The effect of granulocyte-colony stimulating factor, decitabine, and busulfan–cyclophosphamide versus busulfan–cyclophosphamide conditioning on relapse in patients with myelodysplastic syndrome or secondary acute myeloid leukaemia evolving from myelodysplastic syndrome undergoing allogeneic haematopoietic stem-cell transplantation: an open-label, multicentre, randomised, phase 3 trial

Background Relapse remains high in patients with myelodysplastic syndrome-refractory anaemia with excess blasts (RAEB) or secondary acute myeloid leukaemia evolving from myelodysplastic syndrome undergoing allogeneic haematopoietic stem-cell transplantation (HSCT). We aimed to investigate whether granulocyte-colony stimulating factor (G-CSF) and decitabine plus busulfan–cyclophosphamide conditioning reduced relapse compared with busulfan–cyclophosphamide in this population. Methods We did an open-label, randomised, phase 3 trial at six hospitals in China. Eligible patients (aged 14–65 years) had myelodysplastic syndrome-RAEB or secondary acute myeloid leukaemia evolving from myelodysplastic syndrome, and an Eastern Cooperative Oncology Group performance status of 0–2 and HSCT comorbidity index of 0–2. Patients were randomly assigned (1:1) to receive G-CSF, decitabine, and busulfan–cyclophosphamide conditioning or busulfan–cyclophosphamide conditioning. Randomisation was done with permuted blocks (block size four) with no stratification and was implemented through an interactive web-based response system, which was independent of study site staff and investigators. G-CSF, decitabine, and busulfan–cyclophosphamide conditioning comprised G-CSF 5 μg/kg daily subcutaneously (days –17 to –10), decitabine 20 mg/m2 daily intravenously (days –14 to –10), busulfan 3·2 mg/kg daily intravenously (days –7 to –4), and cyclophosphamide 60 mg/kg daily intravenously (days –3 and –2). Busulfan–cyclophosphamide conditioning comprised the same dose and duration of busulfan and cyclophosphamide. The primary endpoint was 2 year cumulative incidence of relapse. All efficacy and safety endpoints were assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02744742; the trial is complete. Findings Between April 18, 2016, and Sept 30, 2019, 297 patients were screened for eligibility, 202 of whom were randomly assigned to G-CSF, decitabine, and busulfan–cyclophosphamide (n=101) or busulfan–cyclophosphamide (n=101) conditioning. 123 (61%) participants were male and 79 (31%) were female. Median follow-up was 32·4 months (IQR 10·0–43·0). The 2-year cumulative incidence of relapse was 10·9% (95% CI 5·8–17·9) in the G-CSF, decitabine, and busulfan–cyclophosphamide group and 24·8% (16·8–33·5) in the busulfan–cyclophosphamide group (hazard ratio 0·39 [95% CI 0·19–0·79]; p=0·011). Within 100 days after transplantation, the most common grade 3–4 adverse events in the G-CSF, decitabine, and busulfan–cyclophosphamide group and the busulfan–cyclophosphamide group were infections (34 [34%] and 32 [32%]), acute graft-versus-host disease (30 [30%] and 30 [30%]), and gastrointestinal toxicity (28 [28%] and 29 [29%]). 11 (11%) patients in the G-CSF, decitabine, and busulfan–cyclophosphamide group and 13 (13%) in the busulfan–cyclophosphamide group died of adverse events. There were no treatment related deaths. Interpretation Our results suggest that G-CSF, decitabine, and busulfan–cyclophosphamide conditioning is a better choice than busulfan–cyclophosphamide conditioning for patients with myelodysplastic syndrome-RAEB or secondary acute myeloid leukaemia evolving from myelodysplastic syndrome undergoing allogeneic HSCT. This conditioning could be a suitable therapuetic option for this patient population. Funding None. Translation For the Chinese translation of the abstract see Supplementary Materials section.