Complete Donor Research Articles

CLIMFILL v0.9: a framework for intelligently gap filling Earth observations

Abstract. Remotely sensed Earth observations have many missing values. The abundance and often complex patterns of these missing values can be a barrier for combining different observational datasets and may cause biased estimates of derived statistics. To overcome this, missing values in geoscientific data are regularly infilled with estimates through univariate gap-filling techniques such as spatial or temporal interpolation or by upscaling approaches in which complete donor variables are used to infer missing values. However, these approaches typically do not account for information that may be present in other observed variables that also have missing values. Here we propose CLIMFILL (CLIMate data gap-FILL), a multivariate gap-filling procedure that combines kriging interpolation with a statistical gap-filling method designed to account for the dependence across multiple gappy variables. In a first stage, an initial gap fill is constructed for each variable separately using state-of-the-art spatial interpolation. Subsequently, the initial gap fill for each variable is updated to recover the dependence across variables using an iterative procedure. Estimates for missing values are thus informed by knowledge of neighbouring observations, temporal processes, and dependent observations of other relevant variables. CLIMFILL is tested using gap-free ERA-5 reanalysis data of ground temperature, surface-layer soil moisture, precipitation, and terrestrial water storage to represent central interactions between soil moisture and climate. These variables were matched with corresponding remote sensing observations and masked where the observations have missing values. In this “perfect dataset approach” CLIMFILL can be evaluated against the original, usually not observed part of the data. We show that CLIMFILL successfully recovers the dependence structure among the variables across all land cover types and altitudes, thereby enabling subsequent mechanistic interpretations in the gap-filled dataset. Correlation between original ERA-5 data and gap-filled ERA-5 data is high in many regions, although it shows artefacts of the interpolation procedure in large gaps in high-latitude regions during winter. Bias and noise in gappy satellite-observable data is reduced in most regions. A case study of the European 2003 heatwave shows how CLIMFILL reduces biases in ground temperature and surface-layer soil moisture induced by the missing values. Furthermore, in idealized experiments we see the impact of fraction of missing values and the complexity of missing value patterns to the performance of CLIMFILL, showing that CLIMFILL for most variables operates at the upper limit of what is possible given the high fraction of missing values and the complexity of missingness patterns. Thus, the framework can be a tool for gap filling a large range of remote sensing observations commonly used in climate and environmental research.

Favorable outcomes with durable chimerism after hematopoietic cell transplantation using busulfan and fludarabine-based reduced-intensity conditioning for pediatric patients with hemophagocytic lymphohistiocytosis

BackgroundThe incorporation of a reduced-intensity conditioning (RIC) regimen in hematopoietic cell transplantation (HCT) for patients with hemophagocytic lymphohistiocytosis (HLH) has decreased early mortality but is associated with a high rate of mixed chimerism and graft failure. Here, we present a successful single-center experience using busulfan and a fludarabine-based RIC regimen for the treatment of HLH.MethodsThe medical records of pediatric patients with HLH who underwent HCT using a busulfan/fludarabine-based RIC regimen between January 2008 and December 2017 were reviewed retrospectively.ResultsNine patients received HCT with a busulfan/fludarabine-based RIC regimen. Three patients had primary HLH, and the other six patients had secondary HLH with multiple reactivations. All three patients with primary HLH had UNC13D mutations. All patients achieved neutrophil and platelet engraftment at a median of 11 days (range, 10‒21) and 19 days (range, 13‒32), and all eight evaluable patients had sustained complete donor chimerism at the last follow-up. Two patients (22%) experienced grade 2 acute graft-versus-host disease (GVHD). Two patients (22%) developed chronic GVHD, and one died from chronic GVHD. One patient (11%) experienced reactivation 4 months after HCT from a syngeneic donor and died of the disease. The 8-year overall survival and event-free survival rates were 78%. No early treatment-related mortality within 100 days after HCT was observed.ConclusionOur experience suggests that a busulfan/fludarabine-based RIC regimen is a viable option for pediatric patients with HLH who require HCT.

BLOOD REPOSITORY MANAGEMENT SYSTEM

To built a solution to the ever growing requirements of blood due to accidents and various health problem the system is developed for accessing the information about various blood banks, and hospitals and their blood stock. The solution should give complete information about blood donor ,and activities of hospitals and blood banks regarding the blood donation. Donors provides with registration process to maintain their information for future donations as well as to make their information available to search. In our project we need to collect the information like name, roll numbers ,bloodgroup, address ,contact number. we are going to create one page in that page having home, search, donor registration, login, contact us, about us. we need to save the information about donors and their details. if any emergency occurs their can contact us for blood donors.we are acting as a mediators between donor and receiver. Receiver can contacts us through our contact numbers(or)websites

Race does not predict pancreas graft failure after pancreas transplantation in the modern era.

African-American (AA) has historically been associated with inferior graft survival after pancreas transplantation. However, with the improvement of immunosuppression and surgical technique, we hypothesized that the racial disparity has been neutralized. We analyzed data from the Scientific Registry of Transplant Recipients (1989-2018). Using Kaplan-Meier estimation and Cox proportional hazards regression, we examined the influence of race on pancreatic graft survival. Before 2009, AA recipients had a higher risk of pancreatic graft failure after adjusting for confounding factors (hazard ratio [HR]: 1.16, 95% confidence interval [CI]: 1.08-1.24), but the risks for Hispanic and Asian recipients were both comparable to their Caucasian counterparts. However, the risk of pancreatic graft failure in AA recipients dropped to 1% and was no longer significant since 2009 (HR: 1.01, 95%CI: 0.88-1.16). Interestingly, donor race showed similar results. Furthermore, the concordance statistic of the complete pancreas donor risk index (including donor race) was 0.582, whereas the concordance did not change when donor race was eliminated from the model. AA and other races have shown similar pancreatic graft survival in the modern era. Furthermore, donor racial disparity also seems neutralized; thus, donor race should not be considered as an indicator of pancreatic donor quality.

RETRACTED: The impact of second-donor lymphocyte infusion on secondary graft failure after allogeneic hematopoietic stem cell transplantation through activation of Foxp3 and regulatory T cells

This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). The Editor of Cytotherapy has retracted this article. The article duplicates significant parts of a paper that had already appeared in Transplantation and Cellular Therapy, Volume 28, Issue 3, 2022, Pages 152.e1-152.e7, https://doi.org/10.1016/j.jtct.2021.12.017 In accordance with Committee on Publication Ethics (COPE) and Elsevier's policies, the authors have been contacted. After considering the author's response, the decision has been made to retract the paper. Redundant publications overweigh the relative importance of published findings and distort the academic record of the authors. One of the conditions of submission of a paper for publication is therefore that authors declare explicitly that the paper has not been previously published and is not under consideration for publication elsewhere. As such this article represents a misuse of the scientific publishing system. The scientific community takes a very strong view on this matter and apologies are offered to readers of the journal that this was not detected during the submission process.

Lineage-specific early complete donor chimerism and risk of relapse after allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia

Recipient–donor chimerism is routinely analyzed after allogeneic hematopoietic stem cell transplantation (HSCT) to monitor engraftment and graft rejection. For malignancies, chimerism can also be used to screen for disease relapse post-HSCT but methodology and interpretation of results are not standardized and likely depend on underlying diagnosis. We have implemented highly sensitive and accurate methodologies for chimerism analysis for the purpose of improving relapse prediction. Here, we report an exploratory retrospective analysis of clinical routine chimerism results from all 154 HSCTs for acute myeloid leukemia (AML) performed at our center during the years 2015–2020 with the aim of suggesting a clinically useful threshold at which risk of relapse is high. Relapse was not reliably predicted based on single elevated chimerism values obtained before time of overt relapse. However, early complete donor chimerism, here defined as recipient DNA < 0.2% in CD33+ cells in any blood or bone marrow sample taken during the first 60 days after HSCT, correlated inversely with relapse during the observation time (log-rank test P = 0.033). We propose that achievement of complete chimerism determined early after HSCT using sensitive methods can be used for risk-stratification of AML patients.

Comparative Analysis of the Treatment of Skin Lesions of the Lower Limbs with Sural Flap versus Propeller Flap.

Objective The objective of the present study was to prospectively compare the sural and propeller flaps for soft-tissues coverage of the lower extremity. The following variables were evaluated: incidence of complete or partial flap loss and donor area morbidity (primary closure versus skin graft). Methods Prospective and randomized analysis of data collected from all patients presenting with soft tissue defects of the lower third of the leg and heel treated with reverse sural or propeller flaps. Results Twenty-four patients aged between 4 and 60 years old were evaluated between 2011 and 2017. Complete coverage was obtained in 22 of the 24 patients (91.6%). Two flaps failed (8.4%). The sural flap, being the most popular option, continues to represent a safe and versatile alternative for skin defects of the lower third of the leg and heel region. Likewise, the propeller flap was a comparable option to treat these challenging defects. Conclusion Sural and propeller flaps are good options for soft tissues coverage of the lower extremity, with low complication rates (partial or total flap loss).

Accurate detection of reemergent anti-donor ABO antibody is crucial for safe transfusion in ABO major incompatible HSCT patient after achieved the stages of full switch to donor type.

Dynamic monitoring ABO chimera including erythroid ABO antigen and anti-A/B is crucial to not only assess the status of erythroid engraftment but also achieve personalized safety transfusion in patients post ABO incompatible hematopoietic stem cell transplantation. Transfusion support for ABO incompatible (ABOi) HSCT patients after achieved complete alteration to donor origin still remains cautious because the instant hematopoietic status on these transplant patients possibly returned to patient origin derived from early disease relapse and graft loss or failure. We reported that reemergent anti-B in a female patients (donor/patient: B/O) at the early phase after achievement complete donor type were not effectively found from partial automatic ABO blood grouping systems, which directly resulted in differential judgement of transplantation stage for about 15 days and disturbed the optimal recommendation on transfusion support. Meanwhile, the solely alteration of ABO chimera was found and earlier than changes of other markers such as MRD diagnosis, chimerism analysis by STR-PCR and sex chromosome assays, which can be an available predictors for bad transplant outcomes such as graft failure.

Human skin-resident host T cells can persist long term after allogeneic stem cell transplantation and maintain recirculation potential.

Tissue-resident memory T cells (TRM) have recently emerged as crucial cellular players for host defense in a wide variety of tissues and barrier sites. Insights into the maintenance and regulatory checkpoints of human TRM cells remain scarce, especially due to the difficulties associated with tracking T cells through time and space in humans. We therefore sought to identify and characterize skin-resident T cells in humans defined by their long-term in situ lodgment. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) preceded by myeloablative chemotherapy unmasked long-term sequestration of host T cell subsets in human skin despite complete donor T cell chimerism in the blood. Single-cell chimerism analysis paired with single-cell transcriptional profiling comprehensively characterized these bona fide long-term skin-resident T cells and revealed differential tissue maintenance for distinct T cell subsets, specific TRM cell markers such as galectin-3, but also tissue exit potential with retention of the transcriptomic TRM cell identity. Analysis of 26 allo-HSCT patients revealed profound interindividual variation in the tissue maintenance of host skin T cells. The long-term persistence of host skin T cells in a subset of these patients did not correlate with the development of chronic GvHD. Our data exemplify the power of exploiting a clinical situation as a proof of concept for the existence of bona fide human skin TRM cells and reveal long-term persistence of host T cells in a peripheral tissue but not in the circulation or bone marrow in a subset of allo-HSCT patients.

Willingness to donate organs - an anonymised survey in the emergency department.

In Switzerland, 519 patients received an organ in 2020. In total, 2124 patients were on the donor organ waiting list in 2020. There are many more people who need an organ than people willing to donate one. Therefore, 43 organs had to be imported from outside of Switzerland and this number was still not sufficient. This disproportion of patients needing an organ and available donor organs is the subject of ongoing discussion. A solution to this problem might be provided by a popular initiative proposing that every single resident of Switzerland should be an organ donor, unless a person explicitly rejects organ donation. We surveyed the patients in a single tertiary care emergency department (ED) to determine whether they had an organ donor card or were registered in the Swiss National Organ Donor Registry (NODR), the frequency of willingness to donate organs and which factors were associated with being an organ donor. In a prospective anonymised survey during July 2019, we enrolled patients who visited a Swiss tertiary care ED, during one week from 8:00 to 18:00, two weeks from 14:00 to 23:00 and one week from 23:00 to 8:00. The patients completed a written, standardised and self-administrated questionnaire during the waiting time in the ED. Descriptive, uni- and multivariable logistic regression analysis were performed. We enrolled 307 ED patients, of whom 62 (20.2%) were donor card holders or were registered in the Swiss NODR. Of these, 53 (85.5%) would be willing to donate organs. The remaining nine (14.5%) were not willed to donate an organ; the reasons for this were very heterogeneous. In contrast, the two leading reasons for willingness to donate organs were: to help after death (94.3%) and to free relatives from the task of making the decision (43.4%). From the 245 (79.8%) participants who did not have an organ donor card or were not registered, 84 respondents (34.3%) lacked knowledge of this topic, 65 (26.5%) had not yet thought about the topic and 51 (20.8%) had not yet had time to take care of this issue. Blood donation (odds ratio [OR] 2.1, 95% confidence interval [CI] 1.1-3.9; p = 0.018) or receiving a transplant in the past (OR 6.1, 95% CI 1.3-29.1; p = 0.023) and having a university degree (OR 1.8, 95% CI 1.0-3.2; p = 0.049) were factors associated with being an organ donor card holder. Only one in five ED patients had a fully completed organ donor card or were registered in the Swiss NODR. Of these, the great majority were willing to donate organs. Most of the ED patients who did not have an organ donor card or were not registered in the NODR lacked knowledge and information about the topic, had not yet thought about it or had not had time to deal with this issue. Factors such as a positive history of blood donation, organ transplantation in the past or having a university degree were associated with having an organ donor card. In order to increase the willingness to donate organs in the future, it is of immense importance to provide better information and more details and knowledge about this important topic.

Living kidney donation and reasons for denial: A report from a Brazilian single-center cross-sectional study

Chronic kidney disease is increasingly more prevalent worldwide, and kidney transplant remains the best option for patient survival. Living kidney transplants (LKT) pose advantages over deceased donor transplants, such as longer graft survival, lower ischemia time, and better HLA match. However, LKT is not always attainable for multiples reasons, with the absence of a suitable living donor being a significant barrier. Therefore, meticulous donor screening must be performed in order to guarantee donation safety. We examined medical appointments of living kidney donors evaluated at Hospital do Rim, São Paulo, between January and December 2020. Reasons for not proceeding with the donation were evaluated and were categorized as medical, surgical, immunological, psychosocial, or other. A total of 506 donor -receptor pairs were enrolled for evaluation during the study period. More than half of screened donor -receptor pairs (N=296, 58.5%) were not considered feasible for LKT. The primary cause for refusal was medical contraindication (32.1%), followed by immune (21.3%) and social (19.3%) causes. In addition, a considerable proportion of patients voluntarily withdrew themselves at variable time points during the evaluation process (N=79). In our center, most patients did not meet the criteria for kidney donation owing to medical reasons, similarly to other centers, and this reflects the importance of meticulous donor screening. In addition, the current Covid -19 pandemic affected the living transplant program, contributing to delayed complete donor and receptor evaluation.

Willingness to donate organs - an anonymised survey in the emergency department.

In Switzerland, 519 patients received an organ in 2020. In total, 2124 patients were on the donor organ waiting list in 2020. There are many more people who need an organ than people willing to donate one. Therefore, 43 organs had to be imported from outside of Switzerland and this number was still not sufficient. This disproportion of patients needing an organ and available donor organs is the subject of ongoing discussion. A solution to this problem might be provided by a popular initiative proposing that every single resident of Switzerland should be an organ donor, unless a person explicitly rejects organ donation. We surveyed the patients in a single tertiary care emergency department (ED) to determine whether they had an organ donor card or were registered in the Swiss National Organ Donor Registry (NODR), the frequency of willingness to donate organs and which factors were associated with being an organ donor.In a prospective anonymised survey during July 2019, we enrolled patients who visited a Swiss tertiary care ED, during one week from 8:00 to 18:00, two weeks from 14:00 to 23:00 and one week from 23:00 to 8:00. The patients completed a written, standardised and self-administrated questionnaire during the waiting time in the ED. Descriptive, uni- and multivariable logistic regression analysis were performed.We enrolled 307 ED patients, of whom 62 (20.2%) were donor card holders or were registered in the Swiss NODR. Of these, 53 (85.5%) would be willing to donate organs. The remaining nine (14.5%) were not willed to donate an organ; the reasons for this were very heterogeneous. In contrast, the two leading reasons for willingness to donate organs were: to help after death (94.3%) and to free relatives from the task of making the decision (43.4%). From the 245 (79.8%) participants who did not have an organ donor card or were not registered, 84 respondents (34.3%) lacked knowledge of this topic, 65 (26.5%) had not yet thought about the topic and 51 (20.8%) had not yet had time to take care of this issue. Blood donation (odds ratio [OR] 2.1, 95% confidence interval [CI] 1.1-3.9; p = 0.018) or receiving a transplant in the past (OR 6.1, 95% CI 1.3-29.1; p = 0.023) and having a university degree (OR 1.8, 95% CI 1.0-3.2; p = 0.049) were factors associated with being an organ donor card holder.Only one in five ED patients had a fully completed organ donor card or were registered in the Swiss NODR. Of these, the great majority were willing to donate organs. Most of the ED patients who did not have an organ donor card or were not registered in the NODR lacked knowledge and information about the topic, had not yet thought about it or had not had time to deal with this issue. Factors such as a positive history of blood donation, organ transplantation in the past or having a university degree were associated with having an organ donor card. In order to increase the willingness to donate organs in the future, it is of immense importance to provide better information and more details and knowledge about this important topic.

Poor graft function - causes and potential solutions

Introduction. Poor graft function is one of the most severe complications after allogeneic hematopoietic stem cell transplantation, which manifests as pancytopenia/cytopenia in the blood count, with the presence of complete or incomplete donor chimerism. There are three entities of graft weakness: 1. poor graft function: pancytopenia with complete donor chimerism, 2. graft failure: pancytopenia with incomplete, i.e., mixed donor chimerism and 3. graft rejection: progressive decline of donor chimerism. Definition. Poor graft function is diagnosed as pancytopenia (hemoglobin &lt; 70 g/L, absolute neutrophil count &lt; 0.5 x 109/L, platelets &lt; 20 x 109/L) for 3 consecutive days from D+28, excluding the presence of severe graft versus host disease and relapse, with complete donor chimerism in poor graft function, and incomplete in graft failure. Risk factors and therapeutic principles. The most common risk factors for poor graft function are a small dose of CD34+ hematopoietic stem cells in the transplant, graft versus host disease, cytomegalovirus infection, the presence of donor-specific antibodies, high serum ferritin, i.e., iron overload, as well as splenomegaly. Pathogenetic mechanisms in the development of poor graft function are still not fully elucidated. The role of the microenvironment of the patient?s bone marrow is also important, as well as disorders of the immune system Therapeutic options for overcoming this complication include using selected ?stem cell boost?, mesenchymal stem cells, and newer medical agents (N-acetyl cysteine, atorvastatin, thrombopoietin receptor agonists). Conclusion. The type of poor function of the graft is defined in relation to the percentage of donor chimerism, and is necessary for planning further treatment strategy.

Clinical roles of TIM-3 in myeloid malignancies and its importance in cellular therapy.

Acute myeloid leukemia (AML), one of the most common hematological malignancies worldwide, is derived from a fraction of stem cells known as leukemic stem cells (LSCs), which possess self-renewal and high propagation capacities. Remaining quiescent and being resistant to conventional chemotherapy, residual LSCs after chemotherapy drive leukemia regrowth, leading to AML relapse. Therefore, the eradication of LSCs is critical for the treatment of AML. We previously identified hepatitis A virus cellular receptor 2 (HAVCR2/TIM-3) as an LSC-specific surface molecule by comparing gene expression in LSCs and hematopoietic stem cells (HSCs). TIM-3 expression clearly discriminated LSCs from HSCs within the CD34+CD38- stem cell fraction. Furthermore, AML cells secrete galectin-9, a TIM-3 ligand, in an autocrine manner, leading to constitutive TIM-3 signaling that maintains the self-renewal capacity of LSCs via the induction of β-catenin accumulation. Thus, TIM-3 is an indispensable functional molecule for human LSCs. Herein, we review the functional aspects of TIM-3 in AML and evaluate minimal/measurable residual disease with a focus on CD34+CD38-TIM-3+ LSCs. Using sequential genomic analysis of identical patients, we determined that CD34+CD38-TIM-3+ cells in the complete remission (CR) phase after allogeneic stem cell transplantation (allo-SCT) are the LSCs responsible for AML relapse. We retrospectively evaluated the incidence of TIM-3+ residual LSCs. All analyzed patients achieved CR and complete donor chimerism at the engraftment phase; however, the high frequency of residual TIM-3+ LSCs within the CD34+CD38- fraction at engraftment was a significant and independent risk factor for relapse. Residual TIM-3+ LSC levels in the engraftment phase had a stronger impact on relapse than did pre-SCT disease status. Therefore, the evaluation of residual TIM-3+ LSCs is a promising approach for predicting leukemia relapse after allo-SCT.

Učestalost slabosti kalema nakon alogene transplantacije matičnih ćelija hematopoeze

Introduction: Poor engraftment represents one of the possible complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT). It presents as pancytopenia or bicytopenia, with or without complete donor chimerism. There are three entities of poor engraftment: poor graft function (PGF), graft failure (GF), and graft rejection (GR). Aim: This study aims to show the frequency of poor engraftment, as well as the frequency of all of its entities individually, among the patients of the Clinic of Hematology of the University Clinical Center of Serbia (UCCS), who underwent allo-HSCT between December 20, 2017 and December 25, 2020, for the purpose of achieving improved management and understanding of this serious complication. Materials and methods: This retrospective cohort study included 58 patients. Diagnosis of poor engraftment was confirmed by pancytopenia (cut off values: hemoglobin &lt; 70g/L; platelet count &lt; 20 x 109 /L; absolute neutrophil count (ANC) &lt; 0.5 x 109 /L), for three consecutive days, as of day D+28, with the exclusion of severe graft versus host disease (GvHD) and relapse, with complete donor chimerism in PGF and with incomplete donor chimerism in GF. GR presented as acute rejection of the graft by the recipient with bone marrow aplasia or pancytopenia. Results: Poor engraftment was confirmed in 13 of 58 patients (22.4%). Patients with PGF were the majority, with 12.1% (seven patients), while patients with GF and those with GR had the same incidence of 5.2% (three patients). Overall survival for patients with poor engraftment after allo-HSCT was five months, which is significantly less than the overall survival of the patients who had good engraftment after allo-HSCT (57 months). Conclusion: The three types of poor engraftment must be precisely discriminated and diagnosed in relation to donor chimerism in order to decrease morbidity and mortality in patients, post allo-HSCT.

S105: ADDING AZATHIOPRINE/HYDROXYUREA PRECONDITIONING TO ALEMTUZUMAB/TBI CONDITIONING IMPROVES DONOR CHIMERISM IN MATCHED SIBLING DONOR STEM CELL TRANSPLANTATION IN ADULT SICKLE CELL DISEASE PATIENTS

Background: Allogeneic hematopoietic stem cell transplantation (HSCT) is currently the only established curative treatment option for sickle cell disease (SCD). In adults, myeloablative conditioning is associated with significant toxicity, primarily due to cumulative organ damage. Matched sibling donor (MSD) transplantation with non-myeloablative conditioning (alemtuzumab/3 Gy total body irradiation (TBI)) has shown promising results in adult SCD patients.1,2 Patients treated with this regimen had their sickle cell phenotype corrected with only mild complications and no reports of graft-versus-host disease (GvHD). However, most of the described patients did not reach complete donor chimerism with graft failure rates of 13%. Furthermore, in almost 10% of patients, immunosuppressives could not be withdrawn because of too low T cell chimerism (<50%).2 We hypothesized that adding azathioprine and hydroxyurea as preconditioning to the alemtuzumab/TBI regimen might improve donor chimerism, reduce the risk of graft failure and improve successful withdrawal of immunosuppressives. Aims: In this study we prospectively investigate the effects of azathioprine/hydroxyurea preconditioning on donor chimerism and graft failure in patients receiving non-myeloablative MSD HSCT for SCD. Methods: Adult SCD patients who had an HLA-identical sibling donor were eligible for this treatment. After 3 months of azathioprine 150mg qd and hydroxyurea 25mg/kg qd, erythrocyte exchange transfusion was performed on day –10, aiming for HbS <30%. Conditioning with alemtuzumab/TBI was started on day –7. Graft versus host disease (GvHD) prophylaxis consisted of sirolimus. Results: As of October 2021, 13 SCD patients (median age 30.6 (range 19–49) years) were transplanted. Twelve patients (92.3%) engrafted successfully. After a median follow-up of 24 months, median donor myeloid and T cell chimerism of engrafted patients were 100% (IQR 84–100%) and 77% (IQR 70.5%-82.5%), respectively. These donor chimerism percentages are higher than previously reported with alemtuzumab/TBI only. All engrafted patients had a corrected SCD phenotype with normalized hemoglobin levels. Patients reaching 1-year post-transplantation were able to stop sirolimus without decreases in chimerism. Summary/Conclusion: Azathioprine/hydroxyurea preconditioning prior to alemtuzumab/TBI results in improved donor chimerism, potentially reducing the risk of graft failure after non-myeloablatieve MSD transplantation in SCD patients. Importantly, all engrafted patients reached donor T cell chimerism >50% at 1-year post-transplantation and were able to stop immunosuppressives as scheduled.

Donor origin precursor B-cell lymphoblastic leukemia post beta-thalassemia haploidentical transplant – A rare case report

Secondary malignancy of donor origin in the form of acute lymphoblastic leukemia (ALL), post-allogeneic hematopoietic stem cell transplant (HSCT) for beta thalassemia (BT) major, is exceedingly rare. A10 year old male child, the first and only product of non-consanguineous conception, was diagnosed with BT major at the age of 9 months when he had diarrhea and his parents (both of whom had thalassemia minor) noticed yellowing of the skin. Until the age of 10 years, he received regular blood transfusion and iron chelation, when the requirements got escalated and he consequently had to undergo myeloablative haploidentical HSCT from his mother. The post-transplant period was uneventful, and follow up with short tandem repeat chimerism analysis revealed complete donor chimerism on all occasions. Five years after the transplant, he developed fever with pancytopenia. Peripheral smear (PS) and bone marrow revealed blasts that were immunophenotypically precursor B-ALL. Cytogenetics revealed twenty diploid female metaphases with modal karyotype 46, XX[20], and again, complete donor chimerism was noted. Thus, a diagnosis of donor cell leukemia (DCL) was considered. Induction chemotherapy was initiated; however, the patient succumbed to systemic sepsis midway through induction therapy. No evidence of leukemia was noted in the patient's mother, who was followed up with PSs for 5 years. DCL has a poor prognosis. Greater understanding of the disease biology could allow for appropriate donor screening, notification and shielding the recipient from DCL and its grave consequences.

Effect of Donor Lymphocyte Infusion From Two Types of Donors on Mixed Chimerism With Secondary Graft Failure After Allogeneic Hematopoietic Stem Cell Transplantation

Mixed chimerism (MC) and secondary graft failure (SGF) with recipient- or donor-type chimerism is a major obstacle in allogeneic hematopoietic stem cell transplantation (HSCT). Donor lymphocyte infusion (DLI) can eradicate minimal residual disease or be used to rescue a hematologic relapse, being able to induce durable remissions after HSCT. This study aimed to analyze the efficacy and immune mechanism of DLI from the original and alternative donor for patients of mixed donor chimerism with SGF. The alternative donor refers to the candidate relative donor who did not initially provide stem cells and includes HLA-matched sibling donor or HLA-haploidentical donor. We conducted a retrospective study of 246 patients with a median age of 37 (9-58) years who had regularly detected MC, complete donor chimera (CC), and regulatory T cells (Treg). The median diagnosis time of SGF was 69 (39-141) days after transplantation. Sixteen patients with SGF received DLI from the alternative donor, including 3 patients who chose DLI from the original donor with no initial response and 13 patients who directly chose DLI from the alternative donor. Sixteen patients with SGF existed mixed chimerism synchronously and the rate calculated overall chimerism of MC was 63% (range 42%-85%) after transplantation. The proportion of Treg decreased significantly in SGF patients from a median of 2.66% ± 0.80% to 0.93% ± 0.57% at a time point after transplantation (P = .02). The DLI of the alternative donor in 14 patients achieved complete response and MC gradually convert to CC state, simultaneously there was significant increase in the Treg fraction (SGF versus complete response: 0.93% ± 0.57% versus 3.61% ± 0.82% [P = .01]). For the clinical nonresponders from 2 types of donors, there was no significant change in MC and Treg cells. The OS and disease-free survival at 2 years after DLI were 69.7% ± 3.19% and 61.3% ± 4.80%, respectively. DLI from the alternative donor may be an effective treatment for MC with SGF, and the mechanism is closely related to the activation of Treg cells level.

Weighted pseudo-values for partly unobserved group membership in paediatric stem cell transplantation studies.

Generalised pseudo-values have been suggested to evaluate the impact of allogeneic stem cell transplantation on childhood leukaemia. The approach compares long-term survival of two cohorts defined by the availability or non-availability of suitable donors for stem cell transplantation. A patient's cohort membership becomes known only after completed donor search with or without an identified donor. If a patient suffers an event during donor search, stem cell transplantation will no longer be indicated. In such a case, donor search will be ceased and cohort membership will remain unknown. The generalised pseudo-values approach considers donor identification as binary time-dependent covariate and uses inverse-probability-of-censoring weighting to adjust for non-identified donors. The approach leads to time-consuming computations due to multiple redefinitions of the risk set for pseudo-value calculation and an explicit adjustment for waiting-time bias. Here, the problem is looked at from a different angle. By considering the probability that a donor would have been identified after ceasing of donor search, weights for common pseudo-values are defined. This leads to a faster alternative approach as only a single risk set is necessary. Extensive computer simulations show that both, the generalised and the new weighted pseudo-values approach, provide approximately unbiased estimates. Confidence interval coverage is satisfactory for typical clinical scenarios. In situations, where donor identification takes considerably longer than usual, the weighted pseudo-values approach is preferable. Both approaches complement each other as they have different potential in addressing further aspects of the underlying medical question.

Post-Transplant Blockade of CXCR4 Improves Complete Remission Rates and Donor Stem Cell Engraftment without Aggravating Gvhd

Allogeneic hematopoietic cell transplantation (allo-HCT) is a promising therapeutic option for hematological malignancies, but relapse resulted predominantly from residual disease in bone marrow (BM) remains the major cause of treatment failure. Using immunodeficient mice grafted with laboratory-generated human B-ALL, our previous study suggested that leukemia cells within the BM were resistant to graft-versus-leukemia (GVL) effects, and mobilization with CXCR4 antagonist may dislodge leukemia cells from BM, rendering them destroyed by GVL effects. In this study, we extended this approach to patient-derived xenograft (PDX) and murine T-ALL and AML models for determining its clinical relevance and effects on GVHD and donor hematopoietic engraftment. We found that post-transplant treatment with CXCR4 antagonist AMD3100 significantly improved eradication of leukemia cells in the BM in PDX mice grafted with B-ALL cells from multiple patients. AMD3100 also significantly improved disease-free remission rates in murine T-ALL and AML models, and promoted donor hematopoietic engraftment in mice following non-myeloablative allo-HCT. Furthermore, post-transplant treatment with AMD3100 had no detectable deleterious effect on acute or chronic GVHD. These findings provide important preclinical data supporting the initiation of clinical trials exploring combination therapy with CXCR4 antagonist and allo-HCT. DisclosuresNo relevant conflicts of interest to declare.