myeloproliferative disorder

**Definition:** Clonal neoplasms of a hematopoietic stem cell producing sustained proliferation of mature, functional myeloid cells (elevated peripheral counts, hypercellular marrow, effective hematopoiesis). This contrasts with MDS (ineffective hematopoiesis, cytopenias, dysplasia) and acute leukemia (maturation arrest, ≥20% blasts in WHO 5th ed. for most AML types).

**Major entities (WHO classification):** 1. **Chronic myeloid leukemia (CML):** t(9;22) Philadelphia chromosome → BCR-ABL1 constitutively active tyrosine kinase. Markedly elevated WBC with left shift (all stages of granulocyte maturation), basophilia, and eosinophilia. Low leukocyte alkaline phosphatase (LAP) vs. leukemoid reaction (high LAP). Splenomegaly. Treat with TKIs (imatinib, dasatinib, nilotinib, bosutinib, ponatinib, asciminib). Phases: chronic → accelerated → blast crisis (myeloid in about 70%, lymphoid in about 30%). Ponatinib is used for T315I mutation. 2. **Polycythemia vera (PV):** JAK2 V617F in about 95% (exon 12 in the rest). Increased RBC mass with low EPO. Findings: pruritus after hot shower (aquagenic pruritus), erythromelalgia, plethora, splenomegaly, headache, and thrombosis (including Budd-Chiari and other unusual sites). Treatment: phlebotomy (goal Hct <45%), low-dose aspirin, hydroxyurea or ruxolitinib for high-risk patients, and ropeginterferon alfa-2b. Differentiate from secondary polycythemia (high EPO) and relative polycythemia. 3. **Essential thrombocythemia (ET):** Sustained platelet count ≥450,000 with JAK2 (about 50–60%), CALR (about 25%), or MPL (about 5%) mutations. Excluding reactive causes (iron deficiency, inflammation, post-splenectomy) and other MPNs is required. Presents with thrombosis, microvascular symptoms (erythromelalgia), and bleeding (acquired von Willebrand syndrome when platelets >1,000,000). Treatment: aspirin; hydroxyurea for high-risk patients (age >60 or prior thrombosis). 4. **Primary myelofibrosis (PMF):** Clonal proliferation of megakaryocytes releases PDGF and TGF-β → marrow fibrosis. Findings: massive splenomegaly (extramedullary hematopoiesis), teardrop cells (dacrocytes), leukoerythroblastic smear, "dry tap" on aspiration, and constitutional symptoms. Treat with JAK inhibitors (ruxolitinib, fedratinib, pacritinib, momelotinib); allogeneic HSCT is the only cure. 5. Others: chronic neutrophilic leukemia, chronic eosinophilic leukemia, and mastocytosis (KIT D816V). Myeloid/lymphoid neoplasms with eosinophilia involve PDGFRA/PDGFRB/FGFR1 rearrangements; PDGFRA/B disease responds to imatinib.

**Key associations/high-yield points:** - **JAK2 V617F** is a gain-of-function mutation → constitutive JAK-STAT signaling (EPO-independent growth). It is present in PV, ET, and PMF, but NOT in CML. - **CML is the only classic MPN that is BCR-ABL1 positive.** The others are termed "Ph-negative MPNs" (or BCR-ABL1-negative). - **Complications:** thrombosis (arterial and venous), hemorrhage, hyperuricemia/gout (high cell turnover), splenic infarcts, and progression to post-PV/post-ET myelofibrosis ("spent phase") or AML. - Hyperviscosity, hyperuricemia, and splenomegaly are common to the group. Treat hyperuricemia with allopurinol when needed. - **Differentials:** leukemoid reaction (high LAP, toxic granulation, no BCR-ABL1), reactive thrombocytosis, secondary polycythemia, MDS, and MDS/MPN overlap (e.g., CMML). - **Diagnosis:** CBC with differential, peripheral smear, molecular testing (BCR-ABL1 by PCR/FISH; JAK2, CALR, MPL), EPO level, and bone marrow biopsy.

**Board pearls:** - Older adult with splenomegaly, high WBC, basophilia, and low LAP → CML → imatinib. - Itching after a shower, high Hct, and low EPO → PV → JAK2 testing and phlebotomy. - Teardrop cells and a dry tap → myelofibrosis. - Persistent platelets >450,000 with a clotting or bleeding history → ET.