The prognostic value of JAK2V617F burden for discontinuation of interferon-α2 in patients with myeloproliferative neoplasms

Abstract Background: Myeloproliferative neoplasms (MPNs) are characterized by clonal proliferation of myeloid cells, driven by somatic mutations such as JAK2V617F (JAK2). Pegylated Interferon-α2 (IFN) has the potential to induce hematologic and deep molecular responses, even with bone marrow normalization observed in some patients after approximately five years of monotherapy. Thus, a new MPN-era with “minimal residual disease” is emerging. We report a large series of MPN-patients, who discontinued IFN after sustained normalization of blood cell counts and a reduction of JAK2variant allele frequency (VAF). This study aimed to explore clinical and molecular factors predicting the feasibility of IFN discontinuation and assess their clinical implications. Methods: We conducted a retrospective review of medical records of patients treated with IFN during 2024 at Zealand University Hospital, Denmark. Inclusion criteria comprised a JAK2 VAF measurement within 3 months before or after the discontinuation, and regular follow-up blood sampling every 3 months to ensure sufficient longitudinal data. Hematologic responses were assessed based on blood cell counts, with complete hematologic responses (CHR) defined according to 2013 IWG-MRT and ELN criteria. Loss of CHR after discontinuation was defined as an event. The distribution of JAK2 VAF was skewed, with many low values and a few high outliers. Therefore, a log2-transformation was applied to achieve a more symmetric distribution and improve clinical interpretability by allowing interpretation per doubling of JAK2 VAF. Univariate Cox proportional hazards models were used for log2-transformed JAK2 VAF at the time of discontinuation, and for the duration of CHR in months prior to discontinuation to assess their association with the duration of the treatment holiday. Subsequently, these variables were combined in a multivariate Cox proportional hazards model to evaluate their independent prognostic value. Statistical significance was defined as P-values < 0.05. All analyses were performed in RStudio. Results: Fifty patients were identified who had discontinued IFN. The median age at MPN diagnosis was 55 years (IQR 50-65). Five patients had essential thrombocythemia, 44 polycythemia vera, and one primary myelofibrosis. The median JAK2 VAF at the time of IFN initiation was 42% (IQR 21-60), whereas it was 3% (IQR 0.85-5.6) at time of discontinuation. 36 patients were treated with IFN monotherapy, while 14 received combination therapy with IFN and ruxolitinib. The median follow-up time was 6.5 years (IQR 5.1-10.2). The univariate analysis (50 patients with 32 events) showed that both the log2-transformed JAK2 VAF at the time of discontinuation and the duration of CHR prior to the discontinuation were significantly associated with the risk of losing CHR during the discontinuation period. Specifically, a doubling in JAK2 VAF was associated with a 50% increased risk (HR 1.5, 95% CI: 1.2–1.8, P = 0.0002), while each additional month of CHR duration was associated with a 3% decreased risk of CHR loss (HR = 0.97, 95% CI: 0.95–0.99, P = 0.01). In the multivariate analysis, the log2-transformed JAK2 VAF remained an independent predictor of the risk of losing CHR during the treatment holiday (HR = 1.5, 95% CI: 1.2–1.9, P = 0.0007), while CHR duration showed a nonsignificant trend toward a protective effect (HR = 0.98, 95% CI: 0.96–1.0, P = 0.07). These findings suggest that JAK2 VAF is the most robust independent prognostic factor for the risk of relapse during the discontinuation period. IFN was reintroduced in all 32 patients who lost CHR after a median of 6 months (IQR 3-29). Response was restored in all relapsing patients, except for one patient who was referred for allogeneic bone marrow transplantation 4.8 years after reintroduction due to progression to myelofibrosis and detection of new additional mutations (including ASXL1), arguing against the development of IFN resistance in post-discontinuation relapses. No patients experienced thrombotic events during or after discontinuation of IFN. Conclusion: This study shows that discontinuation of IFN therapy is feasible in MPN-patients with sustained CHR. A low JAK2 VAF at the time of discontinuation identifies patients with a lower risk of early relapse. Importantly, IFN reintroduction restored response in all relapsing patients, except for one case, suggesting that IFN sensitivity is retained after treatment interruption.