Open Access

Background Whether high-dose cytarabine-based salvage chemotherapy, administered to induce complete remission in patients with poor responsive or relapsed acute myeloid leukaemia scheduled for allogeneic haematopoietic stem-cell transplantation (HSCT) after intensive conditioning confers a survival advantage, is unclear. Methods To test salvage chemotherapy before allogeneic HSCT, patients aged between 18 and 75 years with non-favourable-risk acute myeloid leukaemia not in complete remission after first induction or untreated first relapse were randomly assigned 1:1 to remission induction with high-dose cytarabine (3 g/m2 intravenously, 1 g/m2 intravenously for patients >60 years or with a substantial comorbidity) twice daily on days 1–3 plus mitoxantrone (10 mg/m2 intravenously) on days 3–5 or immediate allogeneic HSCT for the disease control group. Block randomisation with variable block lengths was used and patients were stratified by age, acute myeloid leukaemia risk, and disease status. The study was open label. The primary endpoint was treatment success, defined as complete remission on day 56 after allogeneic HSCT, with the aim to show non-inferiority for disease control compared with remission induction with a non-inferiority-margin of 5% and one-sided type 1 error of 2·5%. The primary endpoint was analysed in both the intention-to-treat (ITT) population and in the per-protocol population. The trial is completed and was registered at ClinicalTrials.gov, NCT02461537. Findings 281 patients were enrolled between Sept 17, 2015, and Jan 12, 2022. Of 140 patients randomly assigned to disease control, 135 (96%) proceeded to allogeneic HSCT, 97 (69%) after watchful waiting only. Of 141 patients randomly assigned to remission induction, 134 (95%) received salvage chemotherapy and 128 (91%) patients subsequently proceeded to allogeneic HSCT. In the ITT population, treatment success was observed in 116 (83%) of 140 patients in the disease control group versus 112 (79%) of 141 patients with remission induction (test for non-inferiority, p=0·036). Among per-protocol treated patients, treatment success was observed in 116 (84%) of 138 patients with disease control versus 109 (81%) of 134 patients in the remission induction group (test for non-inferiority, p=0·047). The difference in treatment success between disease control and remission induction was estimated as 3·4% (95% CI –5·8 to 12·6) for the ITT population and 2·7% (–6·3 to 11·8) for the per-protocol population. Fewer patients with disease control compared with remission induction had non-haematological adverse events grade 3 or worse (30 [21%] of 140 patients vs 86 [61%] of 141 patients, χ2 test p<0·0001). Between randomisation and the start of conditioning, with disease control two patients died from progressive acute myeloid leukaemia and zero from treatment-related complications, and with remission induction two patients died from progressive acute myeloid leukaemia and two from treatment-related complications. Between randomisation and allogeneic HSCT, patients with disease control spent a median of 27 days less in hospital than those with remission induction, ie, the median time in hospital was 15 days (range 7–64) versus 42 days (27–121, U test p<0·0001), respectively. Interpretation Non-inferiority of disease control could not be shown at the 2·5% significance level. The rate of treatment success was also not statistically better for patients with remission induction. Watchful waiting and immediate transplantation could be an alternative for fit patients with poor response or relapsed acute myeloid leukaemia who have a stem cell donor available. More randomised controlled intention-to-transplant trials are needed to define the optimal treatment before transplantation for patients with active acute myeloid leukaemia.

Donor age is one factor to optimize allogeneic hematopoietic cell transplantation (alloHCT). Therefore, we investigated whether young unrelated donors (UD) provide a benefit for older patients with myeloid malignancies compared to HLA-identical sibling donors (MSD). We performed a retrospective registry study on patients ≥50 years who received a first alloHCT between 2010 and 2020. We compared event-free survival (EFS) of patients who were transplanted from MSD aged ≥50 years versus UD aged ≤35 years who were HLA-compatible for HLA-A, -B, -C, and -DRB1. In total, we analyzed data from 3460 patients. With multivariable adjustment EFS (HR 0.86, p = 0.003), OS (HR 0.82, p < 0.001), and risk of relapse (HR 0.84, p = 0.018) were significantly better for HLA-compatible UD compared to MSD. No survival advantage was found, when UD with unfavorable sex or CMV constellation were compared to MSD with favorable constellations. In a meta-analysis on 9905 patients with myeloid malignancies, including ours, we found reduced risk of relapse (pooled HR 0.78, p = 0.006) and better EFS (pooled HR 0.89, p < 0.001) for young matched UD versus MSD. To select young HLA-compatible UD over older MSD may reduce relapse risk and improve survival for older patients with myeloid malignancies.