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1787 Comparative Study of Treosulfan Plus Fludarabine (FT14) with Busulfan Plus Fludarabine (FB4) for Acute Myeloid Leukemia in First or Second Complete Remission: An Analysis from the European Society for Blood and Marrow Transplantation (EBMT) Acute Leukemia Working Party (ALWP)

Program: Oral and Poster Abstracts
Session: 721. Allogeneic Transplantation: Conditioning Regimens, Engraftment and Acute Toxicities: Poster I
Hematology Disease Topics & Pathways:
Adults, AML, Clinical Research, Clinically Relevant, Diseases, Real World Evidence, Therapies, Registries, Myeloid Malignancies, Study Population
Saturday, December 11, 2021, 5:30 PM-7:30 PM

Eleni Gavriilaki, MD, PhD1, Ioanna Sakellari2*, Myriam Labopin3*, Urpu Salmenniemi, MD4*, Ibrahim Yakoub-Agha5, Victoria Potter, MBBS, BSc, FRACP, FRCPA6*, Anna Berceanu, MD7*, Alessandro Rambaldi, MD8, Inken Hilgendorf, MD9*, Nicolaus Kröger, MD10*, Stephan Mielke, MD11, Tsila Zuckerman, MD12, Jaime Sanz13*, Alessandro Busca, MD14*, Hakan Ozdogu, MD15*, Bipin Savani, MD16, Sebastian Giebel, MD, PhD17*, Ali Bazarbachi, MD, PhD18, Alexandros Spyridonidis19*, Arnon Nagler, M.D.20 and Mohamad Mohty, MD, PhD21

1Hematology Department and HCT Unit, George Papanicolaou General Hospital, Thessaloniki, Greece
2Hematology Department – HCT Unit, George Papanicolaou Hospital, Thessaloniki, Greece
3Department of Clinical Hematology and Cellular Therapy, Saint Antoine Hospital, Assistance Publique - Hôpitaux de Paris, Sorbonne Université, Paris, France
4Stem Cell Transplantation Unit, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
5Centre Hospitalier Universitaire de Lille LIRIC, INSERM U1286, Université de Lille, Lille, France
6Department of Haematology, King's College Hospital NHS Foundation Trust, London, United Kingdom
7Department of Clinical Hematology, Besançon University Hospital, Besançon, France
8Hematology and Bone Marrow Transplant Unit, ASST Papa Giovanni XXIII, Bergamo, Italy
9Klinik für Innere Medizin II, Abt. Hämatologie und Internistische Onkologie, Universitätsklinikum Jena, Jena, Germany
10University Hospital Eppendorf, Hamburg, Germany
11Department of Cellular Therapy and Allogeneic Stem Cell Transplantation, Karolinska Institute & University Hospital, Stockholm, Stockholms Laen, Sweden
12Department of Hematology and Hematologic Oncology, Rambam Healthcare Campus, Haifa, Israel, Haifa, Israel
13Department of Hematology, Hospital Universitari i Politècnic La Fe, Valencia, Valencia, Spain
14Department of Oncology and Hematology, SSD Stem Cell Transplant Center, A.O.U. Città della Salute e della Scienza di Torino, Turin, Italy
15Hematology Division, BMT Unit, Haemaology Reserach Laboratory, Training & Medical, Baskent University Hospital, Adana, Turkey
16Department of Medicine, Division of Hematology-Oncology, Vanderbilt University Medical Center, Houston, TX
17Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, Gliwice, Poland
18Bone Marrow Transplantation Program, Department of Internal Medicine, American University of Beirut, Beirut, Lebanon
19BMT Unit, University Hospital of Patras, PATRA, Greece
20Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Ramat-Gan, Israel
21Department of Clinical Hematology and Cellular Therapy, Saint Antoine Hospital, Paris, France

Background: Treosulfan has been increasingly used in reduced toxicity regimens, especially in older or frail patients. Different doses of treosulfan plus fludarabine have shown an advantage over reduced intensity regimens, confirmed by a randomized phase 3 trial utilizing treosulfan 30 g/m² (or FT10) in the majority of patients. However, data comparing fludarabine with higher doses of treosulfan (FT14) to fludarabine combined with myeloablative doses of busulfan are limited.

Aims: We compared outcomes between treatment alternatives of similar conditioning intensity: FT14 (fludarabine 150 or 160 mg/m2 and treosulfan 42g/m2, or FT14) over FB4 (fludarabine 150 or 160 mg/m2 and busulfan 12.8 mg/kg).

Methods: We retrospectively studied consecutive patients from the European Society for Blood and Marrow Transplantation (EBMT) registry, meeting the following inclusion criteria: a) adults diagnosed with acute myeloid leukemia (AML), b) recipients of first allogeneic hematopoietic stem cell transplantation (HSCT) from a matched unrelated or sibling donor between 2010-2020, c) HSCT at first or second complete remission (CR), d) conditioning regimen with either FT14 or FB4. Patients with ex vivo manipulated grafts were excluded. A sub-group analysis was performed according to age (<55 years or ≥55 years).

Results: In total, 2703 patients were included in the analysis comprising 2025 (75%) transplanted with FB4, and 678 (25%) with FT14.

In the sub-group of patients younger than 55 years (n=1676), FT14 recipients (n=236) had a significantly increased age (p<0.001), higher rates of secondary AML (p<0.0001), unrelated donors (p<0.0001), and peripheral blood grafts (p=0.026), but a lower percentage of female donors to male recipients (p=0.008), compared to FB4 recipients (n=1440). Cumulative incidence (CI) of acute graft-versus-host disease (GVHD) grade III-IV was higher in FT14 (9.3% versus 5.8%, p=0.044), but rates of chronic GVHD were similar. With a median follow-up of 24.4 months (range 23.4-25.6), 2-year CI of relapse was higher in FT14 (35.9% versus 27.5%, p=0.025, Figure 1A), while non-relapse mortality was similar between groups (NRM 11.9% versus 7.7%, p=0.28, 1B). This led to lower 2-year leukemia-free survival (LFS 52.2% versus 62.4%, p=0.002, 1C), overall survival (OS 63.2% versus 72.9%, p=0.038, 1D), and GVHD free, relapse free survival (GRFS 41.3% versus 50%, p=0.004) in FT14. In Cox-regression multivariate analysis, conditioning regimen remained an independent predictor of CI of relapse (p=0.011), and LFS (p=0.03).

Similar differences in patient characteristics were observed in patients aged ≥55 years (n=1027). FT14 recipients (n=442) had a significantly increased age (p<0.001), higher rates of secondary AML (p<0.0001), unrelated donors (p<0.0001), adverse cytogenetics (p<0.0001), peripheral blood grafts (p=0.026), but a lower percentage of female to male combinations (p=0.008) compared to FB4 (n=585). Cumulative incidence (CI) of acute graft-versus-host disease (GVHD) grade II-IV was higher in FT14 (7.6% versus 6.5%, p=0.001), with similar rates of chronic GVHD. Nevertheless, with a median follow-up of 29.6 months (range 23.9-34.1), 2-year CI of relapse, NRM, as well as LFS, OS and GFRS were similar between groups.

Conclusion: With the limitations of a retrospective analysis, our large real-world multicenter study suggests that FB4 is associated with better outcomes compared to FT14 in younger patients with AML transplanted in first or second CR. The same was not true for older patients (≥55 years). It should also be noted that FT14 has been selected by treating physicians for higher risk HSCT, including patients who are older, have secondary disease, adverse cytogenetics, and unrelated donors. Therefore, further studies are needed to determine the optimal conditioning regimen for such patient populations.

Disclosures: Gavriilaki: Alexion, Omeros, Sanofi Corporation: Consultancy; Gilead Corporation: Honoraria; Pfizer Corporation: Research Funding. Labopin: Jazz Pharmaceuticals: Honoraria. Yakoub-Agha: Jazz Pharmaceuticals: Honoraria. Hilgendorf: Novartis: Honoraria; AbbVie: Honoraria; Jazz Pharmaceuticals: Honoraria, Other: Travel Support; Celgene: Other: Travel Support; SanofiGenzyme: Other: Travel Support. Kröger: Novartis: Research Funding; Riemser: Honoraria, Research Funding; Sanofi: Honoraria; Neovii: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Gilead/Kite: Honoraria; Celgene: Honoraria, Research Funding; AOP Pharma: Honoraria. Mielke: Gilead/KITE: Other: Travel support, Expert panel ; Miltenyi: Other: Data safety monitoring board; Immunicum: Other: Data safety monitoring board; Novartis: Speakers Bureau; DNA Prime SA: Speakers Bureau; Celgene/BMS: Speakers Bureau. Zuckerman: AbbVie: Honoraria; Orgenesis Inc.: Honoraria; Janssen: Honoraria; BioSight Ltd: Honoraria; Novartis: Honoraria; Gilead Sciences: Honoraria, Speakers Bureau; Cellect Biotechnology: Honoraria. Giebel: Janssen: Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau. Bazarbachi: Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Hikma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Spyridonidis: Menarini: Current Employment. Mohty: Astellas: Honoraria; Amgen: Honoraria; Celgene: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Takeda: Honoraria; Jazz: Honoraria, Research Funding; Adaptive Biotechnologies: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; Bristol Myers Squibb: Honoraria; Janssen: Honoraria, Research Funding; Gilead: Honoraria.

*signifies non-member of ASH