JAK Inhibition in PV Management: Evidence and Clinical Application

Summary for Physicians: Influence of Clinical Trial Data on Second-Line Therapy in PV

Clinical trial data has significantly shaped the approach to second-line therapies in polycythemia vera (PV), offering more targeted and effective treatment options for patients who fail to respond to first-line cytoreductive therapies such as hydroxyurea.

Key Influences From Clinical Trials on Second-Line Therapy:

1. Ruxolitinib (JAK Inhibitor):

• Clinical trials such as the COMFORT-I and COMFORT-II studies have established ruxolitinib as a pivotal second-line therapy for PV, particularly for patients with symptomatic splenomegaly or those who are resistant or intolerant to hydroxyurea (HU).

• Efficacy: Ruxolitinib has shown significant improvements in controlling hematocrit, reducing splenomegaly, and improving quality of life in these patients.

• Indication: This drug is especially beneficial in patients who have poor symptom control, splenomegaly, or refractory disease despite first-line treatments.

1. Interferon-Based Therapy:

• Clinical trial data has highlighted the long-term benefits of pegylated interferon in younger patients and those with a desire for a potentially more disease-modifying therapy.

• Efficacy: Trials such as the PRIMRATE study have shown that interferon can be effective in achieving molecular remission and controlling PV in patients who fail hydroxyurea, especially when a nonmutagenic treatment is preferred (eg, for women of childbearing age or those with significant long-term risks from HU).

• Indication: Interferon is an important second-line option, particularly in younger patients who wish to preserve fertility or avoid long-term HU use.

1. Evolving Understanding of Resistance and Intolerance:

• Clinical trials have provided clarity on when to switch therapies, including assessing resistance (eg, rising hematocrit or leukocytosis) or intolerance (eg, adverse effects from hydroxyurea). This has led to a more individualized approach to therapy, with ruxolitinib and interferon emerging as key alternatives for patients in these situations.

1. Molecular and Genomic Insights:

• Data from clinical trials exploring mutations beyond JAK2 (eg, TET2, ASXL1) has further refined our understanding of prognostic risk and may guide second-line therapy in the future. Patients with high-risk mutations or those who progress to secondary myelofibrosis may benefit from ruxolitinib or a combination of therapies aimed at reducing disease burden and improving survival.

Conclusion: Clinical trial data has significantly broadened the treatment options for PV patients who require second-line therapy. Ruxolitinib and interferon represent the most common second-line choices, with the decision largely driven by patient characteristics, disease features, and the presence of adverse factors such as intolerance or resistance to initial therapies.