Type: Oral
Session: 732. Allogeneic Transplantation: Disease Response and Comparative Treatment Studies: Clinical Outcome: Results of Large Prospective Studies
Hematology Disease Topics & Pathways:
Clinical Practice (Health Services and Quality), Combination therapy, Therapies, therapy sequence
Methods: Newly diagnosed AML patients 60-75 years of age were treated with induction therapy with initiation of a donor search on reaching CR1. Following one consolidation therapy, patients underwent cytogenetic/molecular and comorbidity evaluation and patients with a related or unrelated donor were randomized to SCT or non-SCT (2:1 ratio). SCT was performed after conditioning with fludarabine/200 cGy total body irradiation and cyclosporine /mycophenolate mofetil immunosuppression as previously published (Hegenbart U et al JCO 2006). Non-SCT consolidation was administered according to local protocols. Primary endpoint was leukemia free survival (LFS), secondary endpoints included cumulative incidence of relapse (RI), treatment related mortality (TRM), overall survival (OS) and complications including graft-versus-host disease (GVHD). At the planned first interim analysis based on data from 78 patients, we noted that the LFS was markedly worse than expected, and that the proportional hazard assumption was clearly wrong. The original sample size target of n = 231 was reset to n = 150. Statistical analysis was refocused on the difference in Restricted Mean (RM)-LFS within a time frame of 5 years. The analysis followed the intent to treat principle.
Results: From 2010 to 2017, 245 patients in CR1 (median age 67 years) were registered. After consolidation, 66 patients (29%) failed screening because of relapse/noCR1/no hematological recovery (40.9%), morbidity/informed consent withdrawal/unknown (39.4%), no donor/protocol violation (10.6%) and death (9.1%). Of the remaining 179 patients, 135 (75.4%) had an HLA identical donor and 125 were randomized to SCT (n=83) or non-SCT (n=42). Ten patients were not randomized because they rejected trial participation (n=9) or exposed significant comorbidity (n=1). The recommended time intervals from randomization to SCT (4 weeks) or non-SCT (2 weeks) as defined in the protocol were achieved by 40% and 48% of patients, respectively. The proportions of patients not receiving treatment according to randomization was 20.5% in the SCT arm (relapse n=7; morbidity n=4; withdrawal n=3; unavailable donor n=3) and 16.7% in the non-SCT (relapse n=2; morbidity n=2; withdrawal n=3). After a follow-up of 62 months, the 5-year LFS rates were 28.8% (95%CI: 20.4-40.6) in the SCT and 8.9% (95%CI: 3.1-25.7) in the non-SCT arm. There was a statistically significant difference of 8.9 months (95%CI: 1.3-16.6; p = 0.02) in the primary endpoint RM-LFS favoring SCT (p = 0.02) in multivariate analysis adjusted for donor type and cytogenetic risk (p= 0.01; Figure 1A). RI amounted to 37.8% (95%CI: 27.2-48.4) and 91.1% (95%CI: 80.7-100.0) at 60 months as shown in Figure 1B [HR: 3.1 (1.93-4.98) p<0.0001] and TRM to 26.8% (95%CI: 17.1-36.5) and 0% (95%CI: n.a.-n.a) at 24 months (Figure 1C) in the SCT and non-SCT arm, respectively. Causes of death included infections (39.4%) and GVHD (21.5%). Overall, 12.1% of transplanted patients showed grade III/IV acute GVHD and 37.9% extensive chronic GVHD. OS curves crossed at about 18 months. 5-years OS was 31.3% (95%CI: 22.6-43.2) in the SCT arm and 27.1% (95%CI [15.9-46.4]) in the non-SCT arm. However, 23 of 34 (68%) relapsed non-SCT patients received SCT as part of second line treatment.
Conclusion: This randomized trial demonstrates that SCT is superior to non-SCT consolidation treatment for LFS in elderly AML patients in CR1 on a time horizon of five years. SCT substantially reduces RI that outweighs the associated increased TRM.
Disclosures: Biemond: CSL Behring: Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Membership on an entity's Board of Directors or advisory committees; Chiesi: Membership on an entity's Board of Directors or advisory committees; Modus Therapeutics: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Sanquin: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; GBT: Membership on an entity's Board of Directors or advisory committees, Research Funding. Al-Ali: Abbvie: Consultancy; Deutsche Leukämie und Lymphom Stiftung: Other: Grants and Contracts; BMS: Other: Grants and Contracts; Incyte: Other: Grants and Contracts; Novartis: Consultancy, Honoraria, Other: Support for attending meetings and/or travel and Participation on a Data Safety Monitoring Board or Advisory Board; AOP: Consultancy, Other: Support for attending meetings and/or travel. Chalandon: BMS: Other: consulting fees; Roche: Other: consulting fees + travel support; Amgen: Other: consulting fees + travel support; Astra-Zeneca: Other: consulting fees + travel support; Novartis: Other: consulting fees; Abbvie: Other: consulting fees + travel support; Jazz: Other: consulting fees+ travel support; Gilead: Other: consulting fees + travel support; Pfizer: Other: consulting fees; Incyte: Other: consulting fees + travel support; MSD: Other: consulting fees+ travel support; Servier: Other: consulting fees; Janssen: Other: Travel support. Gahrton: Fujimoto Pharmaceutical Corporation: Membership on an entity's Board of Directors or advisory committees. Haenel: Takeda: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Pfizer: Honoraria; Roche: Consultancy, Honoraria; JAZZ: Consultancy, Honoraria. Hochhaus: Novartis: Research Funding; Pfizer: Research Funding; Bristol Myers Squibb: Research Funding; Incyte: Research Funding. Kröger: Takeda: Consultancy, Honoraria; Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Amgen: Honoraria; DKMS: Research Funding; Riemser: Research Funding; Neovii: Honoraria, Research Funding; Kite: Honoraria; Sanofi: Honoraria; Jazz: Honoraria. Janssen: Roche: Speakers Bureau; Ellipses Pharma: Research Funding; Avillion: Research Funding; Glycomimetics: Research Funding; Uppsala County Council: Research Funding; Pfizer: Consultancy; Incyte Biosciences Benelux BV: Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Research Funding. Jentzsch: Novartis: Honoraria. Mohty: Takeda: Honoraria; Pfizer,: Honoraria; Oncopeptides: Honoraria; Amgen: Honoraria; Astellas: Honoraria; Novartis: Honoraria; Adaptive Biotechnologies: Honoraria; GSK: Honoraria; Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Jazz Pharmaceuticals: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Gilead: Honoraria; Janssen: Honoraria, Research Funding. Schetelig: Abbvie: Honoraria; BMS: Honoraria; Janssen: Honoraria; AstraZeneca: Honoraria; BeiGene: Honoraria; DKMS: Current Employment; TU Dresden, Medical Department I: Current Employment. Schliemann: Jazz: Consultancy, Research Funding; BMS: Consultancy, Other: travel grants; Boehringer-Ingelheim: Research Funding; Astrazeneca: Consultancy; Astellas: Consultancy; Abbvie: Consultancy, Other: travel grants; Philogen S.p.A.: Consultancy, Honoraria, Research Funding; Novartis: Consultancy; Roche: Consultancy; Pfizer: Consultancy. Schwind: Novartis: Honoraria. Stelljes: MSD: Consultancy, Honoraria; Jazz: Honoraria; Kite: Consultancy, Honoraria; MSD Sharp & Dohme: Consultancy; Medac: Honoraria; Novartis: Consultancy, Honoraria; Amgen: Consultancy; Pfizer: Consultancy, Honoraria, Research Funding. Lowenberg: AbbVie: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Catamaran Bio Inc.: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Clear Creek Bio: Consultancy, Honoraria; F. Hoffmann La Roche: Membership on an entity's Board of Directors or advisory committees; Catamaran Bio Inc.: Membership on an entity's Board of Directors or advisory committees.
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