A randomized study of ropeginterferon in combination with bosutinib in newly diagnosed chronic myeloid leukemia (CML) patients in chronic Phase. the bosupeg trial from the Nordic CML study group Free

Prior studies combining pegylated interferon-α to Imatinib and Nilotinib in newly diagnosed CML patients have indicated an additive effect with faster and deeper molecular responses (SPIRIT, TIGER, NordCML002, NiloPEG). In this trial we used a bosutinib (BOS) backbone combined with low-dose ropeginterferon alfa-2b (BESREMi, AOP Health), which in contrast to previously tested interferons has a longer half-life and a more favorable tolerability profile. The aim was to investigate efficacy and tolerability of the combination, with the goal of deepening molecular response to eventually allow a higher proportion of patients to achieve treatment free remission.

Patients were in 1st chronic phase and TKI-naïve. Inclusion criteria were standard including good organ function without history of liver, autoimmune or psychiatric disease. Based on clinical experience to improve tolerability, BOS was introduced at 200 mg OD and the dose titrated to 400 mg OD if tolerated. At month 3 (M3), patients who tolerated ≥300 mg OD and had transaminase levels grade ≤1 were randomized 1:1 for addition of ropeginterferon 50 μg every second week or not. The primary endpoint was MR4 at M12 in the intention-to-treat (IIT) population (all randomized patients). Other endpoints were safety and other response levels (e.g. MR4.5). Data up to M12 are presented. We also examined the response and tolerability of BOS up to M3 as the ramp-up dosing is not standard although frequently used in the clinic.

163 patients were included from 2019 to 2023 in 18 hospitals in Denmark (6), Finland (1), Norway (4) and Sweden (7). Despite gradual up-titration of BOS, many patients experienced toxicity as described in the BOS prescribing information, including grade 2, 3 and 4 transaminase elevations (11%; 16%; 3%). Dose reduction or interruption were insufficient to manage transaminase elevations, which frequently recurred upon BOS re-exposure. Compared with data from the BOS registration study (BFORE), GI AEs were less frequent with our present schedule. Twenty-seven % of patients could not be randomized: 15% for transaminitis, 4% for GI AEs and 8% for other reasons including inability to tolerate BOS 300mg OD. Non-randomized patients had M3 responses on par with randomized patients, indicating no harm of the dosing strategy despite the lower or intermittent BOS dose. Their responses at M6, M9 and M12 were similar to the standard arm.

At M3, 118 patients were randomized, 58 to BOS and 60 to the combination. AEs were distributed evenly between study arms, but hematological toxicity (grades 3-4, 6.7% vs 0%), neuropsychiatric disorders (grade 2, 13% vs 4%) and infections grade 3-4 (13% vs 0%) were more frequent in the combination arm. Of note, transaminase elevations were similarly distributed, but analysis of attributability to the study drugs is ongoing and will be updated

Overall, efficacy in the present study compared favorably with previous experience with BOS. The combination arm demonstrated a clear trend for faster and deeper response at all time points: The combination arm compared with the standard arm showed MR4 or better in 22.0% vs 13.8% at M6, 32.8% vs 17.2% at M9, and 38.3% vs 31.0% at M12. Attainment of MR4.5 or better was at M6, M9 and M12, 11% vs 5,2%, 22,4% vs 6,9% and 31,7% vs 20,7%, respectively. Discontinuation of treatment occurred in 22% of patients in the combination arm and 8,3% in the standard arm, of whom 11,5% and 5% for treatment resistance. The primary endpoint in the IIT dataset was not statistically significantly different between treatment arms; note that all patients were included in the ITT analysis even if no interferon was administered or the TKI was switched. Most switched patients received 1^st and 2^nd generation TKIs, but some were transplanted or received ponatinib. A per protocol analysis and data on drug exposure will be presented at the meeting.

The step-up dosing strategy for BOS reduced GI toxicity, but not transaminitis. Efficacy was excellent in comparison with the registration study (BFORE). The combination of ropeginterferon and BOS was safe and efficacious. Responses occurred earlier and were deeper with the combination.