Molecular response and outcomes in patients with myeloproliferative neoplasms treated with interferon in the real-world setting.

6586 Background: Myeloproliferative neoplasms are clonal stem cell disorders driven by constitutive JAK-STAT signaling, classically via acquisition of the JAK2 V617F mutation. JAK2 variant allele frequency (VAF) correlates with disease phenotype and clinical risk. Interferon (IFN) therapies are immunomodulatory agents with disease-modifying potential, demonstrating reductions in JAK2 allele burden in limited prospective trials. However, IFN therapies are underutilized in clinical practice, and molecular responses are poorly defined. Therefore, we evaluated clinical outcomes and molecular response to IFN therapy in real-world practice, emphasizing long-term JAK2 VAF kinetics. Methods: We conducted a single-center, retrospective study of consecutive patients diagnosed with essential thrombocythemia (ET), polycythemia vera (PV), or pre-fibrotic myelofibrosis (pre-MF) treated with peginterferon alfa-2a or ropegintereron alfa-2b, regardless of prior therapy. Serial JAK2 V617F was measured in peripheral blood using allele-specific PCR. Clinical outcomes, treatment persistence, and longitudinal molecular responses were evaluated. Results: Eighty-two patients were included (median age 50.5 years, 73% female), with diagnosis of PV (76.8%), ET (17.1%), or pre-MF (6.1%); 44 patients (53.7%) were treatment naïve. Median follow-up was 92 mos. from diagnosis and 59 mos. from IFN initiation. At 48 mos., 82% of patients remained on treatment; 12 patients (14.6%) discontinued due to intolerance. Disease progression occurred in one patient. Complete hematologic remission (CHR) was achieved in 80.5% of patients. Median baseline JAK2 VAF was 28%, declining to a median nadir of 4.2% at 41.5 months. Median absolute and relative percent reductions were -18.7 and -81.6%, respectively. VAF reduction ≥50% was achieved by 79% of patients, 19.5% achieved a nadir <1%, and 53.2% achieved nadir <5%. VAF declined progressively until 48 mos. and then remained stable through 72 mos., with later increases mostly attributable to treatment discontinuation. No baseline clinical, molecular, or treatment-related variables predicted depth of molecular response. Treatment-free remission (TFR) was attempted in seven patients after a median of 45 mos. of therapy (mean VAF 0.52%), and median TFR duration was 39 mos. Conclusions: This real-world analysis demonstrates that interferon therapy is feasible and effective in real-world practice. Most patients achieved durable CHR with low rates of treatment discontinuation. Disease progression was exceedingly rare. IFN was associated with substantial and sustained reductions in JAK2 allele burden, supporting its disease-modifying activity outside of the trial setting. These findings reinforce the clinical relevance of serial molecular monitoring and inform emerging approaches to treatment de-escalation in select patients.