Achieving JAK2V617F vaf <20% is associated with prolonged event-free survival in polycythemia vera: A milestone of molecular response Free

Background:In chronic myeloid leukemia (CML), absolute BCR-ABL molecular thresholds serve as validated milestones to predict long-term clinical benefit. In polycythemia vera (PV), JAK2V617F variant allele frequency (VAF) is routinely measured and reflects clonal burden, but lacks similar standing as a therapeutic endpoint. In PV, VAF>50% is associated with increased risk of events¹, but current ELN guidelines limit molecular response assessment to patients with baseline VAF >20%, and emphasize a relative reduction in VAF. However, relative change is inherently ambiguous (e.g., 80% to 40% and 8% to 4% represent the same fold reduction but vastly different disease states)^2,3, and fails to capture the biological significance of achieving or maintaining low VAF. We hypothesized that achieving an absolute JAK2 VAF <20% at any point during the disease course would be associated with prolonged event-free survival (EFS), independent of starting VAF or treatment received.Methods:We analyzed 1058 samples from 214 patients with PV and serial JAK2V617F VAF measurements, linked to clinical outcomes, including myelofibrosis transformation, thrombosis, and death. The cohort was followed longitudinally with a median of 12.0 years. VAF values were categorized as ≤20% or >20%. Time-varying Cox proportional hazards models were used to evaluate associations between achieving VAF <20% at any time point (regardless of baseline) and time to MPN complication (EFS), with adjustments for age >60 at diagnosis and thrombotic history. Additional models explored interactions with baseline VAF category, age at time of first measured VAF, age at time of lowest VAF, and treatment exposure.Results:Achieving JAK2V617F VAF <20% at any time point was associated with significantly prolonged EFS (HR 0.40, 95% CI 0.20–0.77, p=0.006), with consistent results after adjusting for baseline VAF, age, and history of thrombosis. The benefit was more pronounced in patients who started with VAF >20% and subsequently declined (median EFS 18.3, p = 0.04), though patients who started and remained below 20% already had a better EFS (median EFS 27.1). Considering that VAF tends to increase by ~1% per year⁴, maintenance of low VAF defies this biology and is associated with improved outcomes. In contrast, patients who remained >20% or who rose >20% tended to experience earlier events, including myelofibrosis transformation (HR 2.54, p = 0.052). The association was especially strong for myelofibrosis-free survival (HR 0.31, 95% CI 0.12-0.77, p=0.012), suggesting that sustained molecular control may influence disease progression. While being older age at diagnosis (>60) remained a risk factor, the protective effect of achieving VAF <20% persisted across age strata. Unlike MFS, thrombosis-free survival was not linked to this JAK2-mutation milestone.Conclusions:Achieving JAK2V617F VAF <20%—whether through disease biology or therapeutic intervention—is independently associated with prolonged EFS in PV. This absolute molecular threshold avoids the ambiguity of relative change and applies to all patients, not just those with high baseline burden. These findings support the adoption of JAK2 VAF <20% as a molecular response milestone in PV clinical trials, analogous to milestone-based frameworks in CML. Prospective studies are needed to validate this threshold and determine its utility as a surrogate endpoint for disease-modifying activity.

References:

• Guglielmelli P, Loscocco GG, Mannarelli C, et al. JAK2V617F variant allele frequency> 50% identifies patients with polycythemia vera at high risk for venous thrombosis. Blood Cancer J. 2021;11(12):1-9.

• Harrison CN, Nangalia J, Boucher R, et al. Ruxolitinib Versus Best Available Therapy for Polycythemia Vera Intolerant or Resistant to Hydroxycarbamide in a Randomized Trial. Journal of Clinical Oncology. 2023;41(19):3534-3544.

• Kiladjian J, Klade C, Georgiev P, et al. Event‐free survival in early polycythemia vera patients correlates with molecular response to ropeginterferon alfa‐2b or hydroxyurea/best available therapy (PROUD‐PV/CONTINUATION‐PV). Hemasphere. 2025;9(5).

• Kiladjian JJ, Klade C, Georgiev P, et al. Long-term outcomes of polycythemia vera patients treated with ropeginterferon Alfa-2b. Leukemia. 2022;36(5):1408-1411.