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877 Increased LFS Following Hematopoietic Cell Transplantation As Compared to Conventional Consolidation Therapy in Patients >60 Years with AML in First Complete Remission and a Matched Donor: Results of a Randomized Phase III StudyClinically Relevant Abstract

Program: Oral and Poster Abstracts
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
Monday, December 12, 2022: 2:45 PM

Dietger Niederwieser, MD1, Dirk Hasenclever, PhD2*, Wolfgang E. Berdel, MD3, Bart J Biemond4, Haifa Kathrin Al-Ali, MD5*, Yves Chalandon, MD6,7, Michel Van Gelder, MD, PhD8, Christian Junghanss, MD9*, Goesta Gahrton, MD, PhD10, Mathias Haenel, MD11*, Rüdiger Hehlmann, MD12, Thomas Heinicke, MD13*, Andreas Hochhaus14, Simona Iacobelli15,16*, Rien van Marwijk Kooy17*, Nicolaus Kröger, MD18*, Jeroen J.W.M. Janssen, MD, PhD19*, Madlen Jentzsch, MD20*, Frank Breywisch21*, Mohamad Mohty, MD PhD22, Stavroula Masouridi-Levrat, MD23*, Gert Ossenkoppele, MD, PhD24*, Jakob Passweg, MD25*, Wolfram Pönisch, MD26*, Johannes Schetelig, MD, MSc27, Christoph Schliemann, MD28*, Sebastian Schwind, MD29*, Matthias Stelljes, Prof. Dr. med.30, Peter JM Valk, PhD31, Bob Lowenberg, Prof MD PhD32,33,34 and Jan J. Cornelissen, MD, PhD35

1University Leipzig, Leipzig, DEU
2Institute for Medical Informatics, Statistics and Epidemiology (IMISE) for the Clinical Trial Centre 04107 Leipzig, Germany, University of Leipzig, Leipzig, DEU
3Department of Medicine A, Hematology and Oncology, University Hospital Muenster, Muenster, Germany
4Department of Hematology, Amsterdam UMC location University of Amsterdam, Amsterdam, Netherlands
5University Leipzig, Leipzig, Germany
6Geneva University Hospitals, Geneva, Switzerland
7Translational Research Center for Oncohematology, Faculty of Medicine, University of Geneva, Geneva, Switzerland
8Department of Hematology, University Hospital Maastricht, Maastricht, Netherlands
9Departement of Medicine III - Hematology, Oncology, and Palliative Care, University of Rostock, Rostock, Germany
10Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden
11Department of Hematology, Oncology and Bone Marrow Transplantation, Klinikum Chemnitz, Chemnitz, Germany
12Clinical Investigation Center, European Leukemia Net, Weinheim, Germany
13Department of Hematology and Oncology, University Hospital Magdeburg, Magdeburg, Sachsen-Anhalt, Germany
14Department of Internal Medicine 2, Hematology and Oncology, Jena University Hospital, Jena, Germany
15Department of Biology, Centro Di Biostatistica E Bioinformatica Università Tor Vergata, Rome, Italy
16Rome University Tor Vergata, Rome, Italy
17Isala Ziekenhuis Zwolle, Zwolle, Netherlands
18UKE, Hamburg, AL, DEU
19VU University Medical Center, Amsterdam, NLD
20Department for Hematology, Cell Therapy and Hemostaseology, University of Leipzig Medical Center, Leipzig, Sachsen, Germany
21Department of Hematology, Oncology and Palliative Care, Ernst Von Bergmann Hospital, Potsdam, DEU
22EBMT Paris study office / CEREST-TC, Paris, France, Department of Hematology, Saint Antoine Hospital, Paris, France, INSERM UMR 938, Sorbonne University, Paris, France
23Department of Hematology, Geneva University Hospitals, Geneva, Switzerland
24VU University Medical Centers, Amsterdam University Medical Centers, Amsterdam, Netherlands
25University Hospital, Hematology, Basel, Switzerland, Basel, Switzerland
26Department of Hematology and int. Oncology, University of Leipzig, Leipzig, Germany
27Department of Internal Medicine I, University Hospital Carl Gustav Carus, Dresden, Germany
28Department of Hematology, Oncolog and Pneumology, University of Münster, Münster, Germany
29Department for Hematology, Cell Therapy and Hemostaseology, University of Leipzig Medical Center, Leipzig, Saxonia, Germany
30University of Muenster, Muenster, DEU
31Department of Hematology, Erasmus University Medical Center, Rotterdam, Netherlands
32Erasmus University Medical Center, Rotterdam, NLD
33Erasmus MC Cancer Institute, Rotterdam, Netherlands
34Erasmus University Medical Center Rotterdam and Erasmus MC Cancer Institute, Rotterdam, Netherlands
35Erasmus University Medical Center Cancer Institute, Rotterdam, Netherlands

Background: Acute myeloid leukemia (AML) has a dismal prognosis especially in elderly patients where the incidence is highest. In particular the reduced complete remission (CR) and the very high relapse rates (>80%) result in long-term survival of 20% or less. Allogeneic stem cell transplantation (SCT) is the treatment modality with the highest anti-leukemic potential, combining immunological anti-leukemia effects with preparative regimens of variable intensities. Retrospective analyses and comparisons with alternative treatments have indicated a possible advantage of SCT, but selection biases remain a concern. Since randomized trials have been lacking, we investigated the role of SCT in comparison to non-SCT consolidation in an international, multicenter, open label, and randomized phase III trial (EudraCT-Number: 2007-003514-34).

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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