact of Mutational Status

CALR mutation is associated with higher OS rates and lower rate of NRM following allogeneic HCT in patients with PMF as well as post-PV or post-ET MF.169,170 Identification of HMR mutations (ASXL1, EZH2, SRSF2, TP53, IDH1, or IDH2 mutations) may be helpful in decision-making regarding allogeneic HCT in patients with PMF.27,3537,170 CBL, DNMT3A, and U2AF1 were associated with worse OS in patients with MF undergoing allogeneic HCT.171,172 The results from another study also suggest inferior OS with ASXL1 mutations (subdistribution HR, 2.36; 95% CI, 0.85–6.6; P=.09).160

In a study of 133 patients who underwent allogeneic HCT for PMF (n=97) or post-ET/post-PV MF (n=36), the 4-year OS rate was 82% for patients with CALR mutations compared with 56% for patients without CALR mutations (CALR wild-type). The NRM rate was also significantly lower in patients with CALR mutations compared with those with CALR wild-type (4-year NRM rates were 7% and 31%, respectively; P=.024).169 In another study that evaluated the impact of molecular genetics on the outcome after allogeneic HCT in patients with MF (PMF, n=110; post-PV or ET MF, n=46; and MF in transformation, n=13), the results of a multivariate analysis showed that CALR mutation was an independent factor for lower NRM and improved PFS and OS.170 ASXL1 and IDH2 mutations were independent risk factors for lower PFS, whereas no impact was observed for triple-negative patients. As discussed previously, CALR(−)/ASXL1(+) is associated with a poor prognosis (independent of the DIPSS-Plus risk score) in patients with PMF and this subset of patients should be considered for allogeneic HCT earlier in the disease course.41

A small study with 18 patients with primary or post-ET MF found that MPL mutations were associated with a favorable outcome following allogeneic HCT with an OS rate and an RFS rate of 83.5% (95% CI, 65.9%–100%) at 5 years and a relapse rate of 5.5%.173

The addition of mutational status to DIPSS-Plus can help improve the prediction of transplantation outcome.174 Patients with 3 or more mutations along with CALR or JAK2 mutations had higher NRM and risk of relapse after transplant compared with those with fewer mutations.

Treatment Recommendations Based on Symptom Assessment and Risk Stratification

The selection of appropriate treatment should be based on the risk score and the presence of symptoms. A clinical trial or consideration of a clinical trial is recommended for all patients with MF who require treatment with the aim of reducing bone marrow fibrosis, improving cytopenias and symptom burden, restoring transfusion independence, and/or preventing/delaying progression to AML.

Lower-Risk MF

Patients with asymptomatic lower-risk MF should be observed and monitored for signs and symptoms of disease progression with MPN-SAF TSS (MPN-10). Enrollment in a clinical trial is also an option. Ruxolitinib,9799 peginterferon alfa-2a,93 or a clinical trial are included as options for patients with symptomatic disease. Hydroxyurea has been shown to be an effective treatment option for the hyperproliferative manifestations of lower-risk MF (thrombocytosis or leukocytosis). In a small study of 40 patients with symptomatic MF (constitutional symptoms, splenomegaly, thrombocytosis, leukocytosis, pruritus, and bone pain), treatment with hydroxyurea (500 mg/day, subsequently adjusted to the individual efficacy and tolerability) resulted in clinical improvement in 40% of patients.175 Anemia induced by hydroxyurea was manageable with concomitant treatment. The panel has included hydroxyurea as an option for symptomatic lower-risk MF, if the use of cytoreductive therapy would be symptomatically beneficial in selected patients with high platelet counts. Ruxolitinib, peginterferon alfa-2a, and hydroxyurea are listed as useful in certain circumstances options for patients with symptomatic lower-risk MF.

Although the outcomes after allogeneic HCT are better for patients with lower-risk MF, due to the high transplantation-related morbidity and mortality, treatment decisions regarding allogeneic HCT should be individualized.148,162,164 Allogeneic HCT should be considered for lower-risk MF in patients with refractory, transfusion-dependent anemia, circulating blast cells greater than 2% in peripheral blood, adverse cytogenetics, or molecular abnormalities.176 Evaluation for allogeneic HCT is recommended for patients with low platelet counts or complex cytogenetics.

Higher-Risk MF

Evaluation for allogeneic HCT is recommended for all patients with higher-risk MF and allogeneic HCT is recommended for patients who meet transplant eligibility criteria.162 The selection of patients for allogeneic HCT should be based on age, performance status, major comorbid conditions, psychosocial status, patient preference, and availability of caregiver(s).

Early referral to transplant is recommended for planning purposes. Bridging therapy can be used to decrease marrow blasts to an acceptable level prior to allogeneic HCT. The results of recent studies suggest that prior exposure to ruxolitinib may improve outcomes after allogeneic HCT.154,177179 The guidelines recommend continuation of JAK inhibitors near to the start of conditioning therapy for the improvement of splenomegaly and other disease-related symptoms.154,177,178 In a prospective phase II trial, 28 patients with MF were treated with ruxolitinib for at least 8 weeks prior to HCT and followed a taper schedule that ended 4 days before donor cell infusion.154 Twenty-three patients underwent myeloablative conditioning while the remaining 5 underwent RIC. After termination of treatment with ruxolitinib, cytokine release syndrome was not observed and engraftment was successful in all patients. Following transplant, the 2-year OS was 86% (95% CI, 61%–96%). Shanavas et al178 examined data from 100 patients with MF who were treated with JAK inhibitors prior to HCT. Sixty-six patients continued ruxolitinib therapy until transplant. Most of the observed symptoms were consistent with symptoms associated with MF and were mild or moderate. Two patients had a severe adverse occurrence and, as a result, HCT was delayed. Patients who displayed clinical improvement with the use of a JAK inhibitor also had more favorable outcomes posttransplant. At 2 years, the OS was 61% (95% CI, 49%–71%).

Similarly, a study by Chhabra et al177 reported that treatment with ruxolitinib and management of splenomegaly with splenic irradiation prior to transplant, along with fludarabine/busulfan-based conditioning, led to more favorable outcomes. At 3 years, the OS was 81.1% (95% CI, 64.4%–90.5%) and the RFS was 78.4% (95% CI, 61.4%–88.5%). Another study assessing the use of ruxolitinib prior to RIC and transplant in patients with MF found that treatment with ruxolitinib significantly reduced symptom burden.179 Patients did not experience significant side effects while tapering off ruxolitinib and HCT was not delayed.

Ruxolitinib,69,96,103105 fedratinib,72 or clinical trial are options for patients with higher-risk MF with platelet count ≥50 × 109/L who are not candidates for transplant. Ruxolitinib and fedratinib are category 1 recommendations. A study by Hernandez-Boluda et al180 reported that patients with severe thrombocytopenia (platelet count <50 × 109/L) were in a higher risk category and had more instances of anemia and leukopenia. Patients with platelet count <50 × 109/L experience a greater symptom burden and might benefit from symptomatically-guided treatment options.181

Pacritinib has demonstrated significant activity resulting in ≥35% spleen volume reductions and symptom improvement, even in patients with severe baseline cytopenias,74,75 and is an option for patients with higher-risk MF with platelet count <50 × 109/L who are not transplant candidates. Enrollment in an appropriate clinical trial should also be considered as an option for these patients. The use of ruxolitinib at a lower dose (5 mg twice daily) has shown some efficacy, resulting in some reductions in spleen volume and improvement in total symptom score even in patients with low platelet counts at baseline (50–100 × 109/L).182 While ruxolitinib could be considered in patients with symptomatic higher-risk disease with platelet count <50 × 109/L, it is not FDA-approved for this indication.

Management of Treatment-Related Anemia and Thrombocytopenia

In the COMFORT-I and COMFORT-II studies, anemia and thrombocytopenia were managed with dose modifications and RBC transfusions.69,96 Patients enrolled in the COMFORT trials were required to have a baseline platelet count ≥100 × 109/L, and the initial starting dose of ruxolitinib was dependent on the patient's baseline platelet counts.69,96 Preliminary results of a phase II study suggest that a lower initial dose of ruxolitinib (5 mg twice daily) with escalation to 10 mg twice a day may be appropriate in patients with baseline platelet count 50 to 100 × 109/L.182 In the dose-finding phase Ib EXPAND study, ruxolitinib was tolerated at a maximum safe starting dose of 10 mg twice daily in patients with MF with platelet count 50 to 74 × 109/L or 75 to 99 × 109/L.183 Patients with platelet count of 75 to 99 × 109/L displayed higher tolerability. At 48 weeks, 33.3% of patients with platelet count 75 to 99 × 109/L demonstrated a spleen response compared with 30% of patients with platelet count 50 to 74 × 109/L.

The guidelines recommend that the initial dosing of ruxolitinib should be based on the patient's baseline platelet counts (as described in the full prescribing information). However, certain clinical situations may support initiation of ruxolitinib at a lower dose (5 mg twice daily) with subsequent dose modifications based on CBC, which must be performed before initiating ruxolitinib and monitored every 2 to 4 weeks until the dose is stabilized, and then as clinically indicated.182,184 Dose modifications based on insufficient response includes increasing the dose as tolerated, at 4-week intervals, in 5 mg twice daily increments to a maximum of 10 mg twice daily (if platelet count <100 × 109/L) and 25 mg twice daily (if platelet count ≥100 × 109/L).185 See “Special Considerations for the Use of JAK Inhibitors: Ruxolitinib” (MPN-G 2 of 7, available at NCCN.org) for dose modifications for the management of hematologic toxicities.

Treatment Response Criteria

In 2006, the IWG-MRT first published the response criteria for MF, and the responses were categorized as CR, PR, clinical improvement, PD, stable disease, and relapse.186 In 2013, these response criteria were revised by IWG-MRT and European LeukemiaNet (ELN) to include MPN-SAF TSS as a quantifiable tool to assess changes in disease-related symptoms and stricter definitions of RBC transfusion dependency and independency.187 These response criteria were developed mainly for use in clinical trials.

In addition to CR, PR, and clinical improvement, three other response categories (anemia response, spleen response, and symptoms response) were included in the revised 2013 IWG-MRT and ELN response criteria to quantify treatment-induced improvements in symptom burden, particularly anemia, splenomegaly, and constitutional symptoms.187 The revised response criteria recommend that symptoms should be evaluated by the MPN-SAF TSS and that symptom response requires ≥50% reduction in the TSS.65 The revised 2013 IWG-MRT and ELN response criteria also require that a 35% or greater reduction in spleen volume should be confirmed by MRI or CT scan; volumetric imaging of the spleen is typically included in clinical trials to adjudicate this endpoint.187 In addition, a 35% or greater reduction in spleen volume by MRI or CT scan constitutes a spleen response regardless of that reported by physical examination. Additional criteria are also included for PD, stable disease, and relapse.

Morphologic response in bone marrow is required for CR. The criteria for PR require morphologic response in the peripheral blood (but not necessarily in the bone marrow). Patients meeting criteria for CR with inadequate blood count recovery are also included in the PR category to capture those patients who have achieved CR with persistent drug-induced cytopenia despite a morphologically normal bone marrow. The revised response criteria also include response categories for cytogenetic and molecular response. However, these are not required for CR assignment.

Monitoring Response and Follow-up Therapy

The goal of treatment is to reduce symptom burden and minimize the risk of leukemic transformation. Changes in symptom status could be a sign of disease progression. Therefore, change in symptom status should prompt evaluation of treatment efficacy and/or disease status. Evaluation of treatment efficacy should include CBC to assess normalization of blood counts, monitoring symptom status using MPN-SAF TSS, and monitoring spleen size either by palpation or imaging.187

The guidelines recommend monitoring response (anemia response, spleen response, and symptom response), signs, and symptoms of disease progression every 3 to 6 months during the course of treatment. Bone marrow aspirate and biopsy should be performed as clinically indicated (if supported by increased symptoms and signs of progression). Additional molecular testing using a multigene NGS panel to evaluate for HMR mutations associated with disease progression should be considered for patients with PMF and post-PV/ET MF.35,36

Continuation of JAK inhibitors is recommended for patients achieving response to initial treatment. In the COMFORT-I study, the majority of patients (91%) treated with ruxolitinib experienced significant improvements in individual MF-related symptoms (≥50% improvement in total symptom score as assessed by MF-SAF) and quality of life; most importantly, patients with a lesser degree of symptom improvement (<50% improvement in total symptom score) also achieved improvements over placebo on these measures and other patient-reported outcomes.66 The panel acknowledges that clinical benefit may not reach the threshold of the 2013 IWG-ELN Response Criteria (ie, symptom response requires ≥50% reduction in the MPN-SAF TSS) in patients receiving treatment with JAK inhibitors. Continuation of JAK inhibitors is recommended based on the discretion of the clinician, since a symptom response of <50%, as well as spleen volume reduction that does not meet the threshold of greater than 35% (reduction in palpable splenomegaly of <50%), may be clinically meaningful.

Ruxolitinib should be discontinued if there is no response or improvement of symptoms after 6 months. Gradually tapering the dose of ruxolitinib should be considered, when discontinuing or interrupting ruxolitinib for reasons other than thrombocytopenia or neutropenia. See “Special Considerations for the Use of JAK Inhibitors” in the algorithm (at NCCN.org). Disease-related symptoms may return to pretreatment levels over a period of approximately 1 week after discontinuation or interruption of ruxolitinib.188 Low platelet counts (at initiation or completion of therapy) and clonal evolution (acquisition of new mutations while on treatment with ruxolitinib) were associated with a significantly shorter survival after discontinuation of ruxolitinib.189 In a study that evaluated the outcomes of ruxolitinib discontinuation in patients with MF, after a median follow-up of 32 months, the median survival was 14 months among 42 patients who had molecular data at baseline; during follow-up, clonal evolution was seen in 14 patients (33%; ASXL1 mutation in 60% of patients).189 RBC transfusion dependence at baseline was the only clinical variable associated with clonal evolution; survival after discontinuation of ruxolitinib was 6 months for patients with clonal evolution compared with 16 months for those without clonal evolution. A population-based analysis of 290 patients with MF found that 50% of patients developed cytopenias after terminating treatment with ruxolitinib.190 The median OS after discontinuation was 11.1 months (95% CI, 8.4–14.5 months) and the median PFS was 6.0 months (95% CI, 4.4–8.3 months).

For patients with symptomatic lower-risk MF with no response or loss of response following initial treatment, an alternate option not used for initial treatment is recommended (clinical trial, ruxolitinib, peginterferon alfa-2a, or hydroxyurea [if cytoreduction would be symptomatically beneficial]). Pacritinib may also be considered for patients with platelet count <50 × 109/L.

For patients with higher-risk MF with platelet count ≥50 × 109/L who are not transplant candidates and with no response or loss of response after initial treatment, enrollment in a clinical trial or an alternate JAK inhibitor (ruxolitinib or fedratinib) not used before is recommended.73,135 Pacritinib may also be considered in patients with platelet count ≥50 × 109/L with one prior JAK inhibitor.75 Tapering and discontinuation of ruxolitinib according to the prescribing information is recommended prior to the initiation of fedratinib or another therapy.

JAK2 V617F Allele Burden

Reductions in JAK2 V617F allele burden have been seen in patients with MF with long-term fedratinib191 or ruxolitinib therapy.106,192 In the COMFORT-I study, a >50% reduction in JAK2 V617F allele burden was observed in 12% of patients (28 patients); 20 of these patients met the criteria for partial molecular response and 6 patients had JAK2 V617F allele burden values below the quantifiable limit, meeting the criteria for complete molecular response.192 The median times to partial and complete molecular response were 22 months and 28 months, respectively. JAK2 V617F allele burden reductions also correlated with spleen volume reductions. Achievement of JAK2 V617F negativity or JAK2 V617F allele burden reduction after allogeneic HCT has also been associated with a decreased incidence of relapse.193,194

However, at the present time, the utility of JAK2 V617F allele burden reduction as a predictor of treatment efficacy remains unclear. In the 2013 IWG-MRT and ELN response criteria, cytogenetic and molecular responses are not required for CR assignment.187 Therefore, measurement of the JAK2 V617F allele burden is not currently recommended for use in routine clinical practice to guide treatment decisions.

Management of MF-Associated Anemia

Anemia is considered a negative prognostic risk factor for survival in patients with MF.76 Symptomatic anemia is observed in more than 50% of patients at the time of diagnosis.195 It is essential to rule out and treat (if necessary) the most common causes of anemia (eg, bleeding, hemolysis, iron deficiency, vitamin B12, folic acid) before considering other treatment options.

Leuko-reduced RBC transfusion support is recommended for symptomatic anemia. EPO-stimulating agents (ESAs), danazol, luspatercept, and immunomodulatory agents (lenalidomide, thalidomide, and pomalidomide) have also been evaluated for the management of MF-associated anemia. Because MF can be fueled by increased transforming growth factor beta (TGF-β) signaling and anemia related to increased TGF-β can be alleviated by inhibition of TGF-β signaling,196 luspatercept has garnered significant attention in the MF field and is the subject of a randomized phase lll clinical trial for patients with RBC transfusion-dependent MF on JAK2 inhibitor therapy (ClinicalTrials.gov identifier: NCT04717414). Luspatercept-aamt was recently FDA approved for the treatment of anemia that requires two or more RBC transfusions over 8 weeks in adults with very low- to intermediate-risk myelodysplastic syndromes (MDS) with ring sideroblasts or with myelodysplastic/MPN with ring sideroblasts.197

The use of recombinant human EPO or darbepoetin alfa has resulted in anemia responses (transfusion independence with normal hemoglobin levels, sustained increase in hemoglobin levels [>2 g/dL] within 12 weeks, or >50% reduction in transfusion requirements within 12 weeks) in 45%–60% of patients with MF.198200 Lower serum EPO levels (<125 mU/mL), smaller spleen size, and low RBC transfusion requirements have been associated with favorable responses.

In a study of 50 patients with MF and anemia, danazol therapy resulted in an anemia response in 30% of patients, and responses were less frequent in patients with transfusion dependency (19% compared with 44% in patients without transfusion requirements).201 Prostate cancer screening and monitoring of liver function tests, as well as the use of concomitant medications such as statins, are recommended over concerns for increased risk of rhabdomyolysis in patients receiving danazol for the management of MF-associated anemia.

In the phase III MOMENTUM trial, patients with PMF or post-PV/ET MF with DIPSS intermediate-1, intermediate-2, or high-risk disease were randomized 2:1 to receive treatment with momelotinib, a JAK1/2 and ACVR1/ALK2 inhibitor, or danazol.202 The patients had anemia and had previously received treatment with a JAK inhibitor. Preliminary data showed that at 24 weeks, patients in the momelotinib arm had a higher total symptom score response rate (24.6% vs 9.2%; P=.0095), transfusion independence rate (30.8% vs 20.0%; P=.0064), and a spleen volume reduction of 35% or greater (23.1% vs 3.1%; P=.0006) compared with patients in the danazol arm. Thrombocytopenia and anemia were the most common grade 3 or higher treatment-emergent adverse events and were observed in 22% and 8%, respectively, of patients receiving momelotinib, and in 12% and 11%, respectively, in patients receiving danazol.

Thalidomide (in escalating daily doses of 100–800 mg) has demonstrated very minimal efficacy, resulting in anemia response rates of 0%–29%, and is also poorly tolerated.203209 A lower dose of thalidomide (50 mg/day), when used in combination with prednisone, is better tolerated, leading to improved anemia response rates (62%) compared with high-dose thalidomide monotherapy in the management of MF-associated symptomatic anemia (hemoglobin level <10 g/dL or symptomatic splenomegaly).210 Lenalidomide, alone or in combination with prednisone, has also shown modest efficacy in the management of MF-associated anemia, resulting in response rates of 19%–32% with myelosuppression being the most common grade 3 or higher hematologic toxicity.211214 Lenalidomide is more likely to induce better response rates in patients with isolated 5q deletion.215

In an analysis that reassessed the efficacy of thalidomide and lenalidomide in 125 patients with MF treated in 3 consecutive phase 2 trials, the combination of lenalidomide and prednisone was more effective and safer than single-agent thalidomide or lenalidomide.216 After a median follow-up of 42 months, the ORR was 38% for the combination of lenalidomide and prednisone compared with 34% and 16%, respectively, for lenalidomide and thalidomide. There was also a trend for a higher efficacy in patients receiving lenalidomide-based therapy (P=.06), and in a multivariate analysis the lenalidomide-based regimen was the only factor independently associated with a higher response rate.

Pomalidomide has also been evaluated as a treatment option for MF-associated anemia.217,218 In one phase II study, pomalidomide (with or without prednisone) resulted in similar response rates (39%) in patients with MF and anemia and/or thrombocytopenia and/or neutropenia, with a median response duration of 13 months.217 However, in another randomized study that evaluated pomalidomide in patients with MF and RBC transfusion dependence, the RBC transfusion independence response rates were similar for patients treated with pomalidomide and placebo.218

Studies evaluated the combination treatment of ruxolitinib with thalidomide or pomalidomide in patients with MF (ClinicalTrials.gov identifiers: NCT01644110 and NCT03069326).219,220 A response rate of 55% was obtained in a phase II study investigating the combination of ruxolitinib and lenalidomide in patients with PMF or post-PV/ET MF with anemia.221 However, a dose interruption was needed in 75% of patients due to toxicity and the study was terminated early due to lack of efficacy.

Enrollment in a clinical trial is recommended for all patients with MF-associated anemia. Additional treatment options for the management of MF-associated anemia are based on the serum EPO levels as described below.

Serum EPO Less Than 500 mU/mL

ESAs (epoetin alfa and darbepoetin alfa) are recommended for the treatment of MF-associated anemia in patients with serum EPO levels <500 mU/mL. An FDA-approved biosimilar is an appropriate substitute for epoetin alfa.

In the COMFORT-II study, anemia was managed with packed RBC transfusions.222 In a small number of patients (13 of 146 patients) who received both ruxolitinib and an ESA, the use of an ESA with ruxolitinib was well tolerated and did not impact the effectiveness of ruxolitinib. Another study that assessed the use of ESAs along with ruxolitinib (n=9) or the addition of ESAs after treatment with ruxolitinib for a median of 4 months (n=50) in patients with MF also showed that the concomitant use of an ESA with ruxolitinib was effective for the management of anemia in patients with MF.223 Fifty-four percent of patients achieved an anemia response (per IWG-MRT criteria) and, at 5 years, a response was observed in 76% of patients. Spleen reduction was reported in 78% of patients. These findings support the feasibility of administration of ESAs for the management of anemia in patients receiving ruxolitinib. The guidelines recommend continuation of JAK inhibitors (ruxolitinib, fedratinib, or pacritinib) for the improvement of splenomegaly and other disease-related symptoms.

ESAs are less effective for the management of transfusion-dependent anemia.224 Continuation of treatment with ESAs is recommended in patients achieving anemia response; those with no response or loss of response should be managed as described subsequently for patients with serum EPO levels ≥500 mU/mL.

Serum EPO 500 mU/mL or Greater

Danazol, immunomodulatory agents (lenalidomide or thalidomide) with or without prednisone (first as a combination followed by tapering of prednisone over 3 months), or luspatercept are useful in certain circumstances options and are recommended for the treatment of anemia in patients with serum EPO levels ≥500 mU/mL. Enrollment in a clinical trial is preferred. Luspatercept is a category 3 recommendation. A clinical trial of luspatercept is preferred, if available. Continuation of prior treatment is recommended in patients achieving anemia response, and those with no response or loss of response should be managed with another trial of treatment (clinical trial, danazol, immunomodulating agent [lenalidomide or thalidomide] with or without prednisone as described previously, or luspatercept) that has not been used before. These regimens are not FDA-approved for MF.

Disease Progression to Advanced Phase or Transformation to Acute Myeloid Leukemia

MF in accelerated phase (MF-AP) is characterized by the presence of ≥10% (10%–19%) blasts in the peripheral blood or bone marrow, platelets <50 × 109/L, and chromosome 17 aberrations.225 MF in blast phase (MF-BP) is defined by the presence of ≥20% myeloid blasts in either the bone marrow or peripheral blood.49,226

Patients with a blast percentage of 5%–9% in the peripheral blood or bone marrow and those with 10%–19% share similar clinical characteristics.227 In patients with <10% blasts in the peripheral blood or bone marrow, treatment with ruxolitinib improved survival.227,228 Patients with a blast percentage of ≥4% in the peripheral blood or ≥5% in the bone marrow have unfavorable outcomes. OS was not significantly different in patients with 5%–9% blasts in the peripheral blood or bone marrow and in patients with 10%–19% blasts (24 vs 13 months; P=.19).227 Similarly, OS was comparable in patients with 5%–9% blasts in the bone marrow and in patients with ≥10% blasts (22 vs 14 months; P=.73).228

The incidence of transformation to AML is significantly higher for patients with MF than for those with PV and ET, although the risk is very low in patients who remain in chronic phase MF.225,229 Among patients who present with chronic phase MF, development of accelerated phase features during follow-up was associated with short median survival times.225

Treatment with hydroxyurea has been associated with increased risk of transformation to AML in some studies.230,231 These findings, however, were not confirmed in subsequent reports.232234 In a large cohort analysis (n=11,039; 162 patients with transformation to AML/MDS) that evaluated treatment-related risk factors for transformation to AML/MDS in patients with MPN, the use of alkylating agents or a combination of two or more cytoreductive agents—but not treatment with hydroxyurea alone—was significantly associated with an increased risk of transformation to AML.232 The results of another large analysis (649 patients with PMF, post-PV MF, or post-ET MF) identified bone marrow blasts ≥10% and high-risk karyotypes as independent prognostic factors for the transformation to AML.234 Hydroxyurea, however, was not an independent risk factor for transformation to AML.

Mutations in several genes (ASXL1, EZH2, TP53, SRSF2, and IDH1 or IDH2) and other chromosomal abnormalities (eg, aberrations in chromosomes 1q and 9p) have been associated with transformation to AML.27,35,37,235 Molecular testing for AML-associated mutations is recommended as part of initial workup of patients with disease progression to advanced-phase MF or transformation to AML.

Treatment Options

In a retrospective analysis of 91 patients with MF that had transformed to AML, the median OS after transformation to AML was 3 months. Among patients who were treated with AML-type induction chemotherapy, reversal to chronic phase without an increase in the blast percentage occurred in 41% of patients.236 However, it was also associated with a treatment-related mortality rate of 33%. The median OS was 4 months, which was comparable to that observed in patients treated with supportive care or low-intensity chemotherapy (2 months and 3 months, respectively).

Hypomethylating agents (HMAs) (azacitidine or decitabine) have been evaluated in a few small studies as a treatment option for MPN that has transformed to AML.237239 In a small series of 11 patients with MF-BP/AML, decitabine was associated with improved survival in patients who were not eligible for allogeneic HCT.237 At a median follow-up of 9 months, 67% of the patients treated with decitabine were alive. In another series of 54 patients with MPN-BP/AML (21 patients with ET, 21 patients with PV, 7 patients with PMF, and 5 patients with unclassified MPN), first-line therapy with azacitidine resulted in an ORR of 52% (24% CR, 11% PR, 8% bone marrow CR or CR with incomplete recovery of cytopenias, and 9% hematologic improvement).238 The median duration of response and the median OS were 9 months and 11 months, respectively. In a retrospective analysis of 21 patients with MPN-BP/AML and 13 patients with MPN-AP treated with decitabine, the ORRs were 62% (8 of 13 patients) and 29% (6 of 21 patients), respectively, for patients with MPN-AP and MPN-BP/AML.239 The median OS was significantly higher in patients with disease that responded to decitabine (12 vs 5 months, respectively, for patients with MPN-AP; 11 vs 4 months, respectively, for patients with MPN-BP/AML).

In a small study of 21 patients with MPN-AP/BP, decitabine in combination with dose-escalated ruxolitinib resulted in an ORR (by protocol-defined criteria) of 53% (95% CI, 27.8%–77.0%) and a median OS of 7.9 months (95% CI, 4.1 months–not reached).240 The results of a phase II study with 25 patients with MPN-AP/BP demonstrated an ORR of 44% (95% CI, 24.4%–65.1%) and a median OS of 9.5 months (95% CI, 4.3–12.0 months) in patients treated with the combination of ruxolitinib and decitabine.241 A phase 1/2 trial investigating the combination of ruxolitinib and decitabine in patients with post-MPN AML reported an ORR of 45% in the intention-to-treat population and 61% in patients who received the recommended phase II dose.242 A phase II study (ClinicalTrials.gov identifier: NCT04282187) will examine the combination of decitabine with ruxolitinib or fedratinib in patients with accelerated/blast phase MPN prior to HCT. The role of venetoclax combinations has not yet been established in MPN-BP/AML.243

Allogeneic HCT remains the only curative option resulting in long-term disease control in selected transplant-eligible patients who achieve a CR to induction chemotherapy.244247 Early referral to transplant is recommended for planning purposes. Bridging therapy can be used to decrease marrow blasts to an acceptable level before transplant. In one retrospective analysis of 75 patients with MPN-BP, patients who were treated with curative intent (induction chemotherapy with or without allogeneic HCT) had significantly improved survival compared with those treated with noncurative intent (nonintensive chemotherapy or supportive care).246 The 2-year OS rates were 26% and 3%, respectively, and the median survival was 9 months and 2 months, respectively (P<.0001). Among patients treated with curative intent, the ORR to induction chemotherapy was 46% and reversal to chronic phase was observed in 31% of patients, with 17 patients undergoing allogeneic HCT. The OS rate was significantly higher for patients who underwent allogeneic HCT after induction chemotherapy (2-year OS rate was 47% compared with 15% for those who did not undergo allogeneic HCT; P=.03).246 In another retrospective analysis of 46 patients who received allogeneic HCT for MF-BP, the 3-year PFS and OS rates after transplant were 26% and 33%, respectively. The response status before transplant (CR vs no CR) was a significant predictor of OS (69% for CR vs 22% for no CR; P=.008) and PFS (55% and 19%, respectively; P=.02).247 The cumulative incidence of treatment-related mortality was 28% at 1 year and the absence of CR before allogeneic HCT was also associated with significantly increased treatment-related mortality (35% vs 0%; P=.053).

Treatment Recommendations Based on Eligibility for Transplant

The selection of patients for allogeneic HCT should be based on age, performance status, major comorbid conditions, psychosocial status, patient preference, and availability of caregiver(s). Patients may be taken immediately to transplant or bridging therapy can be used to decrease marrow blasts to an acceptable level prior to transplant.

Disease control/reduction in blast counts with HMAs (azacitidine or decitabine), with or without a JAK inhibitor (ruxolitinib, fedratinib, or pacritinib), or intensive AML-type induction chemotherapy, followed by allogeneic HCT is recommended for patients who are candidates for transplant.237,246,247 A clinical trial is also an option for these patients. Enrollment in a clinical trial or treatment with HMAs (azacitidine or decitabine), with or without a JAK inhibitor (ruxolitinib, fedratinib, or pacritinib), or low-intensity AML-type chemotherapy is recommended for those who are not candidates for transplant. AML-type induction chemotherapy regimens are generally used for the management of disease progression to advanced phase or transformation to AML. However, these regimens typically result in poor responses. Based on NGS panel results (eg, if NGS shows particular mutations such as IDH1, IDH2, or FLT3), low intensity or targeted therapy can be considered.248,249 HMAs (azacitidine or decitabine) can be used in combination with a JAK inhibitor (ruxolitinib, fedratinib, or pacritinib) for the palliation of splenomegaly or other disease-related symptoms.240,242 However, the panel notes that there are very limited data regarding the use of fedratinib or pacritinib with HMAs or targeted therapies. While the combination of an HMA and pacritinib has been evaluated in AML and CMML,250,251 the combination has not been evaluated in MPN-AP/BP. Ruxolitinib, fedratinib, or pacritinib may be continued near to the start of conditioning therapy for the improvement of splenomegaly and other disease-related symptoms in patients who are transplant candidates.154,177179

Supportive Care

Supportive care for disease-related symptoms should be an integral part of clinical management during the course of treatment. This should include assessment and monitoring of symptom status, counseling for identification, assessment, and management of cardiovascular risk factors (eg, smoking, diet, exercise, thrombotic and hemorrhagic risk factors).

Transfusion support should include platelet transfusions for thrombocytopenic bleeding or platelet count <10,000 mm3 and RBC transfusions for symptomatic anemia.252 The use of leukocyte-reduced blood products is recommended in transplant candidates to prevent HLA alloimmunization and reduce the risk of cytomegalovirus transmission. Antifibrinolytic agents should be considered for bleeding that is refractory to transfusions. Iron chelation could be considered for patients who have received more than 20 transfusions and/or ferritin greater than 2,500 ng/mL in patients with lower-risk disease. However, the role of iron chelation remains unclear.

Specific warnings and precautions regarding serious bacterial, mycobacterial, fungal, and viral infections, including herpes zoster and John Cunningham virus, which is the causative agent of progressive multifocal leukoencephalopathy, have been reported in patients receiving ruxolitinib and are described in recently updated prescribing information.185 Patients should be monitored for signs and symptoms of infections. Serious infections should be resolved before the start of ruxolitinib. Antibiotic prophylaxis and vaccinations for recurrent infections are recommended as outlined in the NCCN Guidelines for the Prevention and Treatment of Cancer-Related Infections (available at NCCN.org). A recombinant (killed) zoster vaccine may be considered for patients on, or prior to, treatment with a JAK inhibitor. In patients who have had a splenectomy, antibiotic prophylaxis should be given per the Infectious Diseases Society of America Guidelines. Growth factor support (granulocyte colony-stimulating factor [G-CSF] or granulocyte-macrophage colony-stimulating factor [GM-CSF]) should be considered for recurrent infections with neutropenia. However, these should be used with caution in patients with an enlarged spleen since the use of G-CSF or GM-CSF has been associated with splenic rupture.253 Cytoreductive therapy (eg, hydroxyurea) could be considered for the management of hyperproliferative manifestations of PMF (thrombocytosis or leukocytosis).175 Prophylaxis for tumor lysis syndrome should be considered for patients undergoing induction chemotherapy for advanced-stage MF or disease progression to AML (See NCCN Guidelines for Acute Myeloid Leukemia, available at NCCN.org).

Summary

MPN are characterized by a significant symptom burden and a propensity for disease transformation to accelerated and blast phases. The goal of treatment is to reduce symptom burden and the risk of developing thrombotic and hemorrhagic complications. Regular monitoring of disease-related symptoms, assessment of need for cytoreductive therapy, and appropriate evaluation to rule out disease progression should be an integral part of management of patients with MPN.

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