Allo-HCT regimens with low toxicity needed in older patients with acute myeloid leukaemia – Authors' reply

We thank Mohamed Kharfan-Dabaja and colleagues for their comments on our Article. 1 Rambaldi A Grassi A Masciulli A et al. Busulfan plus cyclophosphamide versus busulfan plus fludarabine as a preparative regimen for allogeneic haemopoietic stem-cell transplantation in patients with acute myeloid leukaemia: an open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2015; 16: 1525-1536 Summary Full Text Full Text PDF PubMed Scopus (111) Google Scholar When we designed our study, the main background was represented by the meta-analysis published in 2007 by Cornelissen and colleagues, 2 Cornelissen JJ van Putten WL Verdonck LF et al. Results of a HOVON/SAKK donor versus no-donor analysis of myeloablative HLA-identical sibling stem cell transplantation in first remission acute myeloid leukemia in young and middle-aged adults: benefits for whom?. Blood. 2007; 109: 3658-3666 Crossref PubMed Scopus (400) Google Scholar who set the age of 40 years as the cut-off limit at which patients with acute myeloid leukaemia lose a survival benefit from allogeneic transplantation from a sibling donor. Accordingly, the intent of our study was to show that a reduced toxicity, albeit myeloablative, programme (busulfan plus fludarabine) could substantially reduce the non-relapse mortality, but retain the same anti-leukemia activity of the classic busulfan plus cyclophosphamide programme, in most patients with acute myeloid leukaemia and not only in those older than 60 years. To address the specific questions raised by Kharfan-Dabaja and colleagues regarding the age of patients recruited, we first point out that in our study we enrolled 31 patients aged older than 60 years (14 patients in the busulfan plus cyclophosphamide group and 17 patients in the busulfan plus fludarabine group; 12·3% of the whole study population). After patients aged 60 years or older had received the conditioning treatment, the 1-year non-relapse mortality was 38·5% (95% CI 18·7–79·3) in the busulfan plus cyclophosphamide group versus 11·8% (3·0–46·1) in the busulfan plus fludarabine group (p=0·078). 2-year leukemia-free survival for busulfan plus cyclophosphamide was 53·8% (95% CI 32·6–89·1) versus 47·1% (28·4–77·9) for busulfan plus fludarabine (p=0·75), and overall survival was 61·5% (95% CI 40·0–94·6) versus 52·9% (33·8–82·9; p=0·84). Regarding Kharfan-Dabaja and colleagues' query about patients who received a graft from a HLA-mismatched donor, 23 of these patients were assigned to busulfan plus cyclophosphamide and 23 were assigned to busulfan plus fludarabine; both the 1-year and 2-year non-relapse mortality was 13·0% (95% CI 4·4–38·5) versus 13·0% (4·4–38·5; p=0·98), 2-year leukaemia-free survival was 56·5% (95% CI 39·5–80·9) versus 56·5% (39·5–80·9; p=0·88), and overall survival was 65·2% (95% CI 48·4–87·9) versus 60·1% (42·8–84·2; p=0·95). Finally, in our paper, we clearly reported the low incidence of sinusoidal obstruction syndrome (two patients per group) and the low number of other, any grade, hepatic or pancreatic toxicities. We believe that, no matter the companion drug used, the intravenous rather than oral administration of busulfan largely explains the low incidence of hepatic complications as reported by other registry based 3 Nagler A Rocha V Labopin M et al. Allogeneic hematopoietic stem-cell transplantation for acute myeloid leukemia in remission: comparison of intravenous busulfan plus cyclophosphamide (Cy) versus total-body irradiation plus Cy as conditioning regimen—a report from the acute leukemia working party of the European group for blood and marrow transplantation. J Clin Oncol. 2013; 31: 3549-3556 Crossref PubMed Scopus (110) Google Scholar or prospective studies. 4 Bredeson CN Zhang MJ Agovi MA et al. Outcomes following HSCT using fludarabine, busulfan, and thymoglobulin: a matched comparison to allogeneic transplants conditioned with busulfan and cyclophosphamide. Biol Blood Marrow Transplant. 2008; 14: 993-1003 Summary Full Text Full Text PDF PubMed Scopus (73) Google Scholar Busulfan plus cyclophosphamide versus busulfan plus fludarabine as a preparative regimen for allogeneic haemopoietic stem-cell transplantation in patients with acute myeloid leukaemia: an open-label, multicentre, randomised, phase 3 trialIn older patients with acute myeloid leukaemia, the myeloablative busulfan plus fludarabine conditioning regimen is associated with lower transplant-related mortality than busulfan plus cyclophosphamide, but retains potent antileukaemic activity. Accordingly, this regimen should be regarded as standard of care during the planning of allogeneic transplants for such patients. Full-Text PDF Allo-HCT regimens with low toxicity needed in older patients with acute myeloid leukaemiaWe applaud the efforts of Alessandro Rambaldi and colleagues in completing their important, randomised, phase 3 trial,1 comparing two myeloablative regimens (busulfan plus fludarabine and busulfan plus cyclophosphamide) in patients with acute myeloid leukaemia who received an allogeneic haematopoietic stem-cell transplant. Patients treated with busulfan plus fludarabine had fewer toxic effects than those treated with busulfan plus cyclophosphamide and had about half the non-relapse mortality at 2 years (9·5% vs 18·0%, Gray's test p=0·047) and at 5 years (10·6% vs 19·0%, Gray's test p=0·050). Full-Text PDF