Remission induction versus immediate allogeneic haematopoietic stem cell transplantation for patients with relapsed or poor responsive acute myeloid leukaemia (ASAP): a randomised, open-label, phase 3, non-inferiority trial.

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/m ² intravenously, 1 g/m ² intravenously for patients >60 years or with a substantial comorbidity) twice daily on days 1-3 plus mitoxantrone (10 mg/m ² 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, χ ² 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.
Funding: DKMS and the Gert and Susanna Mayer Stiftung Foundation.
Competing Interests: Declaration of interests MSt has served as a consultant for Pfizer, MSD, Bristol-Myers Squibb (BMS), Incyte, Takeda, and Amgen; as a speaker for Pfizer, Medac, MSD, Jazz Pharmaceuticals, Amgen, Novartis, Gilead, Celgene, BMS, AbbVie, and Incyte; has received research funding from Pfizer; and has received travel support from Medac and Pfizer. JMM received research funding from Janssen, Jazz, Astellas, and Novartis; consulting fees from Janssen, Roche, Gilead, AbbVie, Jazz Pharmaceuticals, Pfizer, Astellas, Novartis, AstraZeneca, and Glycostem; honoraria from Novartis, Roche, Janssen, AbbVie, Pfizer, Sanofi, Astellas, and BeiGene; and travel support from BeiGene. GB has received honoraria from Jazz Pharmaceuticals, Gilead Sciences, Novartis, BMS, and Otsuka; has served as a consultant for Novartis and Gilead Sciences; has received research funding from Novartis; and has received travel support from Gilead Sciences and Jazz Pharmaceuticals. LPM has served as a consultant for Pfizer, Amgen, Gilead Sciences, and Novartis; has received research funding from Amgen; and has received travel support from Gilead Sciences. CSchm has received honoraria for lectures, speaker bureaus, manuscript writing, and educational events from Novartis, Jazz Pharmaceuticals, and Neovii. SWK has received honoraria from Kosmas and Eickeler; and travel support from AbbVie, Jazz Pharmaceuticals, and Alexion Pharmaceuticals. WB has received lecture fees from Medac and participated in advisory boards for Gilead, Novartis, Miltenyi, Janssen, and BMS. EJ has received honoraria for lectures from BMS, Jazz Pharmaceuticals, Kite (a Gilead company), and Amgen; payment for expert testimony from Pierre Fabre; and travel support from Medac. UP has received consulting fees from Novartis, AbbVie, BMS, Silence, Sobi, AstraZeneca, Geron, GSK, Gilead, Jazz Pharmaceuticals, Syros, Akeso, Pierre Fabre, Curis, Galapagos, and Servier; honoraria for lectures from Novartis, AbbVie, BMS, and Janssen; travel support from AbbVie, Janssen, and Jazz Pharmazeuticals; and has participated in data safety monitoring board and advisory board meetings for AbbVie, Novartis, Jazz Pharmaceuticals, Nanexa, BMS, and Blueprint. SAK has served as a consultant for Novartis and Pfizer. MK has received lecture fees from Servier; travel support from Janssen and Kite (a Gilead company); and has participated in data safety monitoring and advisory board meetings for Gilead. KS-E has participated in data safety monitoring and advisory board meetings for Kite (a Gilead company). BH has received travel support from Jazz Pharmaceuticals, Janssen, and Kite (a Gilead company). FS has received lecture fees from Jazz Pharmaceuticals, Medac, and Pfizer; participated in advisory boards for Glycostem; and has received travel support from Servier, Medac, and Janssen. NA has received consulting fees from Amgen, Pfizer, AstraZeneca, and MSD and travel support from Amgen and Pfizer. BS has received travel support from AbbVie and Jazz Pharmaceuticals. CSchl has received honoraria from Novartis, AbbVie, Pfizer, AstraZeneca, and Jazz Pharmaceuticals; has served as a consultant for AbbVie, Jazz Pharmaceuticals, Pfizer, Novartis, Takeda, Roche, AstraZeneca, BMS and Celgene, Astellas Pharma, and Laboratories Delbert; has received research funding from AngioBiomed, Boehringer Ingelheim, and Jazz Pharmaceuticals; and has received travel support from Celgene, PharmaMar, Pfizer, AbbVie, and BMS and Celgene. KS received research funding from Active Biotech; has received honoraria from Novartis, BMS and Celgene, and GSK; has served as a consultant for Novartis, BMS and Celgene, and GSK; and has received travel support from Sobi. FL has received consulting fees, lecture fees, research support, and payments for expert testimony from Novartis and has participated in data safety monitoring board and advisory board meetings for Novartis, Pfizer, Incyte, and Biosciences. OK has received honoraria from Jazz Pharmaceuticals, Stemline Therapeutics, Janssen Oncology, and Pfizer and has received travel support from Jazz Pharmaceuticals and AstraZeneca. JScha has received travel support from Gilead and Jazz Pharmaceuticals. CRe has received travel support from Medac and Gilead Sciences. WEB holds stock and other ownership interests in Philogen; has received honoraria from Philogen; has served as a consultant for Philogen; has received research funding from Philogen; holds international patent rights for vascular targeting of tissue factor and siRNA targeting—so far without any return of money and is co-owner and CEO of two biotech start-ups, Anturec and Elvesca; has given expert testimony for Philogen; and has received travel and accommodation expenses from Philogen. HS holds stock and other ownership interests in Intellia Therapeutics, Biontech, and Arvin and Kymera; has received honoraria from Novartis, Robert-Bosch-Gesellschaft für Medizinische Forschung mbH, and Gilead Sciences; has served as a consultant for Gilead Sciences, IKP Stuttgart, and AbbVie; holds patent and other intellectual properties on Samhd1 modulation for treating resistance to cancer therapy, on oncogene redirection, on companion diagnostics for leukaemia treatment, and on markers for responsiveness to an inhibitor of FLT3. GE owns Cellex Cell Professionals. MB received honoraria from Jazz Pharmaceuticals, Alexion Pharmaceuticals, ActiTrexx, and MSD Oncology and has received travel support from Jazz Pharmaceuticals and MSD. J-HM has received consulting fees from Jazz Pharmaceuticals and Novartis; payments for lectures from BMS, Pfizer, Celgene, Novartis, Jazz Pharmaceuticals, BeiGene, and Daiichi Sankyo; and participated in data safety monitoring board or advisory board meetings for Pfizer and Daiichi Sankyo. JSche participated in advisory boards for AbbVie, AstraZeneca, BeiGene, BMS, Sanofi, Medac, MSD, and Janssen and received lecture fees from Astellas, AstraZeneca, BeiGene, BMS, Novartis, Eurocept, and Janssen. All other authors declare no competing interests.
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