Rapid JAK2 V617F decline predicts response durability: Kinetics of JAK2 V617F in ropeginterferon alfa-2b treated polycythemia vera

Abstract Background: Polycythemia Vera (PV) is a hematopoietic stem cell (HSC) neoplasm defined by the JAK2 V617F mutation, characterized by clonal proliferation of erythroid, myeloid, and megakaryocyte cells. There is increasing evidence that the JAK2 V617F allele burden (JAK2) is linked not only to disease onset but also to increased risk of thrombosis and disease progression such as myelofibrosis (MF). Several studies have shown that bone marrow morphology and JAK2 V617F allele burden can normalize in some patients treated with long-term interferon (IFN) therapy. In particular, some MPN patients with JAK2 <10% and complete hematologic response (CHR) at discontinuation of IFN have maintained their long-term remission without treatment (Oliveira et al., Blood 2020;136). However, studies on JAK2 kinetics and the optimal IFN treatment duration required to mitigate risks of thrombosis or disease progression remain limited. Aims This study aimed to model JAK2 V617F kinetics in PV patients receiving ropeginterferon alfa-2b using serial JAK2 measurements, in order to estimate the treatment duration required to achieve a JAK2 allele burden <10%. We also evaluated whether rapid JAK2 decline was associated with sustained CHR and molecular responses (MR) and with the occurrence of events such as thrombosis, or MF. Methods This phase 2, single-arm, open-label, investigator-initiated clinical trial was conducted at 16 institutions in Korea. Patients were treated with a rapid dose escalation regimen of 250-350-500 mcg, increased every two weeks for up to 48 weeks. Dose intervals were then adjusted in patients who achieved at least one stable CHR. JAK2 V617F allele burden was measured every 12 weeks for at least 2 years using real-time PCR [ipsogen® JAK2 MutaQuant® kit]. To generalize JAK2 V617F kinetics at the population-level, JAK2 V617F kinetics modeling (linear, mono-, and bi-exponential decay models) was performed and the best-fit model was selected by adjusted R² value≥0.6. Maintenance was defined as sustained CHR or MR from the first visit at which the response was achieved, and maintenance loss as any subsequent loss of CHR or MR at scheduled 12-week visits. The Cox model assessed the risk of CHR or MR maintenance loss. Events were defined as the occurrence of thrombosis, or MF, and event-free survival was calculated using Kaplan-Meier method. Results Among 87 patients with ≥3 serial JAK2 data points, 46 patients showed mono-exponential kinetics, 16 bi-exponential, and 25 linear. Of 46 patients with mono-exponential kinetics, 37 patients with adjusted R² values≥0.6 were used to estimate population-level mono-exponential decay model. The estimated half-life of 178.33 days (95% CI 91.72-399.13 days), time to JAK2<10% was 486.1 days (95% CI 250-1088 days), and the time to JAK2 < 1% was 1078.5 days (95% CI 554.7 – 2413.9 days). Patients were stratified by half-life (cutoff: 178.33 days) into shorter half-life group versus longer half-life group. The shorter half-life group showed a trend toward a lower risk of CHR maintenance loss at 2 years (HR=0.19, 95% CI: 0.03-1.41, p=0.10) compared to the longer half-life group, and showed no MR loss throughout the follow-up period, whereas 9 MR-losses occurred in the longer half-life group. The event-free survival at 2-year was 92.44% (95% CI 86.28-99.04%) for the longer half-life group (1 cerebral artery stenosis, 1 cerebral infraction, 1 angina pectoris, 1 hematoma, and 1 MF) and 92.31% (95% CI 78.90-100.00%) for the shorter half-life group (1 coronary artery disease) (p=0.96).Conclusion: This study provides new information on JAK2 kinetics during ropeginterferon alfa-2b treatment with rapid dose escalation. JAK2 declines a mono-exponentially in many patients on ropeginterferon alfa-2b, with population-level reduction below 10% requiring approximately 486.1 days. These results suggest maintaining ropeginterferon alfa-2b treatment for at least 1.3 years to monitor the decline in JAK2. In addition, rapid JAK2 reduction may have a lower tendency for CHR loss and MR loss, suggesting that a treatment strategy that induces a rapid decrease in JAK2 may be important for long-term remission.