Allogeneic Blood Research Articles

Концепция «Менеджмент крови пациенток» в практике акушера-гинеколога: на что обратить внимание?

Aim. To present literature and own data on the implementation of the concept of patient blood management (PBM) in obstetrics and gynecology. Key points. PBM involves “the timely, interdisciplinary application of evidence-based, multimodal medical and surgical concepts aimed at screening, diagnosing and appropriately treating anemia, minimizing surgical, procedural, iatrogenic blood loss, and managing coagulopathy bleeding to improve health outcomes through patient-centered care”. As part of the PBM, it is important for the obstetrician-gynecologist to first screen for iron deficiency (ID) and identify iron deficiency anemia (IDA), prescribe treatment with modern iron preparations. A new generation of ferrous iron preparation with prolonged release is proposed, which minimizes the side effects of therapy. The second aspect is to screen and treat identified coagulation disorders using treatment algorithms based on thromboelastometry data, the third is in the postpartum/postoperative period, screen for and treat iron deficiency and anemia, control coagulation, monitor blood loss and rational use of allogeneic blood components. The results of the introduction of PBM into clinical practice of the National Medical Research Center for Obsterics, Gynecology and Perinatology named after Academician V.I. Kulakov, which allows for timely diagnosis of ID and IDA at the “Anemia-STOP!” Center, rational transfusion of allogeneic blood components, which contributed to a reduction in the volume of procured and transfused donor blood components. Conclusion. The implementation of the PBM concept helps to improve the effectiveness and safety of treatment, while promoting the best use of economic resources. Keywords: patient blood management, obstetrics, gynecology, iron deficiency anemia, new generation ferrous sulfate, coagulation control, efficiency, safety.

Intraoperative tranexamic acid administration in cranial meningioma surgery: a meta-analysis of prospective randomized, double-blinded, and placebo-controlled trials.

Cranial meningioma surgeries often involve significant blood loss and transfusions. Tranexamic acid (TXA) has been used to reduce blood loss in various surgeries. This meta-analysis of randomized placebo-controlled trials (RCTs) evaluates the impact of TXA in cranial meningioma surgery. Pubmed, Web of Science, and Cochrane Library were searched for RCTs. Studies were compared for: Blood loss, operative time, hospital stay, reoperation rates, allogeneic and autologous transfusion, and incidence of complications. Seven RCTs with 490 patients receiving TXA and 491 receiving placebos were included. TXA significantly shortened operative time (Mean Difference (MD): -20.95; 95%CI: -39.94 to -1.95; p=0.03). Blood loss was lower with TXA (MD: -262.7 ml; 95%CI: -397.6 to -127.8; p=0.0001). Odds of reoperation were not significantly different (OR: 0.44; 95%CI: 0.13-1.45; p=0.18). TXA significantly reduced the need for RBC transfusions (OR: 0.47; 95%CI: 0.22-0.99; p<0.05). No significant differences were observed regarding postoperative seizures (OR: 1.06; 95%CI: 0.56-2.03; p=0.85), hydrocephalus (OR: 0.25; 95%CI: 0.03-2.29; p=0.22), or hematoma (OR: 0.52; 95%CI: 0.22-1.28; p=0.16). Hospital stay was shortened in the TXA group (MD: -1.23; 95%CI: -2.41 to -0.05; p=0.04). This meta-analysis suggests that a single intraoperative dose of TXA reduces blood loss, allogeneic blood transfusions and shortens surgery time.

Mini review on Artificial Blood Substitutes: Future perspective of Perfluorocarbon based oxygen carriers

The primary cause of death in the battle field and in civilian trauma is haemorrhagic shock. Around 50% combat deaths occur due to haemorrhage, depending on the severity of bleeding medical supervision can be provided like in catastrophic haemorrhage individual death occurs before providing the medical care and it is not a prehospital combat medical management problem during warfare scenario, even to transport wounded personnel to causality centre often takes 45 minutes to one hours. The hazardous nature of the forward combat areas and hostile operational environment frequently prevents medical personnel from quickly reaching the wounded even if the transport distances are small. Moreover, injuries with penetrating battlefield trauma often have only a "platinum 5 minutes." It is very important for military medical personnel to understand their options for treating haemorrhage quickly and efficiently during combat. Early intervention and definitive treatment could save up to 30% of soldier’s who die of action or of wounds. In view of this there is a requirement for the development of synthetic blood substitutes or oxygen therapeutic agents (OTA) in order to maintain the tissue oxygenation. Blood substitutes are the substances which mimic one of the physiological functions of the blood that is transportation of oxygen and carbon dioxide throughout the body. Blood substitutes or OTAs are being clinically tested as artificial oxygen carriers to improve tissue oxygenation and also to reduce allogenic blood transfusions. Two types of blood substitutes are reported so far: 1. Haemoglobin based oxygen carriers (HBOCs) and 2. Perfluorocarbon based oxygen carriers (PFOCs). PFOCs has huge advantages like universal compatibility, no requirement of cold storage, longer shelf life and no risk of infection transmission. These products have their own limitations and they have been withdrawn from international market for clinical use because of their side effects. It is a challenging task to the scientists to develop a safe, stable and biocompatible blood substitute for combat scenarios and also for civilian applications.

Current role of intraoperative cell salvage techniques in the management of renal tumors with level III and IV inferior vena cava thrombus extension

Background: En bloc removal of the kidney with tumor thrombus excision in a multidisciplinary team remains the standard treatment for renal cell carcinoma (RCC) with tumor thrombus extension. In order to minimize the hemodynamic impact of the surgical blood loss, intraoperative cell salvage (IOCS) techniques can decrease the need for allogeneic blood and prevent blood transfusion related complications. Objective: In this article, we evaluated the safety of IOCS during radical nephrectomy with inferior vena cava thrombectomy under cardiopulmonary bypass with or without deep hypothermic circulatory arrest. Design and method: In this retrospective comparative multicenter analysis, clinical characteristics of 27 consecutive patients who underwent surgery with or without IOCS between 2012 and 2022 in three referral care units were collected into a database. The need for an allogenic blood transfusion (ABT) was also recorded, defined as any transfusion that occurred either intraoperatively or during the hospital stay. Results: The need for ABT in the cell saver arm was significantly smaller due to the reinfusion of rescued blood ( p &lt; 0.015). In multivariate analysis, no cell saver usage was an independent predictor for complications ⩾3 Clavien 3a [odds ratio (OR) 18.71, 95% CI 1.056–331.703, p = 0.046]. No usage of IOCS was an independent predictor for a lower risk of death (OR 0.277, 95% CI 0.062–0.825, p = 0.024). During follow-up, patients who received salvaged blood did not experience an increased risk for developing local recurrence or distant metastases. Conclusion: Transfusion of autologous blood is safe and can be using during nephrectomy and thrombectomy for advanced RCC.

Preoperative continuation of aspirin before isolated heart valve surgery and postoperative bleeding and transfusion: a single-center retrospective study

Background The risks and benefits of preoperative aspirin continuation in patients undergoing isolated heart valve replacement surgery are unclear. We investigated the effect of aspirin continuation on the risk of bleeding and transfusion in these patients. Methods In this single center, retrospective study, among 474 adult patients who underwent isolated heart valve surgery between April 2013 and June 2018, 269 continued aspirin within 5 days before surgery (aspirin group) and 205 patients did not take or stopped aspirin no later than 5 days before surgery (non-aspirin group). The chi-square test, the Mann-Whitney U-test, and the Student’s T-test were used to compare data between the groups. Univariate and Multivariate logistic regressions were used to assess crude and adjusted relationships between outcome and exposure. Results The primary outcome, red blood cell (RBC) transfusion, occurred in 59 patients (22%) of the aspirin group and in 24 patients (12%) of the non-aspirin group (p = 0.004). After adjustment for confounding factors, continuation of aspirin was no longer associated with RBC transfusion (aOR1.8;95%CI,0.98–3.2;p = 0.06). The amount of allogenic blood products, the incidence of surgical re-exploration for bleeding, the volume of re-transfused cell-saved blood, and the cumulative chest tube drainage during the first 24 postoperative hours were similar between groups. Conclusion Preoperative continuation of aspirin in patients undergoing isolated heart valve surgery is neither associated with a higher incidence of RBC transfusion, nor with larger perioperative blood loss, or more frequent surgical revision for bleeding. Trial registration Clinicaltrials.gov (NCT05151796)

Routine use of cell salvage during cesarean section: A practice evaluation.

Intraoperative cell salvage is a well-documented alternative to donor blood transfusion given the scarcity of donor blood pools and the incumbent risk of allogenic blood transfusion. Its use in obstetrics has been limited by concern over fetal alloimmunization due to the risk of fetomaternal hemorrhage. However, there are a paucity of studies reporting on outcome. The aim of this study was to report on a four-year experience of routine use of intraoperative cell salvage and the impact on subsequent pregnancy outcomes. This was a tertiary center retrospective service evaluation cohort study and included all women undergoing cesarean section between December 2014 and November 2018 in a tertiary obstetric unit, identifying women who had reinfusion of intraoperative cell salvage. Data regarding index pregnancy as well as subsequent pregnancies at the hospital were extracted from hospital electronic records. Subsequent pregnancy outcome and maternal antibody status in that pregnancy were collected up until November 2022. During the study period, 6656 cesarean sections were performed, with 436 (6.6%) receiving reinfusion of salvaged blood. The mean volume of reinfused blood was 396 mL. A total of 49 (0.7%) women received donor blood transfusion. Of those who received reinfusion of salvaged blood, 79 (18.1%) women had subsequent pregnancies over the eight-year follow-up period. There was one case (0.23%) of fetal cell alloimmunization demonstrated by the presence of anti-D antibodies on the subsequent pregnancy booking bloods. Routine intraoperative cell salvage may be used to reduce the need for blood transfusion during cesarean section. The risk of fetal cell alloimmunization in a future pregnancy following reinfusion of intraoperative cell salvage is one in 436. Given an apparent small risk of fetal cell alloimmunization, further work is required to establish the safety profile of intraoperative cell salvage in pregnancy.

Efficacy of Triple Prophylaxis for Prevention of Graft-Versus-Host Disease in Matched Sibling Allogeneic Peripheral Blood Hematopoietic Stem Cell Transplantation in Pediatric Patients

BACKGROUND: Graft-versus-host disease (GVHD) continues to compromise the overall success of allogenic hematopoietic stem cell transplantation. It is the most important cause of morbidity and non-relapse mortality after allogeneic hematopoietic stem cell transplantation for malignant disease. In adults, post-transplant cyclophosphamide (Cy-PT) has been shown to be a feasible, economically accessible, and effective strategy to reduce the incidence of GVHD in matched sibling hematopoietic stem cell transplantation in combination with a calcineurin inhibitor plus mycophenolate mofetil (MMF). AIM: Demonstrate the clinical benefit of Cy-PT plus a calcineurin inhibitor combined with MMF for GVHD prophylaxis in HLA-matched, related peripheral blood stem cell transplants in pediatric patients with malignant hematologic neoplasms compared to standard therapy in historical controls. METHODS: A retrospective study was conducted on 22 pediatric patients with malignant hematologic neoplasms who underwent HLA-matched related peripheral blood allogenic stem cell transplantation (alloSCT) between July 2012 and December 2022. A comparison was made between two groups, one with triple prophylaxis using Cy-PT, cyclosporine (CsA), and MMF, and a historical cohort that received standard GVHD prophylaxis based on CsA and methotrexate (MTX). Patients were identified from a hospital registry. Descriptive and inferential statistics will be reported, using SPSS version 25 for analysis. RESULTS: Twenty-two patients received HLA-matched alloSCT from first-degree relatives genotypically identical in HLA-A, HLA-B, and HLA-DRB1 alleles. The demographic characteristics of both groups are summarized in the table. No patient experienced primary graft failure, sinusoidal obstructive syndrome, or hemorrhagic cystitis. Acute GVHD grade II-IV did not develop in patients who received Cy-PT, whereas in the CsA/MTX prophylaxis group, 1 (9%) grade IV patient was observed who died due to this cause before day 100. Two patients (18%) developed Moderate/Severe GVHD in the CsA/MTX group, and 1 (9%) had moderate GVHD in the Cy-PT group. Two-year overall survival was similar between the two groups (Cy-PT 53% and CsA/MTX 67%), as was event-free survival (PTCy 48% vs. CsA/MTX 61%). CONCLUSION: Peripheral blood represents a feasible option in our setting due to rapid graft engraftment, short hospital stays, and low incidence of primary graft failure, but with a higher incidence of GVHD as reported in the literature. We explored the efficacy and safety of triple prophylaxis for HLA-matched alloSCTs from peripheral blood using Cy-PT + CsA + MMF in a small group of patients, with outcomes slightly better than standard prophylaxis. These preliminary results motivate us to continue with this new regimen.

Thromboelastography-Guided Correction of Coagulopathy Before Tunneled Central Venous Access in Critically Ill Patients With Liver Disease: A Propensity Score-Matched Study.

Optimal blood product transfusion strategies before tunneled central venous catheter (CVC) placement are required in critically ill coagulopathic patients with liver disease to reduce exposure to allogeneic blood products and mitigate bleeding and thrombotic complications. This study evaluated the safety and efficacy of a thromboelastography-guided transfusion strategy for the correction of coagulopathy in patients with liver disease compared with a conventional transfusion strategy (using international normalized ratio, platelet count, and fibrinogen) before tunneled CVC insertion. A retrospective propensity score-matched single-center cohort study was conducted at a quaternary care academic medical center involving 364 patients with liver disease (cirrhosis and acute liver failure) who underwent tunneled CVC insertion in the ICU. Patients were stratified into two groups based on whether they received blood product transfusions based on a thromboelastography-guided or conventional transfusion strategy. Primary outcomes that were evaluated included the volume, units and cost of blood products (fresh frozen plasma, cryoprecipitate, and platelets) when using a thromboelastography-guided or conventional approach to blood transfusions. Secondary outcomes included the frequency of procedure-related bleeding and thrombotic complications. The total number of units/volume/cost of fresh frozen plasma (12 U/3,000 mL/$684 vs. 32 U/7,500 mL/$1,824 [p = 0.019]), cryoprecipitate (60 U/1,500 mL/$3,240 vs. 250 U/6,250 mL/$13,500 [p < 0.001]), and platelets (5 U/1,500 mL/$2,610 vs. 13 units/3,900 mL/$6,786 [p = 0.046]) transfused were significantly lower in the thromboelastography-guided transfusion group than in the conventional transfusion group. No differences in the frequency of bleeding/thrombotic events were observed between the two groups. A thromboelastography-guided transfusion strategy for correction of coagulopathy in critically ill patients with liver disease before tunneled CVC insertion, compared with a conventional transfusion strategy, reduces unnecessary exposure to allogeneic blood products and associated costs without increasing the risk for peri-procedural bleeding and thrombotic complications.

Prophylactic common iliac artery temporary clamping versus balloon occlusion for management of placenta accreta spectrum disorders: A prospective clinical trial.

The present study aims to compare prophylactic common iliac artery (CIA) temporary clamping and preoperative balloon occlusion for managing placenta accreta spectrum (PAS) disorders. Between January 2019 and June 2020, 46 patients with PAS disorders were included. Of them, 26 patients were offered CIA balloon occlusion (Group A), while temporary CIA clamping was done for the other 20 patients (Group B). Primary outcomes were procedure-related complications, and secondary outcomes included intraoperative and postoperative complications, reoperation rates, total procedure time, blood loss, and amount of blood transfusion. Blood loss was statistically non-significant higher in group B than in group A (p-value = 0.143). Only one patient in group A and three in group B needed reoperation. The bleeding continued for a mean of 1.6 days in group A and 1.7 days in group B, with non-significant statistical differences between both groups p value = 0.71. Nine patients in group A (34.6%) and four in group B (20%) required ICU admission. The mean Apgar score was 7 and 6.6 in babies of group A and group B patients, respectively. The median number of allogeneic blood transfusions performed was two in patients in group A and 1 in group B (p-value = 0.001). Both techniques offer good choices for patients with PAS to decrease mortality and morbidity rates. The selection of a better technique depends on institutional references and physicians' experience.

Maintenance of the synergistic effects of cord blood cells and erythropoietin combination therapy after additional cord blood infusion in children with cerebral palsy: 1-year open-label extension study of randomized placebo-controlled trial

BackgroundThis 1-year open-label extension study aimed to identify the persistent synergistic effects of allogeneic umbilical cord blood (UCB) cells and erythropoietin (EPO) in children with cerebral palsy (CP) for up to 2 years.MethodsThis open-label extension study followed children with CP who were enrolled in the previous randomized, double blind, placebo-controlled trial. The following groups from the first trial were maintained: (A) UCB + EPO, (B) UCB, (C) EPO, and (D) only placebo, and all the participants had continued active rehabilitation. This extended study started 3 months after termination of the first trial, which had a 1-year follow-up duration. All subjects received single additional UCB intravenous infusion at the extension baseline regardless of their initial allocation. Outcome measures were the gross motor performance measure (GMPM), gross motor function measure-66 (GMFM-66), and Bayley scales of infant development-II (BSID-II), which were followed at 3, 6, and 12 months after the extension baseline. Changes in the outcome scores from the baseline values of the previous trial and this study were analysed.ResultsSixty-nine children (4.29 ± 1.28 years, M:F = 34:35) were included in this study. Each group showed improvements in the outcome measures at 12 months after additional UCB infusion compared to the baseline scores, except for GMFM and GMPM in Group C which were elevated at 3 and 6 months post-therapy. Total subject analyses did not show significant differences in the outcome measures between the four different groups at 3, 6 and 12 months after additional UCB therapy. However, patients with severe dysfunction, whose GMFCS levels were IV and V, revealed a larger improvement of the GMPM score in Group A than in Group D (Ps < 0.05) from the baseline value of the previous trial. The changes in BSID-II mental scale scores were positively correlated with the number of administered total nucleated cells per unit body weight during this one-year extension study period (r = 0.536, P = 0.001).ConclusionsThese results suggest that when administering UCB to treat patients with CP, combination therapy with EPO is more effective, and the effect might last as long as 2 years, especially in patients with severe impairments.Trial registration: CHA Bundang Medical Center IRB, No. 2015–06-093, approved on July 29, 2015, (https://www.e-irb.com:3443/devlpg/nlpgS200.jsp), ClinicalTrials.gov, NCT03130816, retrospectively registered on April 27, 2017 (https://clinicaltrials.gov/ct2/show/NCT03130816?term=NCT03130816&draw=2&rank=1).

A commentary on 'Autologous blood transfusion reduces the requirement for perioperative allogenic blood transfusion in patients undergoing major hepatopancreatobiliary surgery: a retrospective cohort study'.

A commentary on 'Autologous blood transfusion reduces the requirement for perioperative allogenic blood transfusion in patients undergoing major hepatopancreatobiliary surgery: a retrospective cohort study'.

Do Patients with Borderline Anemia Need Treatment before Total Hip Arthroplasty? A Propensity Score-Matched Cohort Study.

Preoperative anemia has been identified as a modifiable risk factor for multiple adverse outcomes. In real clinical practice, considering treatment of anemia would increase costs and delay surgery. Patients undergoing total hip arthroplasty (THA) with mild anemia are usually neglected and still underdiagnosed or inadequately treated. This study investigated the effects of preoperative borderline anemia and anemia intervention before THA on perioperative outcomes. We screened 706 patients from those receiving THA at our hospital from January 2020 to January 2022, with 112 in the borderline anemia group and 594 in the non-anemia group. The cohort for this retrospective study was created by using propensity score matching (PSM) and subgroup analysis. The primary outcome was perioperative blood loss, while secondary outcomes were the rate of allogeneic blood transfusion and human serum albumin transfusion, perioperative laboratory indicators, postoperative length of stay, and complications. The independent sample t-test and the Mann-Whitney U-test were used to analyze continuous data, and the Pearson χ2 -test or the Fisher exact test was used to analyze categorical variables. After PSM, there was no significant difference in perioperative blood loss between patients in the borderline anemia group and the non-anemia group. The primary outcomes of hidden (p = 0.004) and total (p = 0.005) blood loss were significantly lower in the intervention group than in the control group. No statistical differences were found in allogeneic blood transfusion, human serum albumin transfusion, postoperative length of stay, or complications (p > 0.05). Anemia treatments for patients with borderline anemia before THA significantly reduced hidden blood loss and total blood loss in the perioperative period and decreased the drop of hemoglobin and hematocrit without increasing postoperative complications.

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.

Unrevealing Hematopoietic Reconstruction Discrepancies after Allo-UCBT and Allo-PBSCT at Single Cell Resolution

Umbilical cord blood (UCB) and G-CSF mobilizing peripheral blood stem cell (G-PBSC) are the main sources of hematopoietic stem cells for transplantation on clinic. Clinical data have shown that hematopoietic reconstruction in allogeneic cord blood transplantation (allo-UCBT) is significantly delayed compared with allogeneic peripheral blood stem cell transplantation (allo-PBSCT), suggesting that the cellular composition and reconstruction dynamics of UCB are significantly different from that of G-PBSC. Following on the heels of our recently study that found HSC/MPPs show differentiation bias to megakaryocytic-erythroid lineage and strong proliferation tendency, and defined a neutrophil progenitor population named S100A hi Neu2 which is inversely associated with the incidence of GVHD after allo-PBSCT (Yingying Huo et al, Science Immunology 2023), we next aimed to analyze the differences of hematopoietic reconstitution between allo-UCBT and allo-PBSCT and the causes of delayed hematopoietic reconstitution after allo-UCBT. In this study, we collected peripheral blood (PB) and bone marrow (BM) samples from 8 patients with bone marrow failure syndrome (BMFs) who received allo-UCBT (n=4) or allo-PBSCT (n=4) at different time points (d14, d21, d30, d60, d90, d180, d365) after transplantation. At the same time, UCB, G-PBSC and BM of normal children were collected as controls. Lin -CD34 + cells from BM, G-PBSC and UCB were separated by FACS for STRT-seq, the total nucleated cells (TNCs) of all samples were isolated for 10X transcriptome sequencing. We used 276628 hematopoietic cells to map the single cell transcriptome profiles of hematopoietic reconstruction by different transplantation methods and annotated 44 cell types. Compared with the G-PBSC, the immunogenicity of HSC/MPPs in Lin -CD34 + cells derived from UCB decreased, the proportion increased, and the differentiation bias of HSC/MPPs to monocytic and erythroid lineage was stronger, but the differentiation ability to myeloid and megakaryocytic lineage was decreased, the proportion of EBM, MEP and CMP decreased. For TNCs, the proportion of T cells and NK cells increased, and NK_CD56dim_CD16 had a stronger immune function. Compared with allo-PBSCT, the differentiation of HSC/MPPs and CMP into neutrophils in the early stage after allo-UCBT was weakened. The proportion of MEP cells decreased, and the differentiation ability of HSC/MPPs to MEP, HSC/MPPs and MEP to Mk was weakened. In summary, we found that the delayed reconstruction of neutrophils and platelets in patients with allo-UCBT are related to the nature of the graft, suggesting the importance of reasonable intervention of HSC derived from UCB to accelerate platelet implantation.

Higher Infused CD34+ Cell Dose Does Not Influence Clinical Outcomes in Allogeneic Peripheral Blood Stem Cell Transplantation Using Post-Transplant Cyclophosphamide in Children with High-Risk Leukemia

Background: The impact of infused graft cell dose on outcomes, including graft-versus-host disease (GVHD) and relapse, which have been major challenges in allogeneic hematopoietic stem cell transplantation (HSCT), remains unclear. Post-transplant cyclophosphamide (PTCy) has emerged as an effective and safe GVHD prophylaxis strategy, with improved GVHD incidence and relapse-free survival (RFS). Early practice of unmanipulated peripheral blood stem cell transplantation (PBSCT) using PTCy was commonly performed with a restriction on the CD34 + cell dose to minimize the risk of GVHD. However, recent studies demonstrated the protective effect of CD34 + cells on relapse, with no association with GVHD, thereby raising questions about the optimal cell dose. In this context, we aimed to study the impact of infused cell dose on outcomes in children with high-risk leukemia who underwent allogeneic PBSCT using PTCy. Methods: A retrospective analysis was conducted on 50 pediatric patients (median age at diagnosis : 9.3 years, range, 0.3-17.3) with hematologic malignancy (33 acute myeloid leukemia, 12 acute lymphoblastic leukemia, and 4 myelodysplastic syndrome/myeloproliferative neoplasm, 1 other) in first or second remission between 2019 and 2023. They received their first allogeneic PBSCT and donors included matched or mismatched unrelated donors (n=12) and haploidentical family donors (n=38). Conditioning was myeloablative, and PTCy-based GVHD prophylaxis (50mg/kg/day on days 3 and 4) was used for all patients. The patients were divided into three groups based on infused CD34 + cell dose: high dose group (&amp;gt;10 × 10 6/kg, N=10), intermediate dose group (5-10 × 10 6/kg, N=24), and low dose group (&amp;lt;5 × 10 6/kg, N=16). Results: The median age at HSCT was 11.6 years (range, 0.7-24.9). The median dose of infused CD34 + cells and CD3 + cells was 6.5 x 10 6/kg and 48.6 x 10 7/kg, respectively. There was a tendency for the mean dose of infused CD3 + cells to increase in the group with higher infused CD34 + cell dose: 47.6 x 10 7/kg for low dose group, 57.5 x 10 7/kg for intermediate dose group, and 73.4 x 10 7/kg for high dose group ( P=0.053). Patients receiving a higher dose of CD34+ cells had significantly shorter median time to neutrophil engraftment (13 days in high dose group vs. 14 days in intermediate dose group vs. 17 days in low dose group, P&amp;lt;0.001). The time to platelet engraftment was similar among the three groups. There was no difference among high dose, intermediate dose, and low dose groups in the cumulative incidence (CI) of day+100 grades II-IV acute GVHD and moderate to severe chronic GVHD (grades II to IV acute GVHD: 60.0% vs. 63.6% vs. 73.3% [ P=0.988], respectively; moderate to severe chronic GVHD: 22.2% vs. 29.2% vs. 25.0% [ P=0.961], respectively). With a median observation period of 20.4 months (range, 3.0-46.8) from transplant, RFS and overall survival (OS) showed a non-significant trend towards a higher survival rate in the high dose group compared to the other groups (RFS: 76.2% in high dose group vs. 62.1% in intermediate dose group vs. 62.6% in low dose group, P=0.694; OS: 88.9% in high dose group vs. 63.0% in intermediate dose group vs. 76.0% in low dose group, P=0.788). Conclusions: Higher number of infused CD34 + cell dose was associated with faster neutrophil engraftment. For patients in the high dose group (CD34 + cell dose &amp;gt; 10 x 10 6/kg with a relatively higher number of CD3 + cells), a non-significant trend toward a higher survival rate was observed, with no detrimental impact on GVHD. PBSCT in a pediatric patient from an unrelated or haploidentical adult donor may result in a high infused cell dose. Our findings suggest that restricting the number of infused CD34 + cell dose may not be necessary in the setting of allogeneic PBSCT with PTCy. Larger cohort studies are needed to confirm the potential benefits and drawbacks of a higher cell dose in children who receive PBSCT within a PTCy setting.

Haploidentical Donor Transplants with Cytokine Release Syndrome Have Increased Risk of Clinically Significant Early CMV Reactivation Compared with Matched Donor Transplants Receiving Post-Transplant Cyclophosphamide

Background: Post-transplant cyclophosphamide (PTCy) enables safe haploidentical stem cell transplantation by reducing graft-versus-host-disease (GVHD) but is associated with an increased risk of reactivation of Cytomegalovirus (CMV). PTCy has more recently been adopted for matched-donor transplants, where early CMV reactivation may also be more common. This suggests that CMV reactivation is a function of PTCy rather than donor source. However, other studies comparing the rates of CMV in transplants using PTCy-based prophylaxis suggested disparity in donor source may contribute to CMV reactivation. Aim: The goal of this single-centre, retrospective study was to determine if donor type had any impact on CMV reactivation in the setting of PTCy-based GVHD prophylaxis. Methods: The Alfred Hospital Bone Marrow Transplantation Unit has used PTCy for GVHD prophylaxis in both haploidentical and matched-donor allogeneic stem cell transplants (alloSCT) since 2015. A local database search identified 119 allogeneic peripheral blood alloSCT recipients receiving PTCy-based GVHD prophylaxis between February 2015 and December 2022. Matched-donor alloSCTs also received cyclosporin from Day +5 while haploidentical alloSCTs also received tacrolimus and mycophenolate from Day +5. One patient was excluded due to CMV viremia at the time of transplant. Recipients who were CMV seropositive received therapeutic dose valganciclovir 900 mg twice daily from the start of conditioning until the day prior to stem cell infusion. Prophylactic valganciclovir (900 mg daily) was planned upon engraftment for seropositive recipients and those receiving stem cells from a seropositive donor. CMV DNA PCR was performed weekly for the first 100 days post-transplant and beyond when clinically indicated. CMV viremia was defined as any positive CMV PCR (&amp;gt; 34.5 copies/mL) within the first 100 days post-transplant. Therapeutic valganciclovir was initiated for CMV viral loads (VL) &amp;gt; 1,000 copies/mL or earlier for rapidly rising VLs. Cytokine release syndrome (CRS) was defined as fever &amp;gt; 38 degrees Celsius between stem cell infusion and PTCy on Day +3 without an alternate explanation and graded according to CTCAE criteria. CMV donor and recipient negative transplants were excluded from the analysis of the impact of donor disparity on CMV reactivation. Statistical analyses included Fisher's Exact test, one-way ANOVA and Binomial Logistic Regression. Results: Transplant characteristics according to donor source were similar apart from conditioning intensity, where recipients of haploidentical stem cells were more likely to receive myeloablative conditioning (Table 1). The cumulative incidence of moderate-severe chronic GVHD was significantly higher in matched sibling transplants but overall, 12-month GVHD-free and relapse-free survival were similar. As previously reported, CRS (overall and grades II-IV) was significantly more common in haploidentical transplants. Day 100 CMV viremia rates were not statistically different between donor groups. However, haploidentical transplants trended for earlier CMV reactivation (p=0.08), and were significantly more likely to rise above 250 copies/mL (Table 1 and Figure 1). Consequently, haploidentical transplant recipients received significantly more anti-CMV therapy (p=0.009). Multivariable analysis identified haploidentical donor as a major risk factor for CMV &amp;gt; 250 (odds ratio, OR 1.24, p=0.011) and &amp;gt; 1,000 copies/mL (OR 1.41, p=0.032) while transplant for AML/MDS was negatively associated with CMV &amp;gt; 250 (OR 0.19, p=0.009) and CMV &amp;gt; 1,000 copies/mL (OR 0.16, p=0.003). CRS was significantly associated with CMV &amp;gt; 1,000 copies/mL (OR 3.33, p=0.032) but this was no longer significant in multivariable analysis due to the association with haploidentical donor transplantation. Conclusion: This single-center retrospective comparison of PTCy-based transplants shows that haploidentical transplants have increased risk of early and clinically significant reactivation of CMV. Potential explanations include increased immunosuppression with mycophenolate and the presence of CRS, where inflammatory cytokines may de-repress the CMV major immediate early promoter. Selecting this high-risk group (haploidentical transplants with CRS) may be a cost-effective use of letermovir, which can be initiated prior to engraftment.

Azacitidine Combined with Interferon α for Preemptive Treatment of AML/MDS after Allogeneic Peripheral Blood Stem Cell Transplantation：a Prospecitive Phase II Study

Objective : this study investigated the efficacy and safety of azacitidine and interferon α preemptive treatment in the post-transplant in patients with AML/MDS. Methods: between Octorber 1, 2019 and July 31, 2022, a total of 49 patients aged 17 to 62 years were enrolled into this prospective clinical study of post-transplant azacitidine combined with interferon α preemptive treatment. Patients with minimal residual disease (MRD) positive and / or mixed chimerism were scheduled to receive azacitidine, given as 32 mg/m 2 per day subcutaneously for 5 days, and interferon α 3 million units/m 2 per day from 8th day and continued for 28th day for 1 cycle. Results: patients who acquired treatment response were 34 (69.4%), of which turned MRD-negative and obtained complete chimerism were 22 (44.9%) and 5 (10.2%) at 1 cycle, respectively. Median follow-up time after preemptive intervention was 440(range, 45 to 927) days. Cumulative incidences of relapse (CIR) and no relapse mortality (NRM) were 36.7% and 4.1%, respectively. Probabilities of event-free survival (EFS) and overall survival (OS) were 55.1% and 71.4%, respectively. The most common adverse events were graft-versus-host disease (GVHD) (38.8%), liver toxicity (46.9%) and neutropenia (28.6%). Conclusion: these data support the notion that azacitidine combined with interferon α is better used as the preemptive therapy against relapse tendency for patients after allo-HSCT performed for AML/MDS. Side effects were mainly GVHD, reversible cytopenia and hepatic toxicity. This prospective trial in the post-transplant setting was feasible and safe but challenging. This trial was registered at www.clinicaltrials.gov as#NCT04078399.

Cryopreservation Impacts Allogenic Stem Cell Engraftment: Relation between Graft Quality Control and Post-Transplant Clinical Outcome

Introduction: Freezing hematopoietic stem cells (HSC) has been a standard procedure in cellular therapy, either for allogenic, autologous, or cord blood transplantation. While cryopreservation is generally reported in the literature as a safe procedure with little impact on graft quality, some reports suggest significant effects of cryopreserved HSC as compared to fresh cells in the outcome of Hematopoietic Stem Cell Transplantation (HSCT). Recently, the COVID-19 pandemic enforced cryopreservation of HSC to secure allograft transplantation from related and unrelated donors. Modifying our standard practices was a unique opportunity to analyze the impact of this additional procedure on cell quality and HSC engraftment. Method: This study compared the HSCT engraftment from fresh versus cryopreserved allogeneic HSC performed in Necker Hospital (n = 236) between January 2020 to December 2022. We retrospectively collected clinical data on patients from our unicentric PROMISE database and extracted the graft characteristics (cell phenotypes, viability, and clonogenicity) from the quality assurance database. Delayed platelets or neutrophils recoveries, early graft loss, and the need for CD34+ selected stem cell boost were used to define post-transplant graft dysfunctions. Results: 107 pediatric patients with a median age of 3.9 years old and 129 Adult patients underwent primary HSCT in our center during the COVID-19 pandemic. Indications were hematological malignancies (n= 97: Acute leukemia, myelodysplastic syndrome, lymphoma, plasma cell disorders), inborn error diseases (n= 131: primary immune deficiency, hemoglobin disorder, histiocytic disorder), and bone marrow failure (n= 8). Sixty six (28.0%) graft of hematopoietic stem cells were cryopreserved from Bone Marrow (BM) (n = 18, 14.8%) and Peripheral Blood Stem Cells (PBSC) (n = 48, 42.1%). Cryopreservation significantly affects the viability (98.2% fresh vs. 84.4% cryopreserved HSC, p&amp;lt;0.0001) and the clonogenicity (18.7% fresh vs. 8.75% cryopreserved HSC, p&amp;lt;0.0001), whatever the source of stem cells. While cell viability and clonogenicity complied with the international standard before graft infusion, graft dysfunctions were a significant concern for cryopreserved allogeneic transplant (n= 22; 33.3%). Graft dysfunctions in cryopreserved HSC groups occurred with both bone marrow and PBSC. Significantly, dysfunctions increased to 38.5% for cryopreserved BM despite a higher median dose of CD34+/kg infused 15.5 (range, 10.2-20.7). No quality control parameter was predictive of engraftment dysfunction. Discussion conclusion: Cryopreservation of HSC was critical during the SARS-CoV-2 pandemic; however, in our experience, the procedure could impact graft function. Considering the development and worldwide distribution of cell therapy drug products, accurately evaluating the pretransplant graft quality is an issue in predicting the engraftment of HSC.

Randomized, Active-Control Phase 3 Study of Four-Factor Prothrombin Complex Concentrate Versus Frozen Plasma in Bleeding Adult Cardiac Surgery Patients

Background and Significance: Patients following cardiac surgery often develop coagulopathic bleeding and associated poor outcomes. The development of coagulopathy is multifactorial, including anticoagulation, hemorrhage, hemodilution and consumptive losses after tissue injury and during cardiopulmonary bypass (CPB). Reduced thrombin generation due to coagulation factor deficiency is an important contributor to post-CPB bleeding. Prothrombin complex concentrate (PCC; off-label) and frozen plasma (FP) are administered for coagulation factor replacement during surgery. The LEX-211 (FARES-II) study will determine if four-factor PCC (4F-PCC, Octaplex, Octapharma) is clinically non-inferior to FP regarding hemostatic effectiveness in cardiac surgery patients requiring coagulation factor replacement. Study Design and Methods: LEX-211 (FARES-II; NCT05523297) is a multicenter, randomized, active-control, prospective, Phase 3 trial that is being conducted at 13 hospitals in Canada and the United States. The study is being conducted in accordance with the Declaration of Helsinki. The study includes patients ≥18 years old undergoing cardiac surgery with CPB who require coagulation factor replacement due to bleeding and known (e.g., as indicated by international normalized ratio) or suspected coagulation factor deficiency. Exclusion criteria include heart transplant, insertion/removal of ventricular assist devices, high probability of death within 24 hours, severe right heart failure, heparin contraindications, thromboembolic events within the prior 3 months, and IgA deficiency. Patients will be randomized to 4F-PCC or FP when the blood bank receives the first order for coagulation factor replacement (Figure 1). For 4F-PCC dosing, patients weighing ≤60 kg will receive 1,500 international units (IU), and those &amp;gt;60 kg will receive 2000 IU. For FP, patients weighing ≤60 kg will receive 3 U and patients weighing &amp;gt;60 kg will receive 4 U. Patients are treated according to their assigned group until a maximum of 2 doses of 4F-PCC/FP have been administered during the treatment period (24 hours after initiation). If additional treatment is required, patients in both groups receive FP. The primary endpoint is the hemostatic response to 4F-PCC vs. FP, rated ‘effective’ if no further hemostatic intervention (systemic hemostatic agents, i.e., platelets, cryoprecipitate, other coagulation factor products, or a second dose of study drug, or surgical re-opening for bleeding) is required within 60 minutes to 24 hours after initiation of the first dose. Secondary and safety endpoints, with their timings, are described in Table 1. An unblinded interim analysis (100 evaluable patients/group) will test sample size assumptions and enable re-estimation if necessary. Depending upon the interim results, and accounting for dropouts (20% anticipated), the total sample size will range between 513-1,250 patients. The non-inferiority of the primary endpoint of ‘haemostatic response’ will be tested for 4F-PCC vs. FP using a Farrington-Manning score test with a non-inferiority margin of 0.10 at a one-sided significance level alpha of 2.5%. If non-inferiority is demonstrated, the superiority of 4F-PCC with regard to the primary endpoint will be investigated. LEX-211 (FARES-II) is in progress, with the first study site initiated in Q4 2022. Currently, &amp;gt;150 patients have been included in the study. Completion is expected in Q4 2024. The results of this study will inform clinical practice for bleeding cardiac surgery patients requiring coagulation factor replacement, potentially reducing allogeneic blood product usage and improving patient outcomes.

Blinatumomab in Combination with Immune Checkpoint Inhibitors (ICIs) of PD-1 and CTLA-4 in Adult Patients with Relapsed/Refractory (R/R) CD19 Positive B-Cell Acute Lymphoblastic Leukemia (ALL): Results of a Phase I Study

Background: Blinatumomab (blina) improves outcomes in R/R CD19+ ALL compared to chemotherapy. However, the overall response rate to blina was 44%, and median overall survival (OS) is just 7.7 mos (Kantarjian. NEJM. 2017). Preclinical studies show increased PD-L1 expression on leukemic blasts potentially contributes to relapse after blina. The addition of PD-1 +/- CTLA-4 blockade to blina leads to increased in vitro T cell proliferation and enhanced cytotoxicity (Feucht. Oncotarget 2016). Thus, blockade of co-inhibitory pathways may enhance blina efficacy in vivo. We describe results of a multi-center phase I study combining blina with immune checkpoint inhibitors (ICIs) targeting PD-1 (nivolumab) +/- CTLA-4 (ipilimumab). Methods: In a dose-escalation study, we evaluated the safety, tolerability, and preliminary efficacy of blina with nivolumab (nivo) +/- ipilimumab (ipi) using a 3+3 design. Pts ³16 years-old with R/R CD19+ B-ALL or mixed phenotype acute leukemia (MPAL) were eligible. Pts ³60 years could be untreated. Table 1 presents the dose escalation schema. Expansion cohorts of 6 pts were planned at the maximum tolerated dose (MTD) for blina + nivo AND blina + nivo + ipi. Pts received up to 5 cycles of blina and 1 year of ICIs. Pts removed from the study during the blina lead-in (days 1-10) were replaced. Dose-limiting toxicities (DLTs) were defined as grade 3+ non-hematologic toxicities requiring the permanent discontinuation of treatment in the first 42 days. Primary endpoints were toxicities and MTD. Secondary endpoints included complete remission (CR), MRD-negativity at a sensitivity of 0.01%, duration of response and OS from treatment initiation. Results: Twenty-seven pts were enrolled to 3 dose levels (14 DLA1, 3 DLB1, and 10 DLB-1) from September 2017-December 2022. Six pts were replaced (4 prior to ICI dosing and 2 requiring subsequent therapy in the DLT window). The median age of enrolled pts was 55 (range 24-84), 14 were male (52%), and median baseline BM blasts were 60% (range 0.2-98%). Baseline characteristics are presented in Table 2. A single DLT (G4 infusion reaction and G3 hypotension) occurred among 6 pts at DLA1. Based on this safety and efficacy data, blina + nivo was expanded to include 6 additional pts without additional DLTs. There were 2 DLTs at DLB1 (G5 pneumonitis and G2 GVHD), which led to de-escalation to DLB-1, where there was 1 DLT (G3 delirium). Grade 2+ immune-related adverse events attributable to ICIs included pneumonitis (G2+G5), rash (G2+G3), transaminitis (G2+G3), colitis (G3), and hypothyroidism (G2). Grade 3+ adverse events attributable to blina included neutropenia (5-G4+3-G3), dysphasia (2-G3), weakness (G3), seizure (G4), and transaminitis (1-G4+4-G3). Among 22 pts evaluable for response, the CR rate was 68% (100% MRD-negative). Among 13 pts with &amp;gt;50% BM blasts at baseline, 62% achieved CR. Pts with B-myeloid MPAL (0/2) and a history of extramedullary disease (1/4) were less likely to respond. Nine responders subsequently relapsed including 3 with isolated extramedullary disease and 2 with CD19-negative disease. As shown in Figure 1, relapse-free survival (RFS) at 1 year was 27% (95% CI 10-46), while OS at 1 year was 63% (95% CI 38-79). Twelve pts underwent allogeneic blood or marrow transplant (alloBMT) following study treatment. At 1 year for alloBMT pts, RFS was 51% (95% CI 19-76) and OS was 61% (95% CI 26-83). Ongoing analyses of changes in T cell subpopulations, co-signaling molecule expression, and single cell RNA seq results will be presented. Conclusions: Combination therapy with blina and ICIs in R/R ALL is safe, feasible, and associated with a high MRD-negative response rate. Long-term survival was promising in comparison to prior results with blina monotherapy, especially following consolidation with alloBMT. A randomized trial of blina +/- nivolumab is needed to confirm the benefit of this combination.