AUTHORS
Giuliano Filippini Velázquez, MD, Jacques-Emmanuel Galimard2, Alexandros Spyridonidis3, Jakob Passweg, MD, MS4, Nicolaus Martin Kroeger, MD5, Francis Ayuketang Ayuk, MD6, Igor Wolfgang Blau7, Raynier Devillier, PhD8, Caroline Pabst, PD Dr. med.9, Tobias Gedde-Dahl10, Patrice Chevallier, MD, PhD11, Aranzazu Aranzazu Bermudez, MD12, Johan A. Maertens, MD13, Andreas Burchert, MD14, Dominik Schneidawind, MD, PhD15, Katherine Clesham, MBBS, FRPATH16, Friedrich Stölzel17, Georg-Nikolaus Franke Sr, MD18, Gerald Wulf19, Peter Herhaus, MD20, Emanuele Angelucci21, Emma Nicholson22, Matthias Eder23, Bipin Savani, MD24, Mohamad Mohty, MD, PhD25, Christoph Schmid, MD26, Eolia Brissot, MD, PhD27, Fabio Ciceri, MD28
AFFILIATIONS
1 Hematology and Oncology, Section for Stem Cell Transplantation, University of Ausgburg, Augsburg, Germany
2 EBMT Paris Study Unit, Sorbonne University, Saint-Antoine Hospital, AP-HP, INSERM UMRs 938, Paris, France
3 Bone Marrow Transplantation Unit and Institute of Cellular Therapy, University of Patras, Patras, Greece
4 University Hospital Basel, Deptartment of Hematology, Basel, Switzerland
5 University Medical Center Hamburg-Eppendorf, Department of Stem Cell Transplantation, Hamburg, Germany
6 University Medical Center Hamburg-Eppendorf, Department of Stem Cell Transplantation, Hamburg, Germany
7 Charité Universitätsmedizin Berlin, Onkologie und Tumorimmunologie, Berlin, Germany
8 Programme de Transplantation & Thérapie Cellulaire, Marseille, France
9 University of Heidelberg, Medizinische Klinik und Poliklinik V, Heidelberg, Germany
10 Oslo University Hospital, Rikshospitalet Clinic for Cancer Medicine, Section for Stem Cell Transplantation, Oslo, Norway
11 CHU Nantes, Nantes, France
12 Servicio de Hematología-Hemoterapia, Hospital Universitario Marqués de Valdecilla, Sanander, Spain
13 University Hospital Gasthuisberg, Leuven, Belgium
14 Philipps Universität Marburg, Marburg, Germany
15 University Hospital Zürich, Zürich, Switzerland
16 University College London Hospitals NHS Foundation Trust, London, United Kingdom
17 University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany
18 Hematology and Cellular Therapy, University Hospital, Leipzig, Germany
19 University Hospital Goettingen, Department of Hematology and Medical Oncology, Göttingen, Germany
20 Klinikum Rechts der Isar, TUM, Munich, Germany
21 Hematology and Cellular Therapy Unit, AOM-IRCCS Ospedale Policlinico San Martino, Genova, Italy
22 Royal Marsden Hospital, London, London, United Kingdom
23 Hannover Medical School, Hannover, Hannover, Germany
24 Vanderbilt University Medical Center, Department of Hematology, Nashville, United States
25 EBMT Paris Study Unit, Sorbonne University, Saint-Antoine Hospital, AP-HP, INSERM UMRs 938, Paris, France
26 Hematology and Oncology, Section for Stem Cell Transplantation, University of Ausgburg, Augsburg, Germany
27 EBMT Paris Study Unit, Sorbonne University, Saint-Antoine Hospital, AP-HP, INSERM UMRs 938, Paris, France
28 IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy
ABSTRACT
The role of a second allogeneic stem cell transplantation (alloSCT2) as consolidation in patients who achieve complete remission (CR) after salvage therapy for acute myeloid leukemia (AML) relapse following a first alloSCT (alloSCT1) remains uncertain. Moreover, optimal patient selection and transplant strategy, particularly regarding conditioning intensity and donor choice, lack clear evidence. We screened the EBMT registry for patients with AML who had undergone alloSCT1 in first CR (CR1), subsequently relapsed, and received alloSCT2 in second CR (CR2) between 2010 and 2024. Conditioning was classified as myeloablative (MAC) or reduced-intensity conditioning (RIC). Multivariable analyses (MVA) including clinically relevant patient-, disease-, and transplant-related variables were performed to identify prognostic factors.
The study included 708 patients (median age at alloSCT2: 47 years; 48% female). The median interval from alloSCT1 to relapse was 18.9 months and 3.9 months from relapse to alloSCT2. At alloSCT2, 30% had a Karnofsky performance status (KPS) <90. Donors for alloSCT2 were matched siblings (MSD; 15%), haplo-identical family (haplo; 23%), or matched unrelated donors (MUD; 62%); a change of donor for alloSCT2 was documented in 80%. RIC and MAC were used in 51% and 49% of patients, respectively. Compared with RIC recipients, patients receiving MAC were younger (median: 44 vs. 51 years, p<0.001) and had a shorter remission duration after alloSCT1 (median: 17.5 vs 22.7 months, p=0.03). Measurable residual disease (MRD) status pre-alloSCT2 was available for 328 patients, of which 71% were MRD-negative.
Engraftment rate after alloSCT2 was 96%. With a median follow-up of 3.5 years, 2-year overall survival (OS), leukemia-free survival (LFS), relapse incidence (RI), and non-relapse mortality rate (NRM) were 52%, 42%, 39%, and 19%, respectively. None of these outcomes differed significantly between MAC and RIC transplants. At last follow-up, 372 patients had died. Relapse was the most frequent cause of death (64%), followed by infections (19%) and GvHD (10%), without differences between RIC and MAC transplants.
In MVA, a significant improvement over time could be demonstrated for all outcome parameters: For each 5-year increase in year of alloSCT2, the hazard ratios [HR] and 95%-CI for OS, LFS, RI, and NRM were 0.75 (0.63-0.89, p<0.001), 0.78 (0.67-0.91, p<0.001), 0.81 (0.67-0.97, p=0.02), and 0.71 (0.54-0.94, p=0.01), respectively. Consequently, in the last 5-year period (2020-2024) 2y-OS/LFS, and RI/NRM after alloSCT2 were 57.4% (95%-CI: 50.6-63.6)/ 49.2% (95%-CI: 42.7-55.4), and 35.2% (95%-CI: 29.2-41.2)/ 15.6% (95%-CI: 11.5-20.3), respectively. Further variables associated with inferior OS in MVA were age ≥47 years (HR: 1.29), donor/recipient CMV serostatus other than negative/negative (HR: 1.65), adverse cytogenetics (HR: 1.33), remission duration after alloSCT1 ≤12 months (HR: 1.38), and MRD positivity pre-alloSCT2 (HR: 1.45). Further factors for inferior LFS were CMV serostatus (HR: 1.42), remission duration after alloSCT1 ≤12 months (HR: 1.34), and MRD positivity (HR: 1.63). NRM risk was associated with older age (HR: 2.28), KPS <90 (HR: 1.47), CMV serostatus (HR: 1.81), MRD positivity (HR: 1.94), and haplo donor (HR: 2.06). Remission duration ≤12 months after alloSCT1 was the major risk factor for relapse after alloSCT2 (HR: 1.36 [95%-CI: 1.04-1.76] p=0.02), whereas use of a haplo donor for alloSCT2 was associated with lower risk of RI (HR: 0.66 [95%-CI: 0.43-0.99] p=0.04). Neither conditioning intensity nor donor change was significantly associated with outcome.
In conclusion, this large registry analysis demonstrates that alloSCT2 provided favorable outcomes in patients with AML relapse responding to salvage treatment. Outcomes improved significantly over time, reaching >57% 2y-OS in recent years. Established risk factors for outcome (older age, shorter remission duration, CMV seropositivity) were confirmed. Among potentially modifiable factors to improve outcomes, strategies to achieve MRD negativity with maintained KPS before alloSCT2, as well as optimized infection-, and GvHD prophylaxis seemed to be more relevant than change of donor or intensified/MAC conditioning. The use of a haplo donor for alloSCT2 was associated with improved leukemia control, but also with higher NRM (mostly infections). These findings support alloSCT2 as a potentially curative treatment for patients who achieve CR2.
DISCLOSURES
Giuliano Filippini Velázquez, MD: No relevant conflicts of interest to declare.