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Katja Sockel,1 Friedrich Stölzel,1 Franziska Hönl,1 Henning Baldauf,2 Christoph Röllig,1 Martin Wermke,1 Malte von Bonin,1 Raphael Teipel,1 Cornelia Link-Rachner,1 Kalina Brandt,1 Frank Kroschinsky,1 Mathias Hänel,3 Anke Morgner,3 Christian Klesse,2 Gerhard Ehninger,1 Uwe Platzbecker,4 Martin Bornhäuser,1 Johannes Schetelig,1,2,* Jan Moritz Middeke1,* 1Medical Clinic and Policlinic I, University Hospital Carl Gustav Carus and Medical Faculty of the TU Dresden, Dresden, Germany; 2Clinical Trials Unit, DKMS, Dresden, Germany; 3Department of Medicine III, Chemnitz Hospital, Chemnitz, Germany; 4Department of Hematology, Cellular Therapy and Hemostaseology, Leipzig University Hospital, Leipzig, Germany*These authors contributed equally to this workCorrespondence: Jan Moritz Middeke, Medical Clinic and Policlinic I, University Hospital Carl Gustav Carus and Medical Faculty of the TU Dresden, Fetscherstr. 74, Dresden, 01307, Germany, Tel +49-0351-458-15603, Fax +49-0351-458-4373, Email JanMoritz.Middeke@uniklinikum-dresden.deIntroduction: Allogeneic hematopoietic cell transplantation (HCT) during chemotherapy-induced aplasia may offer long-term survival in acute myeloid leukemia (AML) with otherwise poor prognosis including ELN adverse risk, relapsed or refractory disease. However, the value of residual morphologic disease prior HCT in this context has not been conclusively settled until yet. Therefore, we aimed to investigate variables predicting outcome in this unique setting of sequential conditioning therapy, with a focus on pretreatment morphologic blast count. In contrast to the most popular FLAMSA-RIC protocol, we used a melphalan-based conditioning regimen during aplasia.Methods: We retrospectively analyzed data from 173 AML patients who underwent a sequential melphalan-based conditioning therapy between 2003 and 2015 at our centre. All patients participated either in the prospective Phase 2 BRIDGE trial (NCT01295307), the Phase 3 AML2003 study (NCT00180102) or were treated according to this protocol and underwent allogeneic HCT after melphalan-based conditioning in treatment-induced aplasia.Results: Median bone marrow blast count prior to conditioning was 10% (range, 0– 96%). Four year probabilities of EFS and OS were 34% (95% CI, 28– 43%) and 43% (95% CI, 36– 52%), respectively. In multivariate analysis, blast count > 20% was associated with worse EFS (HR = 1.93; p = 0.009) and OS (HR = 1.80; p = 0.026). This effect was not significant anymore for HCT during 1st line therapy.Conclusion: Allogeneic HCT in aplasia with a melphalan-based conditioning regimen has the potential to cure a subset of adverse risk AML patients, even with persistent morphological disease prior HCT. However, a high pre-transplant blast count still indicates patients with a dismal prognosis, especially in the relapsed patient group, for whom post-transplant strategies should be considered to further optimize post HCT outcome.Keywords: acute myeloid leukemia, ELN high risk, AML relapse/refractory, early allogeneic transplantation in aplasia, blast count, melphalan-based conditioning, sequential conditioning

Biobanking provides benefit for future generations by facilitating medical research and subsequent translation and application of research findings. Long-term storage and research involving biological material and associated data necessitate the proper implementation of ethical and legal standards. A key principle includes recognizing informed consent as a crucial element for legitimizing the collection of biological material and data. Furthermore, any collected material and data must be employed exclusively for the research framework that aligns with the explicit consent provided by the participants. Last but not least, data privacy and security are essential in biobanking. This review elucidates chances and limitations of biobanking in the field of allogeneic hematopoietic cell transplantation. We discuss the practical implementation of the requirements, illustrated by the Collaborative Biobank, a collaborative research platform for research in blood cancer., Competing Interests: Declaration of competing interest All authors declare that they have no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Optimizing natural killer (NK) cell alloreactivity could further improve outcome after allogeneic hematopoietic cell transplantation (alloHCT). The donor's Killer-cell Immunoglobulin-like Receptor (KIR) genotype may provide important information in this regard. In the past decade, different models have been proposed aiming at maximizing NK cell activation by activating KIR-ligand interactions or minimizing inhibitory KIR-ligand interactions. Alternative classifications intended predicting outcome after alloHCT by donor KIR-haplotypes. In the present study, we aimed at validating proposed models and exploring more classification approaches. To this end, we analyzed samples stored at the Collaborative Biobank from HLA-compatible unrelated stem cell donors who had donated for patients with acute myeloid leukemia (AML) or myelodysplastic neoplasm (MDS) and whose outcome data had been reported to EBMT or CIBMTR. The donor KIR genotype was determined by high resolution amplicon-based next generation sequencing. We analyzed data from 5,017 transplants. The median patient age at alloHCT was 56 years. Patients were transplanted for AML between 2013 and 2018. Donor-recipient pairs were matched for HLA-A, -B, -C, -DRB1, and -DQB1 (79%) or had single HLA mismatches. Myeloablative conditioning was given to 56% of patients. Fifty-two percent of patients received anti-thymocyte-globulin-based graft-versus-host disease prophylaxis, 32% calcineurin-inhibitor-based prophylaxis, and 7% post-transplant cyclophosphamide-based prophylaxis. We tested several previously reported classifications in multivariable regression analyses but could not confirm outcome associations. Exploratory analyses in 1,939 patients (39%) who were transplanted from donors with homozygous centromeric (cen) or telomeric (tel) A or B motifs, showed that the donor cen B/B -tel A/A diplotype was associated with a trend to better event-free survival (HR 0.84, p=.08) and reduced risk of non-relapse mortality (NRM) (HR 0.65, p=.01). When we further dissected the contribution of B subtypes, we found that only the cen B01/B01 - telA/A diplotype was associated with a reduced risk of relapse (HR 0.40, p=.04) while all subtype combinations contributed to a reduced risk of NRM. This exploratory finding has to be validated in an independent data set. In summary, the existing body of evidence is not (yet) consistent enough to recommend use of donor KIR genotype information for donor selection in routine clinical practice., Competing Interests: All authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer TT declared shared affiliation with the author’s JSc and FH to the handling editor at the time of review., (Copyright © 2024 Schetelig, Baldauf, Heidenreich, Hoogenboom, Spellman, Kulagin, Schroeder, Sengeloev, Dreger, Forcade, Vydra, Wagner-Drouet, Choi, Paneesha, Miranda, Tanase, de Wreede, Lange, Schmidt, Sauter, Fein, Bolon, He, Marsh, Gadalla, Paczesny, Ruggeri, Chabannon and Fleischhauer.)

Abstract: In acute myeloid leukemia (AML), donor natural killer cell killer immunoglobulin-like receptors (KIR) and recipient HLA interactions may contribute to the graft-versus-leukemia effect of allogeneic hematopoietic cell transplantation (HCT). Analyses of individual KIR/HLA interactions, however, have yielded conflicting findings, and their importance in the HLA-matched unrelated donor (MUD) setting remains controversial. We systematically studied outcomes of individual donor-KIR/recipient-HLA interactions for HCT outcomes and empirically evaluated prevalent KIR genotypes for clinical benefit. Adult patients with AML (n = 2025) who received HCT with MUD grafts in complete remission reported to the Center for International Blood and Marrow Transplantation were evaluated. Only the donor-2DL2+/recipient-HLA-C1+ pair was associated with reduced relapse (hazard ratio [HR], 0.79; 95% confidence interval [CI], 0.67-0.93; P = .006) compared with donor-2DL2-/recipient-HLA-C1+ pair. However, no association was found when comparing HLA-C groups among KIR-2DL2+-graft recipients. We identified 9 prevalent donor KIR genotypes in our cohort and screened them for association with relapse risk. Genotype 5 (G5) in all recipients and G3 in Bw4+ recipients were associated with decreased relapse risk (HR, 0.52; 95% CI, 0.35-0.78; P = .002; and HR, 0.32; 95% CI, 0.14-0.72; P = .006; respectively) and G2 (HR 1.63, 95% CI, 1.15-2.29; P = .005) with increased relapse risk in C1-homozygous recipients, compared with other patients with the same ligand. However, we could not validate these findings in an external data set of 796 AML transplants from the German transplantation registry. Neither a systematic evaluation of known HLA-KIR interactions nor an empiric assessment of prevalent KIR genotypes demonstrated clinically actionable associations; therefore, these data do not support these KIR-driven strategies for MUD selection in AML., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)