Efficacy and safety of pegylated interferon alfa-2b combined with tyrosine kinase inhibitors in chronic Phase chronic myeloid leukemia patients with TKI resistance or intolerance

Abstract Background In the TKI era, long-term survival of chronic phase chronic myeloid leukemia (CP-CML) patients approaches that of the general population. However, approximately 10-15% of patients develop TKI resistance or intolerance. Optimizing therapy for this subset remains an unmet clinical need. Prior to TKIs, interferon alfa (IFNα) was first-line therapy for CML. Evidence suggests IFNα retains efficacy in TKI-resistant/intolerant patients, and combination with TKIs may improve rates of treatment-free remission (TFR). Methods This prospective, single-center,single-arm study enrolled chronic-phase chronic myeloid leukemia (CP-CML) patients with resistance or intolerance to tyrosine kinase inhibitors (TKIs). Participants received PEG IFNα-2b (90 μg subcutaneously every 10 days) added to standard-dose TKI therapy. Investigators titrated PEG IFNα-2b dosing and frequency based on individual tolerability. Treatment continued until achievement of major molecular response (MMR) or deep molecular response (DMR, defined as ≥MR4), disease progression, or unacceptable toxicity The primary endpoint is the proportion of patients achieving MMR and DMR with PEG IFNα-2b plus TKI therapy, analyzed using the per-protocol population. The secondary endpoint is the safety profile of the combination therapy. Results Twenty-two patients were enrolled (median age 26.0 years range 10-47;54.5% male). Median follow-up was 72 weeks (range 24-96).Prior TKIs included imatinib, nilotinib, dasatinib, flumatinib,and olverembatinib.By June 30,2025.Sixteen, fourteen, ten, and eight patients completed therapy at weeks 24,48,72,and 96,respectively.Nine patients discontinued treatment due to adverse events.Molecular responses:Week 24: MMR 37.5% (6/16),DMR 6.3%(1/16),Week 48:MMR57.1% (8/14);Week 72: MMR40.0% (4/10); DMR 30.0% (3/10);Week 96: MMR 50.0% (4/8),DMR 25.0% (2/8).Safety:The most common AEs were flu-like symptoms and hematologic toxicities (predominantly grade 1-2).Dose reductions or extended dosing intervals (up to q2 weeks) of PEG IFNα-2b were implemented to manage AEs. Conclusion PEG IFNα-2b combined with TKIs significantly reduces BCR::ABL1 transcript levels, enabling patients with TKI-resistant or intolerant chronic-phase chronic myeloid leukemia (CP-CML) to achieve major molecular response (MMR) and even deep molecular response (DMR), with a favorable safety profile. Keywords:leukemia, myeloid, chronic,tyrosine kinase inhibitors,resistance,intolerancePEG IFNα-2b