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Background: Access to allogeneic haematopoietic stem-cell transplantation (HSCT) remains challenging for older patients (aged >60 years) with acute myeloid leukaemia. We aimed to evaluate the efficacy of venetoclax plus decitabine as first-line therapy and bridge to transplantation in this patient population., Methods: This multicentre, single-arm, phase 2 trial was conducted in 20 Gruppo Italiano Trapianto Midollo Osseo (GITMO) centres in Italy. Patients aged ≥60 and <75 years, with newly diagnosed acute myeloid leukaemia categorised as intermediate or high risk according to 2016 WHO and 2017 European LeukemiaNet, an ECOG performance status of less than 2, and considered fit for allogeneic HSCT were included. Patients received oral venetoclax with a 3-day ramp-up: 100 mg on day 1, 200 mg on day 2, and 400 mg once per day from day 3 of cycle one, and then every 28 days of each cycle (two to four in total). Decitabine was administered intravenously at a dose of 20 mg/m 2 from days 1 to 5 every 28 days. At cycle one, patients were admitted to hospital for a minimum of 24 h, whereas subsequent cycles could be administered on an outpatient basis. Two additional cycles were allowed while waiting for allogeneic HSCT or for those with no response or partial response after cycle two. The primary endpoint was the proportion of patients who had allogeneic HSCT performed during first complete remission, assessed in all patients who received at least one dose of the study medication. This study was registered with ClinicalTrials.gov (NCT04476199, ongoing) and EudraCT (2020-002297-26)., Findings: Between June 1, 2021, and Dec 30, 2022, 93 patients were enrolled and started venetoclax plus decitabine induction (44 [47%] at intermediate risk and 49 [53%] at high risk). The median age was 68·5 (IQR 60·3-74·7). All 93 participants were White, of whom 43 (46%) were female and 50 (54%) were male. The median follow-up was 236 days (IQR 121-506). 64 (69%) of 93 patients reached complete remission and 53 (57%) underwent allogeneic HSCT in complete remission. 53 (83%) of 64 with a complete remission underwent allogeneic HSCT. Five (8%) of 64 patients in complete remission relapsed before transplantation and four died as a consequence. Adverse events (grade ≥3) occurred in 49 (53%) of 93 patients. The most common adverse events were infections (including pneumonia, bacterial sepsis, and SARS-CoV-2 causing seven deaths among 28 [57%] of 49 patients), neutropenia (17 [35%]), thrombocytopenia (two [4%], including one fatal CNS bleeding), and cardiac events (four [8%], including one fatal heart failure). No treatment-related deaths were observed., Interpretation: Venetoclax plus decitabine induction can significantly enhance the feasibility of allogeneic HSCT in older patients with acute myeloid leukaemia who are deemed fit for transplantation., Funding: AbbVie and Johnson & Johnson., Competing Interests: Declaration of interests DR received consulting fees from Medac; honoraria and travel grants from Jazz Pharma, Novartis, MSD, Kite Gilead, and Medac; and has participated in data safety monitoring and advisory board meetings for Novartis, MSD, Kite Gilead, Medac, AbbVie, and Janssen. EB received consulting fees from AbbVie; travel grants from Amgen, Novartis, and AbbVie; and has participated in data safety monitoring and advisory board meetings for Otsuka and Amgen. FO received honoraria from Takeda, Medac, and Kyowa; and travel grants from Roche, Janssen, Kyowa, Takeda, Jazz Pharma, and Medac. RS received a travel grant from Takeda. MaM received honoraria from Novartis, MSD, Astellas Pharma, AbbVie, Takeda, Pfizer, Sanofi, Jazz Pharma, Janssen Cilag, Kite Gilead, Medac, and Bristol Myers Squibb; travel grants from Kite Gilead, Roche, and Janssen Cilag; has participated in data safety monitoring and advisory board meetings for Novartis, Takeda, Kite Gilead, Pfizer, Bristol Myers Squibb, and Janssen Cilag; and served as president of GITMO. CA received honoraria from AbbVie and Jazz Pharma; and has participated in data safety monitoring and advisory board meetings for AbbVie, Jazz Pharma, and Amgen. GB received travel grants from Janssen Cilag and Amgen. AC received honoraria from AbbVie, Menarini (Stemline), Pfizer, Jazz Pharma, and Servier; a travel grant from Jazz Pharma; and has participated in data safety monitoring and advisory board meetings for AbbVie and Menarini (Stemline). CG received consulting fees from AbbVie, Jazz Pharma, Incyte, Bristol Myers Squibb, and Astellas; and a travel grant from Jazz Pharma. PM received honoraria and travel grants from AbbVie and Johnson & Johnson. LG received honoraria from Novartis, MSD, Gilead, AbbVie, Sanofi, and Bristol Myers Squibb; and travel grants from Janssen and AbbVie. CS received honoraria from Jazz Pharma and Kite Pharma; and a travel grant from Jazz Pharma. VR received travel grants from Neovii, Medac, and Jazz Pharma. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

We report the long-term results of a randomized trial (GITMO, AML-R2), comparing 1:1 the combination of busulfan and cyclophosphamide (BuCy2, n = 125) and the combination of busulfan and fludarabine (BuFlu, n = 127) as conditioning regimen in acute myeloid leukemia patients (median age 51 years, range 40-65) undergoing allogeneic hematopoietic stem cell transplantation. With a median follow-up of 6 years, significantly better non-relapse mortality (NRM) was confirmed in BuFlu recipients, which is sustained up to 4 years after transplant (10% vs. 20%, p = 0.0388). This difference was higher in patients older than 51 years (11% in BuFlu vs. 27% in BuCy2, p = 0.0262). The cumulative incidence of relapse, which was the first cause of death in the entire study population, did not differ between the two randomized arms. Similarly, the leukemia-free survival (LFS) and overall survival (OS) were not different in the two cohorts, even when stratifying patients per median age. Graft-and relapse-free survival (GRFS) in BuFlu arm vs. the BuCy2 arm was 25% vs. 20% at 4 years and 20% vs. 17% at 10 years. Hence, the benefit gained by NRM reduction is not offsets by an increased relapse. Leukemia relapse remains a major concern, urging the development of new therapeutic approaches., (© 2024. The Author(s).)

In a first-of-its-kind study, we assessed the capabilities of large language models (LLMs) in making complex decisions in haematopoietic stem cell transplantation. The evaluation was conducted not only for Generative Pre-trained Transformer 4 (GPT-4) but also conducted on other artificial intelligence models: PaLm 2 and Llama-2. Using detailed haematological histories that include both clinical, molecular and donor data, we conducted a triple-blind survey to compare LLMs to haematology residents. We found that residents significantly outperformed LLMs (p = 0.02), particularly in transplant eligibility assessment (p = 0.01). Our triple-blind methodology aimed to mitigate potential biases in evaluating LLMs and revealed both their promise and limitations in deciphering complex haematological clinical scenarios., (© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Domestic dogs have been shown to engage in interspecific communication with their owners using a flexible repertoire of signals (i.e., gaze, vocalizations, and postures). This ability is influenced by ontogenetic development as well as breed selection. Different aspects of this phenomenon have been studied using the out of reach/hidden object task in which a piece of food is shown to the dog and then hidden in an unreachable spot by the experimenter. Dogs' behavioral displays toward the target and the owner (ignorant about the location of the food) have been observed. The complex communicative behavior dogs exhibit in this context is defined as showing behavior and includes attention-getting components directed toward the owner, and directional components directed toward the target. No study has investigated the ontogenetic development of this behavior. In the current study, we compared the showing behavior in 4-6 month old puppies and 2-11 year old adults in an out of reach task involving the hiding of a food reward in one of two cabinets. Dogs were exposed to three conditions: (1) Owner with Food (OF), (2) Owner No Food (ONF), and (3) Alone with food (AF). Dogs showed more gaze alternations when both the food and the owner were present confirming the intentional and referential nature of this behavior. Contrary to our expectations, we found no differences between the showing behaviors of 4-6 month old puppies and adult dogs. This study provides interesting preliminary evidence of showing behavior in puppies. Further studies are needed to gain a deeper understanding of the factors influencing this communicative behavior (i.e., breed, level of training). Furthermore, longitudinal studies should be performed from the age of 2 months up to 1 and 2 years to better clarify the influence of development and experience on showing behavior in domestic dogs., (© 2023. The Author(s).)

The conditioning regimens with different alkylators at different doses can influence the outcome of allogeneic stem cell transplantation (SCT), but conclusive data are missing., Methods: With the aim to analyze real-life allogeneic SCTs performed in Italy between 2006 and 2017 in elderly patients (aged >60 y) with acute myeloid leukemia or myelodysplastic syndrome, we collected 780 first transplants data. For analysis purposes, patients were grouped according to the type of alkylator included in the conditioning (busulfan [BU]-based; n = 618; 79%; treosulfan [TREO]-based; n=162; 21%)., Results: No significant differences were observed in nonrelapse mortality, cumulative incidence of relapse, and overall survival, although in the TREO-based group, we observed a greater proportion of elderly patients ( P  < 0.001); more active diseases at the time of SCT ( P  < 0.001); a higher prevalence of patients with either hematopoietic cell transplantation-comorbidity index ≥3 ( P  < 0.001) or a good Karnofsky performance status ( P  = 0.025); increased use of peripheral blood stem cells as graft sources ( P  < 0.001); and greater use of reduced intensity conditioning regimens ( P  = 0.013) and of haploidentical donors ( P  < 0.001). Moreover, the 2-y cumulative incidence of relapse with myeloablative doses of BU was significantly lower than that registered with reduced intensity conditioning (21% versus 31%; P  = 0.0003). This was not observed in the TREO-based group., Conclusions: Despite a higher number of risk factors in the TREO group, no significant differences were observed in nonrelapse mortality, cumulative incidence of relapse, and overall survival according to the type of alkylator, suggesting that TREO has no advantage over BU in terms of efficacy and toxicity in acute myeloid leukemia and myelodysplastic syndrome., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

Today, allogeneic stem cell transplantation (allo-SCT) can be offered to patients up to age 70 to 72 years and represents one of the most effective curative treatments for many hematologic malignancies. The primary objective of the study was to collect data from the allo-SCTs performed in Italy between 2000 and 2017 in patients aged ≥60 years to evaluate the changes in safety and efficacy outcomes, as well as their distribution and characteristics over time. The Italian Group for Bone Marrow Transplantation, Hematopoietic Stem Cells and Cell Therapy (GITMO) AlloEld study (ClinicalTrials.gov identifier NCT04469985) is a retrospective analysis of allo-SCTs performed at 30 Italian transplantation centers in older patients (age ≥60 years) between 2000 and 2017 (n = 1996). For the purpose of this analysis, patients were grouped into 3 time periods: time A, 2000 to 2005 (n = 256; 12%); time B, 2006 to 2011 (n = 584; 29%); and time C, 2012 to 2017 (n = 1156; 59%). After a median follow-up of 5.6 years, the 5-year nonrelapse mortality (NRM) remained stable (time A, 32.8%; time B, 36.2%; and time C, 35.0%; P = .5), overall survival improved (time A, 28.4%; time B, 31.8%; and time C, 37.3%; P = .012), and the cumulative incidence of relapse was reduced (time A, 45.3%; time B, 38.2%; time C, 30.0%; P < .0001). The 2-year incidence of extensive chronic graft-versus-host disease was reduced significantly (time A, 17.2%; time B, 15.8%; time C, 12.2%; P = .004). Considering times A and B together (2000 to 2011), the 2-year NRM was positively correlated with the Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) score; NRM was 25.2% in patients with an HCT-CI score of 0, 33.9% in those with a score of 1 or 2, and 36.1% in those with a score of 3 (P < .001). However, after 2012, the HCT-CI score was not significantly predictive of NRM. This study shows that the transplantation procedure in elderly patients became more effective over time. Relapse incidence remains the major problem, and strategies to prevent it are currently under investigation (eg, post-transplantation maintenance). The selection of patients aged ≥60 could be improved by combining HCT-CI and frailty assessment to better predict NRM., (Copyright © 2021 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)