Myeloproliferative Neoplasms

MPN Overview - Clonal Chaos Kickoff

• Clonal hematopoietic stem cell (HSC) disorders: Characterized by excessive production of mature myeloid cells.
• Common features: Splenomegaly (due to extramedullary hematopoiesis), marrow hypercellularity, constitutional symptoms, risk of thrombosis/hemorrhage.
• Potential for transformation to myelofibrosis (spent phase) or Acute Myeloid Leukemia (AML).
• WHO classification integrates clinical, morphological, cytogenetic, and molecular (driver mutations) findings.
• Key driver mutations:
  • JAK2 (V617F most prevalent)
  • CALR (calreticulin)
  • MPL (thrombopoietin receptor)

⭐ JAK2 V617F is the most common mutation across Polycythemia Vera (PV), Essential Thrombocythemia (ET), and Primary Myelofibrosis (PMF).

Polycythemia Vera (PV) - Too Much Red

• Clonal, erythroid-dominant MPN: ↑RBC mass. JAK2 V617F (>95%) or exon 12 mutation.
• Sx: Hyperviscosity (headache), plethora, ruddy cyanosis, splenomegaly, thrombosis.
• Dx (WHO): ↑Hb/Hct (Hb >16.5 g/dL (M) / >16 g/dL (W), Hct >49% (M) / >48% (W)), BM panmyelosis, JAK2 mutation. ↓EPO (minor).
• Rx: Phlebotomy (target Hct <45%), low-dose Aspirin (75-100 mg/day). Cytoreduction (e.g., Hydroxyurea) if high-risk.

⭐ Aquagenic pruritus (itching after warm water contact) is a classic and highly specific symptom of PV.

Essential Thrombocythemia (ET) - Platelet Party Peril

• Clonal MPN: ↑ megakaryopoiesis & sustained thrombocytosis (Platelets > 450 x 10^9/L).
• Mutations: JAK2 V617F (~50-60%), CALR (~20-30%), MPL (~5-10%).
• Clinical: Often asymptomatic. Vasomotor (headache, erythromelalgia), thrombosis, hemorrhage. Mild splenomegaly.
• Diagnosis: Exclude reactive thrombocytosis; BM biopsy shows ↑ large, hyperlobulated megakaryocytes.

⭐ CALR mutations are typically found in JAK2 V617F-negative ET and are associated with a lower thrombotic risk compared to JAK2-mutated ET and a more indolent course. Higher platelet counts may be seen.

• Treatment Goal: Prevent thrombosis & hemorrhage. Manage symptoms. Low risk: Aspirin. High risk: Aspirin + cytoreduction (Hydroxyurea).

Primary Myelofibrosis (PMF) - Marrow's Fibrous Fate

• Clonal stem cell disorder: progressive bone marrow (BM) fibrosis, extramedullary hematopoiesis (EMH).
• Mutations: JAK2 V617F (~50-60%), CALR (~25-35%), MPL (~5-10%).
• Clinical: Massive splenomegaly (EMH), anemia, constitutional symptoms (fever, sweats, weight loss).
• Peripheral Smear (PS): Leukoerythroblastosis, dacrocytes (teardrop cells).
• BM Biopsy: Hypercellular early → fibrotic; "dry tap" common.
• Prognosis: DIPSS (Age >65, Hb <10 g/dL, WBC >25x10⁹/L, Blasts ≥1%, symptoms).
• Rx: Ruxolitinib (JAK inhibitor); Allogeneic HSCT (curative).

⭐ Extramedullary hematopoiesis leading to massive splenomegaly is a hallmark of PMF.

Chronic Myeloid Leukemia (CML) - Philly's Famous Fusion

• Patho: Philadelphia (Ph) chromosome t(9;22) → BCR-ABL1 fusion gene → constitutive tyrosine kinase activity. 📌 Philly CML.
• Phases (Bone Marrow Blasts): Chronic <10%, Accelerated 10-19%, Blast Crisis ≥20%.
• Features: Splenomegaly, fatigue, weight loss; marked leukocytosis (myeloid left shift, basophilia), thrombocytosis common.
• Tx & Monitoring: Tyrosine Kinase Inhibitors (TKIs) e.g., Imatinib. Aim for Major Molecular Response (MMR). Allogeneic SCT for resistant/advanced.

  ⭐ Low/absent Leukocyte Alkaline Phosphatase (LAP) score is characteristic, distinguishing CML from leukemoid reaction (high LAP).

High‑Yield Points - ⚡ Biggest Takeaways

• JAK2 V617F mutation is key in Polycythemia Vera (PV), Essential Thrombocythemia (ET), and Primary Myelofibrosis (PMF). CALR/MPL mutations are common in JAK2-negative cases.
• PV presents with ↑RBC mass, ↓EPO levels, aquagenic pruritus, and splenomegaly.
• ET is characterized by marked thrombocytosis; major risks include thrombosis or hemorrhage.
• PMF features progressive bone marrow fibrosis, massive splenomegaly, and leukoerythroblastic picture with teardrop poikilocytes.
• Chronic Myeloid Leukemia (CML) is defined by the BCR-ABL1 fusion gene (Philadelphia chromosome t(9;22)) and responds to Tyrosine Kinase Inhibitors (TKIs).
• All MPNs carry a risk of transformation to Acute Myeloid Leukemia (AML) or a myelofibrotic spent phase (except CML which has blast crisis).