Guideline sources The following summarized guidelines for the evaluation and management of polycythemia vera (PV) are prepared by our editorial team based on guidelines from the British Society for Haematology (BSH 2019), the European Leukemia Net (ELN 2018), and the European Society of Medical Oncology (ESMO 2015). 1 2 3 4 Calculator Calculator Calculat Eastern Cooperative Oncology G Karnofsky performance status s WHO c Guidelines 1. Screening and diagnosis Diagnostic criteria: ELN 2018 https://web.pathway.md/diseases/recqjgqIzaIohaqWO A id li th 2016 i d WHO it i f di i f PV 1/8 6/29/23, 11:17 PM Polycythemia vera Pathway As per ELN 2018 guidelines, use the 2016 revised WHO criteria for diagnosis of PV. E As per ESMO 2015 guidelines, ensure accurate differentiation among the three unique myeloproliferative neoplasm subtypes as well as the exclusion of reactive conditions (in mutation-negative patients only) and disorders, such as myelodysplasia and chronic myeloid leukemia, for appropriate prognosis and treatment decision-making. Do not use the generic diagnostic label 'myeloproliferative neoplasm' alone. A 2. Classification and risk stratification Risk of thrombosis: As per BSH 2019 guidelines: Use age and thrombotic history to define the risk for thrombosis in patients with PV: high risk: age 65 years and/or prior PV-associated arterial or venous thrombosis low risk: age < 65 years and no PV-associated thrombotic history. A Consider classifying some low-risk patients into higher risk in the presence of cardiovascular risk factors, elevated WBC count, extreme thrombocytosis, or hematocrit uncontrolled with venesection. B As per BSH 2019 guidelines: Screen for hypertension, hyperlipidemia, diabetes mellitus, and smoking history in patients with PV. B Assess cardiovascular risk at baseline and annually using a validated score, such as the QRISK score, in patients with PV. B As per ELN 2018 guidelines: Use age and previous thrombosis history to classify patients into low-risk and high-risk categories. E Consider assessing general risk factors for thrombosis, including smoking history, diabetes mellitus, hypertension, and hyperlipidemia. E As per ESMO 2015 guidelines, categorize patients with newly diagnosed myeloproliferative neoplasm at baseline according to the risks associated with the disease. B Prognosis: Consider using the following variables when counseling patients on longer-term prognosis including overall survival and disease transformation risk: age prior thrombosis presence of splenomegaly serum LDH level degree of reticulin staining presence of an abnormal karyotype and JAK2 mutant allele burden. C 3. Diagnostic investigations Genetic testing: https://web.pathway.md/diseases/recqjgqIzaIohaqWO 2/8 6/29/23, 11:17 PM Polycythemia vera Pathway As per BSH 2019 guidelines: Test for JAK2 V617F mutation on a peripheral blood sample with an assay sufficiently sensitive to detect a mutant allele burden as low as 1-3% in patients with persistent, significant, and unexplained erythrocytosis. B Consider obtaining deep sequencing for high-risk mutations, such as ASXL1, SRSF2, and IDH1/2, in selected patients if the presence of these mutations may influence management. C As per BSH 2019 guidelines, test for JAK2 V617F mutation, and for CALR mutation of the former is negative, in patients presenting with splanchnic vein thrombosis not associated with local malignancy. A As per ELN 2018 guidelines, obtain mutational analysis for JAK2V617F on peripheral blood or bone marrow samples in patients with suspected PV. Obtain mutational analysis for JAK2 exon 12 in JAK2V617F-negative patients with suspected PV. E As per ESMO 2015 guidelines, obtain testing for 3 driver mutations in all patients with suspected myeloproliferative neoplasms. B Screening for acquired von Willebrand syndrome: screen for acquired von Willebrand syndrome in patients with a bleeding history. Test for platelet function defect and consult a hemostasis expert if negative. B 4. Diagnostic procedures Bone marrow biopsy: perform bone marrow biopsy in all patients with suspected Philadelphia chromosome-negative myeloproliferative neoplasms, except for patients with PV with Hgb > 18.5 g/dL in males and > 16.5 g/dL in females. E 5. Medical management Treatment targets: As per BSH 2019 guidelines, target hematocrit of < 45% in all patients (including low-risk patients) with PV. A Landmark trials: CYTO-PV In adults patients with JAK2-positive polycythemia vera who were being treated with phlebotomy, hydroxyurea, or both, low-hematocrit targeted therapy was superior to high- hematocrit targeted therapy with respect to death from cardiovascular causes or major thrombotic events. Marchioli R et al. N Engl J Med. 2013 Jan 3. As per ELN 2018 guidelines, treat patients with PV aiming to maintain hematocrit level < 45%. A https://web.pathway.md/diseases/recqjgqIzaIohaqWO 3/8 6/29/23, 11:17 PM Polycythemia vera Pathway As per ESMO 2015 guidelines, consider maintaining hematocrit levels strictly < 45% to efficiently reduce the risk of thrombotic events. B Cytoreductive therapy: As per BSH 2019 guidelines, consider initiating cytoreductive therapy in low-risk patients with: history of treated arterial hypertension, ischemic heart disease, or diabetes mellitus persistent leucocytosis (WBC count > 15 10 /L) uncontrolled hematocrit (or poor tolerability of venesection) extreme/progressive thrombocytosis ( 1, 500 10 /L) and/or hemorrhagic symptoms progressive/symptomatic splenomegaly uncontrolled or progressive disease-related symptoms, such as weight loss and sweats. B Show 6 more As per ELN 2018 guidelines, initiate cytoreductive therapy in high-risk patients, such as age > 60 years, or history of a thrombotic event, A as well as in patients with any of the following: poor tolerance to phlebotomy E aymptomatic or progressive splenomegaly E severe disease-related symptoms E platelets > 1, 500 10 /L E WBCs > 15 10 /L. E Show 4 more As per ESMO 2015 guidelines, initiate cytoreductive therapy, with hydroxyurea B and interferon-alpha as first-line agents, in high-risk patients, i.e., age > 60 years and/or history of a vascular event. B Show 3 more Antiplatelet therapy: As per BSH 2019 guidelines, initiate low-dose aspirin (75-100 mg) in all patients (including low-risk patients) with PV. A As per ELN 2018 guidelines, initiate daily low-dose aspirin in all patients with PV. A As per ESMO 2015 guidelines, initiate low-dose aspirin in patients with PV. A Iron supplementation: initiate iron supplementation in patients with documented severe tissue iron deficiency associated with detrimental symptoms (pica, mouth paresthesia, esophagitis, restless legs). Initiate cytoreductive therapy if hematocrit worsens due to iron therapy. E Management of thrombosis: treat acute arterial or venous thrombosis as per pertinent evidence-based guidelines. A Show 5 more Management of hemorrhage: be cautious when using antiplatelets/anticoagulants in patients with extreme thrombocytosis balancing the thrombotic and bleeding history of the patient. B Show 2 more https://web.pathway.md/diseases/recqjgqIzaIohaqWO 4/8 6/29/23, 11:17 PM Polycythemia vera Pathway Management of pruritus: As per BSH 2019 guidelines, administer H1RAs (including high doses and multiple agents if needed) for the management of pruritus. B Show 5 more As per ESMO 2015 guidelines, consider administering interferon-alpha or JAK2 inhibitors for the treatment of aquagenic pruritus. Consider offering antihistamines, SSRIs, and PUVA therapy as other options. C Management of cardiovascular risk factors: As per BSH 2019 guidelines, offer targeted interventions to reduce cardiovascular risk factors in patients with PV. As per ELN 2018 guidelines, manage cardiovascular risk factors aggressively in all patients with PV. E 6. Therapeutic procedures Therapeutic phlebotomy: As per BSH 2019 guidelines, perform phlebotomy (along with cytoreduction therapy) to maintain hematocrit < 45% for secondary prevention of thrombosis. A As per ELN 2018 guidelines: Perform phlebotomy to maintain the hematocrit level < 45% in all patients with PV. A Withdraw 300-450 mL of blood weekly or twice weekly in the induction phase until the hematocrit target is reached. Decide on the phlebotomy intervals in the maintenance based on hematocrit levels. E As per ESMO 2015 guidelines: Consider performing emergency phlebotomy at diagnosis in patients presenting with very high hematocrit and clinical signs of hyperviscosity. B Consider performing long-term maintenance phlebotomy to control hematocrit levels in patients with PV. B 7. Perioperative care Preoperative management: involve a hematologist in preoperative planning to optimize RBC count control and individualize the perioperative plan. B Show 2 more Perioperative management: consider controlling blood counts preoperatively to standard targets in high-risk patients undergoing surgery, when bleeding is a risk or thromboprophylaxis would normally be prescribed. C 8. Specific circumstances Pregnant patients: ensure a collaborative approach between obstetricians and hematologists to formulate an individualized plan for the pregnancy, delivery, and postpartum period based on https://web.pathway.md/diseases/recqjgqIzaIohaqWO 5/8 6/29/23, 11:17 PM Polycythemia vera Pathway the previous history of thrombosis, hemorrhage, and previous pregnancies. B Show 6 more Patients with idiopathic erythrocytosis: exclude primary and secondary causes of erythrocytosis. B Show 5 more Patients with congenital erythrocytosis: consider initiating low-dose aspirin in patients with congenital erythrocytosis. C Show 4 more Patients with pulmonary disease: Evaluate patients with hypoxic pulmonary disease developing erythrocytosis by a respiratory physician for consideration of long-term oxygen therapy or alternative therapy. A Consider performing venesection to reduce hematocrit to 50-52% in patients being symptomatic as a result of hyperviscosity or having a hematocrit > 56%. C Patients with post-transplant erythrocytosis: treat hypertension and rising hematocrit promptly if persistent (> 1 month) and otherwise unexplained. B Show 4 more Patients with leukemic transformation: consider administering acute leukemia-like regimens in patients with leukemic transformation deemed potential candidates for allo-SCT. Consider offering azacitidine. C Breastfeeding patients: recognize that breastfeeding is contraindicated with cytoreductive therapy. Decide about breastfeeding while taking interferon on an individual basis after discussion regarding possible risks and benefits. B Patients on hormonal therapy: Obtain an individualized risk-benefit assessment to decide on hormonal therapy. B Advise using progesterone-only preparations for oral contraception and avoid combined oral contraceptives. B Clinical findings Patient demographics Symptoms Ashkenazi Jews Abdominal discomfort Abdominal pain Past medical history Aquagenic pruritus Blurry vision Acquired vWD Bone pain Central vein thrombosis Chest pain DVT Confusion Gastrointestinal bleeding Dizziness Gout Early satiety Splanchnic vein thrombosis Easy bruising Stroke Fatigue Superficial vein thrombosis Fever TIA https://web.pathway.md/diseases/recqjgqIzaIohaqWO 6/8 6/29/23, 11:17 PM Polycythemia vera Pathway Generalized pruritus Vital signs Headache Hypertension Night sweats Nosebleed Integument exam Paresthesia Sweating Digital ischemia Tinnitus Erythromelalgia Trouble concentrating Skin erythema Visual disturbances Hematological findings Weight loss RBCs Family history blood Hgb VTE blood neutrophil count blood platelet count Abdominal exam hematocrit Splenomegaly Genetic testing Lab findings Jak2 gene mutation Iron deficiency serum EPO Imaging findings I t i l h h Studies 2013 CYTO-PV In adults patients with JAK2-positive polycythemia vera who were being treated with phlebotomy, hydroxyurea, or both, low-hematocrit targeted therapy was superior to high-hematocrit targeted therapy with respect to death from cardiovascular causes or major thrombotic events. Marchioli R et al. N Engl J Med. 2013 Jan 3. References 1. Mary F F McMullin, Adam J Mead, Sahra Ali et al. A guideline for the management of specific situations in polycythaemia vera and secondary erythrocytosis: A British Society for Haematology Guideline. Br J Haematol. 2019 Jan;184 2 161 175. Open 2. Mary Frances McMullin, Claire N Harrison, Sahra Ali et al. A guideline for the diagnosis and management of polycythaemia vera. A British Society for Haematology Guideline. Br J Haematol. 2019 Jan;184 2 176 191. Open 3. Tiziano Barbui, Ayalew Tefferi, Alessandro M Vannucchi et al. Philadelphia chromosome-negative classical myeloproliferative neoplasms: revised management recommendations from European LeukemiaNet. Leukemia. 2018 May;32 5 1057 1069. Open https://web.pathway.md/diseases/recqjgqIzaIohaqWO 7/8 6/29/23, 11:17 PM Polycythemia vera Pathway 4. A M Vannucchi, T Barbui, F Cervantes et al. Philadelphia chromosome-negative chronic myeloproliferative neoplasms: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015 Sep;26 Suppl 5:v85 99. Open 5. Anand Padmanabhan, Laura Connelly-Smith, Nicole Aqui et al. Guidelines on the Use of Therapeutic Apheresis in Clinical Practice Evidence-Based Approach from the Writing Committee of the American Society for Apheresis: The Eighth Special Issue. J Clin Apher. 2019 Jun;34 3 171 354. Open https://web.pathway.md/diseases/recqjgqIzaIohaqWO 8/8