Myeloproliferative Neoplasms (MPNs): PV, ET, Myelofibrosis, and CML — Overview, Diagnosis & Treatment Options | MyMedicPlus

Myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem cell disorders characterized by excessive proliferation of one or more myeloid cell lines. The classic BCR-ABL1-negative MPNs include polycythemia vera (PV, excessive RBC production), essential thrombocythemia (ET, excessive platelet production), and primary myelofibrosis (PMF, progressive marrow fibrosis). Chronic myeloid leukemia (CML) is a separate Philadelphia chromosome-positive MPN. JAK2 V617F mutation is the hallmark driver of PV, ET, and PMF.

BCR-ABL1-negative MPNs are driven by somatic mutations in JAK2 (V617F in greater than 96% of PV, 60% of ET/PMF), CALR (exon 9 insertions/deletions in 25-30% of ET/PMF), or MPL (W515L/K in approximately 5% of ET/PMF). These mutations converge on constitutive JAK-STAT pathway activation, driving cell proliferation independent of cytokine signaling. CML is caused by t(9;22)(q34;q11.2) Philadelphia chromosome translocation generating the BCR-ABL1 fusion oncogene. Environmental risk factors include ionizing radiation (atomic bomb survivors show increased MPN incidence) and benzene exposure. Most cases are sporadic without identifiable external cause.

PV: ruddy cyanosis (plethora), headache, dizziness, visual disturbances, aquagenic pruritus (itching after warm bath or shower, characteristic), erythromelalgia (burning pain and redness in feet/hands from microvascular disease), and thrombotic events. ET: often asymptomatic; thrombosis (arterial more than venous), erythromelalgia, and migraine headaches. PMF: progressive splenomegaly causing early satiety and abdominal fullness, constitutional symptoms (drenching night sweats, unintentional weight loss, fever), and anemia from marrow failure. CML: fatigue, splenomegaly, weight loss, night sweats, and leukocytosis with left shift on peripheral blood smear.

JAK2 V617F testing by allele-specific PCR is the primary diagnostic test for PV/ET/PMF. CALR and MPL testing are performed when JAK2 is negative. PV diagnosis (WHO 2022): elevated hemoglobin/hematocrit plus JAK2 V617F or elevated EPO-independent erythroid colony formation, plus low serum EPO. ET diagnosis: platelet greater than 450 x10^9/L, typical bone marrow megakaryocyte morphology, and driver mutation. PMF: bone marrow fibrosis grade MF-1 to MF-3 (European Consensus Grading). DIPSS-Plus score (Dynamic IPSS-Plus) stratifies PMF risk: age, WBC, Hgb, constitutional symptoms, blasts, cytogenetics, and transfusion. CML: peripheral blood BCR-ABL1 PCR (quantitative) plus bone marrow chromosome analysis.

PV: phlebotomy (target hematocrit less than 45%), low-dose aspirin, hydroxyurea or pegylated interferon-alpha for high-risk patients; ruxolitinib for hydroxyurea-resistant PV (RESPONSE trial). ET: low-dose aspirin for all; hydroxyurea, anagrelide, or pegylated interferon for high-risk patients. PMF: ruxolitinib (COMFORT trials) for symptomatic splenomegaly or constitutional symptoms; fedratinib, pacritinib (low platelets), or momelotinib (anemia) for ruxolitinib failure; allogeneic SCT for eligible intermediate-2/high-risk DIPSS-Plus patients. CML: imatinib, dasatinib, or nilotinib for chronic phase; ponatinib for T315I mutation; asciminib (STAMP inhibitor) for resistant/intolerant CML; allo-SCT for blast phase CML.

PV: median survival 14-20+ years with current therapy; transformation to MF or AML in approximately 10-15% by 20 years. ET: near-normal life expectancy in low-risk patients; CALR-mutant ET has better prognosis than JAK2-mutant ET. PMF: median OS by DIPSS-Plus risk: low 15+ years, intermediate-1 6.5 years, intermediate-2 2.9 years, high 1.3 years. Allogeneic SCT is curative in 30-50% of eligible intermediate-2/high PMF. CML: 10-year OS greater than 83% with imatinib; treatment-free remission achieved in approximately 50% of deep molecular responders after 5+ years of TKI therapy.

No prevention strategies exist for sporadic MPNs. Avoidance of ionizing radiation and benzene exposure minimizes environmental risk. Aggressive thrombotic risk factor management (blood pressure, diabetes, dyslipidemia, smoking cessation) is essential to reduce the primary morbidity of PV and ET. High-risk PV and ET patients require cytoreductive therapy to reduce thrombotic risk. Blast phase transformation risk in PMF is reduced with ruxolitinib therapy. Monitoring for AML transformation with regular blood counts and periodic bone marrow assessment in intermediate-2/high-risk PMF guides timely allogeneic SCT referral. CML patients on TKI therapy require regular BCR-ABL1 PCR monitoring (every 3 months) to detect molecular resistance early.