Essential thrombocythemia: 2024 update on diagnosis, risk stratification, and management

Abstract

Overview: Essential thrombocythemia is a Janus kinase 2 (JAK2) mutation-prevalent myeloproliferative neoplasm characterized by clonal thrombocytosis; clinical course is often indolent but might be interrupted by thrombotic or hemorrhagic complications, microcirculatory symptoms (e.g., headaches, lightheadedness, and acral paresthesias), and, less frequently, by disease transformation into myelofibrosis (MF) or acute myeloid leukemia.

Diagnosis: In addition to thrombocytosis (platelets ≥450 × 10⁹ /L), formal diagnosis requires the exclusion of other myeloid neoplasms, including prefibrotic MF, polycythemia vera, chronic myeloid leukemia, and myelodysplastic syndromes with ring sideroblasts and thrombocytosis. Bone marrow morphology typically shows increased number of mature-appearing megakaryocytes distributed in loose clusters.

Genetics: Approximately 80% of patients express myeloproliferative neoplasm driver mutations (JAK2, CALR, MPL), in a mutually exclusive manner; in addition, about 50% harbor other mutations, the most frequent being TET2 (9%-11%), ASXL1 (7%-20%), DNMT3A (7%), and SF3B1 (5%). Abnormal karyotype is seen in <10% of patients and includes +9/20q-/13q-.

Survival and prognosis: Life expectancy is less than that of the control population. Median survival is approximately 18 years but exceeds >35 years in younger patients. The triple A survival risk model, based on Age, Absolute neutrophil count, and Absolute lymphocyte count, effectively delineates high-, intermediate-1-, intermediate-2-, and low-risk disease with corresponding median survivals of 8, 14, 21, and 47 years.

Risk factors for thrombosis: Four risk categories are considered: very low (age ≤60 years, no thrombosis history, JAK2 wild-type), low (same as very low but JAK2 mutation present), intermediate (same as low but age >60 years), and high (thrombosis history or age >60 years with JAK2 mutation).

Mutations and prognosis: MPL and CALR-1 mutations have been associated with increased risk of MF transformation; spliceosome with inferior overall and MF-free survival; TP53 with leukemic transformation, and JAK2V617F with thrombosis. Leukemic transformation rate at 10 years is <1% but might be higher in JAK2-mutated patients with extreme thrombocytosis and those with abnormal karyotype.

Treatment: The main goal of therapy is to prevent thrombosis. In this regard, once-daily low-dose aspirin is advised for all patients and twice daily for low-risk disease. Cytoreductive therapy is advised for high-risk and optional for intermediate-risk disease. First-line cytoreductive drugs of choice are hydroxyurea and pegylated interferon-α and second-line busulfan.

Additional content: The current review includes specific treatment strategies in the context of extreme thrombocytosis, pregnancy, splanchnic vein thrombosis, perioperative care, and post-essential thrombocythemia MF, as well as new investigational drugs.