Donor Cord Blood Research Articles

Knowledge and Attitude of Taif University Students on Stem Cell Banking

Abstract: Background and Objectives: The awareness of university students is pivotal to the adaptation of new therapeutic technologies in combating illness and disorders. Stem cells are unique and effective in treating several pathological conditions. This study was an effort to determine the knowledge and attitude of Taif University students toward the banking of stem cells through the donation of umbilical cord blood (UCB). Materials and Methods: The study used a self-administered questionnaire that consisted of items on demographics, knowledge characteristics, and attitude towards banking of UCB as a source of stem cells for the purpose of achieving advanced therapeutic outcomes. The questionnaire was administered to only female students at Taif University during the academic year 2020-21. Both descriptive and inferential analysis were done using SPSSIBM 25 to analyze the data. Results: A total of 604 female students of Taif University responded to our questionnaire. Although most of the participants (70%) lacked sufficient knowledge (less than or equal to 2 out of 4), their attitudes were motivating, with more than 60% rated better than adequate (more than or equal to 3 out of 4). Many study participants have shown an interest in donating umbilical cord stem cells to treat other patients and for research purposes. Conclusion: Students with good knowledge of umbilical cord blood donation and those who are more educated showed a greater level of willingness to participate in banking and donation of stem cells. Therefore, raising awareness about stem cell banking and its importance among young undergraduates, especially female students, is imperative. Key words: Knowledge, Attitude, Taif University, Awareness campaigns, Umbilical Cord blood.

Knowledge and Attitude of Taif University Students on Stem Cell Banking

Abstract: Background and Objectives: The awareness of university students is pivotal to the adaptation of new therapeutic technologies in combating illness and disorders. Stem cells are unique and effective in treating several pathological conditions. This study was an effort to determine the knowledge and attitude of Taif University students toward the banking of stem cells through the donation of umbilical cord blood (UCB). Materials and Methods: The study used a self-administered questionnaire that consisted of items on demographics, knowledge characteristics, and attitude towards banking of UCB as a source of stem cells for the purpose of achieving advanced therapeutic outcomes. The questionnaire was administered to only female students at Taif University during the academic year 2020-21. Both descriptive and inferential analysis were done using SPSSIBM 25 to analyze the data. Results: A total of 604 female students of Taif University responded to our questionnaire. Although most of the participants (70%) lacked sufficient knowledge (less than or equal to 2 out of 4), their attitudes were motivating, with more than 60% rated better than adequate (more than or equal to 3 out of 4). Many study participants have shown an interest in donating umbilical cord stem cells to treat other patients and for research purposes. Conclusion: Students with good knowledge of umbilical cord blood donation and those who are more educated showed a greater level of willingness to participate in banking and donation of stem cells. Therefore, raising awareness about stem cell banking and its importance among young undergraduates, especially female students, is imperative. Key words: Knowledge, Attitude, Taif University, Awareness campaigns, Umbilical Cord blood.

Hematopoietic stem cell transplantation for Inborn Errors of Immunity

Hematopoietic stem cell transplantation for Inborn Errors of Immunity

Review of Unrelated Donor Cord Blood Transplantation in Children over the Past 3 Decades

Review of Unrelated Donor Cord Blood Transplantation in Children over the Past 3 Decades

Single Cord Blood Transplantation Versus HLA-Haploidentical Related Donor Transplantation Using Post-Transplant Cyclophosphamide in Patients with Hematological Malignancies

Introduction: Unrelated cord blood (UCB) and haploidentical related donor transplantation using post-transplant cyclophosphamide (PTCy-haplo) have become alternative options to treat patients with hematological malignancies without a human leukocyte antigen (HLA)-matched donor. Although a previous phase III study showed better outcomes after bone marrow transplantation (BMT) using PTCy-haplo than those after double unit UCB, a donor selection algorithm including peripheral blood stem cell transplant (PBSCT) using PTCy-haplo or high-risk patients remains to be clarified. With the aim to assess the relative efficacies of UCB and PTCy-haplo transplant, we performed a multi-center retrospective analysis to compare the clinical outcomes in patients with hematologic malignancies.Methods: We included 517 patients aged 16 years to 70 years with hematological malignancies who received a first stem cell transplantation using a single UCB unit or PTCy-haplo between 2013 and 2019 in Kyoto Stem Cell Transplantation Group (KSCTG), which is a multi-center group of 18 transplantation centers in Japan. The primary endpoint was to compare overall survival (OS) between the UCB and PTCy-haplo groups. Secondary endpoints were relapse-free survival (RFS), GVHD- and relapse-free survival (GRFS), relapse, non-relapse mortality (NRM), neutrophil engraftment, platelet engraftment, grade II-IV acute graft-versus-host disease (GVHD), grade III-IV acute GVHD, chronic GVHD, and extensive chronic GVHD.Results: Among 517 patients, 460 received single UCB transplant and 57 received PTCy-haplo related donor transplant (53 PBSCT and 4 BMT). The median age of the UCB and PTCy-haplo groups was 55 and 52 years, respectively (P= 0.770). Myeloablative conditioning (MAC) was used more often in the UCB group than in the PTCy-haplo group (P< 0.001). In the PTCy-haplo cohort, the total dose of Cy was 80mg/m 2 (43.9%) or 100mg/m 2 (56.1%), and the median duration of tacrolimus and mycophenolate mofetil use was 173 and 34 days, respectively. The median follow-up periods of survivors were 2.2 and 2.4 years, respectively. OS in the UCB group was comparable to that in the PTCy-haplo group (2-year OS; 53.7%, 53.6%, P= 0.71 and adjusted hazard ratio (aHR) 1.00, P= 0.99), with similar risks of relapse (aHR 0.91, P= 0.99) and NRM (aHR 0.93, P= 0.69). This result was consistent regardless of disease risk. Neutrophil and platelet engraftment were significantly lower (92.2% vs 94.7%, P= 0.042 and 79.8% vs 82.5%, P= 0.003) and the incidence of acute GVHD in the UCB group tended to be higher (gradeⅡ-Ⅳ; aHR 1.64, p= 0.055, grade III-IV; aHR 3.60, P= 0.073) in the UCB group than those in the PTCy-haplo group. However, the incidences of chronic or extensive chronic GVHD after UCB transplant were comparable (chronic; aHR 0.89, p=0.68, extensive chronic; aHR 0.69, P= 0.35) to those after PTCy-haplo transplant. In the subgroup analysis of disease-specific comparison, acute leukemia patients have a significantly lower risk of relapse with UCB transplant (UBC vs PTCy-haplo, HR 0.55, P= 0.030) and lymphoma patients tended to have good results after PTCy-haplo transplant in terms of higher OS (UCB vs PTCy-haplo, aHR 2.13, P= 0.162) and lower relapse (aHR 3.43, P= 0.100). In terms of Cy toxicity in the PTCy-haplo group, transplant with a reduced dose of Cy (80 mg/m 2) tended to show higher OS (2-year OS, 64.8% vs 45.0%) and significantly lower NRM (2-year NRM, 8.0% vs 31.2%) without an increase in gradeⅡ-IV acute GVHD compared to those after standard-dose Cy (100 mg/m 2).Conclusion: Our findings suggest that UCB transplant gives outcomes comparable to PTCy-haplo transplant for patients without an HLA-matched sibling or unrelated donor. DisclosuresKanda: Amgen Astellas BioPharma: Honoraria; Astellas Pharma Inc.: Consultancy, Honoraria; Bristol-Myers Squibb Co: Honoraria; CHUGAI PHARMACEUTICAL Co., Ltd.: Honoraria; DAIICHI SANKYO Co., Ltd.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Eisai: Research Funding; Janssen Pharmaceutical K.K.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kyowa Kirin Co., Ltd.: Honoraria; Megakaryon Co: Honoraria, Membership on an entity's Board of Directors or advisory committees; NextGeM Inc: Patents & Royalties; Novartis Pharma K.K.: Honoraria; Ono Pharma Inc.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Sanofi K.K.: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; SymBio Pharmaceuticals, Ltd.: Membership on an entity's Board of Directors or advisory committees; Takeda Pharmaceutical Company Limited: Honoraria, Membership on an entity's Board of Directors or advisory committees; TEIJIN PHARMA LIMITED.: Honoraria. Imada: Celgene Co., Ltd.: Honoraria; Bristol-Myers Squibb K.K.: Honoraria; Astellas Pharma Inc.: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; Otsuka Pharmaceutical Co. Ltd.: Honoraria; Takeda Pharmaceutical Co. Ltd.: Honoraria; Novartis Pharma K.K.: Honoraria. Kondo: Asahi Kasei Pharmaceutical: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Chugai Pharma: Honoraria; MSD Pharmaceutical: Honoraria; Sumitomo Dainippon Pharma: Honoraria. Takaori-Kondo: Bristol-Myers K.K.: Honoraria; ONO PHARMACEUTICAL CO., LTD.: Research Funding; Celgene: Research Funding.

Impact of COVID-19 Pandemic on Global Unrelated Stem Cell Donations in 2020 - Report from World Marrow Donor Association

Introduction: World Marrow Donor Association (WMDA) promotes global collaboration for the benefit of stem cell donors and transplant patients. WMDA activities include recording the number of unrelated hematopoietic stem cell (HSC) donations globally.Because the COVID-19 pandemic also has an impact on the treatment of patients with other diseases, we hypothesise that it also impacted the practice of unrelated hematopoietic stem cell transplantation (HSCT).We used the 2020 WMDA data to examine the trends in unrelated HSC donations during the COVID-19 pandemic globally, per continent and per country/region.Methods: Donor registries (DRs) and cord blood banks (CBBs) from 61 countries participated in the 2020 survey, compared to 59 countries in the 2019. Slight differences in participation between the data sets of 2019 and 2020 do not explain the trends we observe in HSC donations. Country/region-specific COVID-19 data on cases and deaths were obtained from the data repository operated by the Johns Hopkins University Center for Systems Science and Engineering(https://github.com/CSSEGISandData/COVID-19, accessed July 12, 2021); and population data were retrieved from the Worldometer website(https://www.worldometers.info/, accessed July 12, 2021).Results: HSC donations from unrelated donors (peripheral blood stem cells (PBSC) and bone marrow (BM)) decreased from 20,330 in 2019 to 19,623 in 2020 (-3.5%), compared to an average annual growth rate of 3.9% from 2015 to 2019 (figure 1). The 3.5% decrease is composed of a 29.0% decrease for BM and a 2.6% increase for PBSC, resulting in a drop in the BM share of unrelated HSC donations from 19.3% in 2019 to 14.2% in 2020. The number of cord blood unit (CBU) shipments globally decreased with 3.5% from 2,851 to 2,750. The percentage of national use of HSC products (PBSC and BM) increased from 51.2% to 53.5%.When considering the continent on which the patient is transplanted (table 1), the change rate of use of HSC donated products in 2020 vs. 2019 ranged from -28.0% in South America to +18.2% in Africa. In absolute numbers, the largest decrease of HSC donations occurred for patients in Asia (n=-485) followed by Europe (n=-205), and the largest increase occurred in North America (n=+88) followed by Oceania (n=+25). The share of HSC donations requiring intercontinental transport decreased from 24.6% in 2019 to 21.9% in 2020.In terms of the country/region of transplant (table 2), the largest percentage decrease occurred in Colombia (-90,5%) followed by Russia (-55,5%). In absolute numbers, the largest decrease occurred in Turkey (-147), with Japan following (-128, although Japan saw an increase of CBU use of +106). The highest growth rate was observed in Iran (+28,7%), followed by South Africa (+28,2%). In absolute figures, the greatest increase occurred in Italy (+67). The two countries receiving the largest HSC donation numbers showed no major changes versus the previous year: USA: +0.6% (although a decrease for CBU of -21,0% was observed) and Germany: -2.4%.We did not find any significant correlation between the numbers of COVID-19 cases or COVID-19-related deaths per 1 million inhabitants with the HSC donation numbers (Spearman's r=0.05 for cases and =0.08 for deaths).Discussion: The decline in the number of unrelated HSC donations in 2020 suggests an impact of the COVID-19 pandemic on HSC donation and unrelated HSCT.The significant decrease in BM collections and intercontinental/cross-border shipments can be explained by logistically complex processes, as well the increased risk to the donor of being exposed to an operative procedure. CBU as a stem cell source potentially circumvents these logistical complications. However, on a global scale our data does not show increased use of CBU suggesting that decisions to use CBU as a stem cell source did not change in the pandemic .We were unable to demonstrate a correlation between country/region-specific severity of the pandemic and HSC donation numbers. We suspect this is due to the data quality of reported number of COVID-19 cases and COVID-19-related deaths. Also, we did not gather monthly data and therefore could not specify pandemic waves.In conclusion, we would like to point out the fact that global exchanges of HSC products continued and only decreased slightly is an extraordinary achievement of DRs, CBBs and their donors and is a testament to the importance of international collaborations in the WMDA. [Display omitted] DisclosuresDevine: Orca Bio: Consultancy, Research Funding; Johnsonand Johnson: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Magenta Therapeutics: Current Employment, Research Funding; Tmunity: Current Employment, Research Funding; Vor Bio: Research Funding; Kiadis: Consultancy, Research Funding; Be the Match: Current Employment. Shaw: Orca bio: Consultancy; mallinkrodt: Other: payments. Forman: Mustang Bio: Consultancy, Current holder of individual stocks in a privately-held company; Lixte Biotechnology: Consultancy, Current holder of individual stocks in a privately-held company; Allogene: Consultancy.

Base Editing Repairs the HbE Mutation Restoring the Production of Normal Globin Chains in Severe HbE/β-Thalassemia Patient Hematopoietic Stem Cells and Erythroid Cells

HbE/β-thalassemia is the commonest form of severe β-thalassemia, and comprises approximately 50% of all cases worldwide. HbE/β-thalassemia is caused by the HbE codon 26 G>A mutation on one allele and any severe β 0-thalassemia mutation on the other. These mutations lead to a reduction in β-globin production, resulting in a relative excess in α-globin chains that go on to cause ineffective erythropoiesis. Importantly, individuals with a mutation on one, but not two, alleles have β-thalassemia trait, a carrier state with a normal phenotype. Recent gene therapy and gene editing approaches have been developed to treat β-thalassemia but do not directly repair the causative mutation in-situ. Gene replacement approaches rely on lentiviral vector-based sequence insertion or homology directed repair (HDR). HbF induction strategies also rely on non-homologous end joining (NHEJ) targeting of enhancers in-trans. These approaches, whilst variably successful, are associated with potential safety concerns. Adenine base editors (ABEs) potentially circumvent these problems by directly repairing pathogenic variants in-situ through deamination. ABEs catalyse A-T to G-C conversions through targeting with a Cas9-nickase and single-guide RNA (sgRNA). Conversion of the HbE codon to normal through base editing is an attractive strategy to recapitulate the phenotypically normal β-thalassemia trait state without potentially harmful double-strand breaks or random vector insertions (Figure 1A). ABEs are able to convert the HbE codon (AAG, lys) to wild-type (GAG, glu), but also to GGG (gly) or AGG (arg). GGG at codon 26 is found in a naturally occurring hemoglobin, Hb Aubenas. Heterozygotes have normal red cell indices and are phenotypically normal.We electroporated the latest generation of ABE8 editors (ABE8e, ABE8.13 and ABE8 V106W) as mRNA into WT CD34+ hematopoietic stem and progenitor cells (HSPCs) with sgRNAs targeting the middle A of the WT GAG codon. These had similar editing efficiencies although ABE8 V106W had marginally higher on-target efficiency. V106W has been evolved to have a favourable off-target profile. V106W mRNA/sgRNA was electroporated into 3 different severe HbE/β-thalassemia donor HSPCs. The HbE codon was converted to WT with a mean 28.7% efficiency, to Hb Aubenas 48.6% and to an undescribed AGG codon 2.1%. The mean conversion from HbE to a normal or normal variant was 78.7±8.7% (Figure 1B). The indel rate from inadvertent on-target Cas9 cleavage was below 0.5%. Edited cells did not show any perturbations in erythroid differentiation as assessed by Immunophenotyping and cellular morphology. In differentiated erythroid cells, RT-qPCR showed a mean fall in the α/β mRNA ratio to 0.65±0.08 (unedited patient cells normalised to 1, n=5, Figure 1C), indicating a reduction in the relative excess α-globin gene expression. Protein analysis by CE-HPLC showed a 3.6-fold reduction in HbE levels (SD±1.3) and a 13.5-fold increase in HbA/Hb Aubenas (SD±2.4, Figure 1C and D).To prove that base editing using mRNA was possible in long-term HSCs, CD34+ cells from 4 WT cord blood donors were edited using ABEmax. Mice were culled after 16 weeks, and human cells were collected and transplanted into 7 secondary mice, which were also culled after 16 weeks. Each secondary mouse showed the presence of hCD45+ cells, indicating engraftment of LT-HSCs. All secondary replicates showed editing, with a mean editing efficiency of 34.5% (initial editing 46.3%). In both rounds of mice, there was robust lymphoid and myeloid engraftment and expected levels of erythroid engraftment for the NSG model in bone marrow and spleen. Potential off-target effects were assessed in-vitro by CIRCLE-seq in triplicate. These sites were assessed by targeted oligonucleotide capture of DNA from mRNA edited patient cells to detect in-vivo editing.Together these data provide robust evidence for base editing as an effective and safe therapeutic strategy for HbE/β-thalassemia. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Clinical Outcomes of Unrelated Umbilical Cord Blood Graft vs. Haploidentical Donor Transplantation: Critical Issues for an Adequate Comparison.

Unrelated umbilical cord blood (UCB) and haploidentical grafts have been used for allogeneic hematopoietic stem and progenitor cell (HSPC) transplantation in patients without a related or non-related human leukocyte antigen (HLA)-matched donor. The less stringent HLA-matching requirement in both sources raises an important possibility for patients in need of urgent transplantation to treat any hematological disease. Selection of the best alternative donor is a difficult task that will depend on donor criteria, center experience, patient disease conditions, and risk, among others. Most comparisons available in scientific publications between both graft sources are obtained from retrospective analysis in wide time windows and a heterogeneous number of patients, types of disease, disease stages, previous treatments, graft source, conditioning regimen, graft vs. host disease (GVHD) approach, and evaluable endpoints. There is also an evident impact of the economic traits since low-income countries must consider less expensive treatments to satisfy the needs of the patients in the most effective possible path. Therefore, haploidentical transplantation could be an appealing option, even though it has not been completely established if any chronic treatment derived from the procedure could become a higher cost. In Colombia, there is a huge experience in UCB transplantation especially in units of pediatric transplantation where benign indications are more common than in adults. Due to the availability of a public UCB bank and HLA high-resolution typing in Colombia, there is a wider inventory of cord blood donors. Unfortunately, we do not have an unrelated bone marrow donor registry, so UCB is an important source along with haploidentical transplantation to consider in decision-making. This minireview focuses on comparing the main issues associated with the use of both HSCP sources and provides tools for physicians who face the difficult decision between these alternative donor sources.

Influence of Total Body Irradiation Dose Rate on Idiopathic Pneumonia Syndrome in Pediatric Patients With Acute Leukemia Undergoing Allogeneic Hematopoietic Cell Transplantation

<h3>Purpose/Objective(s)</h3> To evaluate the relationship between total body irradiation (TBI) and other factors in the development of idiopathic pneumonia syndrome (IPS) in pediatric patients undergoing allogeneic hematopoietic cell transplantation (HCT) for acute leukemia. <h3>Materials/Methods</h3> Between 2006-2019, 121 pediatric patients with acute leukemia (84 lymphoblastic, 37 myeloid), ranging in age from 1 to 21 years (median 12), underwent allogeneic HCT at a single institution with matched sibling (n = 33), single unrelated cord blood (sUCB; n = 57), or double unrelated cord blood (dUCB; n = 31) donor. Pretransplantation conditioning included cyclophosphamide (100-120 mg/kg) with (n = 89) or without fludarabine (75 mg/m²) (n = 32). TBI was delivered in 8 b.i.d. fractions of 1.65 Gy over 4 days via opposed lateral beams of 6, 18, or 25 MV prescribed to midplane at umbilicus, with the patient in a semi-recumbent position, and without lung shielding. Aluminum lung compensator was utilized if predicted mid-lung point dose was ≥3% higher than prescription dose (n = 28). Dose rate was specified at 9-20 cGy/min and depended on linear accelerator availability. Patients were stratified by receipt of high-dose-rate (HDR; > 15 cGy/min; 36%) or low-dose-rate (LDR; ≤15 cGy/min; 64%) delivery. IPS was defined as pulmonary injury based on clinical symptoms, radiographic evidence, or pulmonary function testing within 100 days of HCT in the absence of concurrent infection. The association between treatment factors and IPS was examined. <h3>Results</h3> Overall, IPS developed in 22 (18%) patients from day 6 to 83 (median 20) after HCT. On univariate analysis, factors associated with IPS included donor type (matched sibling 12%, sUCB 12%, dUCB 35%, <i>P</i> < 0.01), HDR TBI (35% vs 9% for LDR, <i>P</i> < 0.01), and lower beam energy (35% for 6 MV and 15% for 18/25 MV, <i>P</i> = 0.04). The finding of beam energy significance is likely the result of the 6 MV cohort having a greater dose rate (median 16 cGy/min) than the 18/25 MV cohort (11 cGy/min). On competing risk regression analysis, the pre-specified factors of dose rate, beam energy, lung compensator, age, HCT comorbidity index, and donor type were included in the model. All factors except age (hazard ratio [HR] 1.09, <i>P</i> = 0.20) and lung compensator (HR 1.8, <i>P</i> = 0.17) showed an independent statistically significant association with IPS. Kaplan-Meier estimated 1-year survival was 73% for the entire cohort. Time-dependent effect of IPS did not show an association with overall survival (HR 1.2, <i>P</i> = 0.76). <h3>Conclusion</h3> TBI dose rate is an important variable in the risk of pulmonary toxicity in children treated with allogeneic HCT. TBI dose rates ≤15 cGy/min reduced the risk of posttransplantation IPS and should be strongly considered as an easily implemented parameter in pre-transplantation TBI-based conditioning.

Improved survival of patients with aggressive ATL by increased use of allo-HCT: a prospective observational study

Aggressive adult T-cell leukemia/lymphoma (ATL) is a hematological malignancy that is difficult to treat with chemotherapy alone, and allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative therapy. We conducted a multicenter, prospective, observational study to clarify the treatment outcomes of aggressive ATL in the current era. Between 2015 and 2018, 113 patients aged 70 years or younger with newly diagnosed aggressive ATL were enrolled. The median age at diagnosis was 61 years. Treatment outcomes were compared with those of 1792 ATL patients diagnosed between 2000 and 2013 in our previous retrospective study. The inclusion criteria were the same in both studies. The prospective cohort demonstrated better overall survival (OS) than the retrospective cohort (2-year OS, 45% vs 29%, respectively; P < .001), with a much higher proportion of patients receiving allo-HCT (80% vs 34%, respectively; P < .001) and a shorter interval from diagnosis to allo-HCT (median, 128 vs 170 days, respectively; P < .001). Among the 90 patients who received allo-HCT (cord blood, n = 30; HLA-haploidentical related donors, n = 20; other related donors, n = 14; other unrelated donors, n = 26), the 2-year probabilities of OS, non-relapse mortality (NRM), and disease progression were 44%, 23%, and 46%, respectively. OS and NRM did not differ statistically according to donor type. Our results suggest that increased application of allo-HCT improved the survival of patients with aggressive ATL. The use of cord blood or HLA-haploidentical donors may be feasible for aggressive ATL when HLA-matched related donors are unavailable. This study was registered at the UMIN Clinical Trials Registry as #000017672.

Identification and Successful Re-Consent of Existing Cord Blood Donors for the Creation of Induced Pluripotent Stem Cell Lines

Identification and Successful Re-Consent of Existing Cord Blood Donors for the Creation of Induced Pluripotent Stem Cell Lines

Significance of regional population HLA immunogenetic datasets in the efficacy of umbilical cord blood banks and marrow donor registries: a study of Cretan HLA genetic diversity

Background aimsThe high genetic diversity of HLA across populations significantly confines the effectiveness of a donor or umbilical cord blood search for allogeneic hematopoietic stem cell transplantation (HSCT). This study aims to probe the HLA immunogenetic profile of the population of Crete, a Greek region with specific geographic and historical characteristics, and to investigate potential patterns in HLA distribution following comparison with the Deutsche Knochenmarkspenderdatei (DKMS) donor registry. It also aims to highlight the importance of regional public cord blood banks (PCBBs) in fulfilling HSCT needs, especially in countries with significant genetic diversity. MethodsA cohort of 1835 samples representative of the Cretan population was typed for HLA class I (HLA-A, HLA-B, HLA-C) and class II (HLA-DRB1, HLA-DQB1, HLA-DPB1) loci by high-resolution second field next-generation sequencing. Data were compared with the respective HLA profiles of 12 DKMS populations (n = 20 032). Advanced statistical and bioinformatics methods were employed to assess specific intra- and inter-population genetic indexes associated with the regional and geographic distribution of HLA alleles and haplotypes. ResultsA considerable HLA allelic and haplotypic diversity was identified among the Cretan samples and between the latter and the pooled DKMS cohort. Even though the HLA allele and haplotype frequency distribution was similar to regions of close geographic proximity to Crete, a clinal distribution pattern from the northern to southern regions was identified. Significant differences were also observed between Crete and the Greek population of DKMS. ConclusionsThis study provides an in-depth characterization of the HLA immunogenetic profile in Crete and reveals the importance of demographic history in HLA heterogeneity and donor selection. The novel HLA allele and haplotype frequency comparative data between the Cretan and other European populations signify the importance of regional PCBBs in prioritizing HLA diversity to efficiently promote the HSCT program at the national level and beyond.

Allogeneic hematopoietic stem cell transplantation from unmanipulated haploidentical donor and unrelated cord blood for T-cell lymphoma: a retrospective study from the Société Francophone de Greffe de Moelle et de Therapie Cellulaire.

After chemotherapy, fewer than 30% of patients with T-cell lymphoma (T-NHL) are long-term disease-free survivors. Thus, there is a growing interest in allogeneic stem cell transplantation (alloSCT) and its potential graft-versus-lymphoma effect (GVL) for patient with high-risk or recurrent T-NHL with the aim at providing durable disease control in T-NHL. We conducted this registry study to evaluate the outcome of recipients of alternative donor alloSCT for T-NHL. Patients transplanted with Haploidentical donor (Haplo, n = 41) or Umbilical Cord Blood (UCB, n = 54) were analyzed for overall survival (OS), non-relapse mortality (NRM), relapse, and acute/chronic graft-versus-host disease (aGVHD/cGVHD) incidence. At 2 years, OS and PFS were, respectively, of 59% and 53%, without significant difference between Haplo and UCB. In multivariate analysis, disease status at transplant was an independent risk factor for OS and PFS, and aGVHD III-IV was the main factor for OS and NRM. While no major impact of donor source on survival and mortality was noted, this study suggests that alternative donor transplantation appears feasible and offers benefits to patients with T-cell lymphoma.

Predictive Factors for Outcome of First Allogeneic Transplant for Elderly Patients With Acute Lymphoblastic Leukemia

Introduction/Background: The treatment of acute lymphoblastic leukemia (ALL) in patients older than 70 is extremely challenging with dismal outcome. Allogeneic stem cell transplantation (alloHCT) has seen many advancements in the last decades showing benefits in younger ALL patients, but this treatment modality is decreasingly used with increasing age due to high treatment-related mortality. Patients and Methods: We identified 84 ALL patients 70 to 84 years old allografted In 2002 to 2019 from a matched related (23%), unrelated (58%), haploidentical (17%), or cord blood (2%) donor at EBMT participating centers with a median follow-up of 23 months. Results: The 2-year relapse incidence (RI) and non-relapse mortality were 37% and 28%, respectively, and 2-year leukemia-free survival (LFS), overall survival (OS) and GVHD-free, relapse-free survival (GRFS) were 35%, 39% and 23%, respectively. The strongest predictor of outcome was disease status at transplant whereby patients in first complete remission (CR1) had >50% 2-year OS, reflected in multivariate analysis (MVA) with significant improvement in RI, LFS, and GRFS (HR 0.23, 0.49, and 0.54, respectively). Furthermore, karnofsky score ≥90 reflective of good functional status positively influenced non-relapse mortality in both univariate and MVA (HR 0.37), and interestingly, donor CMV positivity appeared to negatively affect RI, LFS and OS in univariate analysis and RI in MVA (HR 2.87). Conclusion: Our data suggest that alloHCT is an option for elderly ALL patients, particularly those carefully selected and transplanted in CR1 especially if failed or without access to novel non-chemotherapy-based approaches.

Determinants of the intention to donate umbilical cord blood in pregnant women.

Background and ObjectivesUmbilical cord blood (UCB) donation is a behaviour promoted by many countries' health systems. However, UCB donation is not a widespread behaviour among expectant mothers, and little is known about the reasons that may lead to it. The aim of the present study was to analyse the contribution of Theory of Planned Behaviour (TPB) variables among both primiparous and multiparous women in predicting intention to donate UCB.Materials and MethodsThree hundred seventy‐six expectant mothers completed questionnaires that captured sociodemographic data, parity, previous donation, attitudes, subjective norms, perceived behavioural control (PBC) and intention to donate UCB. Multigroup analysis structural equation modelling was conducted using Mplus (version 8.02).ResultsMultigroup path analyses showed that intentions were strongly predicted by subjective norms and moderately predicted by positive attitudes and PBC in both primiparous and multiparous women. TPB constructs explained 71% of the variance in intentions for both groups.ConclusionsFuture interventions to increase intention to donate among primiparous and multiparous women could primarily consider the influence of partner and significant others in determining positive intentions and secondarily target increasing positive attitudes and perceptions of control.

Comparison of long-term outcome for AML patients alive free of disease 2 years after allogeneic hematopoietic cell transplantation with umbilical cord blood versus unrelated donor: a study from the ALWP of the EBMT.

Since cord blood transplantation (CBT) has been associated with high graft-versus-leukemia effects and a low incidence of chronic graft-versus-host disease (GVHD), we hypothesized that long-term outcomes might be better in CBT patients than in those given grafts from unrelated donors (UD). Therefore, we performed a landmark study comparing long-term outcomes in acute myeloid leukemia (AML) patients alive and disease-free 2 years after transplantation who received grafts from either CBT or UD. A total of 364 CBT recipients, 2648 UD 10/10 patients and 681 patients given grafts from UD 9/10 were included. Median follow-up was 6.0 years. Five-year leukemia-free survival (LFS) from transplantation was 86% in CBT patients, 84% in UD 10/10 patients (P = 0.36) and 84% in UD 9/10 patients (P = 0.86). On multivariate analysis, donor type had no impact on LFS. Similarly, no impact of donor type was observed on relapse incidence or non-relapse mortality. Factors associated with poorer LFS on multivariate analysis included higher age at transplantation (P < 0.001), male gender (P < 0.001), second complete remission (CR2) versus CR1 (P = 0.05), secondary AML (P = 0.01), antecedent of chronic GVHD (P < 0.001) and poor-risk cytogenetics (P = 0.01). In conclusion, our study shows that long-term outcome for AML patients in CR two years after transplantation is not impacted by donor type.

Abstract 1813: The genetic makeup of patient-derived xenografts shapes the immune landscape of humanized mice tumors

Abstract The complex interplay between the immune system and cancer cells is challenging to model in preclinical species. Many commonly mutated genes that influence tumorigenesis actively participate in the activation, recruitment or suppression of the immune system. A growing body of clinical findings indicates that defined oncogenic driver mutations correlate with immune contexture and associated immunotherapy responses. The goal of this study was to generate a hematopoietic stem cells (HSCs) transplanted humanized mice model using patient-derived xenografts with defined mutations to understand whether genetic alterations in the cancer cells can influence the tumor's immune landscape. Loss of function in the tumor suppressor gene STK11/LKB1 are observed in 5-30% of NSCLC. Patients with STK11 mutations do not typically respond to immune checkpoint blockade, and analysis of patient tumor biopsies indicates that these tumors are poorly infiltrated by immune cells such as T cells and dendritic cells, but with higher density of suppressive myeloid cells and associated cytokines. Therefore, there is an interest to understand ways to improve IO responses in these patients. To determine whether we could recapitulate this biology in a preclinical model, we implanted three STK11mut and one wild type PDX on humanized mice generated from six cord blood donors, and compared the immune infiltration in these tumors. Our results demonstrate efficient engraftment of human immune cells in the peripheral blood (53.1%), spleen (64.2%), and bone marrow (59.3%) of humanized mice (n=29, animals). Along with T and B cells, myeloid immune populations such as monocytes, macrophages and dendritic cells, which are absent in the previous generation of humanized mice, were present in the peripheral blood (monocytes 4.7%, dendritic cells 7.2% ) and bone marrow (macrophage 27.8%, neutrophils 21.6% and 10.2% dendritic cells ) of humanized mice. Tumor human immune subpopulation cells were significantly different (One-way Anova analysis) between the STK11mut (n=3) vs. wild type (n=1) humanized PDXs models (n=7 animals/PDX model). Three STK11mut tumors had low percentage of human CD45+ leukocytes infiltration (STK11mut; 0.9, 1.1 and 2.3% vs. wt; 6.6%) We also found a significantly reduced percentage of CD8+ cytotoxic T cells (STK11mut; 5.6, 3.2, 3.1% vs. wt; 9.6%) and dendritic cells subsets (STK11mut; 3.6, 2.2, 3.1% vs. wt; 5.6%) in the STK11mut PDXs implanted on humanized mice. We have shown efficient engraftment of a multilineage human immune system in immunodeficient mice and a selective infiltration of human immune cells subsets in PDXs representing a key genetic segment of NSCLC. Our novel humanized PDX model can recapitulate human tumor immune reconstitution, providing a valuable opportunity to evaluate the benefit of immunomodulatory therapies and personalize immune intervention strategies. Citation Format: Maneesh Singh, Laura Bradshaw, Laura B. Prickett, Griffin Matthew, Maryann San Martin, Noel Monks, Lisa Drew, Simon T. Barry, Corinne Reimer, Theresa Proia. The genetic makeup of patient-derived xenografts shapes the immune landscape of humanized mice tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1813.

Hiv Specific T Cells Generated from HIV Naive Adult and Cord Blood Donors Target a Range of Novel Viral Epitopes: Implications for a Cure Strategy after Allogeneic HSCT and CBT

Adoptive T cell therapy has been successful in boosting viral-specific immunity post-HSCT, preventing viral rebound of CMV and EBV. However, the therapeutic use of T cells to boost HIV-specific T cell immunity in HIV+ patients has been met with limited success. Despite multiple attempts to eradicate HIV with allogeneic HSCT, there is only one case of functional HIV cure post-HSCT, the Berlin Patient. Hence, we hypothesized that broadly HIV-specific CD8 and CD4 T-cells (HXTCs) could be expanded from patients on ARVs, as well as HIV negative adult (dHXTCs) and cord blood donors (cbHXTCs), employing a non-HLA restricted approach for the treatment of HIV+ individuals after autologous or allogeneic HSCT.We have expanded autologous HXTCs from HIV+ subjects under NCT02208167. To extend this approach to the allogeneic HSCT setting, we generated dHXTCs from HIV naive adults (n=8) and cbHXTCs from cord blood donors (n=8). IFN-gamma ELISPOT showed dHXTCs were specific against Gag (mean=331.25 SFC/105cells) and Nef (mean=242.63) versus irrelevant antigen (mean=13 SFC) (n=8). Similarly, we are able to produce cbHXTCs (n=8) that showed specificity to Gag (mean=103.252 SFC/105cells), Nef (mean=109.43), or Pol (mean=130.56), (p<0.0001 compared to controls) in IFN-gamma ELISPOT. dHXTC products displayed polyfunctionality, producing proinflammatory TNFα, IL2, IL6, IL8, and perforin responses (p<0.05) to HIV stimulation. Importantly, dHXTCs (p=0.0004) and cbHXTCs (p=0.0003) were able to suppress HIV replication compared with nonspecific CD8+ T cells when co-cultured with autologous CD4+ T cells infected with HIV SF162 at an Effector-to-Target ratio of 20 to 1. Exhaustion marker analysis of cbHXTCs products revealed minimal expression of PD1, TIM3, LAG3, KLRG1, and CD57 (n=3). Epitope mapping revealed that dHXTC and cbHXTC products contained T cells recognizing unique epitopes not typically identified in HIV positive individuals, which may be critical in overcoming viral immune escape post-HSCT.In summary, HIV-specific T cells can be expanded from HIV positive and HIV negative donors for clinical use. Focusing on donors with HLA types that are associated with well characterized HIV responses (HLA A02) or associated with delayed progression to AIDS (HLA B27, B51, B57) may allow us to identify HLA restricted epitopes critical for the successful development of a potent HIV-specific T cell therapeutic. Hence, the administration of HXTCs derived from virus naive donors could offer a unique curative strategy post-allogeneic HSCT and cord blood transplant. [Display omitted] DisclosuresBollard:Torque: Membership on an entity's Board of Directors or advisory committees; Cellectis: Membership on an entity's Board of Directors or advisory committees; Neximmune: Consultancy, Membership on an entity's Board of Directors or advisory committees.

NK Cell Diversity Influences Outcomes after Cord Blood Transplantation

Natural killer (NK) cells are the first subset of lymphocytes to reconstitute, and likely play an important role in the graft-versus-leukemia response early after allogeneic hematopoietic stem cell transplantation. NK cells are highly diverse, and express an array of activating and inhibiting receptors, which delicately regulate their activation status.To provide a framework to better understand NK cell development and maturation after cord blood transplantation (CBT) and its implication on clinical outcomes, we designed a mass cytometry (also known as cytometry by time of flight) panel of 40 monoclonal antibodies recognizing lineage markers, NK cell receptors and transcription factors to interrogate the NK cell repertoire in prospectively collected peripheral blood (PB) samples from 60 CBT recipients. The resultant high-dimensional single cell data were analyzed by t-Distributed Stochastic Neighbor Embedding (t-SNE) dimension reduction algorithm to generate expression profile graphs.With this mass cytometry platform, we first interrogated and compared the NK cell repertoire in CB (n=10) and adult peripheral blood (PB) (n=20) and used inverse Simpson index to measure the diversity of the NK cell populations. NK cells from CB donors had a significantly lower diversity (median 537, range 311-891) compared to NK cells from healthy adult PB donors (median 2858, range 1228-5630; p<0.0001). Since CMV infection has been shown to drive NK cell maturation, we next asked if CMV infection also alters NK cell diversity by comparing the diversity of the NK cell repertoire in CB (n=10), and in PB from adult healthy donors who were either CMV-seropositive (n=10), or CMV-seronegative (n=10). The diversity of the NK cell repertoire was significantly greater in CMV seropositive healthy individuals (median 4217, range 2672-5630) compared to CMV-seronegative healthy adults (median 2247 , range 2026-2468; P=0.0002) and cord blood donors (median 537, range 311-891; P<0.0001), pointing to an important role for CMV infection in driving NK diversity.Harnessing mass cytometry, we undertook an in-depth examination of the NK repertoire in prospectively collected PB samples from 60 CBT recipients. We first sought to determine if CMV infection early after CBT can drive NK cell maturation and accelerate the acquisition of a diverse repertoire. The median time to CMV reactivation for the cohort was 71 days. CMV reactivation in the first 100 days after CBT (n=25) was associated with significantly greater NK diversity (median 844, range 198-1196) when compared to patients without CMV reactivation (median 405, range 110-889; p=0.0003). Notably, CMV augmented NK diversity mainly in the KIR+ population (median 743, range 207-1500) compared to the KIR- population (median 361, range 92-1038; p=0.007); while in the absence of CMV reactivation, NK cell diversity in the KIR+ and KIR- populations remained similar (median 305, range 102-702 vs. median 332, range 54-830; p=0.98). These data indicate that CMV infection augments NK diversity after CBT, and that this effect is most pronounced within the KIR+ population.We next determined if NK cell diversity can influence outcomes by comparing the diversity of the NK cell repertoire in PB samples collected in the first 100 days after CBT from 15 patients who went on to relapse compared to 45 patients who remained in remission for 2 years. NK cell diversity was significantly higher (median 839, range 416-1069) in patients who remained in remission compared to those who progressed and relapsed (median 446, range 328-925; p=0.03). Moreover, the greatest difference in diversity in the two groups was noted within the KIR+ population (median 788, range 101-1500 for patients in remission vs median 320, range 177-857 for patients who relapsed; p=0.002).In summary, we have used multiparametric mass cytometry to examine expression of 40 NK markers, and to gain insights into the diversity of the NK cell repertoire after CBT. We have shown that CB NK cells have a limited NK cell diversity, which increases in breadth and subsets after transplant. Moreover, we observed that CMV infection reconfigures the NK cell compartment and drives the diversity of the NK cell repertoire, especially within the KIR+ population. These data may provide the basis to rationally design therapeutic strategies that can modulate NK diversity in the settings of infection and transplant. DisclosuresNo relevant conflicts of interest to declare.

Pre-Transplant Transferrin Saturation Levels As a Predictive Marker for Invasive Fungal Disease Following Allogeneic Hematopoietic Stem Cell Transplantation

▪IntroductionInvasive fungal disease (IFD) following allogeneic hematopoietic stem cell transplantation (allo-HCT) is a well-known, potentially fatal complication. Previous multicenter, prospective observational studies (Girmenia et al., 2014; Sun et al., 2015) have showed that the incidence of IFD after allo-HCT was approximately 9.0%, and risk factors were disease status, development of IFD prior to allo-HCT, alternative donor source (cord blood donor and unrelated donor), diabetes mellitus, prophylaxis of IFD, and acute or chronic graft-versus-host disease (GVHD).Iron has a pivotal role in various types of fungal growth and iron overload impairs the host immune system, leading to IFD. Moreover, some retrospective studies have reported that elevated pre-transplant serum ferritin levels, as a marker of iron overload, might be associated with the development of IFD (Dadwal et al., 2015). Although use of ferritin and transferrin saturation (TSAT) to assess iron status is extremely common, whether pre-transplant TSAT levels might be related to the development of IFD after allo-HCT has not been fully examined.We therefore investigated risk factors of IFD, including iron overload markers such as ferritin and TSAT.Patients and MethodsWe retrospectively analyzed data from consecutive patients undergoing allo-HCT between 1 April 2007 and 31 December 2014. We excluded three patients with active IFD at initiation of the conditioning regimen and two patients undergoing double-cord blood transplantation. Proven or probable IFD cases were defined as IFD. According to our institution guidelines, we administered IFD prophylaxis in all patients. We used Cox proportional hazards models with time-dependent covariates to investigate risk factors for IFD.ResultsA total of 285 patients were eligible. Twenty-one patients developed IFD within 1 year after allo-HCT. Median time to onset was 77 days (range, 8-363 days). Pathogens included Aspergillus (n=12), Candida (n=2), and others (n=7).Notably, none of our participants from HLA-matched or one-antigen mismatched sibling donors developed IFD. The significant univariate risk factors were as follows: disease status (malignancies in complete remission, non-malignancies, and chronic myelogenous leukemia in chronic phase vs. others), donor type (cord blood vs. haploidentical peripheral blood with post-transplant cyclophosphamide (PT-CY) vs. others), GVHD prophylaxis (calcineurin inhibitor (CNI) plus methotrexate (MTX) vs. CNI plus mycophenolate mofetil (MMF) vs. PT-CY vs. others), use of antithymocyte globulin (ATG), TSAT, and hematologic relapse after transplant or refractory at transplant. However, development of IFD prior to allo-HCT, diabetes mellitus, and acute or chronic GVHD were not related to the development of IFD.In the multivariate model considering pre-transplant factors, although use of ATG (hazard ratio (HR) 2.68, 95% confidence interval (CI): 1.07-6.02, P=0.04) was significant, disease status (HR 2.04, 95% CI: 0.78-5.32, P=0.15) and TSAT (HR 1.02, 95% CI: 1.00-1.03, P=0.07) were marginally but significantly associated with development of IFD. Regarding post-transplant factors, in model 2, hematologic relapse after transplant or refractory at transplant (HR 9.63, 95% CI: 3.86-24.02, P<0.01), TSAT (HR 1.02, 95% CI: 1.00-1.04, P=0.03), CNI plus MMF (vs. CNI plus MTX) among GVHD prophylaxis (HR 3.48, 95% CI: 1.07-11.30, P=0.04) were significant. In model 3, hematologic relapse after transplant or refractory at transplant (HR 10.42, 95% CI: 4.21-25.79, P<0.01), TSAT (HR 1.02, 95% CI: 1.00-1.03, P=0.05), and use of ATG (HR 2.72, 95% CI: 1.08-6.82, P=0.03) were significant. Remarkably, 33 of 55 patients who underwent ATG received PT-CY (n=55) to prevent GVHD.ConclusionOur results suggest that pre-transplant TSAT value might be useful for predicting development of IFD. Further investigation might be warranted to validate the generalizability of this marker. DisclosuresHino:Novartis: Research Funding.