Frederick Fasslrinner1, Johannes Schetelig2, Andreas Burchert3, Michael Kramer2, Rudolf Trenschel4, Ute Hegenbart5, Michael Stadler6, Kerstin Schäfer-Eckart7, Michael Bätzel8, Hans Eich9, Martin Stuschke10, Rita Engenhart-Cabillic11, Mechthild Krause12, Peter Dreger5, Andreas Neubauer3, Gerhard Ehninger2, Dietrich Beelen4, Wolfgang E Berdel13, Timo Siepmann14, Matthias Stelljes13, Martin Bornhäuser15. 1. Department of Internal Medicine, University Hospital Carl Gustav Carus, Dresden, Germany; Division of Health Care Sciences, Center for Clinical Research and Management Education, Dresden International University, Dresden, Germany. 2. Department of Internal Medicine, University Hospital Carl Gustav Carus, Dresden, Germany. 3. Department of Hematology, Oncology and Immunology, University Hospital Marburg, Marburg, Germany. 4. Department of Bone Marrow Transplantation, University Hospital, University of Duisburg-Essen, Essen, Germany. 5. Department of Medicine V, University of Heidelberg, Heidelberg, Germany. 6. Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany. 7. Medical Center, Nürnberg Nord Hospital, Nürnberg, Germany. 8. Center for Hematopoietic Cell Transplantation, DKD Helios Klinik, Wiesbaden, Germany. 9. Department of Radiation Oncology, University Hospital Münster, Münster, Germany. 10. Department for Radiation Oncology, University Hospital, University of Duisburg-Essen, Essen, Germany. 11. Department of Radiotherapy, University Hospital Marburg, Marburg, Germany. 12. Department of Radiation Oncology, University Hospital Carl Gustav Carus, Dresden, Germany; German Cancer Consortium (DKTK), partner site Dresden, Dresden, Germany; National Center for Tumor Diseases (NCT), partner site Dresden, Dresden, Germany. 13. Department of Medicine A, University Hospital Münster, Münster, Germany. 14. Department of Neurology, University Hospital Carl Gustav Carus, Dresden, Germany; Division of Health Care Sciences, Center for Clinical Research and Management Education, Dresden International University, Dresden, Germany. 15. Department of Internal Medicine, University Hospital Carl Gustav Carus, Dresden, Germany; German Cancer Consortium (DKTK), partner site Dresden, Dresden, Germany; National Center for Tumor Diseases (NCT), partner site Dresden, Dresden, Germany. Electronic address: martin.bornhaeuser@uniklinikum-dresden.de.
Abstract
BACKGROUND: The impact of the intensity of conditioning before allogeneic haemopoietic cell transplantation (HCT) has been studied in a randomised phase 3 trial comparing reduced-intensity conditioning with myeloablative conditioning in patients with acute myeloid leukaemia in first complete remission. Because of the short follow-up of the original trial, whether reduced-intensity conditioning increases the risk of late relapse compared with myeloablative conditioning remained unclear. To address this question, we present retrospective 10-year follow-up data of this trial and focus on late relapse. METHODS: The original randomised phase 3 trial included patients aged 18-60 years, with intermediate-risk or high-risk acute myeloid leukaemia, an adequate organ function, and an available HLA-matched sibling donor or an unrelated donor with at least nine out of ten HLA alleles matched. Patients were randomly assigned (1:1) to 120 mg/m2 fludarabine combined with four 2 Gy doses of total-body irradiation (reduced-intensity conditioning) or six 2 Gy doses of total-body irradiation and 120 mg/kg cyclophosphamide (myeloablative conditioning). The primary and secondary efficacy endpoints of this trial have been published previously. In this retrospective, long-term follow-up analysis, data were collected from medical reports from individual participating study centres, and from physician and patient interviews. Endpoints included in this analysis were cumulative relapse incidence, overall survival, disease-free survival, and non-relapse mortality in the original study population and in patients alive and relapse-free at 12 months after HCT (landmark analysis). 10-year time to event rates were calculated in the intention-to-treat population and were compared with the Gray test. The trial is registered with ClinicalTrials.gov, number NCT00150878. FINDINGS: In the original trial, 195 patients were randomly assigned to receive reduced-intensity conditioning (n=99) or myeloablative conditioning (n=96). For this retrospective analysis, data were collected with a nearly complete follow-up (completeness index 99%). Median follow-up time for surviving patients was 9·9 years (IQR 8·5-11·4), during which the cumulative incidence of relapse in the complete study population was identical in both groups (30% [95% CI 20-39] in the reduced-intensity conditioning group vs 30% [21-40] in the myeloablative conditioning group; Gray test p=0·99). Relapse occurred at a median of 5·0 months (IQR 3·0-8·8) in the reduced-intensity conditioning group versus 9·5 months (4·5-20·5) in the myeloablative conditioning group. 10-year disease-free survival was 55% (95% CI 45-66) in the reduced-intensity conditioning group and 43% (34-55) in the myeloablative conditioning group (hazard ratio [HR] 0·76 [0·51-1·14]; p=0·19). 10-year non-relapse mortality was 16% (95% CI 8-24) in the reduced-intensity conditioning group and 26% (17-36) in the myeloablative conditioning group (subdistribution HR 0·60 [95% CI 0·32-1·11]; Gray test p=0·10). The incidence of long-term toxicities associated with total-body irradiation was comparable; secondary malignancies occurred in six (6%) of 94 patients in the reduced-intensity conditioning group and five (6%) of 90 in the myeloablative conditioning group (p=1·00). INTERPRETATION: There is no evidence that reduced-intensity conditioning increases the risk of late relapse compared with myeloablative conditioning. Given that the reduced-intensity conditioning group in the original trial was associated with lower early morbidity and toxicity, reduced-intensity conditioning with moderately reduced total-body irradiation doses could be the preferred conditioning strategy for patients with acute myeloid leukaemia who are younger than 60 years and transplanted in first complete remission. FUNDING: None.
RCT Entities:
BACKGROUND: The impact of the intensity of conditioning before allogeneic haemopoietic cell transplantation (HCT) has been studied in a randomised phase 3 trial comparing reduced-intensity conditioning with myeloablative conditioning in patients with acute myeloid leukaemia in first complete remission. Because of the short follow-up of the original trial, whether reduced-intensity conditioning increases the risk of late relapse compared with myeloablative conditioning remained unclear. To address this question, we present retrospective 10-year follow-up data of this trial and focus on late relapse. METHODS: The original randomised phase 3 trial included patients aged 18-60 years, with intermediate-risk or high-risk acute myeloid leukaemia, an adequate organ function, and an available HLA-matched sibling donor or an unrelated donor with at least nine out of ten HLA alleles matched. Patients were randomly assigned (1:1) to 120 mg/m2 fludarabine combined with four 2 Gy doses of total-body irradiation (reduced-intensity conditioning) or six 2 Gy doses of total-body irradiation and 120 mg/kg cyclophosphamide (myeloablative conditioning). The primary and secondary efficacy endpoints of this trial have been published previously. In this retrospective, long-term follow-up analysis, data were collected from medical reports from individual participating study centres, and from physician and patient interviews. Endpoints included in this analysis were cumulative relapse incidence, overall survival, disease-free survival, and non-relapse mortality in the original study population and in patients alive and relapse-free at 12 months after HCT (landmark analysis). 10-year time to event rates were calculated in the intention-to-treat population and were compared with the Gray test. The trial is registered with ClinicalTrials.gov, number NCT00150878. FINDINGS: In the original trial, 195 patients were randomly assigned to receive reduced-intensity conditioning (n=99) or myeloablative conditioning (n=96). For this retrospective analysis, data were collected with a nearly complete follow-up (completeness index 99%). Median follow-up time for surviving patients was 9·9 years (IQR 8·5-11·4), during which the cumulative incidence of relapse in the complete study population was identical in both groups (30% [95% CI 20-39] in the reduced-intensity conditioning group vs 30% [21-40] in the myeloablative conditioning group; Gray test p=0·99). Relapse occurred at a median of 5·0 months (IQR 3·0-8·8) in the reduced-intensity conditioning group versus 9·5 months (4·5-20·5) in the myeloablative conditioning group. 10-year disease-free survival was 55% (95% CI 45-66) in the reduced-intensity conditioning group and 43% (34-55) in the myeloablative conditioning group (hazard ratio [HR] 0·76 [0·51-1·14]; p=0·19). 10-year non-relapse mortality was 16% (95% CI 8-24) in the reduced-intensity conditioning group and 26% (17-36) in the myeloablative conditioning group (subdistribution HR 0·60 [95% CI 0·32-1·11]; Gray test p=0·10). The incidence of long-term toxicities associated with total-body irradiation was comparable; secondary malignancies occurred in six (6%) of 94 patients in the reduced-intensity conditioning group and five (6%) of 90 in the myeloablative conditioning group (p=1·00). INTERPRETATION: There is no evidence that reduced-intensity conditioning increases the risk of late relapse compared with myeloablative conditioning. Given that the reduced-intensity conditioning group in the original trial was associated with lower early morbidity and toxicity, reduced-intensity conditioning with moderately reduced total-body irradiation doses could be the preferred conditioning strategy for patients with acute myeloid leukaemia who are younger than 60 years and transplanted in first complete remission. FUNDING: None.
Authors: Betül Oran; Kwang Woo Ahn; Caitrin Fretham; Amer Beitinjaneh; Asad Bashey; Attaphol Pawarode; Baldeep Wirk; Bart L Scott; Bipin N Savani; Christopher Bredeson; Daniel Weisdorf; David I Marks; David Rizzieri; Edward Copelan; Gerhard C Hildebrandt; Gregory A Hale; Hemant S Murthy; Hillard M Lazarus; Jan Cerny; Jane L Liesveld; Jean A Yared; Jean Yves-Cahn; Jeffrey Szer; Leo F Verdonck; Mahmoud Aljurf; Marjolein van der Poel; Mark Litzow; Matt Kalaycio; Michael R Grunwald; Miguel Angel Diaz; Mitchell Sabloff; Mohamed A Kharfan-Dabaja; Navneet S Majhail; Nosha Farhadfar; Ran Reshef; Richard F Olsson; Robert Peter Gale; Ryotaro Nakamura; Sachiko Seo; Saurabh Chhabra; Shahrukh Hashmi; Shatha Farhan; Siddhartha Ganguly; Sunita Nathan; Taiga Nishihori; Tania Jain; Vaibhav Agrawal; Ulrike Bacher; Uday Popat; Wael Saber Journal: Transplant Cell Ther Date: 2021-08-14
Authors: Bart L Scott; Marcelo C Pasquini; Mingwei Fei; Raphael Fraser; Juan Wu; Steve M Devine; David L Porter; Richard T Maziarz; Erica Warlick; Hugo F Fernandez; Robert J Soiffer; Edwin Alyea; Mehdi Hamadani; Asad Bashey; Sergio Giralt; Nancy L Geller; Eric Leifer; Christopher S Hourigan; Gege Gui; Adam Mendizabal; Mary M Horowitz; H Joachim Deeg; Mitchell E Horwitz Journal: Transplant Cell Ther Date: 2021-02-26
Authors: Christopher S Hourigan; Laura W Dillon; Gege Gui; Brent R Logan; Mingwei Fei; Jack Ghannam; Yuesheng Li; Abel Licon; Edwin P Alyea; Asad Bashey; H Joachim Deeg; Steven M Devine; Hugo F Fernandez; Sergio Giralt; Mehdi Hamadani; Alan Howard; Richard T Maziarz; David L Porter; Bart L Scott; Erica D Warlick; Marcelo C Pasquini; Mitchell E Horwitz Journal: J Clin Oncol Date: 2019-12-20 Impact factor: 44.544