Polycythemia vera (PV)

Diagnostic Criteria (WHO 2022)

• Major: (1) Hb >16.5 (M) / >16.0 (F) g/dL OR Hct >49% (M) / >48% (F) OR increased red cell mass (>25% above mean normal predicted value); (2) hypercellular BM with panmyelosis and pleomorphic megakaryocytes; (3) JAK2 V617F or JAK2 exon 12 mutation.
• Minor: low serum EPO.
• Diagnosis: all 3 major OR first 2 major plus the minor criterion.
• DDx erythrocytosis: secondary (hypoxia, sleep apnea/COPD/altitude/cardiopulmonary shunt; tumor, RCC/HCC; exogenous EPO/androgens), Chuvash/HIF mutations, post-transplant erythrocytosis. PV is characterized by LOW EPO plus a JAK2 mutation.

Presenting Signs

• Splenomegaly, plethora, systemic hypertension, hepatomegaly, gout, cutaneous ulcers.

Risk Stratification & Goals

• Risk: low risk = age <60 AND no thrombosis history; high risk = age ≥60 OR thrombosis history.
• Risk factors for thrombosis: age ≥60, history of prior thrombosis, high phlebotomy rate, uncontrolled blood counts.
• Treatment goals: Hct <45% for both men and women (CYTO-PV); a lower target in women is sometimes suggested but not established by outcome data; reduce thrombosis risk (CYTO-PV trial, Marchioli NEJM 2013, strict Hct <45 reduced thrombosis approx. 4-fold).

Treatment

• Phlebotomy plus low-dose ASA: for ALL PV patients (low and high risk). ASA 81 to 100 mg daily (ECLAP, Landolfi NEJM 2004, used 100 mg). Goal Hct <45%.
• Cytoreduction (high-risk PV): hydroxyurea or ropeginterferon alfa-2b-njft (Besremi, FDA Nov 12, 2021, the first IFN approved for PV; NCCN preferred regardless of treatment history) 1st-line. 2nd-line: ruxolitinib (RESPONSE trial, for HU-resistant/intolerant; FDA Dec 2014).
• Ropeginterferon alfa-2b-njft (Besremi): long-acting pegylated mono-PEG IFN; q2wk SC (later q4wk). PROUD-PV / CONTINUATION-PV (Gisslinger Lancet Haematol 2020; 5-yr Kiladjian Hemasphere 2023), superior complete hematologic response with improved disease burden vs HU at 36 mo (53% vs 38%; CHR without spleen criterion 71% vs 51%); molecular/JAK2 V617F allele-burden responses assessed separately and persisting at 5 yr. FDA Nov 12, 2021, first IFN approved for PV. AEs: flu-like symptoms, depression/mood, hepatic enzyme elevation, autoimmune flares. Avoid in active psychiatric or autoimmune disease.
• Ruxolitinib for PV: 10 mg PO BID start. RESPONSE (Vannucchi NEJM 2015, with splenomegaly) and RESPONSE-2 (Passamonti Lancet Haematol 2017, no splenomegaly), superior Hct control plus spleen plus symptoms vs best available therapy. In RESPONSE, 222 patients with disease for at least 24 weeks, inadequate response to or intolerance of hydroxyurea, prior phlebotomy, and splenomegaly were enrolled; 21% of ruxolitinib-treated patients achieved reduced phlebotomy need plus spleen volume reduction vs 1% on best available therapy. MAJIC-PV (Harrison JCO 2023), superior complete hematologic response and event-free survival vs BAT in HU-resistant/intolerant PV. FDA Dec 2014 for HU-resistant/intolerant PV. Side effects: cytopenias, herpes zoster, increased non-melanoma skin cancer (squamous/basal, annual dermatology exam).
• Sequencing pearl: if a patient does not tolerate hydroxyurea or ruxolitinib, peginterferon alfa-2a is an option.
• Aspirin: all PV; consider BID dosing in extreme thrombocytosis or recurrent events. Avoid in uncontrolled thrombocytosis (>1.5M) due to acquired vWD risk.
• Anticoagulation for venous thrombosis and other standard indications; arterial events are generally managed with antiplatelet therapy and risk-factor control (anticoagulation only for specific indications).
• Pruritus management: common and debilitating; SSRIs (paroxetine), antihistamines, narrowband UVB, ruxolitinib particularly effective.
• Rusfertide (Mimrylo, hepcidin mimetic, FDA approved Aug 28, 2026 for erythrocytosis in adults with PV): PTG-300, weekly SC; controls erythrocytosis without phlebotomy. VERIFY phase 3 (Kremyanskaya/Hoffman, ASCO 2025), primary endpoint met (77% clinical responders vs 33% placebo, weeks 20 to 32); 73% phlebotomy-free vs 22%. NDA accepted with priority review; FDA approved Aug 28, 2026. Class AEs: injection-site reactions (mostly G1-2).
• Erythromelalgia: burning pain in extremities; treat with ASA, response is characteristic.

Indications to Deploy Cytoreductive Therapy

• New thrombosis, acquired von Willebrand disease, and/or disease-related major bleeding.
• Frequent and/or persistent need for phlebotomy with poor tolerance of phlebotomy.
• Symptomatic/progressive splenomegaly.
• Symptomatic thrombocytosis.
• Progressive leukocytosis.
• Progressive disease-related symptoms (e.g., night sweats).
• Vasomotor/microvascular disturbances not responsive to aspirin (e.g., chest pain).

Complications & Transformation

• Thrombosis (40 to 50%): arterial > venous; CVA, DVT/PE, renal/portal vein thrombosis, Budd-Chiari syndrome; unusual sites (splanchnic vein thrombosis, BCS or PVT often heralds occult MPN, so test JAK2 in any unprovoked splanchnic VTE).
• Hemorrhage (~15%): acquired vWD with extreme thrombocytosis (>1.5M), vWF cleaved by ADAMTS13. Bleeding is promoted by antiplatelet therapy, thrombocytopenia (post-PV MF), and reticulin fibrosis at presentation.
• Post-PV myelofibrosis (PPMF): ~15 to 30% at 15 years.
• Leukemic transformation: ~6% at 15 years; ~5 to 10% lifetime. HU does NOT increase leukemic risk per modern data; alkylators (chlorambucil, busulfan) and 32P are therapy-related leukemogens.