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Myeloproliferative Neoplasms (MPNs)

BASICS

Description

  • Clonal disorders from pluripotent hematopoietic stem cells
  • Main types: Chronic Myelogenous Leukemia (CML), Polycythemia Vera (PV), Essential Thrombocythemia (ET), Primary Myelofibrosis (PMF)
  • WHO classification (2016) includes: CNL, CEL-NOS, MPN-unclassifiable (rare)
  • CML: myeloid precursor proliferation
  • PV: erythrocytosis
  • ET: thrombocytosis
  • PMF: marrow fibrosis, extramedullary hematopoiesis
  • MPNs can transform into one another; natural history can last decades; all carry risk of complications

EPIDEMIOLOGY

  • Median age >60 years
  • Incidence (per 100,000/year):
  • CML: 1.6
  • PV: 0.8
  • ET: 1.0
  • PMF: 0.5

ETIOLOGY & PATHOPHYSIOLOGY

  • Genetic mutations activating hematopoiesis → proliferation of myeloid, erythroid, megakaryocyte lineages
  • CML: 9:22 translocation (Philadelphia chromosome) → BCR-ABL1 fusion gene (constitutively active tyrosine kinase)
  • PV, ET, PMF: "Driver" mutations (JAK2, MPL, CALR)
  • JAK2 V617F: 95% PV, 55% ET, 65% PMF
  • JAK2 exon 12: 4% PV
  • MPL: 3% ET, 5% PMF
  • CALR: 25% ET, PMF
  • Risk factors: Ionizing radiation, familial cases (rare)

COMMONLY ASSOCIATED CONDITIONS

  • Thrombotic events: CVA, TIA, DVT, portal vein thrombosis
  • Hemorrhagic events: acquired von Willebrand disease
  • Anemia, marrow fibrosis, osteosclerosis
  • Extramedullary hematopoiesis
  • Blast transformation to acute leukemia

DIAGNOSIS

History

  • Constitutional symptoms: fatigue, weakness, night sweats, fevers, weight loss
  • GI: abdominal fullness, discomfort, early satiety
  • Musculoskeletal: bone pain
  • Neurologic: headache, dizziness, transient visual disturbance
  • Other: depression, sexual dysfunction, insomnia
  • Disease-specific:
  • CML: excess sweating, gout
  • PV: aquagenic pruritus, erythromelalgia, facial plethora, gout, tinnitus
  • PMF: fullness/pain, early satiety, GI bleed, bone pain
  • ET: lightheadedness, visual disturbance, chest pain, erythromelalgia, pregnancy loss

Physical Exam

  • Pallor, splenomegaly, hepatomegaly
  • CML: gouty tophi
  • PV: BP ↑, conjunctival injection, facial plethora
  • ET: petechiae, livedo reticularis
  • PMF: lymphadenopathy, marked splenomegaly

Differential Diagnosis

  • CML: leukemoid reaction, other leukemias
  • PV: secondary polycythemia
  • ET: reactive thrombocytosis, MDS, TPO gene mutations
  • PMF: secondary fibrosis, myeloma, lymphoma, autoimmune

Diagnostic Tests

  • CBC, peripheral smear, renal/liver function, LDH, uric acid
  • Molecular testing: BCR-ABL (CML), JAK2, MPL, CALR
  • Bone marrow biopsy/aspiration: diagnosis, staging
  • Other labs: EPO, iron studies, vWF

WHO Criteria Highlights

  • CML: Leukocytosis with BCR-ABL fusion
  • PV: Hb >16.5 (M)/16.0 (F), marrow hypercellularity, JAK2+, low EPO
  • ET: Platelet ≥450 × 10⁹/L, megakaryocyte proliferation, JAK2/CALR/MPL+, absence of other myeloid neoplasms
  • PMF: Megakaryocyte proliferation/atypia + reticulin/collagen fibrosis, JAK2/CALR/MPL+ (or other clonal marker), leukoerythroblastosis, ↑LDH, palpable spleen, anemia

TREATMENT

General Measures

  • PV: Phlebotomy (goal Hct <45% M, <42% F), aspirin, risk factor management
  • PMF: Transfusion as needed; reduce CV risk

Medications

CML

  • First-line: Tyrosine kinase inhibitors (TKIs):
  • 1st gen: imatinib
  • 2nd gen: nilotinib, dasatinib, bosutinib
  • 3rd gen: ponatinib
  • Chronic phase: 1GTKI/2GTKI; high-risk: 2GTKI
  • Accelerated/blast phase: 2GTKI/3GTKI, consider transplant; blast phase—add induction chemo

PV

  • Aspirin (81–100 mg daily)
  • High-risk: cytoreduction (hydroxyurea, interferon-α)
  • 2nd-line: JAK2 inhibitor (ruxolitinib)

ET

  • Aspirin (as above) for thrombosis/microvascular events/JAK2+
  • Cytoreduction: hydroxyurea (high risk), or for progressive thrombocytosis, bleeding, splenomegaly
  • 2nd-line: interferon-α or anagrelide

PMF

  • JAK2 inhibitor (ruxolitinib) for plt ≥50×10⁹/L, or low-risk with symptoms
  • 2nd-line: hydroxyurea, interferon-α, or new JAK2 inhibitor
  • Anemia: EPO-stimulating agents (if EPO<500), danazol, prednisone, lenalidomide, thalidomide

Surgery/Procedures

  • Allogeneic stem cell transplant: CML (accel/blast), high-risk PMF
  • Splenectomy: severe/symptomatic PMF
  • Palliative radiation: extramedullary hematopoiesis

ONGOING CARE

Patient Education

  • Avoid situations that ↑ thrombosis risk
  • With splenomegaly: avoid trauma (rupture risk)

PROGNOSIS

  • CML: prognosis depends on phase and response; chronic phase with good response = near-normal lifespan; blast phase median survival ~1 year
  • PV: median survival 14 yrs (24 yrs if <60y)
  • ET: median survival 20 yrs (33 yrs if <60y)
  • PMF: median survival 6 yrs (15 yrs if <60y)
  • Driver mutation prognosis: CALR = better; JAK2 or triple-negative = worse
  • Leukemic transformation: PMF (20%), PV/ET (~8%)

ICD-10 CODES

  • D47.1: Chronic myeloproliferative disease
  • C92.10: CML, BCR/ABL-positive, not in remission
  • D45: Polycythemia vera

Clinical Pearls

  • MPNs: mutations activating hematopoiesis → myeloid, erythroid, megakaryocyte proliferation
  • CML: granulocytosis; PV: erythrocytosis; ET: thrombocytosis; PMF: fibrosis, extramedullary hematopoiesis
  • Shared origins, overlapping features, risk of transformation
  • Complications: thrombosis, hemorrhage, transformation to acute leukemia, marrow fibrosis