Polycythemia vera and essential thrombocythemia: 2021 update on diagnosis, risk‐stratification and management

Abstract

Disease overview: Polycythemia vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms (MPN) respectively characterized by clonal erythrocytosis and thrombocytosis; other disease features include leukocytosis, splenomegaly, thrombosis, bleeding, microcirculatory symptoms, pruritus and risk of leukemic or fibrotic transformation. Diagnosis: Bone marrow morphology remains the cornerstone of diagnosis. In addition, the presence of JAK2 mutation is expected in PV while approximately 90% of patients with ET express mutually exclusive JAK2, CALR or MPL mutations (so called driver mutations). In ET, it is most important to exclude the possibility of prefibrotic myelofibrosis. Survival: Median survivals are approximately 15 years for PV and 18 years for ET; the corresponding values for patients age 40 or younger were 37 and 35 years. Certain mutations (mostly spliceosome) and abnormal karyotype might compromise survival in PV and ET. Life-expectancy in ET is inferior to the control population. Driver mutations have not been shown to affect survival in ET but risk of thrombosis is higher in JAK2 mutated cases. Leukemic transformation rates at 10 years are estimated at <1% for ET and 3% for PV. Thrombosis risk: In PV, two risk categories are considered: high (age > 60 years or thrombosis history present) and low (absence of both risk factors). In ET, four risk categories are considered: very low (age ≤ 60 years, no thrombosis history, JAK2 wildtype), low (same as very low but JAK2 mutation present), intermediate (age > 60 years, no thrombosis history, JAK2 wild-type) and high (thrombosis history present or age > 60 years with JAK2 mutation). Risk-adapted therapy: The main goal of therapy in both PV and ET is to prevent thrombohemorrhagic complications. All patients with PV require phlebotomy to keep hematocrit below 45% and once-daily or twice-daily aspirin (81 mg), in the absence of contraindications. Very low risk ET might not require therapy while aspirin therapy is advised for low risk disease. Cytoreductive therapy is recommended for high-risk ET and PV, but it is not mandatory for intermediate-risk ET. First-line drug of choice for cytoreductive therapy, in both ET and PV, is hydroxyurea and second-line drugs

Prevention and Management of Thrombosis in BCR/ABL-Negative Myeloproliferative Neoplasms

“…The gain-of-function V617F mutation in exon 14 is harbored by approximately 96, 55, and 65% of patients with PV, ET, and PMF, respectively, where mutations in exon 12 can be detected in 3% of V617F-negative PV patients. 17 The second most common mutation in MPN involves the calreticulin gene (CALR), and occurs in 25 to 35% of patients with PMF and 15 to 24% with ET. 18 Finally, mutations in the TPO receptor gene MPL are present in 4% of ET and 8% of PMF cases.…”

“…CALR and MPL mutations are rarely reported in PV. 17 Several studies have evaluated the association between JAK2V617F and the severity of MPN disease. In particular, two meta-analyses have evidenced a correlation between JAK2 mutation and the risk of thrombosis in ET.…”

“…Based on the aforementioned studies, PV patients are classified as high risk if older than 60 years or present a history of thrombosis, and low risk in the absence of both risk factors. 17 Until recently, the same risk stratification has been used in ET. 38 Since the role of JAK2 mutation and CV risk factors have emerged as independent predictors of thrombosis in ET, 15 these variables have been evaluated in risk stratification.…”

“…Twice daily (BID) aspirin should be considered in low-risk patients with inadequate control of microvascular symptoms, CV risk factors, or leukocytosis, and in high-risk patients with a history of arterial thrombosis. 17 Phlebotomy is recommended in all PV patients, and controlled evidence supports the practice of maintaining the hematocrit at less than 45%. 29 In adjunction, high-risk patients should receive cytoreductive therapy to minimize their risk of thrombosis.…”

“…According to the 2021 updated recommendations on PV and ET management, very low-risk patients with ET might not require any therapy unless in the presence of CV risk factors, where OD low-dose aspirin therapy is advised. 17 A recent study compared the efficacy of OD vs BID and thrice daily (TID) aspirin in ET, based on hypothesis that increased platelet number and turnover might compromise durable inhibition of platelet COX-1; accordingly, BID/TID was more effective than OD dosing in reducing platelet activation, measured by serum thromboxane B2 level. 56 To date, it seems reasonable to use BID aspirin in patients with arterial thrombosis, or in the presence of CV risk factors associated to older age or JAK2 mutations.…”