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

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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.

Diagnosi s

In addition to thrombocytosis (platelets ≥450 × 10 ⁹/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.

Related collections

Most cited references 164

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Age-related clonal hematopoiesis associated with adverse outcomes.

Siddhartha Jaiswal, Pierre Fontanillas, Jason Flannick … (2014)

The incidence of hematologic cancers increases with age. These cancers are associated with recurrent somatic mutations in specific genes. We hypothesized that such mutations would be detectable in the blood of some persons who are not known to have hematologic disorders. We analyzed whole-exome sequencing data from DNA in the peripheral-blood cells of 17,182 persons who were unselected for hematologic phenotypes. We looked for somatic mutations by identifying previously characterized single-nucleotide variants and small insertions or deletions in 160 genes that are recurrently mutated in hematologic cancers. The presence of mutations was analyzed for an association with hematologic phenotypes, survival, and cardiovascular events. Detectable somatic mutations were rare in persons younger than 40 years of age but rose appreciably in frequency with age. Among persons 70 to 79 years of age, 80 to 89 years of age, and 90 to 108 years of age, these clonal mutations were observed in 9.5% (219 of 2300 persons), 11.7% (37 of 317), and 18.4% (19 of 103), respectively. The majority of the variants occurred in three genes: DNMT3A, TET2, and ASXL1. The presence of a somatic mutation was associated with an increase in the risk of hematologic cancer (hazard ratio, 11.1; 95% confidence interval [CI], 3.9 to 32.6), an increase in all-cause mortality (hazard ratio, 1.4; 95% CI, 1.1 to 1.8), and increases in the risks of incident coronary heart disease (hazard ratio, 2.0; 95% CI, 1.2 to 3.4) and ischemic stroke (hazard ratio, 2.6; 95% CI, 1.4 to 4.8). Age-related clonal hematopoiesis is a common condition that is associated with increases in the risk of hematologic cancer and in all-cause mortality, with the latter possibly due to an increased risk of cardiovascular disease. (Funded by the National Institutes of Health and others.).

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Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence.

Giulio Genovese, Anna K. Kähler, Robert Handsaker … (2014)

Cancers arise from multiple acquired mutations, which presumably occur over many years. Early stages in cancer development might be present years before cancers become clinically apparent. We analyzed data from whole-exome sequencing of DNA in peripheral-blood cells from 12,380 persons, unselected for cancer or hematologic phenotypes. We identified somatic mutations on the basis of unusual allelic fractions. We used data from Swedish national patient registers to follow health outcomes for 2 to 7 years after DNA sampling. Clonal hematopoiesis with somatic mutations was observed in 10% of persons older than 65 years of age but in only 1% of those younger than 50 years of age. Detectable clonal expansions most frequently involved somatic mutations in three genes (DNMT3A, ASXL1, and TET2) that have previously been implicated in hematologic cancers. Clonal hematopoiesis was a strong risk factor for subsequent hematologic cancer (hazard ratio, 12.9; 95% confidence interval, 5.8 to 28.7). Approximately 42% of hematologic cancers in this cohort arose in persons who had clonality at the time of DNA sampling, more than 6 months before a first diagnosis of cancer. Analysis of bone marrow-biopsy specimens obtained from two patients at the time of diagnosis of acute myeloid leukemia revealed that their cancers arose from the earlier clones. Clonal hematopoiesis with somatic mutations is readily detected by means of DNA sequencing, is increasingly common as people age, and is associated with increased risks of hematologic cancer and death. A subset of the genes that are mutated in patients with myeloid cancers is frequently mutated in apparently healthy persons; these mutations may represent characteristic early events in the development of hematologic cancers. (Funded by the National Human Genome Research Institute and others.).

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The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms

Joseph D. Khoury, Eric Solary, Oussama Abla … (2022)

The upcoming 5th edition of the World Health Organization (WHO) Classification of Haematolymphoid Tumours is part of an effort to hierarchically catalogue human cancers arising in various organ systems within a single relational database. This paper summarizes the new WHO classification scheme for myeloid and histiocytic/dendritic neoplasms and provides an overview of the principles and rationale underpinning changes from the prior edition. The definition and diagnosis of disease types continues to be based on multiple clinicopathologic parameters, but with refinement of diagnostic criteria and emphasis on therapeutically and/or prognostically actionable biomarkers. While a genetic basis for defining diseases is sought where possible, the classification strives to keep practical worldwide applicability in perspective. The result is an enhanced, contemporary, evidence-based classification of myeloid and histiocytic/dendritic neoplasms, rooted in molecular biology and an organizational structure that permits future scalability as new discoveries continue to inexorably inform future editions.