Residency · Residency · Hematology Thrombosis

Myeloproliferative Neoplasms - PV, ET, and Myelofibrosis

Introduction

The classical BCR-ABL1-negative myeloproliferative neoplasms encompass polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). These are clonal stem cell disorders driven by constitutive activation of the JAK-STAT signaling pathway. Three canonical driver mutations, JAK2, CALR, and MPL, account for approximately 90% of MPNs. The natural history of these diseases is characterized by thrombotic and hemorrhagic complications, and they carry a variable risk of transformation to myelofibrosis or acute leukemia.

Molecular Pathogenesis

Driver Mutations

The JAK2 V617F mutation is a gain-of-function point mutation in exon 14 that results in constitutive activation of the JAK-STAT signaling cascade. It is present in approximately 97% of PV cases, 55 to 60% of ET cases, and 55 to 65% of PMF cases. JAK2 exon 12 mutations account for approximately 3% of PV and are characteristically associated with isolated erythrocytosis in younger patients.

CALR (calreticulin) mutations are frameshift mutations in exon 9, with two principal variants: type 1 (a 52-base pair deletion, more commonly found in myelofibrosis) and type 2 (a 5-base pair insertion, more commonly found in ET). CALR mutations are present in approximately 25 to 30% of both ET and PMF cases. Notably, CALR-mutated myelofibrosis, particularly with type 1 mutations, carries a better prognosis than JAK2- or MPL-mutated disease.

MPL (thrombopoietin receptor) mutations, most commonly W515L and W515K, are found in approximately 3 to 5% of ET and 5 to 10% of PMF cases. Triple-negative disease, defined by the absence of JAK2, CALR, and MPL mutations, accounts for 10 to 15% of ET and 5 to 10% of PMF. These patients may harbor non-canonical JAK-STAT pathway mutations and carry a higher risk of leukemic transformation.

Additional Mutations (Prognostic Impact)

High molecular risk (HMR) mutations include ASXL1, EZH2, SRSF2, IDH1/2, and U2AF1 Q157. The presence of one or more of these mutations confers an adverse prognosis in myelofibrosis. ASXL1 is the most clinically impactful adverse mutation, present in approximately 20 to 35% of MF patients. TP53 mutations are associated with leukemic transformation. TET2 and DNMT3A mutations are epigenetic regulators that are common across MPNs and contribute to clonal expansion.

Polycythemia Vera (PV)

Diagnosis (WHO 2022)

The WHO 2022 diagnostic criteria for PV include three major criteria: hemoglobin above 16.5 g/dL in males or above 16 g/dL in females, or hematocrit above 49% in males or above 48% in females, or an increased red cell mass; bone marrow biopsy showing hypercellularity with trilineage proliferation (panmyelosis) including prominent erythroid, granulocytic, and megakaryocytic expansion with pleomorphic mature megakaryocytes; and the presence of JAK2 V617F or JAK2 exon 12 mutation. The minor criterion is a subnormal serum erythropoietin level. Diagnosis requires all three major criteria, or the first two major criteria plus the minor criterion. The 2022 hemoglobin and hematocrit thresholds are lower than historical criteria, reflecting the intent to detect early or masked PV that might otherwise be missed.

Clinical Features

Erythrocytosis leads to hyperviscosity, manifesting as headache, dizziness, visual changes, tinnitus, and the plethoric facial appearance characteristic of PV. Aquagenic pruritus, occurring after bathing, is a distinctive symptom mediated by histamine release from increased basophils and mast cells. Splenomegaly is present in approximately 70% of patients, and hepatomegaly is common. Thrombosis is the major risk of PV, with arterial thrombosis more common than venous, and includes Budd-Chiari syndrome, portal vein thrombosis, stroke, and myocardial infarction. Hemorrhagic complications occur particularly when platelet counts exceed 1,000,000 per microliter, due to acquired von Willebrand syndrome. Constitutional symptoms including fatigue, night sweats, and weight loss are common and contribute significantly to disease burden.

Risk Stratification for Thrombosis

Risk stratification for thrombosis in PV divides patients into two groups. Low-risk patients are those younger than 60 years with no prior history of thrombosis. High-risk patients are those aged 60 or older or those with a prior thrombotic event.

Treatment

All patients with PV require phlebotomy to maintain a target hematocrit below 45%, as established by the CYTO-PV trial, which demonstrated that a hematocrit target below 45% was associated with markedly reduced thrombotic events compared to a target of 45 to 50%. Low-dose aspirin at 81 mg daily is indicated for all patients based on the ECLAP trial, which demonstrated a reduction in thrombotic events without increased major bleeding.

High-risk patients require the addition of cytoreductive therapy. Hydroxyurea is the standard first-line cytoreductive agent, initiated at 500 to 1000 mg daily and titrated to achieve hematocrit, white blood cell count, and platelet count targets. Interferon-alfa, specifically ropeginterferon alfa-2b (Besremi), is an important first-line alternative, particularly for patients younger than 60 years. Unlike hydroxyurea, interferon-alfa can induce molecular responses by reducing the JAK2 V617F allele burden, raising the possibility of genuine disease modification. The PROUD-PV and CONTINUATION-PV trials demonstrated that ropeginterferon was non-inferior to hydroxyurea with deeper molecular responses at 5 years of follow-up. Ropeginterferon is FDA-approved for PV at a starting dose of 100 mcg subcutaneously every 2 weeks, titrated to 250 to 500 mcg every 2 weeks. Ruxolitinib, a JAK1/2 inhibitor, is the standard second-line option for hydroxyurea-resistant or hydroxyurea-intolerant PV, based on the RESPONSE trial, which demonstrated that 60% of patients achieved hematocrit control compared to 20% with best available therapy, along with improvements in splenomegaly and symptom burden.

Aspirin at low-dose 81 mg daily is indicated for all patients unless contraindicated. Twice-daily aspirin dosing may be considered for patients with refractory microvascular symptoms, supported by some evidence of improved symptom control.

<image>A treatment algorithm for polycythemia vera. Start with "Confirmed PV (JAK2 V617F or exon 12)." First step: ALL patients → phlebotomy (target Hct <45% per CYTO-PV) + aspirin 81 mg daily. Second step: risk stratify → Low risk (age <60, no thrombosis history): phlebotomy + aspirin alone. High risk (age ≥60 OR prior thrombosis): add cytoreduction. Show two first-line cytoreduction options: Hydroxyurea (500-1000 mg daily, titrate) and Ropeginterferon alfa-2b (especially if <60, pregnancy desired, or disease modification goal). If resistant/intolerant to hydroxyurea → Ruxolitinib (RESPONSE trial: 60% Hct control). Include EHA criteria for hydroxyurea resistance/intolerance in a sidebar. Show monitoring parameters: CBC q1-3 months, JAK2 allele burden (if on IFN). Clean clinical algorithm with decision diamonds and treatment boxes.</image>

Essential Thrombocythemia (ET)

Diagnosis (WHO 2022)

The WHO 2022 diagnostic criteria for ET require a sustained platelet count of 450,000 per microliter or greater. Bone marrow biopsy demonstrates megakaryocyte proliferation with large, mature, hyperlobated megakaryocytes without significant granulocyte or erythroid proliferation. The disease must not meet criteria for PV, PMF, CML, MDS, or other myeloid neoplasms. A JAK2 V617F, CALR, or MPL mutation should be present; in the absence of these driver mutations, the diagnosis requires exclusion of reactive thrombocytosis.

Risk Stratification (IPSET-Thrombosis Revised)

The revised International Prognostic Score for Essential Thrombocythemia (IPSET-Thrombosis) stratifies patients into four risk categories. Very low-risk patients are those younger than 60 with no thrombosis history and JAK2 wild-type status. Low-risk patients are younger than 60 with no thrombosis but are JAK2 V617F-positive. Intermediate-risk patients are aged 60 or older with no thrombosis and JAK2 wild-type. High-risk patients are those aged 60 or older with JAK2 V617F positivity or those of any age with prior thrombosis.

Treatment

Very low-risk patients require observation only; aspirin is not routinely recommended, as there are insufficient data demonstrating benefit, and there is a potential bleeding risk with extreme thrombocytosis. Low-risk patients receive aspirin at 81 mg daily. Intermediate-risk patients receive aspirin, with cytoreduction considered on an individualized basis depending on cardiovascular risk factors. High-risk patients require aspirin plus cytoreduction.

Hydroxyurea is the first-line cytoreductive agent, with benefit confirmed in the PT-1 trial. Anagrelide is an alternative that reduces platelet counts through megakaryocyte inhibition; however, the ANAHYDRET and PT-1 trials suggest a greater risk of arterial thrombosis and myelofibrosis transformation compared to hydroxyurea, relegating anagrelide to second-line status. Interferon-alfa (pegylated formulation) is a first-line alternative that is particularly preferred in young patients and during pregnancy. For patients with extreme thrombocytosis exceeding 1,000,000 to 1,500,000 per microliter, VWF activity and antigen levels along with ristocetin cofactor should be checked, as acquired von Willebrand disease may be present. In such cases, aspirin should be withheld until the platelet count is reduced to avoid paradoxical bleeding.

Primary Myelofibrosis (PMF)

Diagnosis (WHO 2022)

The WHO 2022 diagnostic criteria for PMF include major criteria of megakaryocyte proliferation with atypia accompanied by reticulin or collagen fibrosis (grade 2 or greater), the presence of a JAK2, CALR, or MPL mutation (or other clonal marker), and not meeting criteria for other myeloid neoplasms. Minor criteria include anemia not attributable to comorbid conditions, leukocytosis of 11,000 or greater, palpable splenomegaly, elevated LDH, and a leukoerythroblastic blood smear. Pre-fibrotic myelofibrosis is characterized by megakaryocyte atypia without significant fibrosis (MF-0 to MF-1) and often presents with thrombocytosis. While its prognosis is better than overt myelofibrosis, it is worse than essential thrombocythemia.

Clinical Features

Splenomegaly, which is often massive, results from sequestration and extramedullary hematopoiesis and is the clinical hallmark of myelofibrosis. Constitutional symptoms are prominent and include profound fatigue, night sweats, weight loss, fevers, bone pain, and early satiety from splenic compression. Cytopenias are common, with anemia being the most prevalent; white blood cell and platelet counts are variable. The peripheral blood smear is characteristically leukoerythroblastic, demonstrating nucleated red blood cells, teardrop cells (dacrocytes), and immature myeloid cells. Extramedullary hematopoiesis may occur in the spleen, liver, lungs, peritoneum, and other sites. Thrombotic and hemorrhagic complications reflect the disordered hematopoiesis and hemostasis. Transformation to acute myeloid leukemia occurs in 15 to 20% of patients at 10 years.

Risk Stratification

The DIPSS-Plus scoring system incorporates age above 65, constitutional symptoms, hemoglobin below 10 g/dL, white blood cell count above 25,000, peripheral blood blasts of 1% or greater, platelet count below 100,000, transfusion dependence, and unfavorable karyotype (including complex karyotype, trisomy 8, monosomy 7 or del(7q), inv(3), i(17q), and monosomy 5 or del(5q)). The MIPSS70+ (Mutation-enhanced International Prognostic Scoring System) integrates molecular data, including high molecular risk mutations and CALR type 1 status, with clinical variables and provides more accurate prognostication for transplant decision-making. The GIPSS (Genetically Inspired Prognostic Scoring System) relies exclusively on cytogenetics and mutations and offers a simplified tool for transplant-eligible patients.

Treatment

Symptomatic/Splenomegaly Management

Ruxolitinib (Jakafi) is a JAK1/2 inhibitor that forms the backbone of symptomatic therapy for myelofibrosis. The COMFORT-I and COMFORT-II trials demonstrated that ruxolitinib achieved a 50% or greater reduction in spleen volume in 42% of patients compared to 1% with placebo, along with significant symptom improvement. Long-term follow-up has suggested an overall survival benefit. Dosing is based on platelet count: 20 mg twice daily for platelets above 200,000, 15 mg twice daily for platelets between 100,000 and 200,000, and 5 mg twice daily for platelets between 50,000 and 100,000. Key toxicities include anemia (often dose-limiting), thrombocytopenia, and infections including tuberculosis reactivation, progressive multifocal leukoencephalopathy, and herpes zoster reactivation. A critical safety consideration is the ruxolitinib discontinuation syndrome: abrupt cessation can cause an acute relapse of symptoms, splenomegaly, cytopenias, and hemodynamic instability. The drug should be tapered over 7 to 10 days.

Fedratinib (Inrebic) is a JAK2-selective inhibitor that demonstrated spleen and symptom responses similar to ruxolitinib in the JAKARTA trial. It carries a risk of Wernicke encephalopathy due to thiamine depletion, and thiamine levels must be monitored. Fedratinib is used primarily as second-line therapy after ruxolitinib failure.

Pacritinib (Vonjo) is a JAK2/IRAK1 inhibitor evaluated in the PERSIST-2 trial. It is specifically indicated for myelofibrosis with platelets below 50,000, a setting where ruxolitinib cannot be safely dosed. Pacritinib is administered at 200 mg twice daily; gastrointestinal toxicity is common.

Momelotinib (Ojjaara) is a JAK1/2 and ACVR1 inhibitor evaluated in the MOMENTUM trial. Its unique therapeutic advantage is improvement in anemia through ACVR1 inhibition, which reduces hepcidin levels and thereby improves iron availability for erythropoiesis. Momelotinib is approved for myelofibrosis with anemia and may reduce transfusion burden while simultaneously controlling splenomegaly and symptoms.

Anemia Management

Anemia in myelofibrosis is managed with transfusion support and erythropoietin-stimulating agents when the endogenous erythropoietin level is below 500 mU/mL. Danazol at 200 to 600 mg daily achieves an anemia response in approximately 30% of patients. Luspatercept was evaluated in the INDEPENDENCE trial for myelofibrosis-associated anemia, produced positive results, and has received FDA approval for this indication. Momelotinib, as described above, also addresses the anemia component of myelofibrosis.

Curative Intent

Allogeneic hematopoietic stem cell transplantation is the only curative therapy for myelofibrosis. Transplant should be considered for patients with DIPSS intermediate-2 or high-risk disease, or intermediate-1 risk with high-risk features such as HMR mutations or transfusion dependence. Reduced-intensity conditioning is preferred, and 5-year overall survival rates are approximately 50 to 60%. The MIPSS70+ v2.0 score guides transplant decision-making, with a score of 4 or higher favoring transplantation. For patients receiving ruxolitinib as a bridge to transplant, the drug must be tapered gradually and should never be abruptly discontinued before conditioning.

Key Clinical Pearls

• Phlebotomy target of Hct <45% applies to ALL PV patients (CYTO-PV); Hct 45-50% has significantly higher thrombotic risk
• Ropeginterferon alfa-2b can induce molecular responses in PV (reduce JAK2 V617F burden); it is disease-modifying, unlike hydroxyurea
• CALR type 1 mutation in MF confers the best prognosis; triple-negative MF has the worst
• Ruxolitinib withdrawal must be gradual (7-10 day taper); abrupt discontinuation can cause life-threatening inflammatory rebound
• Pacritinib is the only JAK inhibitor safely used with platelets <50,000; essential for cytopenic MF
• Momelotinib uniquely addresses both splenomegaly and anemia in MF through dual JAK/ACVR1 inhibition
• Acquired von Willebrand syndrome occurs with extreme thrombocytosis (>1,000,000-1,500,000); check VWF activity before starting aspirin

References

1. Tefferi A. Primary myelofibrosis: 2023 update on diagnosis, risk-stratification, and management. Am J Hematol. 2023;98(5):801-821.
2. Vannucchi AM, et al. Ruxolitinib versus standard therapy for the treatment of polycythemia vera (RESPONSE). N Engl J Med. 2015;372(5):426-435.
3. Gisslinger H, et al. Ropeginterferon alfa-2b versus standard therapy for polycythemia vera (PROUD-PV/CONTINUATION-PV). Lancet Haematol. 2020;7(3):e196-e208.
4. Verstovsek S, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis (COMFORT-I). N Engl J Med. 2012;366(9):799-807.
5. Oh ST, et al. Momelotinib vs danazol in patients with myelofibrosis and anaemia (MOMENTUM). Lancet. 2023;401(10373):269-280.

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