What are the implications of a JAK2 (Janus kinase 2) negative mutation in Polycythemia Vera (PV)?

From the Guidelines

JAK2-negative polycythemia vera (PV) mutations require comprehensive genetic testing beyond standard JAK2V617F screening, including JAK2 exon 12 sequencing, and management follows the same principles as JAK2-positive disease, with phlebotomy, low-dose aspirin, and cytoreductive therapy for high-risk patients. The presence of alternative mutations such as exon 12 mutations in the JAK2 gene, CALR mutations, or MPL mutations can be identified in these cases 1.

Diagnosis and Management

• Diagnosis requires comprehensive genetic testing to identify alternative mutations
• Management includes phlebotomy to maintain hematocrit below 45%, low-dose aspirin for thrombosis prevention, and cytoreductive therapy for high-risk patients
• Cytoreductive therapy options include hydroxyurea, interferon-alpha, or ruxolitinib, with hydroxyurea and interferon-alpha recommended as first-line treatments for high-risk patients 1

Prognosis and Monitoring

• Regular monitoring of blood counts and thrombotic risk is essential regardless of mutation status
• The clinical course can be similar to JAK2-positive disease, with a risk of thrombotic events and transformation to myelofibrosis or acute myeloid leukemia
• Prognostic scoring systems, such as the International Prognostic Scoring System (IPSS), can be used to predict survival and guide management decisions 1

Treatment Considerations

• Hydroxyurea is a well-known cytoreductive agent with good efficacy and tolerance in most patients, but may have a leukaemogenic risk with prolonged exposure 1
• Interferon-alpha has been shown to induce a high rate of haematological response and reduce the malignant clone, but is not approved for the treatment of PV 1
• Ruxolitinib, a JAK2 inhibitor, can be effective in reducing symptoms and improving quality of life, but its use in JAK2-negative PV is not well established 1

From the Research

Jak2 Negative PV Mutations

• The majority of Polycythemia Vera (PV) cases are associated with a JAK2 gene variant, with over 95% of patients having this mutation 2.
• However, there are cases where PV patients test negative for the JAK2 mutation, and other mutations such as TET2, ASXL1, SRSF2, IDH2, RUNX1, and U2AF1 may be present 3.
• These alternative mutations can have prognostic significance, with some being associated with adverse outcomes 3.
• The diagnosis of PV in JAK2 negative cases may require additional testing, such as bone marrow examination and morphologic confirmation 3.
• Treatment options for JAK2 negative PV patients are similar to those for JAK2 positive patients, with a focus on reducing thromboembolic events and minimizing the risk of myelofibrosis and acute leukemia 4.
• JAK inhibitors, such as ruxolitinib, may be effective in treating PV patients, including those with JAK2 negative mutations, although their use is currently approved for high-risk PV patients inadequately controlled by or intolerant to hydroxyurea 5.

Clinical Characteristics and Treatment

• PV patients, including those with JAK2 negative mutations, may present with erythrocytosis, leukocytosis, thrombocytosis, splenomegaly, pruritus, and constitutional symptoms 2, 6.
• Treatment goals include reducing thromboembolic events, minimizing the risk of myelofibrosis and acute leukemia, and alleviating symptoms 2, 6.
• Phlebotomy and low-dose aspirin are commonly used in the treatment of PV, with cytoreductive therapy reserved for high-risk patients 2, 4.
• JAK inhibitors, such as ruxolitinib, may be used in high-risk PV patients, including those with JAK2 negative mutations, to reduce splenomegaly and alleviate symptoms 5.