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Myeloproliferative neoplasms (MPNs)

Malignant Hematology·MPN·2026
Myeloproliferative Neoplasms (MPNs)

Overview

  • Definition: clonal hematopoietic stem-cell disorders with effective proliferation of one or more myeloid lineages (RBC, WBC, platelet) driven by activated tyrosine kinase signaling, with preservation of relatively normal terminal maturation and increased peripheral blood counts.
  • Classic Philadelphia-negative MPNs: polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF), with variable risk of thrombosis, bleeding, and fibrotic/blastic transformation.
  • Philadelphia-positive: CML (see separate note). Other: chronic neutrophilic leukemia, chronic eosinophilic leukemia, MDS/MPN overlap (separate category): CMML, aCML (WHO5: MDS/MPN with neutrophilia), MDS/MPN-RS-T (WHO5: MDS/MPN-SF3B1-T), MDS/MPN-U (WHO5: MDS/MPN-NOS).
  • Pathophysiology: constitutive activation of JAK-STAT signaling produces cytokine-independent myeloid proliferation. JAK2 V617F lies in the pseudokinase domain and causes autoactivation.

At a glance: PV, ET and PMF

BCR::ABL1-negative MPNs: diagnosis, risk and managementWHO 2022 / ICC 2022 criteria; NCCN and ELN risk
EntityDiagnosisRiskManagement
PVPolycythemia vera Median OS ~14 yr (~24 yr if age <60)
JAK2 ~97%CALR 0MPL 0
 Major
  1. Hb >16.5 g/dL (M) / >16.0 (F), or Hct >49% / >48%
  2. Marrow: hypercellular, trilineage growth (panmyelosis), pleomorphic mature megakaryocytes
  3. JAK2 V617F or JAK2 exon 12 mutation
Minor
  1. Subnormal serum EPO
Diagnosis: all 3 major, or major 1 + 2 plus the minor criterion Check EPO and exclude secondary erythrocytosis: hypoxia (COPD, OSA, altitude, smoking), testosterone, SGLT2 inhibitors, EPO-secreting tumors (RCC, HCC). Chuvash (VHL) polycythemia: EPO normal or high. Suspect post-PV MF when phlebotomy needs fall, Hb drops, spleen enlarges, symptoms and LDH rise. 		LowAge <60 and no thrombosis history

All patients: phlebotomy to Hct <45% (CYTO-PV) + aspirin 81 mg daily (BID if refractory vasomotor symptoms); treat CV risk factors.

Anticoagulate for active thrombosis.

Cytoreduce even when low risk if: poor tolerance or frequent need for phlebotomy, symptomatic or progressive splenomegaly, PLT >1,500 or acquired VWD, progressive leukocytosis, or severe symptom burden. Ropeginterferon is an option in low-risk PV.
HighAge ≥60 or prior thrombosis

Phlebotomy + aspirin + cytoreduction:

  • Hydroxyurea: first line
  • Interferon (peginterferon alfa-2a): preferred if young or pregnant (most pregnancy data); ropeginterferon lowers JAK2 allele burden but has limited pregnancy evidence
  • Ruxolitinib: HU resistance or intolerance, especially with splenomegaly or pruritus (RESPONSE)
  • Rusfertide (Mimrylo): weekly SC hepcidin mimetic for erythrocytosis, added to standard care; clinical response (no phlebotomy eligibility or phlebotomy) weeks 20 to 32: 76.9% vs 32.9% (VERIFY)FDA Aug 2026
ETEssential thrombocythemia Median OS ~20 yr ~10% to MF, <5% to AML
JAK2 50 to 60%CALR 20 to 25%MPL 3 to 5%Triple neg ~10 to 15%
 Major
  1. PLT ≥450 ×109/L
  2. Marrow: megakaryocyte proliferation, large mature hyperlobulated forms
  3. Not meeting criteria for CML, PV, PMF, MDS or other myeloid neoplasm
  4. JAK2, CALR or MPL mutation
Minor
  1. Other clonal marker, or no evidence of reactive thrombocytosis
Diagnosis: all 4 major, or major 1 to 3 plus the minor criterion Exclude reactive thrombocytosis: iron deficiency, infection or inflammation, asplenia, malignancy. PLT >1,000: check for acquired VWD (VWF ristocetin cofactor activity) before aspirin. Higher bleeding risk in CALR-mutated ET (higher platelets, acquired VWD; lower thrombosis risk). Prefibrotic PMF mimics ET: marrow biopsy is required. 		Very lowAge ≤60, JAK2 wild type, no thrombosis

Observation. Aspirin only if CV risk factors or vasomotor symptoms (avoid if acquired VWD).
LowAge ≤60, JAK2 mutated, no thrombosis

Aspirin 81 mg daily (BID if CV risk factors, if no bleeding). No cytoreduction.
IntermediateAge >60, JAK2 wild type, no thrombosis

Aspirin 81 mg daily if no bleeding. Consider cytoreduction for PLT >1,000 to 1,500, acquired VWD, or symptoms.
HighThrombosis at any age, or age >60 + JAK2 mutated

Cytoreduction + aspirin (anticoagulate if venous thrombosis):

  • Hydroxyurea: first line (PT-1: HU + aspirin beat anagrelide + aspirin)
  • Ropeginterferon alfa-2b: any genotype, including first line; superior durable response vs anagrelide (SURPASS-ET)FDA Aug 2026
  • Interferon: preferred in pregnancy and young patients
  • Anagrelide: second line; PDE3 inhibitor; more arterial thrombosis, bleeding and marrow fibrosis; palpitations, cardiomyopathy
No ruxolitinib in ET (not approved; MAJIC-ET showed no response benefit over best available therapy).
PMFPrimary myelofibrosis Median OS ~6 yr (wide range by risk) ~10 to 20% to AML at 10 yr
JAK2 50 to 60%CALR 25 to 30%MPL 5 to 10%Triple neg ~5 to 10%
 Major
  1. Megakaryocyte proliferation and atypia with reticulin or collagen fibrosis grade ≥2
  2. JAK2, CALR or MPL, or another clonal marker (ASXL1, EZH2, IDH1/2, SRSF2, SF3B1), or no reactive fibrosis
  3. Not meeting criteria for another myeloid neoplasm
Minor (≥1, confirmed twice)
  1. Anemia not due to another condition
  2. WBC ≥11 ×109/L
  3. Palpable splenomegaly
  4. LDH above ULN
  5. Leukoerythroblastosis
Diagnosis: all 3 major plus ≥1 minor Fibrosis grade <2 = prefibrotic PMF. Post-PV and post-ET MF are separate entities (MYSEC-PM for prognosis). 		DIPSS-plus
DIPSS int-1 / int-2 / high1 / 2 / 3
PLT <100 ×109/L1
RBC transfusion need1
Unfavorable karyotype*1
DIPSS: Hb <10 = 2; age >65, WBC >25, blood blasts ≥1%, constitutional symptoms = 1 each (0 low; 1 to 2 int-1; 3 to 4 int-2; 5 to 6 high) Lower riskLow: 0 pts (mOS 15.4 yr)
Int-1: 1 pt (mOS 6.5 yr)
  • Asymptomatic: observation (especially CALR mutated)
  • Anemia: ESA if EPO <500; danazol; momelotinib (anemia benefit); lenalidomide or thalidomide ± prednisone, especially del(5q)
  • Symptoms or splenomegaly: ruxolitinib, or hydroxyurea
Luspatercept for MF anemia missed its primary endpoint (INDEPENDENCE); not approved in MF.
Higher riskInt-2: 2 to 3 pts (mOS 2.9 yr)
High: ≥4 pts (mOS 1.3 yr) MIPSS70+ v2.0 adds high-risk mutations (ASXL1, SRSF2, EZH2, IDH1/2, U2AF1 Q157); CALR type 1 favorable.

Evaluate for alloHCT (only curative option).

JAK inhibitor by platelet count and anemia:

  • PLT ≥50: ruxolitinib (cytopenias, zoster and TB, withdrawal syndrome: taper) or fedratinib (Wernicke encephalopathy: check and replace thiamine)
  • PLT <50: pacritinib (JAK2/FLT3/IRAK1; diarrhea, bleeding, QT)
  • Anemia dominant: momelotinib (ACVR1 inhibition lowers hepcidin)

Splenic RT for refractory splenomegaly or extramedullary hematopoiesis.

Investigational: pelabresib, imetelstat, navtemadlin (navitoclax MF development discontinued).
All MPNs can progress: marrow or blood blasts 10 to 19% = accelerated phase; ≥20% = blast phase (secondary AML, poor prognosis).
*Unfavorable karyotype: complex, or 1 to 2 abnormalities including +8, −7/7q−, i(17q), inv(3), −5/5q−, 12p−, 11q23 rearrangement. Survival figures: Mayo cohorts (Tefferi 2014; Gangat 2011).
JAK2CALRMPLTriple negative

General Features

  • Growth factor hypersensitivity: demonstrable in vitro colony assays (endogenous/cytokine-independent colonies).
  • Epidemiology: collective incidence approx. 2 to 3/100,000/year (PV ~0.8, ET ~1.0, PMF ~0.5); peak frequency in the 5th to 7th decades of life.
  • Bone marrow: HYPERCELLULARITY with megakaryocyte hyperplasia or dysplasia.
  • Clinical hallmarks: thrombotic/bleeding diathesis; splenomegaly and hepatomegaly; extramedullary hematopoiesis.
  • Natural history: spontaneous transformation to myelofibrosis and/or acute myeloid leukemia (AML), especially myelofibrosis.

Driver Mutations & Prevalence

  • JAK2 V617F: PV ~95%, ET ~50 to 60%, PMF ~50 to 60%; somatic gain-of-function in exon 14.
  • JAK2 exon 12: ~3% of PV (often JAK2 V617F-negative PV); isolated erythrocytosis without ↑ WBC/platelets.
  • CALR (calreticulin), exon 9: ET ~20 to 25%, PMF ~25 to 30%; type 1 (52-bp deletion) and type 2 (5-bp insertion). Type 1 confers better prognosis in PMF; CALR is thought to mediate MPL (thrombopoietin receptor) activation via novel binding.
  • MPL W515L/K: ET ~3 to 5%, PMF ~5 to 10%; thrombopoietin receptor.
  • Triple-negative (no JAK2/CALR/MPL): ~10 to 15% ET, ~5 to 10% PMF, worse prognosis in PMF (often carry other adverse mutations).
  • High-molecular-risk (HMR) mutations in PMF: ASXL1, EZH2, SRSF2, IDH1/2 (MIPSS70 and MIPSS70-plus); MIPSS70-plus v2.0 adds U2AF1 Q157. Confer worse prognosis. Used in MIPSS70 and MIPSS70-plus scoring.
  • Clonal hierarchy: MPN driver mutations may be preceded by CHIP-like clones; HMR mutations confer worse prognosis especially in PMF.

JAK2 Structure-Function

  • The mutation occurs in JH2 (the pseudokinase domain), which normally exerts negative regulation over JH1 (the kinase domain). Loss of this autoinhibition results in constitutive JAK-STAT activation.

Calreticulin (CALR) Biology

  • Endoplasmic reticulum (ER) resident protein; provides quality control of protein folding (chaperone function) and binds/stores Ca2+.
  • Mutations occur as heterozygous insertions and/or deletions in exon 9.
  • ALL mutations cause a +1 bp frameshift leading to a novel C-terminal peptide.
  • CALR can be detected by IHC.

Other (Non-driver) Mutations

  • While JAK2, CALR, and MPL are the driver events, mutations in other genes, particularly TET2, ASXL1, and DNMT3A, are found in over half of MPN patients.
  • Less common: splicing regulators (SRSF2, SF3B1, U2AF1, ZRSR2) and other regulators of chromatin/epigenetics/signaling (EZH2, IDH1, IDH2, CBL, KRAS, NRAS, STAG2, TP53).
  • These additional mutations are more frequent in PMF and advanced disease than in PV/ET, and several correlate with poorer prognosis (EZH2, IDH1, IDH2, SRSF2, U2AF1, and ASXL1 in PMF).

WHO 2022 Diagnostic Highlights

  • PV: Hb >16.5 (M) / 16.0 (F) g/dL or Hct >49% (M) / 48% (F); BM hypercellularity with trilineage proliferation; JAK2 mutation. Subnormal serum EPO supportive (minor criterion).
  • ET: platelets ≥450K, BM with megakaryocyte proliferation (large/mature), exclusion of other MPN/MDS, JAK2/CALR/MPL or other clonality; rule out reactive thrombocytosis.
  • PMF: prefibrotic (overt megakaryocytic atypia, no/minimal fibrosis) vs overt (MF-2/3 reticulin/collagen fibrosis, leukoerythroblastic, splenomegaly); WHO 2022 retained both stages.

Common Themes Across MPNs

  • Thrombosis: arterial > venous (especially in PV/ET); ~20% have thrombosis at or before diagnosis; splanchnic vein thrombosis (Budd-Chiari, portal vein), always work up for occult MPN even with a normal CBC (JAK2 testing).
  • Hemorrhage: especially with extreme thrombocytosis (>1000K) due to acquired von Willebrand syndrome (large vWF multimers cleaved).
  • Pruritus (PV, aquagenic), erythromelalgia, splenomegaly, fatigue, B symptoms, cytopenias (especially in MF).
  • Transformation: to MF (post-PV/post-ET MF) and to AML (~5 to 20% over 10 to 20 years depending on MPN type and risk factors).
  • Risk stratification: thrombosis risk for PV (age ≥60 or prior thrombosis = high risk; conventional criteria only); for ET (IPSET-thrombosis adds JAK2+); for PMF (DIPSS, DIPSS-plus, MIPSS70, MIPSS70-plus Version 2.0, GIPSS).

Treatment Strategies

  • PV: phlebotomy to Hct <45%, low-dose aspirin; cytoreduction (hydroxyurea, ropeginterferon, ruxolitinib if HU-intolerant) for high-risk disease.
  • ET: aspirin (CV risk-based); cytoreduction (HU, anagrelide [PT-1 trial, HU plus aspirin superior to anagrelide plus aspirin], pegylated interferon).
  • PMF: 4 FDA-approved JAK inhibitors, ruxolitinib (1L, 2011), fedratinib (post-rux or 1L, 2019), pacritinib (platelets <50k, 2022), momelotinib (anemia, 2023). Allo-HSCT for fit patients with DIPSS-plus int-2/high or MIPSS70-plus high/very-high.
  • Pegylated interferon / ropeginterferon (Besremi, FDA 2021): younger PV/ET; molecular response, may be disease-modifying.
  • Aspirin: standard in PV and most ET (per IPSET-thrombosis risk).
  • Hydroxyurea: 1L cytoreduction for high-risk PV/ET.
  • MF novel combos (2024 to 2025): MANIFEST-2 (pelabresib BET-i plus rux vs rux), SVR35 met (66% vs 35%) but TSS50 NOT met, FDA path uncertain. TRANSFORM-1 (navitoclax plus rux), SVR met but symptoms not, navitoclax MF development discontinued 2024.
  • Ropeg-IFN ET approval: FDA Aug 31, 2026 approved ropeginterferon alfa-2b for adults with ET (SURPASS-ET vs anagrelide in HU-resistant/intolerant ET, durable response 43% vs 6%). Deep molecular response and disease-modifying potential in Ph-negative MPNs (PV and ET).
  • Rusfertide (hepcidin mimetic, VERIFY ASCO 2025): phase 3 met, 77% clinical responders vs 33% placebo in PV; 73% phlebotomy-free; FDA approved Aug 28, 2026 (Mimrylo) for erythrocytosis in adults with PV.

High-Yield Pearls

  • JAK2 V617F in >95% of PV, classic association.
  • CALR-mutated ET = lower thrombosis risk than JAK2+ ET (OS advantage not clearly independent of age).
  • HMR mutations (ASXL1/EZH2/SRSF2/IDH1-2/U2AF1) drive PMF prognosis.
  • Splanchnic vein thrombosis: check JAK2 even with a normal CBC.
  • Acquired von Willebrand syndrome: bleeding with extreme thrombocytosis >1000K.
  • Allo-HSCT: only curative therapy for MPNs; reserved for DIPSS/MIPSS70+ intermediate-2/high MF, plus selected intermediate-1 with high-risk mutations, unfavorable karyotype, transfusion dependence or excess blasts; risk-stratify post-PV/ET MF by MYSEC-PM; also blast-phase MPN after cytoreduction.
  • Ropeginterferon: disease-modifying potential; younger PV.
Veli Bakalov MD, Board Review Notes 2026