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Identifying the JAK2^V617F mutation has improved understanding of what causes overproduction of red blood cells, platelets, and neutrophils in polycythemia vera.

Advancements in the last 2 decades have shifted how clinicians approach the assessment and management of polycythemia vera (PV). A pivotal factor in the change was the discovery of the V617F mutation in the Janus kinase 2 (JAK2) gene in 2005, according to a paper in memo — Magazine of European Medical Oncology.

Identifying the JAK2^V617F mutation led to a better understanding of what causes the overproduction of red blood cells, platelets, and neutrophils in patients with PV. It also clarified the characteristics of JAK2^V617F heterozygote and homozygote cells and their clonal growth features in PV.

“Today, there is an emphasis on risk assessment in PV that goes beyond traditional blood count metrics to also include the specific impact of the JAK2^V617F allele burden, which influences both thrombosis risk and disease progression,” Michael Doubek, PhD, and colleagues wrote.

Managing the variant allele frequency (VAF) of JAK2^V617F is crucial in the care of patients with PV. Clinical trials have shown direct associations between reducing VAF and better outcomes, specifically improved blood count control, lowered thrombosis risk, and slowed PV progression.

Impact of JAK2^V617F on PV Treatment

However, “treatments that neither target the clonal expansion of JAK2^V617F nor decrease JAK2^V617F VAF are not fully addressing the risks of thrombosis and disease progression,” the authors wrote. “Here, critical opportunities for the implementation of disease-modifying therapies are missed.”

Prolonged administration of PV treatment is necessary for molecular response. However, this can lead to problems with tolerability, immune suppression, and cancer development.

“In this context,” the authors advised, “continued exposure to treatments that place JAK2^V617F hematopoietic stem cells under selection stress without effectively suppressing clonal growth may select for mutations that drive disease progression or even the development of [acute myeloid leukemia].”

PV treatment algorithms are expected to evolve as emerging and encouraging evidence on new medications and novel therapies continues to grow, according to the paper. The medical community’s knowledge of and impact on patient outcomes is also expanding.

“Ultimately, through the understanding of these molecular origins, we will pave the way for more effective therapies giving [patients with PV] and those with clonal hematopoiesis of indeterminate potential the best chance to live a long and normal life, without the burden brought about by their medical condition,” Dr. Doubek and colleagues wrote.