Unrelated Donor Hematopoietic Stem Cell Research Articles

Unrelated hematopoietic stem cell donor registries: present reality and future prospects.

Stem cell donor registries play an important role in providing stem cell products from unrelated donors to patients with severe blood diseases. In this review, important aspects of donor registry work, current challenges and possible future developments are discussed. The current growth in global unrelated stem cell donations is in line with the long-term trend, indicating that donor registries have overcome the COVID-19 pandemic. A key challenge for donor registries is the recruitment of donors from disadvantaged populations to create greater equity in access to unrelated stem cell transplantation. In addition, recruiting young donors and increasing the availability of donors who are already registered are important goals. In recent years, numerous studies have looked at the context of these themes and the development of possible solutions. The international community of donor registries, together with the World Marrow Donor Association, has helped many patients in need of a stem cell transplant over the past decades and is, therefore, a bright example of international collaboration for a good cause. It is currently addressing a number of challenges to effectively help as many patients as possible from various populations also in the future.

Study on the Construction of Family Support System for Unrelated Hematopoietic Stem Cell Donation Volunteers

There are millions of patients in urgent need of hematopoietic stem cell transplantation in China, but the matching success rate of unrelated hematopoietic stem cells is only 1/400 ~ 1/10000. Since the establishment of China Bone Marrow Bank in 1992, only more than 14,000 patients have been successfully matched. According to the survey, a large number of volunteers in China will eventually choose to refuse to donate hematopoietic stem cells, which is closely related to the public's lack of understanding of hematopoietic stem cell donation. Unrelated volunteers can get less support from family members than related hematopoietic stem cell donors, which leads to their lower donation rate. Therefore, it is of great practical significance to study the family support system of unrelated hematopoietic stem cell donation volunteers.

Risk prediction and function evaluation by T-cell epitope model and expression model of HLA-DPB1 mismatching in unrelated-donor hematopoietic stem cell transplantations

Objective: To evaluate the risk prediction and assessment function of HLA-DPB1 T-cell epitope (TCE) model and expression model in human leukocyte antigen (HLA)-matched unrelated hematopoietic stem cell transplantation (MUD-HSCT) with HLA-DPB1 mismatching. Methods: A total of 364 (182 pairs) potential MUD-HSCT donors and recipients confirmed by HLA high-resolution typing in Shaanxi Blood Center from 2016 to 2019 were analyzed retrospectively. Of the 182 recipients, there were 121 males and 61 females with an average age of (26.3±14.2) years. Of the 182 donors, there were 148 males and 34 females with an average age of (33.7±7.5) years. Polymerase chain reaction-sequence-based typing (PCR-SBT), next-generation sequencing (NGS) and polymerase chain reaction-sequence specific oligonucleotide probe (PCR-SSO) based on LABScan®3D platform were used for high-resolution typing of HLA-A, B, C, DRB1, DQB1, DPB1 gene, and PCR-SBT was used for single nucleotide polymorphism (SNP) typing. TCE model and expression model were used to predict and evaluate the HLA-DPB1 mismatch pattern and acute graft-versus-host-disease (aGVHD) risk. Results: A total of 26 HLA-DPB1 alleles and their 3'-UTR rs9277534 SNP genotypes were detected in this study population, and two new alleles HLA-DPB1*1052∶01 and HLA-DPB1*1119∶01 were found and officially named. The overall mismatch rate of HLA-DPB1 in MUD-HSCT donors and recipients was 90.66% (165/182). In TCE model, the HLA-DPB1 mismatch rates of permissible mismatch (PM) and non-permissible mismatch (non-PM) were 47.80% (87/182) and 42.86% (78/182), respectively. The non-PM in GvH direction was 13.73% (25/182), and which in HvG direction was 29.12% (53/182). A total of 73 pairs of donors and recipients in TCE model met the evaluation criteria of expression model. Among of TCE PM group, recipient DP5 mismatches accounted for 34.25% (25/73) were predicted as aGVHD high risk according to expression model. For the TCE non-PM group, both the recipient DP2 mismatches of 6.85% (5/73) and recipient DP5 mismatches of 10.86% (8/73) were predicted to be at high risk for aGVHD. Risk prediction by TCE model and expression model was 27.27% concordant and 16.97% unconcordant. Conclusions: TCE model and expression model are effective tools to predict aGVHD risk of MUD-HSCT. Comprehensive application of the two models is helpful to the hierarchical assessment of HSCT risk.

Factors Associated with Opting Out of an Unrelated Hematopoietic Stem Cell Donor Registry: Differences and Similarities across Five Key Groups of Young Race/Ethnically Diverse Potential Donors in the United States

Young adults from underserved racial/ethnic groups are critically needed as unrelated hematopoietic stem cell (HSC) donors, yet they are more likely than other groups to opt out of donation after having matched a patient. Understanding which factors are most strongly associated with opting out among young underserved racial/ ethnic registered donors compared with their White counterparts will provide the basis for specific interventions to improve donor retention. We sought to determine the key, modifiable psychosocial, registry-related, and donation-related characteristics that are uniquely associated with opting out across 5 key racial/ethnic groups of young HSC donor registry members who had been contacted as a potential match for a patient. This study examines data from a large cross-sectional survey of young (age 18 to 30) registry members shortly after they preliminarily matched a patient (CT-stage) and continued toward or opted out of donation (CT-C and CT-NI), stratified by racial/ethnic group and sex. We assessed psychosocial, registry-related, and donation-related characteristics for all participants. We used chi-squared and F tests to assess differences between racial/ethnic groups. A separate logistic regression analysis for each racial/ethnic group was conducted to quantify adjusted associations between each variable and opting out. Then, we compared these associations across the racial/ethnic groups by evaluating the interaction effect between each variable and racial/ethnic group, with the same outcome (CT-C versus CT-NI) in question. Nine hundred thirty-five participants were surveyed, including 284 White, 165 Hispanic, 191 Black, 192 Asian/Pacific Islander, and 103 Multiracial/multiethnic participants. There were significant differences across racial/ethnic groups in values/goals, religious objections to donation, HSC-related medical mistrust, and parental involvement in donation decisions. Adjusted logistic regression subgroup analyses indicated that ambivalence was strongly associated with opting out across all racial/ethnic groups. Greater focus on intrinsic life goals (e.g., raising a family, becoming a community leader, influencing social values) was associated with opting out in the Multiracial/multiethnic, Hispanic, and Asian/Pacific Islander groups. Healthcare mistrust and insufficient registry contact was a significant factor for Hispanic participants. Protective factors against opting out included remembering joining the registry (Black participants), and parental support for donation decision (Asian/Pacific Islander participants). The performance of each logistic regression model was strong, with area-under-the curve ≥.88, CT-stage outcome classification accuracy ≥89%, and good fit between expected and observed opt-out probabilities. In the analysis across different racial/ethnic groups, the only significant interaction was race/ethnicity by whether more contact with the registry would have changed the decision at CT-stage; this variable was significant only for the Hispanic group. In the within-group analysis for Hispanic participants, the "more registry contact" variable was strongly associated with opting out (odds ratio 5.8, P = .03). Consistent with a growing body of HSC donor research, ambivalence was a key factor associated with opting-out for all racial/ethnic groups. Other key variables were differentially associated with opting-out depending on racial/ethnic group. Our study highlights key variables that registries should focus on as they develop targeted and tailored strategies to enhance commitment and reduce attrition of potential donors.

Matched Unrelated Donor (MUD) Hematopoietic Stem Cell Transplant in Thalassemia Patient: An Outcome-Based Analysis of Pediatric Cohort in Tertiary Cancer Care Centre of North India

Matched Unrelated Donor (MUD) Hematopoietic Stem Cell Transplant in Thalassemia Patient: An Outcome-Based Analysis of Pediatric Cohort in Tertiary Cancer Care Centre of North India

Reduced human leukocyte antigen mismatching is associated with more favourable outcomes after unrelated donor haematopoietic stem cell transplantation.

The patient-donor human leukocyte antigen (HLA) match remains the most important prognostic factor for successful unrelated donor haematopoietic stem cell transplantation (UD-HSCT). This single-centre study comprised 125 adult patients with malignant haematological diseases undergoing their first UD-HSCT. The primary goal of this study was to validate the impact of HLA matching on HSCT outcomes, specifically at the HLA-DPB1 and HLA-DRB3/4/5 loci. A multivariable Cox regression analysis with a backward selection algorithm was employed to assess the associations of selected prognostic factors with outcomes after UD-HSCT. Any HLA locus mismatch was found to be associated with an increased incidence of grade II-IV acute graft versus host disease (aGvHD) at 100 days (p=.031; hazard ratio [HR] 1.935) and 6 months (p=.004; HR 2.284) after HSCT. The results of the following analyses also confirmed the strong impact of HLA-DPB1-only mismatch on the incidence of grade II-IV aGvHD at 100-day (p=.006; HR 2.642) as well as at 6-month (p=.007; HR 2.401) time periods. The HLA-DPB1-only mismatch was also shown to be statistically significantly associated with lower relapse incidence (p=.034; HR 0.333). The impact of the HLA-DRB3/4/5 mismatch on outcomes was inconclusive, though the two and more HLA-DPB1+DRB3/4/5-only mismatches showed a trend towards worse outcomes than a single mismatch. Based on our findings and those of more comprehensive studies, the extended HLA loci typing of patients and donors is suggested to avoid unexpected HLA mismatches during the UD selection.

Lymphoid Malignancies in Shwachman-Diamond Syndrome: Incidence, Clinical Features, and Outcomes from the North American SDS Registry

Introduction: Many marrow failure conditions are associated with myeloid malignancy predisposition and a subset carry an increased risk of both myeloid and lymphoid malignancies. The increased risk of myeloid malignancy is known in Shwachman-Diamond syndrome (SDS), however, the risk of lymphoid malignancy in SDS has not been previously reported. Through the North American SDS Registry (SDSR), we identified patients with SDS diagnosed with lymphoma. We report the clinical features and outcomes in these patients as well as the incidence rates of lymphoma, MDS, and AML in this cohort. Methods: Patients with biallelic SBDS mutations enrolled on the SDSR were included for analysis. Age- and sex-specific incidence rates from the SEER Program (2016-2020) were multiplied by person-years of observation to obtain expected numbers of events. The crude rate per 100,000 (100,000*observed number of malignancies/person-years of follow-up) and the standardized incidence ratio (SIR) were calculated. Results: Out of a total of 217 patients with SDS with biallelic SBDS mutations in the SDSR, we identified 3 subjects who developed lymphoma. Case 1: A male patient with biallelic SBDS mutations (c.258 + 2T>C; c.653G>A, p.Arg218Gln) presented with dyspnea and was diagnosed with primary mediastinal B-cell lymphoma at age 16 years. Bone marrow exam was negative for lymphoma but revealed a new del20q clone. He received 6 cycles of R-CHOP. His course was complicated by febrile neutropenia, pleural effusion, deep vein thrombosis, and decreased cardiac ejection fraction requiring subsequent omission of doxorubicin and carvedilol initiation. He is in remission >3 years from diagnosis. Case 2: A male patient with biallelic SBDS mutations (c.258 + 2T>C; c.183_184TA>CT, p.Lys62*) was diagnosed at age 23 years with diffuse large B-cell lymphoma (DLBCL) of the distal stomach and duodenal bulb. Bone marrow exam was negative for malignancy but demonstrated an abnormal karyotype: 46,XY,t(11;16)(q23;q24), del(20)(q11.2q13.3)[9]/46,XY[11]. He received 5 cycles of R-CHOP therapy, which was complicated by febrile neutropenia and S. aureus sepsis. Four years later, he was diagnosed with relapsed DLBCL of the distal ileum and concurrent AML with 5q deletion. He achieved complete remission of both malignancies after 2 cycles of cyclophosphamide, vincristine, prednisone, obinutuzumab, azacitidine, and venetoclax. Therapy was complicated by B. cereus bacteremia with brain abscesses and endocarditis and C. difficile infection. He underwent a matched unrelated donor hematopoietic stem cell transplant and is in remission >180 days from transplant. Case 3: A male patient with biallelic SBDS mutations (c.258 + 2T>C; c.183_184TA>CT, p.Lys62*) was diagnosed with Stage IVB classical Hodgkin lymphoma at age 12 years after presenting with mediastinal syndrome. Bone marrow biopsy was negative for findings suggestive of MDS or malignancy, however, the initial PET-CT was consistent with medullary involvement. He initiated therapy with steroids, doxorubicin, vinblastine, dacarbazine, and brentuximab vedotin and received focal radiation. His course was complicated by recurrent febrile neutropenia, C. difficile colitis, and cellulitis. Due to infectious complications and delayed count recovery after 2 cycles, despite chemotherapy dose reductions, he was transitioned to brentuximab and nivolumab. He demonstrated complete response by Deauville criteria prior to cycle 5 of brentuximab and nivolumab. Among 217 patients with biallelic SBDS mutations in the SDSR, the median age was 12.8 years (range: 0.3 - 52.8). The observed number, rates, and SIR for lymphoma, MDS, and AML are given in Table 1. A high SIR indicates a higher incidence in the SDSR relative to the SEER population in 2016-2020. The observed rate of lymphoma was 28.5 times higher in SDS than the expected rate in the general population. Conclusions: The incidence of lymphoma among patients with SDS is increased relative to the general population but is lower than the incidence of MDS or AML. Increased toxicity with standard therapies was observed in these patients. Given the increased risk of MDS/AML in SDS, which may be further increased by antecedent chemotherapy, non-genotoxic therapies should be investigated for lymphoma in SDS. Our results show that SDS should be added to the list of marrow failure conditions predisposing to both myeloid and lymphoid malignancies.

SMC4 Loss of Function Is a New Cause of Inherited Bone Marrow Failure

Inherited bone marrow failure syndromes (IBMFS) are a rare, heterogenous group of syndromes that are characterized by cytopenias, bone marrow hypocellularity, and in many cases an increased risk of transformation to myeloid malignancy. Presentation with severe pancytopenias at birth is reported but occurs very rarely, and more often neonatal pancytopenia is attributed to congenital and acquired infections or other acquired causes. We present the case of a preterm neonate with pancytopenia from birth and bone marrow failure of no known infectious, other acquired, or genetic etiology. Antenatal findings were notable for non-immune hydrops fetalis at 30 weeks of gestation prompting delivery. The initial laboratory evaluation revealed a normocytic, reticulocytopenic, severe anemia; leukopenia with an absolute neutrophil count of 500; and severe thrombocytopenia. Viral testing, including parvovirus, rubella, herpes simplex virus, cytomegalovirus, adenovirus, and enterovirus, was negative. Additional testing, including a chromosomal microarray, mitochondrial genome sequencing, chromosome stress testing, neonatal alloimmune thrombocytopenia panel, and telomere length analysis, was non-diagnostic. Bone marrow biopsy showed a remarkably hypoplastic marrow without evidence of dysplasia or cytogenetic abnormalities. The proband underwent matched unrelated donor hematopoietic stem cell transplant, and died approximately one month later from post-transplantation complications including hepatic veno-occlusive disease, thrombotic microangiopathy, CNS and pulmonary hemorrhages, pseudomonal sepsis, and multi-organ dysfunction. Autopsy was significant for microscopic pancreatic atrophy with lipomatous hypertrophy and osteopenia. The proband and parents underwent clinical exome testing which was non-diagnostic and then consented to research reanalysis of the exome data. Research reanalysis identified the infant was compound heterozygous for predicted deleterious variants in the Structural Maintenance of Chromosomes 4 gene (SMC4), inherited in trans from each unaffected parent (c.2478_2479ins10 splice site variant predicted to alter splicing and c.T591G; p.Y197X). Germline variants in SMC4 have not been reported as a cause of human disease; however, somatic variants are observed in several cancers including in acute myeloid leukemia (AML). SMC4 is a highly conserved protein that forms a heterodimer with Structural Maintenance of Chromosomes 2 (SMC2) in the condensin II protein complex. This complex is important for chromosome condensation, cell division, and DNA repair. Within hematopoietic tissue, SMC4 expression is higher in hematopoietic stem and progenitor cells when compared with mature lineage cells. Given the predicted loss of function from both SMC4 variants, we performed RNAseq on proband and control fibroblasts. This showed a roughly 10-fold decrease in total SMC4 transcript levels (Figure 1A). A significant proportion of the transcript present was comprised of an aberrantly spliced transcript characterized by exon 15 skipping. We therefore hypothesized that loss of SMC4 expression leads to a cell intrinsic defect in hematopoiesis. To test this hypothesis, we used CRISPR-Cas9 gene editing to generate knockout of SMC4 in human cord blood CD34+ hematopoietic stem/progenitor cells (HSPCs) before culturing cells in an all-colony forming unit (CFU) assay. Using two independent small guide RNAs, we were able to achieve approximately 80% knock-down. After 14 days in culture, we observed a striking decrease in CFUs when compared with controls, though the composition of colony types was relatively unchanged (Figure 1B). Using next-generation sequencing, we observed a significant decrease in remaining SMC4 genome edits at the end of the culture period, suggesting a relative disadvantage of SMC4-edited cells for survival and/or proliferation. In summary, we describe a preterm infant with congenital bone marrow failure without an identifiable cause and link this phenotype to biallelic loss-of-function variants in SMC4. This is the first study identifying SMC4 as a novel gene that causes inherited bone marrow failure, and further experiments are underway to validate this finding.

Outcomes after Bone Marrow Versus Peripheral Blood Stem Cell Matched Unrelated Donor Hematopoietic Stem Cell Transplantation

Background: Matched unrelated donors (MUD) have become an acceptable alternative donor for patients requiring potentially curative hematopoietic stem cell transplantation (HSCT) and lacking a matched sibling donor. Patients may undergo a bone marrow (BM) or peripheral blood stem cell (PBSC) graft, with previous studies showing similar survival outcomes. However, BM grafts have shown a lower incidence of chronic graft-versus-host disease (GVHD) but a higher relapse rate and slower engraftment. We aimed to compare the outcomes of BM versus PBSC in patients undergoing MUD HSCT. Methods: For this retrospective single-center study, we included all (n=276) adult MUD HSCT recipients at the University of Kansas Medical Center who had at least one year of follow-up (August 2016 to July 2021). We conducted a bivariate analysis using chi-squared and ANOVA tests. The Kaplan-Meier and regression analyses were also performed. Data analyses were conducted using SPSS version 28. Statistical significance was considered at p<0.05. Results: Our study included 276 MUD patients including 110 PBSC (40%) and 166 BM (60%) grafts. The median age was 55 (range 21-77) years, and 158 patients (57%) were males. Eighteen patients (6%) were ethnic minorities, and 89 (32%) patients had a Karnofsky performance status of ≥90%. 118 (43%) patients had a hematopoietic cell transplantation-specific comorbidity index of 3 or higher. Hematologic diseases included acute myeloid leukemia (n=119, 43%), myeloid disorders (n=77, 28%), acute lymphoblastic leukemia (ALL) (n=35, 13%), Lymphoma (n=15, 5%), and others (n=30, 11%). Sixty-two percent of patients were in complete remission at the time of transplantation, and patients not in remission included myelodysplastic syndrome, myelofibrosis, and lymphoma patients. Reduced-intensity conditioning (RIC, n=162, 58%) and myeloablative conditioning (MAC) (n=114, 41%) were used. The median follow-up was 55 (21-73) months. Overall survival (OS) was not reached in either BM or PBSC MUD HSCT group, while a median disease-free survival of 45 and 49 months was noted in PBSC and BM groups respectively (p=0.915). We observed similar rates of relapse (25% vs 27%, p=0.413), one-year overall survival (75% vs 72%, p=0.679), one-year disease-free survival (63% vs 62%, p=1.00), and one-year non-relapsed morality (NRM, 23% vs 21%, p=0.779) after PBSC or BM graft. Bone marrow graft recipients had delayed engraftment of neutrophils (20 days vs 16 days, p<0.001) and platelets (>20 K/uL: 24 days vs 16 days, p<0.001; >50 K/uL: 28 days vs 18 days, p=0.006) compared to PBSC recipients. Bone marrow graft recipients had similar rates of grade II-IV acute GVHD (50% vs 52%, p=0.714) and grade III-IV GVHD (12% vs 11%, p=0.847), but lower rates of 1-year chronic GVHD (39 % vs 55%, p=0.014) compared to PBSC recipients. In the subgroup analysis stratified by conditioning intensity, faster engraftment of neutrophils (median 16 vs 21 days, p<0.001) and platelets (>20 K/uL: 18 days vs 27 days, p<0.001; >50 K/uL: 18 days vs 33 days, p<0.001) was observed with PBSC as compared to BM graft in myeloablative transplant recipients, while there was no statistically significant association with the rates of acute or chronic GVHD, NRM, Relapse, DFS, and OS after a PBSC or BM graft. Among the RIC transplant recipients, faster neutrophil engraftment (mean 17 vs 20 days, p<0.001) and higher 1-year extensive chronic GVHD (52% vs 32%, p=0.015) were observed with PBSC compared to BM graft whereas no statistically significant difference was noted in platelet engraftment, acute GVHD, NRM, Relapse, DFS, and OS after a BM or PBSC graft. Conclusions: Allogeneic matched unrelated donor hematopoietic stem cell transplant recipients had similar rates of overall and disease-free survival, relapse, non-relapse mortality, and acute GVHD after a bone marrow or peripheral blood stem cell graft; however, delayed neutrophil and platelet engraftment with a lower incidence of chronic GVHD was noted after a bone marrow graft compared to peripheral blood stem cell graft.

ATG versus PTCy in matched unrelated donor haematopoietic stem cell transplantations with non-myeloablative conditioning.

Graft-versus-host disease (GvHD) is a serious complication of allogeneic haematopoietic stem cell transplantation (HSCT). Both anti-thymocyte globulin (ATG) and post-transplant cyclophosphamide (PTCy) are used as lymphocyte-depleting strategies, yet a systematic comparison of transplantation outcomes between these two methods in matched unrelated donors (MUD) transplantations with non-myeloablative conditioning (NMC) is lacking. Adult patients with haematological malignancies who had undergone MUD HSCT with NMC regimens between 2014 and 2021 at 2 centres in Amsterdam (ATG: n = 95, PTCy: n = 90), were included in this retrospective study. Patient characteristics were comparable between the groups. The cumulative incidence of acute GvHD grade II-IV was 48% in the ATG group compared to 21% in the PTCy group (p < 0.001). The 3-year moderate/severe chronic GvHD was similar in both groups (p = 0.69). While the relapse rate was comparable between the groups (ATG 31% vs. PTCy 34%, p = 0.94), non-relapse mortality tended to be higher in the ATG group (17% vs. 9%, p = 0.069). Overall survival was similar in both groups (p = 0.12). In conclusion, PTCy-based regimens resulted in a significantly lower rate of acute GvHD than ATG-containing regimens in MUD transplantations with NMC. Whether PTCy results in improved overall survival as compared to ATG needs to be elucidated in larger prospective studies.

Outcomes of patients with hematological malignancies who undergo unrelated donor hematopoietic stem cell transplantation with ATG-Fresenius versus ATG-Genzyme

To compare the outcomes of patients with hematological malignancies who received ATG-Fresenius (ATG-F) 20 mg/kg versus those who received ATG-Genzyme (ATG-G) 10 mg/kg in an unrelated donor hematopoietic stem cell transplantation (HSCT) procedure, a total of 186 patients who underwent their first allogeneic HSCT with an unrelated donor were retrospectively analyzed. One hundred and seven patients received ATG-F, and seventy-nine patients received ATG-G. Multivariate analysis showed that the type of ATG preparation had no effect on neutrophil engraftment (P = 0.61), cumulative incidence of relapse (P = 0.092), nonrelapse mortality (P = 0.44), grade II-IV acute graft-versus-host disease (GVHD) (P = 0.47), chronic GVHD (P = 0.29), overall survival (P = 0.795), recurrence-free survival (P = 0.945) or GVHD-free relapse-free survival (P = 0.082). ATG-G was associated with a lower risk of extensive chronic GVHD and a higher risk of cytomegaloviremia (P = 0.01 and HR = 0.41, P < 0.001 and HR = 4.244, respectively). The results of this study suggest that the preparation of rabbit ATG used for unrelated HSCT should be selected based on the incidence of extensive chronic GVHD of each center, and the posttransplant management strategy should be adjusted according to the ATG preparation.

357 - Outcomes after HLA-Mismatched Unrelated Donor Hematopoietic Stem Cell Transplantation with Post-Transplant Cyclophosphamide for Graft-Vs-Host Disease Prophylaxis: A Systematic Review and Meta-Analysis

357 - Outcomes after HLA-Mismatched Unrelated Donor Hematopoietic Stem Cell Transplantation with Post-Transplant Cyclophosphamide for Graft-Vs-Host Disease Prophylaxis: A Systematic Review and Meta-Analysis

305 - Unrelated and Haploidentical Donor Hematopoietic Stem Cell Transplantation (HSCT) for Severe Aplastic Anemia in Pediatric and Young Adult Population: Single Center Experience

305 - Unrelated and Haploidentical Donor Hematopoietic Stem Cell Transplantation (HSCT) for Severe Aplastic Anemia in Pediatric and Young Adult Population: Single Center Experience

Human Leucocyte Antigen System and Selection of Unrelated Hematopoietic Stem Cell Donors: Impact of Patient-Donor (Mis)matching and New Challenges with the Current Technologies.

The selection of hematopoietic stem cell donors for allogeneic transplantation (allo-HSCT) is mainly driven by human leucocyte antigen (HLA) matching between patient and donor, with HLA-identical matched siblings being the preferred choice in most situations. Although other clinical and demographical variables matter, especially, donor age, which is unequivocally associated with better transplant outcomes, the histocompatibility criteria have a central role in the search for the best donor, particularly in the setting of unrelated allo-HSCT where HLA disparities between patient and donor are frequent. The present review is focused on the role of HLA incompatibilities on patient outcome according to the most recent literature, in an attempt to guide transplant physicians and search coordinators during the process of adult unrelated-donor selection. The technological progresses in HLA typing, i.e., with next-generation sequencing (NGS), now allow disclosing a growing number of HLA incompatibilities associated with a heterogeneous and sometimes unknown spectrum of clinical severity. Their immunogenic characteristics, i.e., their position inside or outside the antigen recognition domain (ARD), their permissiveness, their intronic or exonic nature and even the expected expression of the HLA loci where those mismatches occur, will be presented and discussed here, integrating the advances in the immunobiology of transplantation with survival and toxicity outcomes reported in the most relevant studies, within the perspective of improving donor selection in the current practice.

National experience with adenosine deaminase deficiency related SCID in Polish children.

Deficiency of adenosine deaminase (ADA) manifests as severe combined immunodeficiency (SCID), caused by accumulation of toxic purine degradation by-products. Untreated patients develop immune and non-immune symptoms with fatal clinical course. According to ESID and EBMT recommendations enzyme replacement therapy (ERT) should be implemented as soon as possible to stabilize the patient's general condition, normalize transaminases, treat pulmonary proteinosis, bone dysplasia, and protect from neurological damage. Hematopoietic stem cell transplantation (HSCT) from a matched related donor (MRD) is a treatment of choice. In absence of such donor, gene therapy (GT) should be considered. HSCT from a matched unrelated donor (MUD) and haploidentical hematopoietic stem cell transplantation (hHSCT) are associated with worse prognosis. We retrospectively evaluated the clinical course and results of biochemical, immunological and genetic tests of 7 patients diagnosed in Poland with ADA deficiency since 2010 to 2022. All patients demonstrated lymphopenia affecting of T, B and NK cells. Diagnosis was made on the basis of ADA activity in red blood cells and/or genetic testing. Patients manifested with various non-immunological symptoms including: lung proteinosis, skeletal dysplasia, liver dysfunction, atypical hemolytic-uremic syndrome, and psychomotor development disorders. Five patients underwent successful HSCT: 3 patients from matched unrelated donor, 2 from matched sibling donor, and 1 haploidentical from a parental donor. In 4 patients HSCT was preceded by enzyme therapy (lasting from 2 to 5 months). One patient with multiple organ failure died shortly after admission, before the diagnosis was confirmed. None of the patients had undergone gene therapy. It is important to diagnose ADA SCID as early as possible, before irreversible multi-organ failure occurs. In Poland HSCT are performed according to international immunological societies recommendations, while ERT and GT are less accessible. Implementation of Newborn Screening (NBS) for SCID in Poland could enable recognition of SCID, including ADA-SCID.

Matched unrelated donor hematopoietic stem cell transplant in a child with chronic myeloid leukemia

Matched unrelated donor hematopoietic stem cell transplant in a child with chronic myeloid leukemia

Factors Associated with Opting Out of Donation among Registered Young Unrelated Hematopoietic Stem Cell Donors

Young adults enrolled in hematopoietic stem cell (HSC) donation registries, including the Be The Match registry in the United States, often opt out of the registry when a potential recipient is identified. This results in a limited supply from the most desirable allogeneic source of HSCs used in transplantation to treat serious health conditions. The differences in demographic, psychosocial, registry-related, and donation-related characteristics between those who continue to donation and those who opt out may elucidate the modifiable risk factors for attrition, but these characteristics have not been extensively studied in young donors up to age 30 years. Our goal was to study demographic, psychosocial, registry-related, and donation-related characteristics in a group of young HSC donor registry members who had recently been contacted about a potential recipient, to determine the key characteristics that differ between those who continued toward donation and those who opted out and to examine the extent of these differences. We conducted a cross-sectional survey in a random sample of young (age 18 to 30 years) current and former registry members, stratified by race/ethnicity and sex. Demographic, psychosocial (eg, life goals, HSC allocation mistrust), registry-related (eg context and motive for joining the registry), and donation-related (eg, ambivalence, religious objections to donation, knowledge about donation) characteristics were assessed. Chi-square and 2-sample t tests were used to examine differences between those who continued (CT-C group) and those who opted out (CT-NI group). Hierarchical logistic regression was used to estimate adjusted covariate effects on the odds of opting out. A total of 935 participants were surveyed. Donation-related knowledge was higher in the CT-C group than in the CT-NI group. HSC allocation mistrust, religious objections, and concerns about donation were higher in the CT-NI group. After adjusting for covariates in a logistic regression model, we found that having more intrinsic life goals, having more ambivalence, and talking with registry staff only once/twice were significantly associated with opting out of the registry. Ambivalence had the strongest association with opting out. In contrast, remembering joining the registry, believing that parents would support donation, and having medical concerns were significantly associated with continuing toward donation. This effect of medical concerns on donation was discovered only after adjusting for the related but distinct ambivalence variable, with the remaining effect of medical concerns relating to engagement with the donation process and information-seeking. The model had strong discriminative ability (area under the receiver operating characteristic curve=.92) and classification accuracy (86.6%). Our data indicate that among young adult members of a national HSC donor registry, ambivalence and limited contact with registry staff were more strongly associated with opting out of donation. Medical concerns were associated with continuing toward donation. Further studies are needed to confirm a causal link between medical concerns and continuing to donation among young donors. Our study suggests that these concerns might not be directly related to attrition, whereas other factors (eg, ambivalence, low donation-related knowledge) are associated with attrition and thus should be targeted for attrition reduction strategies.

Basiliximab in the Prevention of aGVHD for Unrelated Donor Hematopoietic Stem Cell Transplantation in Patients with Thalassemia Major: A Prospective, Multicenter, Open-Label, Randomized Controlled Study

Background: Hematopoietic stem cell transplantation (HSCT) is currently the only clinical cure for thalassemia major (TM). Graft-versus-host disease (GVHD) and transplant-related mortality (TRM) remain major barriers to clinical outcomes in TM-unrelated donor transplantation (MUD-HSCT). Aims: The role of Basiliximab in preventing acute graft-versus-host disease (aGVHD) after MUD-HSCT in thalassemia major (TM) is still unknown. We performed a prospective, multicenter, open-label, randomized controlled trial (RCT). The study is registered at www.clinicaltrials.gov as #NCT02342145. PATIENTS AND METHODS: Patients with TM with unrelated donor were randomly assigned to a basiliximab group (20 mg/kg basiliximab on days 0 and +4, respectively, plus tacrolimus [FK506], methotrexate [MTX], and mycophenolate mofetil [MMF]) and a control group (FK506, MTX, and MMF). The primary end point of this study was grade 2-4 aGVHD on day 100. Results: From April 2015 and September 2021, a total of 205 TM patients were enrolled. The ratio of male to female was 123 to 82 with a median age of 7 years (range, 2-19 years). Patients were randomly assigned to the basiliximab group of 102 and the control group of 103. Comparison of the basiliximab group and the control group, the cumulative incidence rate of grade 2-4 aGVHD was 24.5% and 29.1%, respectively (P=0.456), and the cumulative incidence rate of grade 3-4 aGVHD was 8.8% and 14.6% (P=0.201); the cumulative incidence rate of moderate or severe chronic GVHD was both 2.9%; median days of neutrophil engraftment were +11.8 and +11.6 days, respectively (P=0.701), platelets Implantation days were +15.4 and +13.5 days (P=0.126); TRM was 3.6% and 7.1% (P=0.249), over survival (OS) was 96.4% and 92.0% (P=0.188), respectively and thalassemia-free survival (TFS) of the two groups was also the same as the OS. There was no significant difference between the basiliximab and control groups with regard to cytomegalovirus reactivation, Epstein-Barr virus reactivation, and transplant-related complications. Subgroup analysis according to the degree of HLA matching showed that the 9/10 mismatch group had significantly lower OS and TFS than the 10/10 matched group (both 82.6% v 96.5%, P=0.004). The 3-year OS and TFS of the entire cohort (205 TM patients ) were 94.1% and 94.0%, respectively(Table 1, Fig 1). CONCLUSION: This first prospective randomized study showed basiliximab at a dose of 20 mg on day 0 and day+ 4 did not reduced the incidence of both aGVHD and cGVHD in patients with TM after MUD-HSCT. The incidence of aGVHD in unrelated donor transplants for TM patients is still high, 9/10 mismatched unrelated donor transplants had poor result when comparing 10/10 matched donor transplants for TM patients. Unrelated donors are still a very good alternative source of donors. The TFS of TM patients treated by unrelated donor transplantation can reach 94.0%. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Combination of Cytogenetic Classification and MRD Status Correlates with Outcomes of Autologous Versus Allogeneic Stem Cell Transplantation in Adults with B Cell-Acute Lymphoblastic Leukemia in First Remission

Objectives: To analyze overall survival (OS), leukemia-free survival (LFS), cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) of patients with B cell-acute lymphoblastic leukemia (B-ALL) who received autologous or allogeneic stem cell transplantation and to provide the basis for the choice of transplantation method. Methods: We retrospectively investigated the outcomes of 388 adult patients with B-ALL in our center. The OS, LFS, CIR and NRM rate and the impact of minimal residual disease (MRD) within 3 chemotherapy cycles along with risk classification were explored. Results: Both univariate and multivariate analysis found that negative MRD within 3 chemotherapy cycles was the important factor associated with the prognosis. As to 355 patients who obtained first complete remission (CR1), we divided patients into 3 groups according to the risk stratification and MRD status within 3 chemotherapy cycles. For patients with negative MRD within 3 chemotherapy cycles and standard-risk group, the 3-year OS (82.5% vs 74.1%, P=0.364), LFS (74.5% vs 74.1%, P=0.904), CIR (25.5% vs 17.6%, P=0.648) and NRM rates(0% vs 8.3%, P=0.234) were not significantly different between autologous hematopoietic stem cell transplantation (auto-HSCT) and allogeneic hematopoietic stem cell transplantation (allo-HSCT) group（Figure 1）. In patients with negative MRD and high-risk factors, although auto-HSCT group and allo-HSCT group had similar 3-year OS(72.7% vs 68.5%, P=0.436) and LFS rate (62.8% vs 56.0%, P=0.375) , the lower NRM (1.5% vs 25.1%, P=0.000) was offset by higher CIR(35.7% vs 18.9%, P=0.018) in auto-HSCT group compared with allo-HSCT group（Figure 2）. As for other patients with high-risk factors and positive MRD after 3 chemotherapy cycles, the prognosis of auto-HSCT group was evidently worse than those of allo-HSCT group as there was a lower trend of 3-year OS (50.0% vs 66.0%, P=0.077), LFS rate (30.8% vs 47.1%, P=0.398) and significantly higher CIR rate(71.4% vs 39.1%, P=0.018) in auto-HSCT group compared to allo-HSCT group（Figure 3）. MRD within 3 chemotherapy cycles was also related to the selection of allogeneic transplantation methods and pretreatment schemes. The 3-year OS (67.4% vs 60.8% vs 65.2%, p=0.735), LFS (56.3% vs 48.3% vs 58.3%, P=0.538), CIR (21.7% vs 23.3% vs 13.3%, P=0.784) and NRM rate (22.1% vs 28.4% vs 28.3%, P=0.672) were similar in matched sibling donor hematopoietic stem cell transplantation (MSD-HSCT), haploid hematopoietic stem cell transplantation (haplo-HSCT) and unrelated donor hematopoietic stem cell transplantation (URD-HSCT) group patients who achieved negative MRD within 3 chemotherapy cycles. While MSD-HSCT group tended to have lower 3-year LFS (33.0% vs 54.1% vs 41.7%, P=0.198) and higher CIR rate (53.2% vs 33.7% vs 46.2%, P=0.233) when comparing with haplo-HSCT and URD-HSCT group patients whose MRD were still positive within 3 chemotherapy cycles. Moreover, in patients who achieved negative MRD within 3 chemotherapy cycles, there was no significant difference in 3-year CIR rate (24.5% vs 23.1%, P=0.784) between TBI group and non-TBI group, but the lower OS (64.2% vs 76.3%, P=0.027) and LFS (54.4% vs 71.3%, P=0.091) was mainly due to the higher NRM rate (17.8% vs 5.6%, P=0.062) in TBI group. For MRD positive patients, TBI group had advantages over non-TBI group, demonstrating a trend of higher 3-year OS (65.0% vs 42.9%, P=0.105), LFS (44.8% vs 27.1%, P=0.138), lower CIR (43.6% vs 63.8%, P=0.106) and similar NRM rate (11.7% vs 9.1%, P=0.671). In addition, we found that 8 most frequently mutated genes were KMT2D、FAT1、NRAS、PAX5、KRAS、SETD2、ASXL1、PTPN11 in 175 patients with preliminary second generation sequencing results（Figure 4）. Mutations in CARD11 and NOTCH signaling pathway were correlated with lower LFS (CARD11: 56.3% vs 16.7%, P=0.002; NOTCH signaling pathway: 59.2% vs 38.8%, P=0.049)（Figure 5）. Conclusions: Auto-HSCT with maintenance therapy after HSCT and non-TBI pretreatment schemes appears to be an attractive treatment option for patients with B-ALL especially for those who achieved negative MRD within 3 chemotherapy cycles. For MRD positive patients, allogeneic transplantation and TBI pretreatment schemes may be more effective. Key words: auto-HSCT, allo-HSCT, acute lymphoblastic leukemia, minimal residual disease Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Immunotherapy with CD25/CD71-allodepleted T cells to improve T-cell reconstitution after matched unrelated donor hematopoietic stem cell transplant: a randomized trial

Background aimsDelayed immune reconstitution is a major challenge after matched unrelated donor (MUD) stem cell transplant (SCT). In this randomized phase 2 multi-center trial, Adoptive Immunotherapy with CD25/71 allodepleted donor T cells to improve immunity after unrelated donor stem cell transplant (NCT01827579), the authors tested whether allodepleted donor T cells (ADTs) can safely be used to improve immune reconstitution after alemtuzumab-based MUD SCT for hematological malignancies. MethodsPatients received standard of care or up to three escalating doses of ADTs generated through CD25+/CD71+ immunomagnetic depletion. The primary endpoint of the study was circulating CD3+ T-cell count at 4 months post-SCT. Twenty-one patients were treated, 13 in the ADT arm and eight in the control arm. ResultsThe authors observed a trend toward improved CD3+ T-cell count at 4 months in the ADT arm versus the control arm (230/µL versus 145/µL, P = 0.18), and three ADT patients achieved normal CD3+ T-cell count at 4 months (>700/µL). The rates of significant graft-versus-host disease (GVHD) were comparable in both cohorts, with grade ≥2 acute GVHD in seven of 13 and four of eight patients and chronic GVHD in three of 13 and three of eight patients in the ADT and control arms, respectively. ConclusionsThese data suggest that adoptive transfer of ADTs is safe, but that in the MUD setting the benefit in terms of T-cell reconstitution is limited. This approach may be of more use in the context of more rigorous T-cell depletion.