Myeloproliferative disorders, or myeloproliferative neoplasms (MPNs), are a group of conditions that cause abnormal growth of blood cells in the bone marrow. They include polycythemia vera (PV), essential thrombocythemia or thrombocytosis (ET), pre-primary myelofibrosis, primary myelofibrosis (PMF), chronic myelogenous leukemia (CML), and chronic neutrophilic leukemia (CNL) (Khoury et al., 2022; Arber et al., 2022; Thiele et al., 2023). The diagnosis of an MPN is suspected based upon clinical, laboratory, and pathological findings, including bone marrow morphology and identification of certain pathogenic/likely pathogenic (P/LP) variants (Khoury et al., 2022; Arber et al., 2022; Thiele et al., 2023). Patients with MPNs may be clinically asymptomatic, but MPNs confer a risk for progression to acute myeloid leukemia, also called blast-phase MPN (Lasho et al., 2018). MPNs are related but distinct from myelodysplastic syndromes (MDS). In general, MDS are characterized by ineffective or dysfunctional blood cells, while MPN are characterized by an increase in the number of blood cells (Khoury et al., 2022; Arber et al., 2022).

JAK2, CALR, and MPL are genes involved in the growth and survival of various cell types. The presence of somatic driver P/LP variants within these genes is part of the World Health Organization (WHO) diagnostic criteria for MPNs, and molecular testing may be necessary to confirm a diagnosis (Khoury et al., 2022). CML is distinguished from the other MPNs by the presence of a BCR-ABL1 fusion gene. Targeted genetic testing of the JAK2, CALR, and MPL genes is helpful for individuals with other forms of MPNs who would not otherwise meet clinical diagnostic criteria (Khoury et al., 2022; Arber et al., 2022; Thiele et al., 2023). There is some evidence that non-driver P/LP variants in additional genes such as ASXL1, TET2, and TP53 can help to predict a poor prognosis for some patients with MPNs, but the utility of testing these genes is not fully established (McClure et al., 2018; Grinfeld et al., 2018). Importantly, P/LP variants in many of these genes have also been detected in older individuals with no other clinical evidence of myeloid disease, a scenario known as clonal hematopoiesis of indeterminate potential (CHIP) (Khoury et al., 2022; Arber et al., 2022; Thiele et al., 2023). Therefore, genetic testing should only be performed when there is reasonable clinical suspicion of disease (Khoury et al., 2022; Arber et al., 2022). For those with suspicion of an MPN, the National Comprehensive Cancer Network® (NCCN®) recommends a diagnostic work-up including FISH or multiplex RT-PCR for BCR-ABL1 to exclude a diagnosis of CML, as well as molecular testing for JAK2 V617F. If negative for the JAK2 V617F mutation, testing should be performed for CALR and MPL for patients with suspicion of ET or MF, and JAK2 exon 12 testing for patients with suspicion of PV (NCCN, Myeloproliferative Neoplasms v.1.2025). Alternatively, NCCN guidelines indicate that molecular testing using a multigene NGS panel that includes JAK2, CALR, and MPL can be used as part of the initial workup for all patients (NCCN, Myeloproliferative Neoplasms v.1.2025).

When a diagnosis of an MPN has been established, the main clinical concern is typically the risk for progression to a more severe malignancy (Szuber et al., 2019). Several studies have evaluated the genomic profiles of patients with stable MPNs compared with those whose disease progressed to blast phase. Even when testing is performed at the time of initial diagnosis, an increased number of genomic aberrations has been associated with an increased risk of disease progression to myelofibrosis or acute leukemia. The specific copy number variation may also help predict the type of progression for example, 1q and 9p deletions are associated with risk for myelofibrosis, and 3q, 5q, 7p, 7q, 19q, and 22q deletions are associated with acute myeloid leukemia (Kanagal-Shamanna et al., 2018). Traditionally, these copy number changes have been identified with karyotype or targeted FISH studies. Testing with chromosomal microarray has a higher resolution and can identify a higher proportion of MPN patients who have an increased risk of progression (Kanagal-Shamanna et al., 2018). However, this type of evaluation has not yet been incorporated into current practice guidelines in the United States. After diagnosis of an MPN is confirmed, NCCN guidelines recommend next generation sequencing (NGS) for mutational prognostication (NCCN, Myeloproliferative Neoplasms v.1.2025). NGS may also be useful to establish clonality in certain individuals, such as those with triple-negative non-mutated JAK2, MPL, and CALR (NCCN, Myeloproliferative Neoplasms v.1.2025; Palumbo et al., 2019). Unfortunately, even patients who have been categorized with a low risk of progression may still have a decreased life expectancy compared to the general healthy population (Szuber et al., 2019).

Polycythemia Vera

PV is a chronic myeloproliferative disease characterized by increased hemoglobin, hematocrit, and red blood cell mass. There is an associated increased risk for thrombosis and transformation to acute myelogenous leukemia or primary myelofibrosis; however, patients are often asymptomatic. The WHO criteria for diagnosis includes presence of the somatic JAK2 V617F pathogenic variant or functionally similar exon 12 pathogenic variant. Other diagnostic criteria include elevated hemoglobin and abnormal bone marrow morphology (Khoury et al., 2022; Arber et al., 2022; Thiele et al., 2023). The JAK2 V617F pathogenic variant is present in the vast majority (greater than 90%) of cases of PV. Functionally similar P/LP variants in JAK2 exon 12 account for most remaining cases of JAK2 V617F pathogenic variant-negative PV. These P/LP variants lead to sustained activation of the JAK2 protein, which causes excess red blood cell production, independent of erythropoietin levels. Together, they are identified in 98% of PV cases and lead to high diagnostic certainty (Barbui et al., 2015; Szuber et al., 2019). Absence of a JAK2 P/LP variant, combined with normal or increased serum erythropoietin level, greatly decreases the likelihood of a PV diagnosis.

Essential Thrombocythemia or Thrombocytosis

ET is a disorder of sustained increased platelet count, characterized by persistently elevated platelet count greater than 450,000 per microliter (Khoury et al., 2022; Arber et al., 2022; Thiele et al., 2023). Individuals will ET will demonstrate megakaryocytic hyperplasia (seen in bone marrow without evidence of reactive thrombocytosis), a JAK2 V617F or other clonal marker, and will not meet WHO criteria for CML, PV, PMF, MDS or other myeloid neoplasm. In addition, patients can have splenomegaly and a clinical course complicated by thrombotic or hemorrhagic episodes (or both) (Khoury et al., 2022; Arber et al., 2022; Thiele et al., 2023). Among the MPNs, ET tends to have a longer natural history and progression to acute myeloid leukemia is rare (Ayres-Silva et al., 2018). Survival rates among patients with ET are slightly higher than those of PV (Szuber et al., 2019).

The majority of patients with ET (60%) carry a somatic JAK2 V617F pathogenic variant. CALR P/LP variants are found in about 25% of cases, while a smaller percentage (5-10%) have activating P/LP variants in MPL. Up to 11% of patients with ET have triple negative disease, in which none of these three genes have detectable P/LP variants (Szuber et al., 2019). P/LP in CALR may suggest a more indolent course (Klampfl et al., 2013). It is important to note that JAK2, CALR, and MPL variant screening cannot alone distinguish ET from masked PV, prefibrotic/early primary myelofibrosis, or other causes of thrombocytosis. Therefore, bone marrow biopsy is important in the diagnostic workup of these conditions (Barbui et al., 2015).

Primary Myelofibrosis

PMF is a rare disorder in which the bone marrow is replaced with fibrous tissue, leading to bone marrow failure. Progression of the disease can include transformation to acute myeloid leukemia (Tefferi, 2018). Clinical features are similar to ET, and affected individuals can be asymptomatic in the early stages of the disease (Tefferi, 2018; Khoury et al., 2022; Arber et al., 2022). For such patients, treatment may not initially be necessary. Therapy for patients with PMF is generally symptomatic and aimed at preventing complications, though allogeneic hematopoietic stem cell transplant remains the only curative treatment for this condition (Tefferi, 2018).

Diagnosis of PMF is based on bone marrow morphology. Demonstration of somatic driver variants is supportive but not essential in the diagnostic workup (Tefferi, 2018). Somatic molecular markers in PMF patients are similar to those in patients with ET and include JAK2 V617F, MPL, and CALR. Somatic P/LP variants in JAK2, CALR, and MPL are identified in 55-67%, 15-20%, and 6-10% of cases, respectively (Szuber et al., 2019).

Additional genes may have diagnostic or prognostic significance for patients with PMF. The GIPSS (genetically-inspired prognostic scoring system) is a validated tool that uses molecular variant and karyotype data to predict prognosis and guide treatment (Tefferi, 2018). Specifically, NCCN guidelines note that somatic variants in ASXL1, EZH2, IDH1, IDH2, TET2, TP53, and SRSF2 have been independently associated with inferior overall and/or leukemia-free survival or leukemic transformation (NCCN, Myeloproliferative Neoplasms v.1.2025). The presence or absence of these markers may be of assistance making the diagnosis of PMF and/or in treatment decision-making for individuals with PMF who are being considered for allogeneic hematopoietic cell transplantation (Lasho et al., 2018; Wong and Pozdnyakova, 2019).

Chronic Neutrophilic Leukemia

CNL is a rare myeloproliferative neoplasm characterized by leukocytosis and hypercellular bone marrow. Patients with CNL are typically asymptomatic, or present only with fatigue (Venugopal and Mascarenhas, 2018). The diagnosis may be suspected when white blood cell count is greater than or equal to 25 × 10^9/L, of which more than 80% are neutrophils and less than 10% are circulating neutrophil precursors. Bone marrow biopsy will exhibit neutrophil granulocytes increased in percentage and number (Khoury et al., 2022; Arber et al., 2022). 

Historically, the diagnosis of CNL was often based on exclusion of any other identifiable cause of neutrophilia, including P/LP variants such as BCR-ABL1 and JAK2. WHO diagnostic criteria include the presence of somatic activating P/LP variants within the CSF3R gene (most commonly T618I) as one essential criteria for the diagnosis for CNL (Khoury et al., 2022).

Oncogenic P/LP variants in the CSF3R gene are found in greater than 60% of CNL patients (Khoury et al., 2022). These activating variants lead to preferential downstream kinase signaling. It has been proposed that individuals with CNL caused by CSF3R P/LP variants may derive clinical benefit from treatment with a JAK1/2 inhibitor such as ruxolitinib, though results of clinical trials have been varied (Venugopal and Mascarenhas, 2018). P/LP variants in SETBP1, ASXL1, SRSF2 and U2AF1 are also present in a large percentage of patients with CNL (Szuber et al., 2024; Szuber et al., 2020). The presence or absence of these markers may be of assistance in treatment decision-making for individuals with CNL who are being considered for allogeneic hematopoietic cell transplantation (Szuber et al., 2024). Currently, hematopoietic stem cell transplantation is the only curative treatment (Venugopal and Mascarenhas, 2018).

Hypereosinophilic Disorders

Hypereosinophilic disorders (HES) are hematological (primary or clonal) disorders of persistently elevated eosinophil count which may be associated with organ damage. Although sustained eosinophilia may impact nearly any organ system, dermatological symptoms are most common, followed by pulmonary, gastrointestinal, and cardiac (Shomali and Gotlib, 2022). Cardiac manifestations such as progressive heart failure are characterized by eosinophilic-mediated tissue damage which involves a multistep process of endocardial damage, platelet thrombus, fibrous thickening of the endocardial lining and eventual restrictive cardiomyopathy (Shomali and Gotlib, 2022). 

The WHO has defined criteria for the classification of the various subtypes of HES (Shomali and Gotlib, 2022). Disease prognosis and treatment relies on the identification of the specific subtype. There are four subtypes of HES: 1) myeloid/lymphoid neoplasms with PDGFRA rearrangement; 2) myeloid/lymphoid neoplasms with PDGFRB rearrangement; 3) myeloid/lymphoid neoplasms with FGFR1 rearrangement; 4) myeloid/lymphoid neoplasms with PCM1-JAK2 rearrangement (Shomali and Gotlib, 2022). Additionally, there is the “chronic eosinophilic leukemia, not otherwise specified” (CEL, NOS) MPN subtype which is separate from HES. The historical criteria for HES was arbitrarily defined as persistent and marked absolute eosinophil count (AEC) of greater than 1.5 × 10^9 /L in the peripheral blood for more than 6 months with tissue damage present (Shomali and Gotlib, 2022). However, as some patients must receive expedited treatment to minimize organ damage, the requirement that eosinophilia persist for more than 6 months is less consistently supported today (Shomali and Gotlib, 2022). Additionally, patients with lower eosinophil count can present with significant tissue involvement and end-organ damage (Shomali and Gotlib, 2022). 

To make a diagnosis of HES, secondary causes of eosinophilia must first be eliminated (these include infections, allergy/atopy, drug-reaction, collagen-vascular disease and metabolic disease) (Shomali and Gotlib, 2022). Once secondary causes have been eliminated, the work-up for primary eosinophilia includes an extensive evaluation of blood and/or bone marrow for serological and other laboratory features, including F1P1L1-PDGFRA fusion by FISH or RT-PCR (blood or marrow), T-cell receptor gene arrangement (blood or marrow), immunophenotyping (blood or marrow), NGS myeloid panel (blood or marrow), and standard karyotyping (marrow) among other things (Arber et al., 2022; Shomali and Gotlib, 2022). 

Juvenile Myelomonocytic Leukemia

Juvenile myelomonocytic leukemia (JMML) is a rare aggressive neoplasm of infancy or early childhood. Approximately 90% of JMML patients have either inherited or somatic P/LP variants in the RAS/MAPK pathway (PTPN11, KRAS, NRAS, CBL, or NF1). Molecular testing (germline and somatic) for these genes can be important in the diagnostic workup of children suspected to have JMML (Rudelius et al., 2023; Arber et al., 2022; Khoury et al., 2022).

Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Myeloproliferative Neoplasms v.1.2025. © National Comprehensive Cancer Network, Inc. 2025. All rights reserved. Accessed [March 26, 2025]. To view the most recent and complete version of the guideline, go online to NCCN.org.

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