Donor Type Research Articles

Impact of spin-flip scattering on spin current and inverse Spin-Hall effect in silicon doped by bismuth, antimony or phosphorus

The influence of spin-flip scattering on the generation of spin currents in n-type silicon is studied. Doping of silicon by heavy donors, such as bismuth or antimony, leads to an additional spin scattering of conduction electrons on the impurity-induced spin-orbit potential. Based on the diffusion model and the theory of spin pumping spin current and inverse-spin-Hall effect voltage are considered for different types of donors with various concentrations and spin diffusion lengths. Calculations yield the dependence of the inverse spin-Hall effect signal on the parameters of bismuth-doped silicon layers and also explain the absence of such signal for silicon layers doped by phosphorus or antimony.

Long-Term Social Outcomes of Pediatric Liver Transplant Recipients: Transition From Childhood to Adulthood.

Chronic disorders may negatively affect people's learning status, marital status, occupational life, and social life. Liver transplant is the only curative treatment for chronic liver diseases. This study was undertaken to evaluate the psychosocial effects of liver transplant in adult patients who had undergone liver transplant during the pediatric period compared with psychosocial facts in the general population. We retrospectively reviewed adult patients (>18 years of age) who had received liver transplant as children. We compared sex, age at the time of transplant, current age, type of donor, graft survival status, marital status, age at first delivery, number of children, educational status, and occupational status in the study population versus the general (normal) population. To compare the liver transplant patients included in the study with the general population correctly, we used data from the Turkish Statistical Institute. Among 77 liver transplant patients included in our study, the mean age at transplant was 10.9 years (range, 0.5-16 y) and the mean age at the time of the study was 25.2 years (range, 18-42 y). Of the patients, 61 (79.2%) were single and 16 (20.8%) were married. Patients in the study population married at a younger age than the general population (25.5 vs 28.1 y for men, 24.3 vs 25.4 y for women). Of 16 married patients, 9 (56.2%) had a healthy child or children. The percentage of patients who graduated from higher education or were continuing their higher education process was higher in our study population than in the general population (36.3% vs 22.8%). Among our study population, 37 patients (48%) were workers. Liver transplant had no negative effects on the social, educational, and professional lives among adults in our study who received transplants in the pediatric period.

The impact of cryoprotectant exposure time on post-thaw viability of autologous and allogeneic hematopoietic stem cells and leukocyte subpopulations.

Although the use of cryoprotectant dimethyl sulfoxide (DMSO) is the gold standard in cryopreservation of hematopoietic stem cells, it is well known that it has a negative effect on cell viability. The aim of this prospective study was to examine how the length of post-thaw exposure to DMSO affects the cell viability and stability of peripheral blood stem cell (PBSC) samples. Additionally, the effects of donor type and pre-cryopreservation storage time on post-thaw viability during the stability study were evaluated. In 30 autologous and 30 allogeneic PBSC samples viable CD34+, CD14+, CD19+, CD16+/56+, and CD3+ cells were determined immediately after thawing, and one-and three-hours post-thaw. Analysis of the absolute count of viable cells in thawed samples showed a significant difference between all measurement points for CD34+ (p < 0.001), CD14+ (p < 0.001), and CD19+ cells (p < 0.001). No significant differences were observed for post-thaw stability of allogeneic samples analysed between products stored before cryopreservation ≥ 24 hours (N = 20), and those stored < 24 hours (N = 10), except for viable CD3+/CD4+ cells after three hours post-thaw (p = 0.028). In conclusion, DMSO had different effects on leukocyte subpopulations in cryopre-served PBSC samples. The type of donors and the length of storage before cryopreservation did not affect the post-thaw stability of cryopreserved PBSC samples.

Post-Transplantation Cyclophosphamide-Based Graft-versus-Host Disease Prophylaxis in HLA-Matched and Haploidentical Donor Transplantation for Patients with Hodgkin Lymphoma: A Comparative Study of the Lymphoma Working Party of the European Society for Blood and Marrow Transplantation

Post-transplantation cyclophosphamide (PTCy) has emerged as a promising approach for preventing graft-versus-host disease (GVHD) in allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, there is a lack of studies examining the impact of this GVHD prophylaxis when different donor types are used in patients with Hodgkin lymphoma (HL). This study compared the outcomes of patients with HL undergoing HSCT from HLA-matched donors, including matched sibling donors (MSDs) and matched unrelated donors (MUDs), and haploidentical donors, using PTCy as the GVHD prophylaxis approach in all cohorts. We retrospectively compared outcomes of allo-HSCT from 166 HLA-matched donors (96 sibling and 70 unrelated donors) and 694 haploidentical donors using PTCy-based GVHD prophylaxis in patients with HL registered in the European Society for Blood and Marrow Transplantation database from 2010 to 2020. Compared to HLA-matched HSCT, haploidentical donor HSCT was associated with a significantly lower rate of platelet engraftment (86% versus 94%; P < .001) and a higher rate of grade II-IV acute GVHD (34% versus 24%; P = .01). The 2-year cumulative incidence of nonrelapse mortality (NRM) was significantly lower in the HLA-matched cohort compared to the haploidentical cohort (10% versus 18%; P = .02), resulting in a higher overall survival (OS) rate (82% versus 70%; P = .002). There were no significant differences between the 2 cohorts in terms of relapse, progression-free survival, or GVHD-free relapse-free survival. In multivariable analysis, haploidentical HSCT was associated with an increased risk of grade II-IV acute GVHD and NRM and worse OS compared to HLA-matched HSCT. Our findings suggest that in the context of PTCy-based GVHD prophylaxis, transplantation from HLA-matched donors appears to be a more favorable option compared to haploidentical HSCT.

Haploidentical and Matched Sibling Transplantation for Acute Myeloid Leukemia: A Hospital-Based Study.

Allogeneic peripheral blood stem cell transplantation (PBSCT) has been increasing for the last years in Latin America. The objective of this study was to describe clinical outcomes in acute myeloid leukemia (AML) receiving allogeneic PBSCT between 2013 and 2019 in a single center of Cali, Colombia. A retrospective cohort study was conducted in Fundacion Valle del Lili. Patients diagnosed with AML who received an allogeneic PBSCT between 2013 and 2019 using human leukocyte antigen (HLA)-matched sibling donors (MSDs) or haploidentical related donors (HRDs) with myeloablative conditioning regimen were included. Cases with diagnosis of promyelocytic leukemia, myelodysplastic syndrome-related AML and therapy-related AML were excluded. Data were obtained directly from the hospital PBSCT database and clinical records. A total of 50 patients were included (HRD, n = 32; MSD, n = 18). Sixty-two percent was in the first complete remission (CR1) at the time of the transplant, of which 26% were MSD and 74% were HRD. The European Group for Blood and Marrow Transplantation (EBMT) risk score was: 44% vs. 50% low, 28% vs. 28% intermediate and 28% vs. 22% high for MSD vs. HRD, respectively. Overall survival at 5 years for MSD was 62% (95% confidence interval (CI): 31-83%) and 43% (95% CI: 25-60%) for HRD. Event-free survival was 56% (95% CI: 26-78%) and 35.6% (95% CI: 18-53%), respectively. Non-relapse mortality at day-100 was 6% (95% CI: 0.8-35%) and 20% (95% CI: 9-39%). Relapse at5 years was 18% (95% CI: 4-58%) and 25% (95% CI: 10-52%). Overall mortality rate was 46%. The grade II-IV, III-IV acute graft-versus-host disease and severe chronic graft-versus-host disease was 44%, 11% and 12% for MSD, and 43%, 9% and 0% for HRD. These results underline that MSD remains the first donor choice for AML patients in CR1 when available. HRDs are still our next option among alternative donors. It is necessary to find strategies that have a positive impact on those outcomes that markedly affect the quality of allogeneic PBSCT and the prognosis of patients. Comparative, randomized, prospective studies with longer follow-up of haploidentical allogeneic PBSCT with other donor types are required to definitely establish its role among alternative donors.

Comparing Older Matched Related to Younger Matched Unrelated Donors in Acute Myeloid Leukemia in Remission Using Post-Transplant Cyclophosphamide

Backgroud. Over the past 25 years, the landscape of allogeneic stem cell transplantation (allo-SCT) changed from being rarely performed in patients 50 years or older to accounting for a little less than half of the transplantations reported in USA and Europe. Older patients will on average have older matched related siblings (MRD) being considered as donors with issues such as comorbidities, risk of clonal haematopoiesis of indeterminate potential, and impaired immune and regenerative potential of stem cells. Although younger HLA-matched unrelated donors (MUD) are an important alternative in this context, it remains unclear whether the use of MUD is associated with better outcomes. This is especially true in the context of post-transplant cyclophosphamide (PTCy) as graft-versus-host disease (GvHD) prophylaxis. Methods. The aim of this study was to compare the graft-relapse-free survival (GRFS) for patients diagnosed with acute myeloid leukemia (AML) in first complete remission (CR1), aged 50y or more, and having received a first allo-SCT from a 10/10 MUD younger than 40y or a MRD older than 50y using PTCy for in-vivo T-cell depletion. All transplants were performed between 2015-2021 at the EBMT centres. Results. A total of 410 consecutive patients were included, 172pts receiving a MRD, 238pts transplanted from a MUD. All patients with detailed conditioning regimen dosages were classified according to the transplant conditioning intensity (TCI) score in low (1-2), intermediate (2.5-3.5), high (4-6). TCI-score was available for 345 patients and was as follows: low in 53pts (36.8%), intermediate in 79pts (54.9%) and high in 12pts (8.3%) for MRD, low in 91pts (45.3%), intermediate in 93pts (46.3%) and high in 17pts (8.5%) for MUD (p=0.26). Only patients with available TCI-score were analysed. In univariate analysis the 2-year GRFS was 58% (49.8-65.3%) for TCI intermediate-high and 43.1% [34.3-51.5] for TCI low (p=0.005). In TCI-score intermediate-high non-relapse mortality (NRM) wasn't higher compared to TCI-score low (12.7% [12.2-24] vs 13.7% [8.4-20.3], p=0.53) but relapse incidence (RI) was lower (17.7% [12.2-24] vs 33.2% [25.1-41.5], p=0.003). As a strong interaction between TCI-score and type of donor was found, we compared transplant outcomes between MRD and MUD separately for TCI-score low and TCI-score intermediate-high. In TCI-score low, 2-year GRFS was 44.4% [33.5-54.8] for MUD and 40.9% [26.4-54.9] for MRD (p=0.83) (Figure 1A). In multivariable analysis (MVA) type of donor was not a risk factors for neither GRFS (HR 0.98, CI: 0.57-1.69; p=0.95) nor for any other transplant outcome. In TCI-score intermediate-high, 2-year GRFS was 67.2% [55.8-76.2] for MUD and 46.1% [34.4-57.1] for MRD (p=0.001) (Figure 1B). In MVA MUD were associated to better GRFS (HR 0.41, CI: 0.24-0.7; p=0.001), lower NRM (HR 0.19, CI: 0.07-0.55; p=0.002) and lower RI (HR 0.32, CI: 0.14-0.73; p=0.007) without advantages in terms of neither aGvHD nor cGvHD. Conclusions. In patients with AML in CR1, aged 50y or more and receiving a conditioning regimen with TCI-score ≥ 2.5 in the PTCy setting, a MUD younger than 40y is associated to longer GRFS, lower NRM and lower RI compared to a MRD older than 50y. For patients receiving regimens with TCI-score low transplant outcomes are independent on the type of HLA-matched donor.

Clinical Determinants of Early Mortality Following Allotransplantation for Acute Lymphoblastic Leukemia in a Brazilian Multicenter Registry

Introduction: Allogeneic stem-cell transplantation (HSCT) continues to be a potentially curative approach for acute lymphoblastic leukemia (ALL). However, one of the primary challenges in HSCT remains the transplantation-related mortality (TRM), even though the overall complications and mortality rates have decreased over time. Notably, in developing countries, previous research on HSCT has highlighted that early mortality plays a significant role in their comparatively worse outcomes. Therefore, it is crucial to identify the factors involved in early mortality to enhance cure rates. Considering this, our study aims to investigate the risk factors associated with early mortality following HSCT for ALL in Brazilian centers. Methods: This is a retrospective registry study. Patients with ALL or ambiguous lineage leukemia above 16 years who underwent a first HSCT in 5 Brazilian centers between January 2007 and December 2017 were included. Early mortality (EM) was defined as death within 100 days from HSCT. A multivariable analysis (MVA) was performed using logistic regression, with the Akaike's information criteria used for model selection. A p-value&amp;lt;0.05 was considered statistically significant. Results: Overall, 275 patients were included in this study. Baseline characteristics are summarized in Table 1. The median age was 31y (range, 16-65) and 58.5% were male. The Philadelphia chromosome was reported in 35% and most patients were in first complete remission (CR1) (66%). Matched sibling donor (MSD), matched unrelated donor (MUD), mismatched unrelated donor (MMUD), haploidentical donor, and umbilical cord were reported in 53%, 19%, 9%, 19%, and 5%, respectively. The median donor age was 31y (range, 4-64) and 54.4% were male. EM rate was 24.4%. Univariate analysis pointed some factors statistically related to EM, as it follows: graft source (p&amp;lt;0.001), baseline KPS (p=0.03), gender (female vs. male, 16.7 vs 27.9%, p=0.03), Ph-positive status (p=0.03), refractory disease status (p=0.015), umbilical cord blood source (p=0.01), and donor age (p=0.08). There was no difference regarding EM rates between public and private centers (24.5 vs. 19%, p=0.463). The best multivariable model included gender, Ph-status, donor type and donor age as final variables for EM. In our cohort, Ph-positive status (OR = 2.83), donor age (OR = 1.05), and the use of MUD (OR = 3.68) were independently associated with early transplant-related mortality. Regarding the cause of EM, 69% were related to infection, and 19.5% were caused by acute GVHD. Interestingly, EM was higher in Ph-positive patients with no major molecular remission (BCR-ABL≥0.1%) - 40 vs. 3.6%, p=0.008). Cumulative incidence of acute GVHD at day 100 was 48.3% by competitive analysis. Only 3 out of 62 deaths in EM group were due to disease relapse. Remaining deaths were secondary to bacterial infection (52%), followed by acute GVHD (17.8%) and fungal infection (8.9%), mainly. Conclusions: This study represents the largest analysis in Brazil to assess early transplant-related mortality in ALL patients. Reducing EM rates is particularly important in resource-constrained settings to improve outcomes. While the overall patient characteristics were similar to other registry analyses, the EM rate in this study was higher than that reported in other cohorts worldwide. Notably, transplant-related factors such as donor age and type, in addition to Ph-positive status, were found to be associated with EM, outweighing previously known factors like conditioning intensity and the use of total body irradiation. These findings could aid in enhancing donor selection in Brazil and optimizing HSCT indications in specific subsets.

Outcomes of Patients Undergoing Fludarabine and Melphalan-Based Conditioning with Post-Transplant Cyclophosphamide for Peripheral Blood Stem Cell Allogeneic Hematopoietic Cell Transplant: Donor Type Effect

Background Reduced intensity conditioning (RIC) has expanded eligibility of older patients (pts) with hematological disorders for allogeneic hematopoietic cell transplant (HCT). Fludarabine and melphalan (FM) has been shown to improve disease control with an acceptable toxicity profile when combined with CNI-based GVHD prophylaxis regimens. The emergence of post-transplant cyclophosphamide (PTCy) as GVHD prophylaxis has improved outcomes of HCT across different HLA disparities and improved accessibility of HCT, especially in patient with no available matched donor. With recent data showing improved outcomes with RIC (Bolaños-Meade et al. NEJM 2023 and Shaw et al, JCO 2021), PTCy has been proposed as the standard of care for GVHD prophylaxis regardless of donor type. Herein, we report the largest experience with FM and PTCy as GVHD prophylaxis. Methods We retrospectively reviewed pts who underwent FM-based PBSC HCT with PTCy as GVHD prophylaxis at City of Hope from January 2015 to December 2021. Descriptive statistics were used to describe baseline characteristics. Kaplan-Meier Curves and log-rank tests were used to calculate and compare overall survival (OS) and disease-free survival (DFS), respectively. Cumulative incidence of relapse (CIR), non-relapse mortality (NRM) and GVHD were calculated and compared via a competing-risk analysis and Gray's test, respectively. Multivariate analyses (MVA) were performed using the multivariable Cox regression model for OS and DFS, and multivariable Fine and Gray regression model for the other variables. The primary aim was to evaluate the effect of donor types on HCT outcomes. Results Baseline characteristics of 248 pts are summarized in Table 1. The median age was 63 (range, 20-82). 63.9% were male. The most common diagnoses were AML (n=90), MDS/MPN (n=58), lymphoma (n=40), and ALL (n=39). Of 248 pts, 89 (35.9%) received HCT from a matched related/unrelated donor (MRD/MUD), 118 (47.6%) from a haplo-identical (haplo) donor and 49 (19.8%) from a mismatched unrelated donor (MMUD). The median times to neutrophil and platelet engraftment were 18 days (range, 18-19) and 32 days (range, 30-34), respectively. On MVA, MRD/MUD was associated with faster engraftment over haplo donors for neutrophils (hazard ratio [HR] 0.64, 95% CI, 0.47,0.87, P=0.015) and for platelets (0.49, 95% CI, 0.34-0.70, p&amp;lt;0.001), compared to MRD/MUD but there was no difference in engraftment between haplo and MMUD. With a median follow-up for surviving pts of 24.4 months (range, 3.3-81.2), the 2-year OS and DFS for the all pts were 60.4% (95% CI, 53.7-66.5) and 55.5% (95% CI, 48.9-61.6), respectively. The 2-year OS and DFS for pts receiving haplo donors, MMUD, and MRD/MUD were 56.1%, 52.6%, and 72.5%, and 50.7%, 46.7%, and 68.4%, respectively (Figure 1). On MVA, compared with MRD/MUD, the 2-year OS was lower with haplo (HR 2.02, 95% CI, 1.19-3.42) and with MMUD (HR 2.03, 95% CI, 1.11-3.72 (p=0.023), while there was no difference between haplo and MMUD. Additionally, donor age &amp;gt;=35 years was associated with lower OS (HR 1.57, 95% CI, 1.04-2.35, p=0.031). There was a trend toward lower DFS with haplo (HR 1.61 (95% CI, 1.00-2.60)) and with MMUD, HR 1.73 (95% CI, 0.99-3.02, (p=0.093) when compared with MRD/MUD. 2-year NRM and CIR for all pts were 27.7% (95% CI, 22.1-33.5) and 16.8% (95% CI, 12.3-21.9), respectively. There were no differences in CIR based on donor type on MVA (p=0.87). NRM was higher in haplo and MMUD compared to MRD/MUD but this lost significance (p=0.13) in MVA after adjusting for KPS (HR 1.79, 95% CI, 0.98-3.26, p=0.019) and donor age &amp;gt;=35 years (HR: 1.87, 95% CI, 0.93-3.74, p=0.049). Day 100 CI of grade 2-4 and grade 3-4 acute GVHD for all pts were 39.5% (95% CI, 33.4-45.6) and 14.5% (95% CI, 10.5-19.2) and the 1-year CI of extensive chronic GVHD was 31.0% (95% CI, 25.2-37.0) There were no differences in grade 3-4 acute GVHD at day 100 or 1-year CI of extensive chronic GVHD based on donor type (p=0.46 and 0.13, respectively), although MVA revealed a strong trend towards a higher CI of grade 2-4 aGVHD at day 100 with MMUD group, HR 1.73 (95% CI, 1.02,2.95), p=0.079) Conclusions FM with PTCy was associated with promising disease control and acceptable NRM. Outcomes of pts undergoing MRD/MUD appears to be superior in this setting due to decreased NRM, while outcomes of pts undergoing HCT with haplo or MMUD are comparable. Donors &amp;lt;35 years was the strongest predictor of improved outcomes.

Outcomes of Tcrαβ and CD19-Depleted Hematopoietic Stem Cell Transplantation from Matched, Mismatched Unrelated and Haploidentical Donors for Pediatric Patients with Hematological Malignancy: A Meta-Analysis

Introduction: TCR αβ+/CD19+ depletion in hematopoietic stem cell transplantation (HSCT) is an emerging graft manipulation technique to help overcome the HLA barrier in the mismatched or haploidentical transplant setting and reduce or prevent graft-versus-host disease. Limited research has explored the impact of various donor sources, and type of malignancy on the outcomes of TCR αβ+/CD19+ depleted HSCT for acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and myelodysplastic syndrome (MDS). Therefore, we performed a comprehensive meta-analysis of published clinical studies using individual patient data (IPD) to address this scientific gap. Methods: This meta-analysis combined patient-level data from studies involving AML/MDS and ALL patients treated with TCR αβ+/CD19+ depleted HSCT. By utilizing the IPDfromKM technique, we reconstructed time-to-event data from aggregated Kaplan-Meier curves, specifically focusing on overall survival (OS), disease-free survival (DFS), and GVHD-free, relapse-free survival (GRFS). Additionally, we conducted parallel meta-analyses to calculate the pooled incidences of GVHD, graft failure, mortality, as well as CMV and EBV reactivation, and sinusoidal obstruction syndrome (SOS) using aggregate data. All analyses were performed using STATA software. Our comprehensive literature search included publications up to May 2023, excluding studies with significant sample overlap. Results: The meta-analysis incorporated 817 children with AML/MDS or ALL from 12 studies. Successful primary engraftment was observed in 95% of patients (95% CI: 92 - 98), with an average time to neutrophil and platelet engraftment of 12 days. The incidence of acute GVHD grades I-II was 24% (95% CI: 14 - 34), while grades III and IV were 11% (95% CI: 3.0 - 0.18). Chronic GVHD was observed in 19% of patients (95% CI: 11 - 28). The relapse and graft failure rates were 25% (95% CI: 19 - 32) and 6% (95% CI: 2.0 - 9.0), respectively. The all-cause mortality was 34% (95% CI: 29 - 38), with HSCT-related mortality at 11% (95% CI: 8.0 - 13), while relapse-related mortality accounted for 22% (95% CI: 17 - 28). At a median follow-up of 2.55 years, the 1-year and 5-year OS rates were 74.7% (95% CI: 60.6 - 78.3) and 64.4% (95% CI: 59.9 - 68.5), respectively. No significant differences in OS were found between ALL and AML/MDS patients (HR= 0.99, 95% CI: 0.48 - 2.02, P=0.98) or between different donor types (Figure 1A). The DFS rates at 1- and 5-year were 72.8% (95%CI: 67.6 - 77.3) and 61.8% (95%CI: 56.1 - 67.0), respectively. No significant differences in DFS were observed between ALL and AML/MDS patients (HR = 0.74 95%CI: 0.48 - 1.14, P=0.17) or between different donor types (Figure 1B). The overall 1- and 5-year GRFS rates were 71.1% (95% CI: 64.1 - 77.4) and 63.0% (95% CI: 55.3 - 69.8), respectively. The overall incidence of CMV and EBV reactivation was 33% (95% CI: 19 - 46) and 16% (95% CI: 0 - 38), respectively. Conclusions: Our meta-analysis confirms the effectiveness and safety of TCRαβ and CD19-depleted HSCT for hematological malignancies, demonstrating high engraftment success, low graft failure, and a manageable incidence of acute and chronic GVHD. The consistently favorable outcome data across different donor types and malignancies support the broad applicability of this form of graft manipulation.

Comparison of Outcomes of Hematopoietic Cell Transplantation (HCT) for Asymptomatic Patients with Sickle Cell Disease (SCD) and That of Propensity Matched Symptomatic Patients Undergoing HCT

Introduction Hematopoietic cell transplantation (HCT), a potential curative option for sickle cell disease (SCD) has typically been offered to patients with severe disease manifestations. With improved outcomes, especially in young children receiving HCT from HLA identical donors, some clinicians are performing HCT for patients without severe manifestations. HCT is associated with risk of substantial short-term morbidity, death, and long-term sequelae. Performance of HCT in patients who have not yet suffered from complications of SCD, raises unique issues of cost-benefit tradeoff, ethics, and healthcare equity. Further, it is unknown whether patients who have not suffered complications of SCD would have better outcomes following HCT. The objective of this study was to compare the outcomes for asymptomatic patients in patients undergoing HCT for SCD and propensity matched symptomatic SCD patients undergoing HCT. Methods: We queried the HCT for SCD dataset of patients undergoing HCT between 1990-2022 and reported to the Center for International Bone Marrow Research (CIBMTR) registry. Transplant essential data had been submitted for all patients while a subset of patients was assigned to the comprehensive research form (CRF) track. On these patients HCT centers submitted detailed SCD specific baseline data, as well as outcomes relevant to SCD and organ specific complications. The main reason for HCT is one of the variables collected in the CRF. Thus, we selected patients in the CRF track for further study. We describe demographics, baseline characteristics, transplant essential outcomes including overall survival (OS) and event free survival (EFS), graft failure (GF), Acute graft versus host disease (aGVHD) and chronic GVHD (cGVHD), venocclusive disease of the liver (VOD), post-transplant pneumonia/acute chest syndrome or other pulmonary complications(ACS), nephropathy, stroke, avascular necrosis (AVN), vasocclusive crises (VOC). We created a propensity score model, adding baseline variables. For each categorical outcome variable, frequency tables and tests of difference in proportions were derived. Descriptive statistics and tests of difference in means were derived for the two numeric outcome variables. In addition, survival analysis (Cox regression modeling) was conducted to determine the time until an individual experienced graft failure or death and whether event rates were associated with group classification adjusting for age and donor type. Results: For the entire cohort of 1718 patients undergoing HCT from 1990 to 2022 patients were followed for a median 47.8 months (0.3-312.9), 73.4% of patients with age at HCT &amp;lt;18 years and 74.7% with Karnofsky-Lansky score ≥ 90. The 3-year OS was 91.2%, 3-year EFS 75.5%, and GF rate was 17.9%, aGVHD grades II-IV occurred in 18.3%, and cGVHD developed in 22.3%. A total of 763 patients were assigned to the CRF track. The main reason for HCT was reported for these patients, and 49 patients were reported to be asymptomatic at baseline. In the asymptomatic patients majority of the HCT were performed for patients under the age of 10 years (n = 33) in patients with Hemoglobin SS (n = 45) and most occurred between 2013-2018 (n = 24). Average follow up period was 48 months. The most common graft source and conditioning regimens utilized were bone marrow (n = 35) HLA identical sibling donor type (63.2%, n = 31), and reduced intensity conditioning (n = 25) respectively. Other donor types included HLA mismatched relative (n = 9), mismatched unrelated donor and cord blood (n = 5), and matched unrelated was used in 4 patients. There was one death, at 16.5 months with cGvHD. GF occurred in 14.3%, OS was 97.9%, EFS 83.67%, 20.4% developed aGvHD and 28.5% developed cGvHD and none developed secondary malignancies or post-transplant lymphoproliferative disorders. Propensity matched control group (Figure 1) was constructed based on age at HCT, donor type, graft type, HCT comorbidity index, SCD type. There was good variable balance with a small standardized mean difference for matched observations. There were no statistically significant differences in least mean squares for EFS, death, OS, GF, AGVHD, CGVHD, VOD, VOC, AVN, stroke or ACS between the propensity matched groups ( Figure 1). Discussion: Complications and outcomes of HCT in asymptomatic patients with SCD patients is similar to that in propensity matched symptomatic SCD patients undergoing HCT.

Post-Transplant Cyclophosphamide-Based Prophylaxis and Its Impact on the Immune Reconstitution and the Incidence of Infectious Complications

Introduction PTCY-based prophylaxis is becoming increasingly prevalent across allogeneic hematopoietic cell transplantation (allo-HCT) due to its efficacy on GVHD prevention. However, using PTCY has been associated with delayed engraftment, immune reconstitution, and high infectious complications. Although different studies have investigated how PTCY interacts with infectious risk after allo-HCT, whether the incidences of these complications differ depending on donor type has not been widely investigated. At our institution, PTCY-based prophylaxis has become our institutional prophylaxis irrespectively of the selected donor type. This study explores the incidences of infectious complications and immune cell reconstitution dynamics in patients undergoing allo-HCT with PTCY and according to the donor type selected. Methods This study included the 253 consecutive adults who underwent peripheral blood allo-HCT with PTCY at our institution between 2013 and 2021. Retrospective data was updated in June 2023. All patients received levofloxacin 500mg daily from day +1 until neutrophil engraftment. No patient received letermovir. Cumulative incidences (CI) analyses have been estimated considering death as competing event and reported at day +30, +100, +180, and 1-year. Infection density was calculated by dividing the number of infections of a patient by the observed time period after allo-HCT. Immune reconstitution was evaluated by the measurement of lmmunoglobulin (IgG), CD4+T-cell (CD4) and CD8+T-cells (CD8) levels in alive patients without relapse history. Results The median age was 53 years (range, 18-70 years), with 44 (17.6%) patients older than 65. Acute myeloid leukemia was the most common underlying diagnosis (38%), and 103 (41%) patients received myeloablative conditioning regimens. As reported in Table 1, 120 (47.4%) patients received grafts from HLA-matched donors, 84 (33.2%) from 9/10 HLA mismatched unrelated donors (MMUD) and 49 (19.4%) from haploidentical donors (haplo-HCT). To perform the statistical analysis, the study cohort was divided into 3 groups according to donor type. Baseline characteristics were balanced between these 3 groups, except for the proportion of patients with HCT-CI&amp;gt;3, higher in HLA-matched donor group (p=0.028). As shown in Table 1, 244 (96%) patients engrafted. The median of days to neutrophil and platelet engraftment, and the CIs of clinically relevant acute and chronic GVHD did not differ according to the donor type. Moreover, the duration of the immunosuppression and post-transplant outcomes were similar in all groups. Bacterial bloodstream infections (BSI) were predominantly diagnosed within the first 30 days post allo-HCT, and with a tend to higher incidence in allo-HCT performed from HLA-matched donors (p=0.07). CMV reactivation was the most frequent viral infection in all groups, occurring mostly between days +30 and +100, and with a higher CI in the MMUD group (p=0.033). CMV disease, grade 2-4 BK hemorrhagic cystitis, VHH6 reactivation/disease and fungal infection CIs were not prevalent post-transplant complications generally occurring during the first 100 days after allo-HCT, with comparable CI differences among the 3 groups. The CI of respiratory viral infections increased steadily during the first year after allo-HCT, with similar incidences among the 3 study groups. Infection density analysis showed comparable volume of infections complications in the 3 study groups. As shown in Figure 1, a higher infection density was observed during the first 100 days after allo-HCT (with approximately 1 or 2 number of infections occurring during that time period in most of the patients). After day +100, the number of infections progressively decreased during the post-transplant follow-up. Immune reconstitution was measured in 139 (55%) alive patients. IgG, CD4, and CD8 levels tended to normalize in most patients from day 180 onwards, with median days to normalization of 208, 216, and 203 days, respectively, and with no differences according to donor type. Conclusions Patients undergoing allo-HCT with PTCY-based prophylaxis have a relevant infectious density rate during the peri-engraftment phase with no differences according to donor type. Infectious complications decreased 6 months after allo-HCT, and in parallel with discontinuation of immunosuppression and immune reconstitution with no differences according to donor type.

Routine Computed Tomography before Pediatric Hematopoietic Stem Cell Transplantation and Association with Length of Stay and Early Non-Relapse Mortality

Introduction: Computerized tomography (CT) scans of the sinus, chest, abdomen, and pelvis are often performed in children prior to hematopoietic stem cell transplantation (HSCT) to evaluate for occult infections. Identification of infectious abnormalities could allow for pre- or post-HSCT infection prophylaxis to reduce morbidity or mortality. However, the association of abnormal pre-HSCT and adverse outcomes post-HSCT has not been previously examined. Additionally, routine imaging may identify incidental non-infectious findings, potentially necessitating additional diagnostic workup and unnecessary radiation exposure. In this study, we sought to investigate the prevalence of abnormal findings on CT scans in children undergoing HSCT and their association with post-HSCT length of stay (LOS) and early non-relapse mortality (NRM). Methods:We constructed a retrospective cohort of children, adolescents, and young adults (0-26y) who received a HSCT at Children's of Alabama between 2003 and 2019. Institutional Review Board approval was obtained prior to data collection. Eligibility included availability of pre-HSCT CT reports which were abstracted by the study team from medical records and were coded as either normal, infectious, or non-infectious abnormalities. Demographic (age at HSCT, sex, race/ethnicity) and HSCT characteristics (indication [primary diagnosis], type of HSCT [allogeneic, autologous], cell source, donor type) were abstracted from medical records. Vital status at day +100 was ascertained and causes of death were classified as relapse-related mortality and NRM. Post-HSCT outcomes of interest included length of stay (using day of HSCT as day 0) and day +100 NRM. Association between abnormal pre-HSCT CT and LOS was modelled using linear regression after adjusting for age at HSCT, sex, race/ethnicity, primary diagnosis, type of HSCT, cell source and donor type. Stratified analyses for patients with infectious abnormalities and those who received allogeneic HSCT were performed. Association between pre-HSCT abnormal CT and early (day +100) NRM was examined using logistic regression after adjusting for above covariates. Results: Overall, 236 patients met eligibility for inclusion. Cohort characteristics are included in Table. Median age at HSCT was 5.8y (range, 0.1-26), 54.7% were male and 57.6% were non-Hispanic white. Most patients received an allogeneic HSCT (66.1%); most common source of stem cells was bone marrow (60.3%), and most common donor was matched unrelated (40.7%). The most common anatomic location imaged using CT scan was chest (91%) followed by abdomen (89%), pelvis (87%), sinus (57%), head (46%) and neck (8.5%). An abnormal pre-HSCT CT scan was identified in 99 patients (41.9%). Infectious abnormalities were identified in 73 (31%) and a non-infectious abnormality was identified in 26 (11%). Sinus CT was most likely to demonstrate any abnormality. Compared to no abnormality, infectious abnormality was more commonly noted in patients with acute lymphoblastic leukemia (20.4% vs 27.4%, P=0.01) and acute myeloid leukemia (8.0% vs 23.3%, P=0.01). Abnormalities noted on CT scans are shown in Figure. The most commonly identified infectious abnormalities were sinusitis (58.9%), lung densities (20.5%), and enteritis (8.2%). The most common non-infectious abnormality noted was active primary disease (15.4%). No association between an abnormal pre-HSCT CT scan and LOS was noted after adjusting for covariates ( b=1.0, 95% confidence interval [CI]= -6.2-8.3, P=0.8). Similarly, there was no association between infectious abnormalities noted on pre-HSCT CT and LOS ( b= -0.4, 95% CI=-5.8-5.1, P=0.9) or among patients undergoing an allogenic HSCT ( b=1.0; 95% CI=-6.2-7.4, P=0.8). Five patients died by day +100 due to NRM (respiratory failure=2, graft-vs-host disease=1, intracranial bleed=1, multi-organ failure=1). However, this was not significantly associated with abnormal pre-HSCT CT scan (odds ratio=1.9, 95%CI=0.1-87.8, P=0.7) Discussion: We show that routine pre-HSCT CT scans identify abnormalities in over 40% of children, adolescent and young adults undergoing HSCT, however, these are not associated with greater length of stay post-HSCT or early mortality. Future research is needed to understand the utility of pre-HSCT CT scans in identifying patients at risk of post-HSCT adverse events.

Clinical Factors but Not Somatic Mutations Predict for Survival in Patients with Myelofibrosis Undergoing Allogeneic Hematopoietic Cell Transplant: Analysis of the North American Myelofibrosis Transplant Outcome (NAMTO) Study

Introduction: Myelofibrosis (MF) is a clonal hematologic malignancy characterized by constitutive JAK-STAT activation and aberrant cytokine signaling. Allogeneic hematopoietic stem cell transplantation (allo-HCT) remains the only potentially curative therapy in MF. The contribution of disease-, patient- and donor-related factors to allo-HCT outcomes remains to be fully elucidated, as well as the presence of somatic mutations in genes such as ASXL1, EZH2, SRSF2, U2AF1 and IDH1/2 which are associated with worse prognosis in MF patients (pts). In this large multi- center retrospective analysis, we aimed to study the impact of clinical and molecular mutations on transplant outcomes. Methods: This analysis including 498 pts from 11 centers in North America and Canada. Univariate proportional-hazard Cox regression analysis stratified by center was used to assess the association of patient, transplant, and disease characteristics on overall survival (OS). Baseline patient demographic data and disease characteristics were selected as covariates in the multivariate analysis. Results: Pts transplanted between 2002-2021 were included in this analysis. Baseline and transplant characteristics are summarized in table 1. The 1- and 2-year OS was 77% (95% CI; 73-81) and 70% (95% CI; 66-74) and non-relapse mortality (NRM) 19% (95% CI: 17-21) and 23% (95% CI: 19-27), respectively. The cumulative incidence (CMI) of relapse at 1- and 2-years was 12% (95% CI; 10-14) and 16% (95% CI; 12-20). The CMI of acute graft versus host disease (aGVHD) grade II-IV was 31% (95% CI; 27-35) at 3 months and 42% (95% CI; 38-46) at 1-year post-transplant and grade was III-IV 13% (95% CI; 11-15) and 18% (95% CI; 14-22), respectively. The CMI of neutrophil engraftment at 1 and 3 months was 90% (95% CI: 87-93) and 97% (95% CI: 95-95) and for platelets 55% (95% CI: 50-59) and 80% (95% CI: 76-83). Univariate analysis included pts (age and gender), transplant (donor type and conditioning regimen intensity) and disease characteristics (DIPSS, mutations, cytogenetics (CG), blood counts, and spleen size). Hemoglobin &amp;gt; 10 g/dL (HR .5, 95% CI .34 -.73 p=3 x 10 -4) and platelets &amp;gt;50× 10 9/L (HR .59, 95% CI .42-.81, p=.0013) prior to transplant were associated with improved OS. High risk DIPSS was associated with decreased OS (p=0.0002). Mutations in ASXL1, EZH2, IDH1/2, U2AF1 and SRSF2 were not associated with decreased OS in this analysis (Figure 1). However, mutations in ZRSR2 were associated with inferior OS (HR 2.07, 95% CI 1.08-3.95, p=.0252). Lastly, JAK2 which had the most frequent mutations was not associated with OS (HR .0.93, 95% CI .65-1.31). There was no association between the CG risk groups and OS. Splenomegaly, measured radiographically, had no impact on OS but was strongly associated with engraftment (better engraftment defined as HR&amp;gt;1). For platelets, spleen size of 15.6-18.9 cm HR of 0.69 (95% CI .47-1, p=.0489) and size &amp;gt;18.9-22.5 cm HR of 0.48 ( 95% CI .33-.7, p=1x10^-4). For neutrophils, spleen size &amp;gt;19.9-22.5 cm had a HR of 0.68, (95% CI .48-.96, p=.0268) and size&amp;gt;22.5 cm had a HR of 0.65 (95% CI .46-.91, p=.0114). Mismatched unrelated (MMURD) and haplo identical donors had no impact on survival but were associated with delayed platelet engraftment; MMURD (HR .67, 95% CI .47-.96, p=.0298) and haploidentical donors (HR .56, 95% CI .39-.8, p=.0017). In a multivariate analysis adjusted for age, gender, highest DIPSS, donor type and conditioning regimen, platelets &amp;gt; 50× 10 9/L (HR .61, 95% CI .44-.87, p=.0053) hemoglobin &amp;gt;10 g/dL (HR .6, 95% CI .4-.9, p=.0244) and lower DIPSS at the time of transplant were associated with improved OS. Conclusions: In this large multicenter analysis only clinical variables; hemoglobin and platelets, were found to be associated with OS after allo-HCT in MF patients. Somatic mutations associated with poor prognosis were not associated with OS suggesting that transplant can overcome their negative impact. Splenomegaly was associated with delayed engraftment but not OS. Interestingly, using alternative donors (MMURD and haplo identical) didn't have a negative effect on OS, possibly reflecting the use of post-transplant cyclophosphamide for GVHD prophylaxis in recent years. These results highlight the importance of biologic factors in the prognostication of outcomes in MF pts undergoing allo-HCT independent of somatic mutations. Supported by the American Society of Hematology (ASH) and MPN Research Foundation

Impact of Concurrent and Previous Multidrug Resistant Bacteria Colonization in Adult Allogenic Hematopoietic Stem Cell Transplant Patients with Acute Leukemia: A Single Center Retrospective Study

Background Multidrug resistant bacteria (MDRB) pose a major challenge in allogenic hematopoietic stem cell transplant (allo-HSCT) since patient colonization with Gram - or Gram + MDRB has been identified as a risk factor for infections, acute graft versus host disease (aGVHD) and reduced overall survival (OS). Nevertheless, data on the prognostic value of MDRB colonization are still scarce, and whether it should represent a limit to allo-HSCT eligibility is controversial. Few data are also available on the impact of previously detected colonization that are absent at transplant time. Methods This is a retrospective single center study on 60 patients with acute myeloid or lymphoblastic leukemia who underwent allo-HSCT from January 2014 to March 2023 according to JACIE standards.All patients were treated at our department starting from induction. In each hospital stay MDRB colonization was assessed by rectal swabs performed at admission, and thereafter weekly. In case of fever 3 sets of blood culture from peripheral vein and central venous catheters, urine culture and chest X-ray were performed, and empiric antibiotic therapy initiated. In MDRB colonized patients, targeted antibiotic therapy was administered if clinically indicated. All patients received fluroquinolones as antimicrobial prophylaxis. Data were retrieved from hospital records. Aim of the study To assess the epidemiology of MDRB colonization and the related impact on allo-HSCT outcome in terms of MDRB-related infections, aGVHD within day 100, OS and non-relapse mortality (NRM). Results MDRB colonization was detected in 26/60 (43.4%) patients, in 13 (21.7%) at hospital admission and in additional 13 (21.7%) after allo-HSCT. Overall, 33 MDRB strains were isolated (Table 1). Among patients colonized at hospital admission, Gram - MDRB accounted for 10/16 (62.5%) strains, mostly Escherichia Coli producing extended-spectrum beta-lactamases (ESBL) and Klebsiella Pneumoniae ESBL, while Gram + MDRB were 6 (37.5%), mostly represented by vancomycin-resistant Enterococcus faecium (VRE). In 14/16 (87.5%) cases the colonization has been previously detected, in 78.5% since the first two hospital stays. Among patients with positive rectal swabs after allo-HSCT, Gram - MDRB accounted for 16/17 (94.1%) strains, mostly Escherichia Coli ESBL and Klebsiella Pneumoniae ESBL (1 producing carbapenemases). In these patients the rectal swab turned out positive after a median time of 10 (2-24) days after allo-HSCT, mostly during neutropenia. Albeit absent at hospital admission, 13/17 (76.5%) MDRB strains had been previously isolated in the same patients, being firstly identified during the first two hospital stays in 76.9% cases. No significant differences in patient baseline characteristics, leukemia classification, type of donor and conditioning or hospitalization length were observed between MDRB carriers (26, 43.4%) and non-carriers (34, 56.8%) (Table 2). During the whole hospital stay, 18/26 (69%) carriers and 32/34 (94%) non-carriers reported at least one febrile event (p=0.01). Only carriers experienced MDRB (Gram -) infections based on blood (4, 22%) and urine (7, 38%) culture, while the rate of positive chest X-ray (4, 22,2% vs 5, 15.6%, p=0.5) did not differ. Targeted antibiotics were administered to 14/18 (77.8%) febrile carriers, in 10 (71%) at fever onset and in 4 (29%) at fever persistence. Four (22.2%) did not receive treatment because not clinically indicated. Intensive care unit was never required in both cohorts. The incidence of aGVHD was similar between carriers and non-carriers (10, 38.5% vs 17, 50%, p=ns), but the proportion of grade 2-4 tended to be higher in the first group (70% vs 35.5%, p=0.08). Overall, 73% patients are alive with a median follow-up of 18 (0.8-49) months. Median OS was not reached in both groups (p=0.09). There was no difference in NRM between carriers and non-carriers (5, 19% vs 2, 6%, p=0.11). Conclusion In our series 43.3% of allo-HSCT patients were colonized by MDRB that, in line with recent literature, were mostly Gram -. The absence of life-threatening infections and the non-significantly inferior OS and NRM in colonized patients suggest that a careful investigation of concurrent and previous colonization and a prompt use of targeted antibiotics may temper the negative impact of MDRB-related infections in adult acute leukemia patients undergoing allo-HSCT. Larger prospective studies are awaited.

Allogeneic Hematopoietic Cell Transplantation in the Elderly Results in Similar Survival with Matched Related or Unrelated and Haploidentical Donors: A Report from the Société Francophone De Greffe De Moelle Et De Thérapie Cellulaire (SFGM-TC)

Introduction Higher patient age is no longer considered to be a barrier for allogeneic hematopoietic cell transplantation (HCT). We sought to study the impact of different types of donors on the outcomes of HCT in subjects aged 65 years (y) or more, and to evaluate the determinants of these outcomes. Methods SFGM-TC registry data on first HCTs performed between January 2013 and July 2021 in patients aged 65 y or more, with myeloablative or reduced-intensity conditioning, and a 10/10 human leukocyte antigen (HLA) matched sibling donor (MSD), matched unrelated donor (MUD) or haploidentical donor (HAP) were analyzed. Main exclusion criteria were: MSD/MUD-HCT performed without anti-T lymphocyte globulin (ATG), and HAP-HCT performed without post-transplant cyclophosphamide (PTCY). Univariate analyses according to donor type, as well as multivariable analyses were performed. Results A total of 1176 patients met the eligibility criteria (215 MSD, 721 MUD, 240 HAP). Median follow-up was 2.8 y. In univariate analysis, there was no difference between donor types in terms of 3-y overall survival (OS: MSD 50%, MUD 49%, HAP 49%, p=0.52), progression-free survival (PFS: MSD 41%, MUD 45%, HAP 44%, p=0.51) and graft-versus-host disease-free, relapse-free survival (GRFS: MSD 34%, MUD 32%, HAP 35%, p=0.67). With MSD, the cumulative incidence of progression at 3 y was significantly higher at 47% (MUD 29%, HAP 29%, p&amp;lt;0.001), and non-relapse mortality (NRM) significantly lower at 12% (MUD 26%, HAP 27%, p&amp;lt;0.001). These MSD results were confirmed in multivariable analysis. Incidence of acute graft-versus-host disease (GVHD) at 180 days was lower with MSD: grades II-IV 21% (MUD 35%, HAP 38%, p&amp;lt;0.001) and grade III-IV 8% (MUD 13%, HAP 15%, p=0.05). Incidence of chronic GVHD at 2 y was comparable between MSD, MUD and HAP transplants: moderate to severe 14%, 18% and 15%, respectively, and severe 5%, 6% and 5%, respectively. Conclusions In patients aged 65 y or more, MSD/MUD HCT performed with ATG and HAP HCT performed with PTCY yielded similar survival outcomes. MSD HCT is associated with a lower acute GVHD and NRM but a higher relapse risk. Reducing the toxicity of MUD and HAP HCT may yield better results than with MSD HCT in this population. Acknowledgements: Nicole Raus, Data manager coordinator, SFGM-TC. Viviane Fossat, Secretary, SFGM-TC.

Pre-Transplant Levels of Multiparametric Flow-Cytometry Measurable Residual Disease (MFC-MRD) Predict Outcomes in Children with Acute Myeloid Leukemia Given Allogeneic Hematopoietic Stem Cell Transplantation

Background: Measurable residual disease assessed by multiparametric flow-cytometry (MFC-MRD) is largely used in trials for childhood de novo acute myeloid leukemia (AML) in the early phase of treatment, to stratify patients into different risk groups and to tailor treatment. Despite this, unlike acute lymphoblastic leukemia, the impact of MFC-MRD before allogeneic hematopoietic stem cell transplantation (HSCT) on patients' outcomes has yet to be established. The aim of this study was to evaluate the prognostic role of MFC-MRD before HSCT in a cohort of children with AML treated in centers belonging to Associazione Italiana Ematologia/Oncologia Pediatrica (AIEOP) cooperative group. Patients and Methods: We analyzed MFC-MRD in 208 pediatric patients affected by de novo AML who underwent a first allo-HSCT after a myeloablative conditioning regimen in an AIEOP Centre between 12/2011 and 12/2021. Assessment of MFC-MRD was performed on BM sample within 60 days from the transplantation date. Analysis of 5-10 color-panel MFC-MRD was centrally performed at the Laboratory of Diagnosis and Research, University of Padova, according to standardized operating procedures previously described (Buldini et al., BJH 2017). We defined MFC-MRD positivity as the presence of at least 50 leukemic events of 500,000 acquired nucleated cells. Five-year overall (OS) and event-free survival (EFS) were estimated using Kaplan and Meier method and differences between groups were tested using the log-tank test; the cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) were calculated using the Fine&amp;Gray method to take into account the respective competitive risks. Results: Median age at HSCT of these 208 patients was 7.8 years (range 0.4-23.3); 168 patients (80.8%) were transplanted in CR1, 30 (14.4%) in CR2 and 10 (4.8%) in CR3 or more advanced disease. Forty-eight patients (23.1%) were transplanted from a matched family donor, 85 (40.9%) from an unrelated donor (59 fully-matched and 26 mismatched), while 75 (36%) from a partially matched family donor. The source of stem cells was bone marrow in 117 patients (56.2%), peripheral blood in 81 (39%) and cord blood in 10 (4.8%). Median time from MRD evaluation and HSCT was 22 days (range, 6-57). Overall,168 out of 208 (78.9%) patients were MFC-MRD negative in the pre-HSCT BM, while 44/208 (21.1%) showed a positive MFC-MRD. Among those, MFC-MRD was &amp;lt; 0.1% in 12/44 (27%) patients, 0.1-&amp;lt;1% in 16 patients (36.5%) and ≥ 1% in 16 patients (36.5%). The 5-year OS and EFS of the whole cohort were 79.2% and 65.7%, respectively, while CIR and NRM were 24.7% and 8.6%. Notably, patients with negative MFC-MRD had a significantly better 5-yr OS and EFS (Fig.A) as compared to those with any MFC-MRD positivity (OS 86.3% vs 50.2%; EFS 71.6% vs 42.4%, p &amp;lt;0.0001 in both analysis). CIR significantly differed between patients with MFC-MRD negative and positive (21.1% vs 43.9%, p=0.001) (Fig.B). We also observed a higher NRM in patients with MFC-MRD positivity (13.6%) as compared to those with negative MFC-MRD (7.2%), although this was not statistically significant (p=0.1). Disease status (CR1 vs CR2 vs other CR) did also influence EFS (69.9% vs 55.6% vs 23.3%, p&amp;lt;0.001), OS (83.2% vs 66.6% vs 40.6%, p=0.02) and CIR (21.1% vs 37.7% vs 66.6%, p&amp;lt;0.001), while other variables (including year of HSCT, type of donor and stem cell source employed) did not. In a multivariable model for OS, EFS and CIR, including MFC-MRD, disease status and year of HSCT, MFC-MRD (pos vs neg) remained statistically significant (HR for OS 3.5, p=0.0004; HR for EFS 2.38, p=0.003; HR for CIR 2.14, p=0.02). In addition, advanced disease phase was an independent risk factor for CIR (HR 1.81, p=0.008). Conclusion: These data document the independent prognostic value of MFC-MRD before HSCT in a large cohort of pediatric AML patients, using a centralized evaluation by 5-10 color MFC. Patients with negative MFC-MRD before HSCT have a significantly lower risk of treatment failure. In light of these results, we recommend monitoring MFC-MRD before HSCT in pediatric AML patients as a critical tool for therapy-intervention decision before or after HSCT (e.g., additional treatment for improving leukemia control or less intensive/shorter GvHD prophylaxis) with the aim to improve patients' outcomes.

Encouraging Outcome of AML with t(8;16) Following Allogeneic Stem Cell Transplantation in First Remission - a Retrospective Analysis on Behalf of the Acute Leukemia Working Party of the EBMT

In the 2022 European Leukemia Net (ELN) risk classification, acute myeloid leukemia (AML) with translocation t(8;16) was newly classified as AML defined by specific cytogenetic abnormalities, associated with unfavorable prognosis. Translocation (8;16)(p11;p13) is a rare abnormality in AML with female preponderance and occurs more frequently in secondary AML (sAML), especially therapy-related, than in de novo disease. Clinically, AML with t(8;16) is associated with high risk of bleeding, occurrence of extramedullary manifestations, myelomonocytic differentiation, and signs of hemophagocytosis in the bone marrow. The translocation leads to the fusion of acetyltransferase KAT6A (also known as MOZ or MYST3) and CREB binding protein ( CREBBP) genes, both of them involved in hematopoiesis. ELN risk stratification of AML with t(8;16) was based on studies that included relatively low numbers of patients receiving allogeneic stem cell transplantation (alloSCT). In the largest report by Kayser et al. ( Br J Haematol 2021) 21 patients (15 transplanted in first complete remission [CR1], median follow-up 5.5 years) were analyzed. A 5-year overall survival (OS) of 38% was achieved after alloSCT compared to 11% in patients who received chemotherapy only. The aim of our study was to evaluate the outcome of patients with AML harboring t(8;16) after alloSCT in a larger cohort from the EBMT registry. All types of donor, conditioning regimen and graft were included. Sixty patients were identified, of whom 44 had been transplanted in CR1. Median follow-up from alloSCT was 72.3 months, median age was 46.3 years, and 73.3% were female. Karnofsky performance status was &amp;gt;80% in 59 patients, one had missing data. At 2 years after alloSCT, OS and leukemia free survival (LFS) of the entire cohort were 42.7% and 42.2%, respectively, (28.6% and 14.3% in patients transplanted in advanced disease). Cumulative incidence of relapse (RI) and non-relapse mortality (NRM) at two years was 36.9% and 15.3%, respectively, in patients transplanted in CR1, and 78.6% and 7.1%, respectively, in patients transplanted in advanced disease. The 44 patients transplanted in CR1 were analyzed in detail. Basic characteristics were comparable to the entire cohort as described above. Twenty-two of the patients had de novo, 22 had sAML. According to the ELN 2017 classification (not yet including t(8;16) as a factor for poor prognosis), 54.5% had an intermediate and 45.5% an adverse cytogenetic risk. Furthermore, 38.8% had a complex karyotype. Donors were matched related in 34%, matched unrelated in 54%, haploidentical in 5% and cord blood in 7%. Conditioning was myeloablative in 52.3%, whereas 47.7% had received reduced intensity conditioning. Among patients transplanted in CR1, 2- and 5-year OS from alloSCT was 48% and 39.9%, the respective LFS was 46.8% and 35.5%. On multivariate analysis (MVA), harboring t(8;16) within a complex karyotype was the major risk factor for outcome, being associated with higher RI (hazard ratio [HR] 3.38, p=0.01), lower LFS (HR 4.17, p=0.016), and lower OS (HR 3.08, p=0.017). In contrast, patients with t(8;16) outside of a complex karyotype achieved excellent results (Figure 1). Besides a complex karyotype, MVA revealed sAML as an additional, independent risk factor with a higher RI (HR 3.73, p=0.026). Age was the major factor for NRM, reaching 5% vs. 26.5% in patients below or above the median (p=0.02). In conclusion, according to the largest series analyzed in this setting so far, overall results after alloSCT in AML with t(8;16) transplanted in CR1 were favorable, especially in patients without multiple additional cytogenetic abnormalities, achieving a low risk of relapse and a 5-year OS &amp;gt;60%. Hence, alloSCT in CR1 appears to abrogate the unfavorable prognostic value of this translocation. Whether or not t(8;16) does have any additional influence on the outcome of patients with a complex karyotype remains to be evaluated. Figure Legend Figure 1: Outcome of AML with t(8;16) with and without complex karyotype

Comparative Study for Haplo, MSD and MUD Allo-Hcts for Core-Binding Factor AML Patients in CR2: A Study from the Global Committee and the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation

Background Although core-binding factor acute myeloid leukemia (CBF-AML) generally has a favorable prognosis, relapse occurs in ~40% of cases. Allogeneic hematopoietic cell transplantation (allo-HCT) is recommended when patients achieve second complete remission (CR2). However, transplant outcomes and donor preference for these patients remain unclear. We compared in an EBMT global multi-center registry-based analysis the outcomes following allo-HCT using either haploidentical donors (HAPLO), matched siblings donors (MSD), or 10/10 matched unrelated donors (MUD). Methods Data from 865 de novo adult CBF AML patients in CR2 receiving allo-HCT in 227 EBMT centers from 2010-2022 were analyzed. Transplants from mismatched UD (&amp;lt;10/10), umbilical cord blood or grafts with ex-vivo manipulation were excluded. Univariate analyses and Cox regression models were used. Results Results from 329 MSD, 374 MUD, and 162 HAPLO HCTs were analyzed. For the entire cohort, median age was 43y (range: 18-76). Inv(16)/CBFBMYH11 was detected in 503 patients (58%) and t(8;21)/RUNX1-RUNX1T1 was detected in 362 patients (42%). Peripheral blood was the major graft source (86.1%), and myeloablative conditioning was used for the majority (60.1%) of all allo-HCTs. Female-to-male transplants were more common in the MSD group (25.5%) than in the HAPLO (19.8%) or MUD (14.2%) group, respectively (p&amp;lt;0.01). 83% of patients in the HAPLO group received post transplant cyclophosphamide (PTCy) as graft-versus-host disease (GVHD) prophylaxis. Engraftment rates were higher in the MSD (98.8%) and MUD (98.9%) than in the HAPLO (94.9%) group (p&amp;lt;0.01). Original disease was the major cause of death for the MSD and MUD cohorts, while in the HAPLO group, it was infection. On univariate analysis, HAPLO HCT was associated with a higher 2-year non-relapse mortality (NRM) (MSD 17.1%, MUD 15.3%, HAPLO 25.7%). The 180-day cumulative incidence of grade II-IV acute GVHD was higher in HAPLOs (14.8%) than in MSD (6.8%) or MUD (7.9%) recipients, respectively . No significant difference was observed among the three cohorts for 2-year leukemia-free survival (LFS), overall survival (OS) and GVHD-free/relapse free survival (GRFS). CBF-AML with inv(16) was associated with lower relapse incidence RI (18.1%) than with t(8;21) (28.3%), which contributed to better OS (75.7% vs 59.8% at 2 years), LFS (65.8% vs 51.2%) and GRFS (50.8% vs 38.5%) . Older patient age i.e., above the median age, was associated with a higher NRM (22.4% vs 13.3%) and a lower OS (63.8% vs 74.8%) than younger age i.e., below the median age. Peripheral blood grafts were associated with higher incidences of chronic GVHD (41.5% vs 25.8%) and extensive cGVHD (21.6% vs 9.7%) than bone marrow grafts. On multivariate analysis, no significant difference was observed among HAPLO, MSD and MUD allo-HCTs on NRM. HAPLO HCT was associated with lower RI compared to MSD (hazard ratio [HR]=0.56, 95% CI 0.32-0.97; p&amp;lt;0.05) and MUD (HR=0.57, 95% CI: 0.33-0.99, p&amp;lt;0.05) while there was no significant differences between the 3 types of donors on LFS, OS and GRFS. CBF-AML with t(8;21) was associated with both higher RI (HR=1.79, 95% CI 1.3-2.47; p&amp;lt;0.01) and higher NRM (HR=1.58, 95% CI 1.1-2.27; p&amp;lt;0.01) than CBF-AML with inv(16), which led to worse LFS, OS and GRFS. Higher age (per 10 year) was associated with higher risk of NRM (HR=1.29, 95% CI 1.11-1.5; p&amp;lt;0.01) and worse OS (HR=1.13, 95% CI 1.01-1.27; p=0.03). Conclusions For CBF-AML patients in CR2, haploidentical HCTs were associated with a lower RI compared to MSD and MUD allo-HCTs. HAPLO achieved similar LFS, OS and GRFS to MSD or MUD, respectively. In addition, CBF AML with inv(16) had better outcomes than with t(8;21) after allo-HCT.

Allogeneic Hematopoietic Cell Transplantation in the 7 th Decade of Life and Beyond

Background The upper age limit for patients undergoing allogeneic hematopoietic cell transplantation (HCT) has increased over the past several years due to continued improvements in supportive care and increased expertise in management of older recipients of allogeneic HCT. This change is particularly important for hematologic malignancies such as acute myeloid leukemia (AML) where the median age at diagnosis is in the late 60s and HCT provides, in many instances, the only potential chance of cure. While some previous analyses have suggested favorable post-HCT outcomes for older AML patients in general, information is limited about allogeneic HCT for patients aged 70 years or older. Here, we set out to retrospectively analyze post-HCT outcomes for those aged 70+ and compare these outcomes to those aged 60-69 in a large single-center observational study. Methods Eligible patients were identified using our Fred Hutchinson Cancer Center database of transplant outcomes. All patients signed consents at time of HCT. Severity of disease was categorized as previously described (McDonald GB et al Ann Intern Med 2020). Kaplan-Meier estimates were used to evaluate overall survival (OS) and relapse-free survival (RFS); cumulative incidence estimates were used to summarize relapse and non-relapse mortality (NRM). Multivariable Cox regression models were fit to compare outcomes across age groups after adjusting for potential imbalances in various factors between groups. In addition, we used a multivariable model for overall mortality (OM) to identify risk factors for death in this population. Results We identified 1237 patients given allogeneic HCT between 2000-2022 aged at least 60 years old, 229 (18.5%) of whom were of age 70+. Baseline characteristics included severity of disease, donor type, patient CMV serostatus, conditioning intensity (Table 1). The median OS among patients 60-69 was 2.8 years (95% confidence interval, 2.4-3.6 years) and among those 70+, 1.8 years (1.3-2.9 years). Point estimates of OS at 3, 5, and 7 years were 49% (46-52%), 46% (43-49%), and 37% (34-40%), respectively for patients aged 60-69, and 43% (36-49%), 38% (31-45%), and 28% (21-36%), respectively, for patients age 70+. In the subgroup of patients age 75+ (n=29), the 3- and 5-year point estimates of OS were each 41% (22-59%). The unadjusted hazard ratio (HR, 70+ vs. 60-69) for death was 1.24 (1.04-1.49, p=0.02). However, after adjusting for various factors (Table 2), the adjusted HR for death was 1.02 (0.76-1.36, p=0.90), suggesting the apparent reduction in OS for the 70+ group relative to the 60-69 group was largely due to a higher proportion of adverse risk factors in the 70+ group. Median RFS for the two groups were 1.9 years (1.4-2.3 years) and 1.3 years (0.9-1.8 years), respectively. Similar to the HR for death, the unadjusted HR for RFS failure was significant at 1.23 (1.03-1.46, p=0.02), but the adjusted HR for was no longer significant at 0.96 (0.72-1.26, p=0.74). The unadjusted and adjusted HRs for relapse were 1.10 (0.84-1.44, p=0.51) and 0.77 (0.50-1.17, p=0.22), respectively, and for NRM 1.33 (1.06-1.67, p=.02) and 1.12 (0.77-1.61, p=0.56), respectively. Factors that were demonstrably associated with increased mortality included severity of disease, patient/donor CMV serostatus, conditioning intensity, and type of donor (Table 2). Conclusions We report here on one of the largest groups of patients aged 70+ receiving allogeneic HCT in a single center. Our results suggest that allogeneic HCT is feasible and potentially safe in this age group as compared to the group aged 60-69. These results should be encouraging for consideration of patients 70+ for allogeneic HCT. We are in process of complementing our analyses with information on comorbidities. On the other hand, 7-year OS for all older pts (60-80.9 years old) ranged from 28-37%, highlighting the need for dedicated HCT trials targeting this group of older patients to further improve outcomes.

Evaluation of the Impact of the Disease Risk Index and Pre-Transplant Measurable Residual Disease By Flow Cytometry As Prognostic Factors in Allogeneic Hematopoietic Cell Transplantation in Patients with Acute Myeloid Leukemia

Introduction: Allogeneic hematopoietic cell transplantation (HCT) is the therapy with the best curative potential for patients with intermediate/high-risk acute myeloid leukemia (AML). Although many factors may influence the outcomes of allogeneic HSCT, risk stratification and disease status at the time of transplant are two of the strongest prognostic factors of post-transplant survival². In this context, the Disease Risk Index (DRI) was developed and validated in a cohort of more than 13.000 patients and stratifies patients into 4 groups with different overall survivals (OS)². Measurable residual disease (MRD) is also an important and consolidated biomarker for the prognosis, monitoring, and treatment effectiveness evaluation³. Objective: To compare the impact of the pre-transplant DRI and MRD in patients with AML in OS and leukemia-free survival of patients treated with allogeneic HSCT in a private institution in Brazil from January 2017 to May 2023. Methods: This is a retrospective, unicentric study. MRD was evaluated immediately before transplantation by 10-color flow cytometry and was considered positive if ≥0.1%. DRI was grouped into two groups: low/intermediate risk and high/very high risk. Statistical analyzes were performed using the Cox regression model. Results: With a median follow-up of 18 months, a total of 57 patients were included, 34 of whom had negative MRD and 23, positive. The mean ages in these groups were 55 and 60 years, respectively. HCT-CI was 0-2 in 91% of the patients in the MRD-negative group, and in 78% of the MRD-positive group. The type of donors was similar in both group (MRD positive or negative): 20-30% of related donors, 25-40% of haploidentical and 40-45% unrelated donors. The reduced-intensity conditioning regimen (RIC) was the used in 70% of the patients. In the MDR + group, peripheral stem cell source was more used than in the MDR negative group. In univariate analysis, DRI had an impact on overall survival (OS) with an HR=3.52 (95%CI 1.46 - 8.5) and p=0.075 for low/intermediate risk compared with high/very high risk, while in the multivariate analysis this impact was not maintained with HR=2.31 (95%CI 0.92 - 5.82) and p=0.075. A pre-transplant positive MRD was a risk factor for death in univariate analysis, with an HR=5.99 (95%CI 2.93- 26.82) and p&amp;lt;0.001. The impact of MRD HR 8.87 (2.93 - 26.83) and p &amp;lt; 0.001, age HR 1.09 (1.04 - 1.15) with p = 0.001 and bone marrow source HR 0.29 (0.08 - 1.06) are prognostic factors even when controlled for age, cell source and type of transplant. One-year overall survival in the MRD-negative group was 90% (79-100%), and 53% (36-80%) in the MRD-positive group. Additionally, one-year leukemia-free survival in the MRD-negative group was 70% (55-89%) and 45% (28-72%) in MRD-positive. Conclusion: Our results show that both DRI and pre-transplant MRD may have an impact on OS and LFS, although pre-transplant MRD seemed to perform better than DRI in multivariable analysis in patients with acute myeloid leukemia undergoing hematopoietic cell transplantation.