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Purpose of Review <p>Polycythemia vera (PV) is a Philadelphia chromosome-negative myeloproliferative neoplasm (MPN) caused by a somatic gain-of-function mutation of the <i>Janus kinase2</i> (<i>JAK2)</i> gene in hematopoietic stem and peripheral blood cells, leading to erythrocytosis which is often accompanied by leukocytosis and thrombocytosis. Historically, PV management has mainly focused on maintaining hematocrit (HCT) levels below 45% to reduce major thrombotic risk, improving symptoms and monitoring disease progression. Phlebotomy alone or in combination with cytoreductive therapy, where indicated, form the current standard of care. This review explores the potential correlation between the depletion of neoplastic clones in patients with PV with the achievement of durable complete molecular remission (CMR), and long-term treatment effects on thrombotic events and survival, as well as implications for re-defining treatment goals.</p> &#xa0;Recent Findings <p>Past management practices do not ideally optimize outcomes for patients with PV. Specifically, these approaches do not adequately address the underlying risk of disease progression driven by the neoplastic cells carrying mutated <i>JAK2</i> and additional mutations.</p> <p>Patients with PV who are treated with interferon-based therapies can achieve complete hematologic response, together with a significant reduction of <i>JAK2</i>V617F Variant Allele Frequency (VAF). Continued reduction of the <i>JAK2</i>VAF may lead to CMR and is correlated with in vivo drug exposures and durable improvement of thrombotic risk, as well as increased probability of event-free survival (EFS). The results indicate that reduction in <i>JAK2</i>V617F VAF, and by extension depletion of neoplastic cells, is essential for favorable long term clinical outcomes in patients with PV.</p> Summary <p>Emerging data suggest a direct correlation between deep reduction in <i>JAK2</i>V617F VAF as a measure of suppressing neoplastic cells and improved probability of EFS and delayed disease progression. These observations suggest a treatment paradigm shift from solely managing symptoms and preventing thrombotic events, toward achieving durable clonal depletion with potential for remission and preventing transformation to myelofibrosis or acute myeloid leukemia.</p> <p>Integration of molecular biomarkers into risk-adapted treatment algorithms may enable personalized approaches to achieve deep molecular responses and durable disease modification in PV. Clonal molecular response, therefore, deserves attention as a biomarker of response that should be evaluated in clinical trials, as well as for treatment monitoring.</p>

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Emerging Significance and Implications of a Durable Complete Molecular Remission in the Treatment of Polycythemia Vera

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月8日

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  • Minghui Duan,
  • Prithviraj Bose,
  • Anthony M. Hunter,
  • Albert Qin,
  • Long Chang,
  • Wenxin Li,
  • Daoxiang Wu,
  • Raajit K. Rampal

摘要

Purpose of Review

Polycythemia vera (PV) is a Philadelphia chromosome-negative myeloproliferative neoplasm (MPN) caused by a somatic gain-of-function mutation of the Janus kinase2 (JAK2) gene in hematopoietic stem and peripheral blood cells, leading to erythrocytosis which is often accompanied by leukocytosis and thrombocytosis. Historically, PV management has mainly focused on maintaining hematocrit (HCT) levels below 45% to reduce major thrombotic risk, improving symptoms and monitoring disease progression. Phlebotomy alone or in combination with cytoreductive therapy, where indicated, form the current standard of care. This review explores the potential correlation between the depletion of neoplastic clones in patients with PV with the achievement of durable complete molecular remission (CMR), and long-term treatment effects on thrombotic events and survival, as well as implications for re-defining treatment goals.

 Recent Findings

Past management practices do not ideally optimize outcomes for patients with PV. Specifically, these approaches do not adequately address the underlying risk of disease progression driven by the neoplastic cells carrying mutated JAK2 and additional mutations.

Patients with PV who are treated with interferon-based therapies can achieve complete hematologic response, together with a significant reduction of JAK2V617F Variant Allele Frequency (VAF). Continued reduction of the JAK2VAF may lead to CMR and is correlated with in vivo drug exposures and durable improvement of thrombotic risk, as well as increased probability of event-free survival (EFS). The results indicate that reduction in JAK2V617F VAF, and by extension depletion of neoplastic cells, is essential for favorable long term clinical outcomes in patients with PV.

Summary

Emerging data suggest a direct correlation between deep reduction in JAK2V617F VAF as a measure of suppressing neoplastic cells and improved probability of EFS and delayed disease progression. These observations suggest a treatment paradigm shift from solely managing symptoms and preventing thrombotic events, toward achieving durable clonal depletion with potential for remission and preventing transformation to myelofibrosis or acute myeloid leukemia.

Integration of molecular biomarkers into risk-adapted treatment algorithms may enable personalized approaches to achieve deep molecular responses and durable disease modification in PV. Clonal molecular response, therefore, deserves attention as a biomarker of response that should be evaluated in clinical trials, as well as for treatment monitoring.