Efficacy of Ropeginterferon Alpha 2b in Inducing Treatment Free Remission in Chronic Myeloid Leukemia - an International, Randomized Phase III Trial (ENDURE, CML-IX) of the German CML-Study Group

Background: Only a minority of chronic myeloid leukemia (CML) patients can eventually successfully discontinue tyrosine kinase inhibitor (TKI) therapy after achieving a stable deep molecular remission. Mechanisms underlying a durable treatment free remission (TFR) are not well understood but supposedly involve restoration of anti-CML immunity. It was therefore hypothesized that interferon alpha (IFN) - a potent inducer of Th1-immunity and prior standard therapy in CML - might improve the TFR probability. Randomized trials to improve TFR rates in CML are currently lacking. ENDURE, CML-IX (NCT03117816) is a multicenter, international phase III trial evaluating the role of a novel form of pegylated proline interferon-alpha 2b (ropeg-interferon-alpha, ropeg-IFN) in inducing TFR.

Patients and Methods: CML patients in stable deep molecular remission (MR⁴ or better for at least 12 months prior to screening) and with history of at least 3 years of TKI exposure were eligible to participate in this study. Patients in stable molecular remission could also be included if they had failed a former TKI discontinuation attempt (2^nd stopper). Patients were randomized 1:1 to receive either ropeg-IFN 100μg s.c. every 2 weeks for 15 months (ropeg-IFN arm) or no further treatment after TKI stop treatment (no treatment arm). The primary efficacy endpoint of the trial was molecular relapse free survival (MRFS) with molecular relapse being defined as loss of major molecular remission (MMR), which is any increase of the BCR::ABL1 transcript level to >0.1% according to the international scale (IS). Time to relapse is defined as the time from randomization to relapse. Secondary endpoints were MRFS at month 6, 12 and 24 after TKI discontinuation. BCR::ABL1 measurable residual disease (MRD) was monitored from peripheral blood and centrally assessed for all centers in Germany and locally at the French centers. There was a post study follow up to collect clinical and molecular data.

Results: Between May 2017 and June 2021, 203 evaluable patients (68 female, 135 male) with a median age of 55 years were randomized at 24 centers in Germany and 3 centers in France to receive ropeg-IFN (n=95) or no treatment (n=108) after TKI stop. For 77 patients in the ropeg-IFN arm (81%) and 86 patients in the no treatment arms (80%) it was their first TKI discontinuation attempt. At the time of data cut off in June 2022, the median observation time for all patients was 36 months. The hazard ratio (HR) of molecular relapse for the ropeg-IFN cohort versus the no treatment cohort was 1.03 (95% CI, 0.68 to 0.1.55; log-rank P=0.89). The Kaplan-Meier probabilities of molecular relapse free survival (MRFS) by 6, 12, and 24 months after TKI discontinuation were 73% (95%-CI: 62-81%), 64% (95-CI: 53-73%) and 56% (95%-CI: 45-66%) for the ropeg-IFN versus 67% (95-CI: 57-75%), 60% (95-CI: 50-69%) and 59% (95%-CI: 49-68%) for no treatment (Figure 1). The MRFS at months 6 and 12 after TKI stop (secondary endpoints) were 70% (95%-CI: 60-79%) and 64% (95%-CI: 53-73%) in 91 patients for ropeg-IFN group versus 65% (95-CI: 56-74%) and 59% (95-CI: 49-68%) in 107 and 104 patients for the no treatment group. Of 90 patients who were candidates for restarting TKI due to MMR loss, 82 patients were actually evaluable for TKI restart. Of those, 77 patients re-achieved at least MMR within 12 months (median time to reestablishing MMR was three months). Of the 5 patients who did not regain MMR, one patient withdrew consent and others were treated for only 1, 3, 4, and 11 months after TKI restart. Ropeg-IFN was well tolerated. Hematological and non-hematological WHO grade 3/4 toxicity occurred in 23 patients in the ropeg-IFN (31 adverse events) and in 20 patients in the no treatment arm (26 adverse events). Three deaths were reported on study which were unrelated to CML (cardiac arrest, fall from stairs, unknown). A detailed safety analysis will be presented at the meeting.

Conclusion: Ropeg-IFN maintenance after discontinuing TKI-monotherapy does not increase the proportion of patients, who persistently maintain at least an MMR. The German CML-V (TIGER) trial currently explores the impact of IFN maintenance on TFR when patients receive a combination of TKI plus IFN before TKI stop.

Burchert:Gilead: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; AOP Health: Honoraria, Research Funding. Saussele:Novartis: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Roche: Honoraria; Pfizer: Honoraria. Hochhaus:Incyte: Research Funding; Pfizer: Research Funding; BMS: Research Funding; Novartis: Research Funding. Gattermann:BMS: Honoraria; Celgene: Honoraria; Takeda: Research Funding; Novartis: Honoraria. Crysandt:Astra Zeneca: Honoraria; Novartis: Honoraria; Pfizer: Honoraria. Schafhausen:Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: e.g. travel support; AOP Orphan: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: e.g. travel support; Blueprint Medicines: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: e.g. travel support; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: e.g. travel support; Merck Serono: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: e.g. travel support; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: e.g. travel support; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: e.g. travel support; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: e.g. travel support; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: e.g. travel support; Sobi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: e.g. travel support. Radsak:Novartis: Honoraria; Cogent: Consultancy; CORAT: Consultancy; BMS: Honoraria; SOBI: Honoraria; Takada: Honoraria; AOP: Honoraria; Daiichi Sankyo: Honoraria. Goebeler:AMGEN, BMS, Janssen-Cilag, Novartis: Honoraria. Teichmann:Astellas: Consultancy; BMS: Consultancy, Honoraria; Pfizer: Consultancy; Sobi: Consultancy, Honoraria; AOP: Honoraria; Boehringer-Ingelheim: Honoraria; BeiGene: Other; Gilead: Other: n. Krause:Art-tempi: Honoraria; Kosmas: Honoraria; Abbvie: Other: Expenses. Klausmann:BMS , Novartis, Abvie, Biotest, Octapharm, Geron: Honoraria. Stegelmann:Incyte: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria; AOP Pharma: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Etienne:Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte Biosciences: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Göthert:Proteros Biostructures: Honoraria; zr pharma&: Honoraria; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; AOP Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Abbvie: Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees; Imago Bioscience: Membership on an entity's Board of Directors or advisory committees. Ernst:Janssen: Other: travel grant. Aminossadati:AOP Health: Research Funding. Wittenberg:AOP Health: Research Funding. Schade-Brittinger:AOP Health: Research Funding. le Coutre:Incyte: Honoraria; Novartis: Honoraria; Pfizer: Honoraria. Nicolini:Pfizer: Membership on an entity's Board of Directors or advisory committees; Incyte biosciences: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sun Pharma Ltd: Consultancy; KARTOS: Consultancy; Novartis Services, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

pegylated interferon alpha 2b to maintain molecular remission