Ropeginterferon Regimen Does Not Sustain Treatment-Free Remission in CML

Administering ropeginterferon-alfa 2b (Besremi) after tyrosine kinase inhibitor (TKI) discontinuation did not improve the rate of sustained treatment-free remission (TFR) among patients with chronic myeloid leukemia (CML), according to data from the phase 3 ENDURE trial (NCT03117816) published in Leukemia.¹

Among patients assigned to ropeginterferon-alfa 2b or observation following TKI discontinuation, the rates of molecular relapse-free survival (MRFS) were 73% (95% CI, 62%-81%) vs 67% (95% CI, 57%-75%), respectively, at 6 months, 64% (95% CI, 53%-73%) vs 60% (95% CI, 50%-69%) at 12 months, and 56% (95% CI, 45%-66%) vs 59% (95% CI, 49%-68%) at 24 months (HR, 1.024; 95% CI, 0.679-1.546; P = .91). Additionally, post hoc analyses among those with a first discontinuation attempt (n = 108) and a treatment duration exceeding 6 years demonstrated favorable TFR outcomes in the ropeginterferon-alfa 2b arm, although this did not show statistical significance.

“Although the ENDURE trial failed to confirm a benefit in its primary endpoint, it was crucial in objectively testing and contextualizing previous non-randomized or translational evidence that had suggested an interferon-related improvement in TFR rates,” lead study author Andreas Burchert, MD, from the Department of Hematology and Oncology at University Hospital Giessen and Marburg of Marburg University in Marburg, Germany, wrote with coauthors in the publication.¹ “In this sense, the ENDURE trial may be regarded as concluding the long-standing exploration of interferon-α [IFN]–based strategies in CML, pending a clearer mechanistic distinction between IFN- and TKI-associated pathways to TFR.”

In the international phase 3 ENDURE trial, 203 patients who initially experienced stable deep molecular remissions following TKI therapy were randomly assigned 1:1 to receive ropeginterferon alfa-2b at 100 µg subcutaneously every 2 weeks for 15 months (n = 95) or undergo observation alone (n = 108) after discontinuing TKI therapy.

The trial’s primary end point was MRFS, with relapse defined as the loss of major molecular remission (MMR).² Secondary end points included overall survival, adverse effects (AEs), and quality of life.

Patients 18 years and older with BCR-ABL–positive, CML in chronic phase and a transcript level of at least MR4 per international scale were eligible for enrollment on the trial. Other eligibility criteria included having adequate organ function and hematological parameters and no prior exposure to IFN.

Patients received prior TKIs for a median of 7.8 years (range, 2.5-19.7) before discontinuing treatment. The median duration of latest stable MR4 or better was 3 years (IQR, 2-5), and the median observation time for all patients was 36 months (IQR, 25-48) as of the data cutoff of June 2022.

Among 83 patients with available molecular data after restarting TKIs, the median time to re-achieving MMR was 3 months (IQR, 2-4). With a median observation time of 36 months (IQR, 25-48), no patients had disease progression, although 3 died after 9, 15, and 16 months. No deaths were related to CML.

At least 1 AE occurred in 86.1% (n = 174/202) of patients in the safety population, including 92.6% (n = 87) in the ropeginterferon-alfa 2b arm and 80.6% (n = 87) in the observation arm. Additionally, there were 32 and 26 grade 3/4 toxicities in the ropeginterferon-alfa 2b and observation arms, respectively. Regarding 21 patients with 29 reported serious AEs, 7 SAEs in 6 patients were potentially related to ropeginterferon-alfa 2b (n = 5) or surveillance (n = 2).

Overall, the investigators concluded that maintenance therapy with ropeginterferon-alfa 2b was well tolerated among patients with CML who experienced TFR. There were no new safety signals.

References

1. Burchert A, Nicolini FE, le Coutre P, et al. Randomized phase 3 trial of ropeginterferon alfa-2b versus surveillance after tyrosine kinase inhibitor discontinuation in chronic myeloid leukemia (ENDURE/CML-IX). Leukemia. Published online January 12, 2026. doi:10.1038/s41375-025-02859-1
2. ENDURE - efficacy and safety of AOP2014 with CML patients in remission (ENDURE-CML-IX). ClinicalTrials.gov. Updated March 31, 2023. Accessed January 26, 2026. https://tinyurl.com/3f8neeyb