Unrelated Donor Research Articles

Permissible HLA mismatches in 9/10 unrelated donor pediatric stem cell transplants using HLA-EMMA: an EBMT Inborn Errors Working Party study

AbstractAllogeneic hematopoietic stem cell transplantation (HSCT) with mismatched unrelated donors (MMUD) is associated with inferior outcome compared with matched unrelated donors (MUDs). We aimed to identify permissible mismatches using HLA epitope mismatch algorithm, which determines permissibility by analyzing amino acid sequences, in a single-center cohort of 70 pediatric 9/10 MMUD HSCTs and 157 10/10 MUDs for comparison. Amino acid matching was evaluated for the whole HLA protein, the α-helices, and the β-sheets, in both host vs graft (HvG) and graft vs host (GvH) direction. Superior event-free survival (EFS) was found in 13 patients permissibly mismatched in the HvG direction (totalHvG, 92% vs 58% at 1 year; P = .009) and in 21 patients matched on the α-helices (αHvG, 90% vs 53%; P = .002). These rates were similar to EFS rates in patients with 10/10 MUDs (90% vs 80%; P = .60). EFS was not related to β-sheet amino acid matching, nor to matching in the GvH direction. Overall survival (OS) rates trended similarly to those of EFS for amino acid mismatches (totalHvG, 92% vs 74%; P = .075; αHvG, 90% vs 71%; P = .072). These findings were reproduced in an EBMT Registry inborn errors cohort of 271 pediatric 9/10 MMUD HSCTs and 929 10/10 MUD HSCTs, showing a significant effect of αHvG matching on both OS and EFS and similar OS and EFS between αHvG matched MMUDs and 10/10 MUDs. In summary, HvG amino acid matching on the α-helices identifies 9/10 MMUDs with permissible mismatches, which are correlated with favorable transplant outcomes similar to those of matched donors.

Outcomes of hematopoietic stem cell transplantation in 813 pediatric patients with Fanconi anemia

AbstractAllogeneic hematopoietic stem cell transplantation (HSCT) is the only established curative option for Fanconi anemia (FA)–associated bone marrow failure (BMF)/aplastic anemia (AA) and acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS). We performed a retrospective multicenter study on 813 children with FA undergoing first HSCT between 2010 and 2018. Median duration of follow-up was 3.7 years. Median age at transplant was 8.8 years (IQR, 6.5-18.1). Five-year overall survival (OS), event-free survival (EFS), and graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS) were 83% (95% confidence interval [CI], 80-86), 78% (95% CI, 75-81), and 70% (95% CI, 67-74), respectively. OS was comparable between matched family donor (MFD; n = 441, 88%) and matched unrelated donor (MUD; n = 162, 86%) and was superior to that of mismatched family donor (MMFD) or mismatched unrelated donor (MMUD; n = 144, 72%) and haploidentical donor (HID; n = 66, 70%; P < .001). In multivariable analysis, a transplant indication of AML/MDS (vs AA/BMF), use of MMFD/MMUD and HID (vs MFD), and fludarabine-cyclophosphamide (FluCy) plus other conditioning (vs FluCy) independently predicted inferior OS, whereas alemtuzumab vs antithymocyte globulin was associated with better OS. Age ≥10 years was associated with worse EFS and GRFS. Cumulative incidences (CINs) of primary and secondary graft failure were 2% and 3% respectively. CINs of grade 3 to 4 acute GVHD and chronic GVHD were 12% and 8% respectively. The 5-year CIN of secondary malignancy was 2%. These data suggest that HSCT should be offered to patients with FA with AA/BMF at a younger age in the presence of a well-matched donor.

Outcomes with low dose anti-thymocyte globulin based graft versus host disease prophylaxis after mismatched unrelated donor allogeneic hematopoietic cell transplantation.

Anti-thymocyte globulin (ATG) based graft versus host disease (GVHD) prophylaxis is widely used for mismatched unrelated donor allogeneic hematopoietic cell transplantation (HCT) although optimal dose remains unclear. Although recent literature suggested improved outcomes with PTCy-based regimens when compared to ATG-based regimens these studies used doses of ATG ≥5 mg/kg. Thus, we analyzed outcomes of HLA 9/10 MMUD allogeneic HCTs using lower-dose ATG-based regimens at our center. We retrospectively analyzed outcomes of HLA 9/10 MMUD allogeneic HCTs using lower dose ATG-based regimens for all adults undergoing allogeneic HCT at The Ottawa Hospital from 2015 to 2022. Data regarding demographics, conditioning regimen, dose of ATG, rates of GVHD, duration of remission, and survival, were collected and analyzed. Seventy-seven (n = 77) patients (males 62.3%; median age 50 years) underwent allogeneic HCT from MMUD. Majority(81%; n = 63) received 2.5 mg/kg of rabbit ATG and remaining 18.2% (n = 14) received 4.5 mg/kg. Grade II-IV acute GVHD occurred in 24.7% (n = 19) while any chronic GVHD occurred in 32.5% (n = 25) patients. After a median follow-up of 21 months, relapse occurred in 28.6% of patients. Two-year OS, GRFS, CIR, and NRM were 60.6%, 45.3%, 16.9%, and 18.2% respectively. Dose of ATG (2.5 mg/kg vs. 4.5 mg/kg) was not associated with outcomes in either univariate or multivariate analyses. When compared to published studies using ATG doses ≥5 mg/kg, GVHD prophylaxis using lower dose ATG may potentially lead to improved outcomes in patients undergoing MMUD allogeneic HCT. Further studies are needed to directly compare lower dose ATG to PTCy-based regimens to determine ideal GVHD prophylaxis for these patients.

Measurable residual disease testing by next generation sequencing is more accurate compared with multiparameter flow cytometry in adults with B-cell acute lymphoblastic leukemia

Results of measurable residual disease (MRD)-testing by next-generation sequencing (NGS) correlate with relapse risk in adults with B-cell acute lymphoblastic leukemia (ALL) receiving chemotherapy or an allotransplant from a human leukocyte antigen (HLA)-identical relative or HLA-matched unrelated donor. We studied cumulative incidence of relapse (CIR) and survival prediction accuracy using a NGS-based MRD-assay targeting immunoglobulin genes after 2 courses of consolidation chemotherapy cycles in 93 adults with B-cell ALL most receiving HLA-haplotype-matched related transplants. Prediction accuracy was compared with MRD-testing using multi-parameter flow cytometry (MPFC). NGS-based MRD-testing detected residual leukemia in 28 of 65 subjects with a negative MPFC-based MRD-test. In Cox regression multi-variable analyses subjects with a positive NGS-based MRD-test had a higher 3-year CIR (Hazard Ratio [HR] = 3.37; 95 % Confidence Interval [CI], 1.34–8.5; P = 0.01) and worse survival (HR = 4.87 [1.53–15.53]; P = 0.007). Some data suggest a lower CIR and better survival in NGS-MRD-test-positive transplant recipients but allocation to transplant was not random. Our data indicate MRD-testing by NGS is more accurate compared with testing by MPFC in adults with B-cell ALL in predicting CIR and survival. (Registered in the Beijing Municipal Health Bureau Registration N 2007-1007 and in the Chinese Clinical Trial Registry [ChiCTR–OCH–10000940 and ChiCTROPC-14005546]).

Tacrolimus versus cyclosporine a combined with post-transplantation cyclophosphamide for AML In first complete remission: a study from the acute leukemia working party (EBMT)

Choice of calcineurin inhibitor may impact the outcome of patients undergoing T-cell replete hematopoietic cell transplantation (HCT) with post-transplant cyclophosphamide (PT-Cy) and mycophenolate mofetil (MMF) for prophylaxis of graft-versus-host disease (GVHD). We retrospectively analyzed 2427 patients with acute myeloid leukemia (AML) in first remission transplanted from a haploidentical (n = 1844) or unrelated donor (UD, n = 583) using cyclosporine A (CSA, 63%) or tacrolimus (TAC, 37%) and PT-Cy/MMF. In univariate analysis, CSA and TAC groups did not differ in 2-year leukemia-free or overall survival, cumulative incidence (CI) of relapse or non-relapse mortality. CI of severe grade III-IV acute GVHD was lower with TAC (6.6% vs. 9.1%, p = 0.02), without difference in grade II-IV acute GVHD or grade III-IV acute GVHD/severe chronic GVHD, relapse-free survival (GRFS). In multivariate analysis, TAC was associated with a lower risk of severe grade III-IV acute GVHD solely with haploidentical donors (HR 0.64 [95% CI, 0.42–0.98], p = 0.04), but not UD (HR 0.49 [95% CI, 0.2–1.21], p = 0.12). There was no significant difference for chronic GVHD. In conclusion, PT-Cy/MMF-based GVHD prophylaxis resulted in favorable OS and GRFS, irrespective of the CNI added. In haploidentical HCT, TAC seemed to prevent severe acute GVHD more effectively than CSA without impact on other outcome parameters.

Haploidentical Versus Mismatched Unrelated Donor Hematopoietic Cell Transplantation: HLA Factors and Donor Age Considerations

HLA-mismatched unrelated donors and haploidentical related donors are suitable stem cell sources for hematopoietic cell transplantation (HCT) when patients lack HLA-matched donors. Clinical outcome after mismatched HCT is influenced by HLA factors including the similarity of peptide-binding motifs (PBMs) between the patient and unrelated donor, and of the HLA-B leader in unrelated and haploidentical donors. Whether these factors can aid in the selection between mismatched unrelated and haploidentical donors is not known. To address this question, we investigated outcomes between the two donor types defined by matching for the PBM and leader peptide. We compared PBM-matched (n = 614) and mismatched (n = 958) MMUDs with calcineurin-inhibitor-based prophylaxis to four haploidentical groups that received post-transplant cyclophosphamide (PTCy)-based prophylaxis. The haploidentical groups were B-leader matched/DRB1-mismatched (n = 722), B-leader matched/DRB1-matched (n = 154), B-leader mismatched/DRB1-mismatched (n = 493), and B-leader mismatched/DRB1-matched (n = 63). Multivariate analysis showed that the B-leader matched/DRB1-mismatched haploidentical group had the best overall survival (OS) compared to the PBM-matched MMUD, while other haploidentical groups had comparable OS. The PBM-mismatched MMUD showed the poorest outcomes, similar to the B-leader mismatched/DRB1-matched haploidentical group. Among non-HLA factors, donor age was the most significant predictor of OS. These results suggest that a B-leader matched/DRB1 mismatched haploidentical donor might be the preferred choice among donors of similar age. If such a donor is not available, the youngest donor from either PBM-matched unrelated or other haploidentical groups could be a beneficial choice. These findings need validation with both donor groups receiving PTCy-based graft-versus-host disease prophylaxis.

Donor vs. Donor or Recipient vs. Recipient? A Singular Case of Post Hematopoietic Stem Cell Transplantation Autoimmune Hemolytic Anemia in a Pediatric Patient

Hematopoietic Stem Cell Transplantation (HSCT) is a curative treatment for certain blood disorders, but can lead to complications such as Autoimmune Cytopenia (AIC), particularly Autoimmune Hemolytic Anemia (AIHA). AIHA after HSCT often involves donor-derived antibodies attacking donor red blood cells, but this case report describes a unique case in a 7-year-old male with beta-thalassemia major. Following HSCT, he developed AIHA nine months after transplantation from an unrelated donor. Despite initially successful engraftment, chimerism analysis revealed a decline in donor cells coincident with the onset of AIHA. The patient had severe hemolysis, a positive Direct Coombs Test (DAT) for IgG and C3d, and several antibodies including anti-e, anti- C, and anti-D. Treatment with cyclosporine and prednisone initially stabilized his condition, but discontinuation resulted in relapse, worsening chimerism, and increased antibody titers. Analysis confirmed the predominance of recipient immune cells, suggesting that AIHA was driven by the recipient's immune response against his own red blood cells. This case emphasizes the complexity of immune reconstitution after HSCT and highlights a recipient-versus-recipient mechanism in post-transplant AIHA.

Childhood myelodysplastic syndromes: Is cytoreductive therapy useful before allogeneic hematopoietic stem cell transplantation?

For most patients with childhood myelodysplastic syndrome (cMDS), allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only curative option. In the case of increased blasts (cMDS-IB), the benefit of pretransplant cytoreductive therapy remains controversial. In this multicenter retrospective study, the outcomes of all French children who underwent allo-HSCT for cMDS reported in the SFGM-TC registrybetween 2000 and 2020 were analyzed (n = 84). The median age at transplantation was 10.2 years. HSCT was performed from matched sibling donors (MSD) in 29% of the cases, matched unrelated donors (MUD) in 44%, haploidentical in 6%, and cord blood in 21%. Myeloablative conditioning was used in 91% of cases. Forty-eight percent of patients presented with cMDS-IB at diagnosis (median BM blasts: 8%). Among them, 50% received pretransplant cytoreductive therapy. Five-year overall survival (OS), cumulative incidence of nonrelapse mortality (NRM), and relapse were 67%, 26%, and 12%, respectively. Six-month cumulative incidence of grade II-IV acute graft-versus-host disease was 46%. Considering the whole cohort, age under 12, busulfan/cyclophosphamide/melphalan conditioning or MUD were associated with poorer 5-year OS. In the cMDS-IB subgroup, pretransplant cytoreductive therapy was associated with a better OS in univariate analysis. This seems to be mainly due to a decreased NRMsince no impact on the incidence of relapse was observed. Overall, those data may argue in favor of cytoreduction for cMDS-IB. They need to be confirmed on a larger scale and prospectively.

Age, GVHD prophylaxis, and timing matter in thrombotic microangiopathy after haematopoietic cell transplantation-Asecondary CIBMTR analysis.

Most reports of risk factors (RF) for developing transplant-associated thrombotic microangiopathy (TA-TMA) and death are derived from paediatric and young adult cohorts, with minimal data on differences in RF and outcomes by age. In this secondary CIBMTR analysis, we used a previously prepared dataset that included all first allogenic haematopoietic cell transplantation (HCT) recipients with malignant or non-malignant diseases between 2008 and 2016. The incidence of TA-TMA 6 months post HCT was similar in children and adults 2.1% and 2.0% respectively. Grade 2-4 acute graft-versus-host disease (aGVHD) was a significant adjusted RF for developing TA-TMA in both children and adults. In adults, additional adjusted RFs for TA-TMA included female sex and black race, and in children an unrelated donor. Compared to a calcineurin inhibitor and sirolimus, other forms of GVHD prophylaxis had an adjusted decreased risk of developing TA-TMA in adults. Adjusted RF for death in those with TA-TMA (n = 652) included age ≥18 years old, early onset of TA-TMA diagnosis (<100 days post HCT), grade 3-4 aGVHD and a performance score of <90 prior to HCT. In this cohort, the incidence of TA-TMA was similar in children and adults, and TA-TMA timing was a newly identified RF for death.

Optimisation of global stem cell donor recruitment based on analysis of unsuccessful donor searches.

Despite over 41 million registered potential volunteer stem cell donors worldwide, many patients in need of a transplant do not find an HLA-matched unrelated donor or cord blood units, with the respective odds differing significantly between various populations. In this study, we analysed data of 2205 unsuccessful real-life donor searches sent to the DKMS Registry to identify populations in which further donor recruitment would be associated with particularly large patient benefits. For that purpose, we estimated haplotype frequencies of 67 donor populations at various sample sizes and entered them into two different mathematical models. These models assessed patient benefits from population-specific donor recruitment, operationalised by the number of originally unsuccessful searches that may become successful due to new donors. Consistently, across the different mathematical models and sample sizes, we obtained several countries from East and Southeast Asia (Thailand, Vietnam, China, and the Philippines) and the population of Asians in the USA as countries/populations where donor recruitment activities would be particularly beneficial for patients. We also identified various countries in Southeast and Central Europe as possible target regions for donor recruitment with above-average patient benefits. The results presented are registry-specific in the sense that they were obtained by optimising unsuccessful searches that had been sent to the DKMS Registry. Therefore, it would be desirable to apply the presented methods to a global data set that includes all unsuccessful stem cell donor searches worldwide and uses population-specific haplotype frequencies based on all donors available in the WMDA Search & Match Service.

Donor types and outcomes of transplantation in myelofibrosis: a CIBMTR study

AbstractWe evaluate the impact of donor types on outcomes of hematopoietic cell transplantation (HCT) in myelofibrosis, using the Center for International Blood and Marrow Transplant Research registry data for HCTs done between 2013 and 2019. In all 1597 patients, the use of haploidentical donors increased from 3% in 2013 to 19% in 2019. In study-eligible 1032 patients who received peripheral blood grafts for chronic-phase myelofibrosis, 38% of recipients of haploidentical HCT were non-White/Caucasian. Matched sibling donor (MSD)–HCTs were associated with superior overall survival (OS) in the first 3 months (haploidentical hazard ratio [HR], 5.80 [95% confidence interval (CI), 2.52-13.35]; matched unrelated (MUD) HR, 4.50 [95% CI, 2.24-9.03]; mismatched unrelated HR, 5.13 [95% CI, 1.44-18.31]; P < .001). This difference in OS aligns with lower graft failure with MSD (haploidentical HR, 6.11 [95% CI, 2.98-12.54]; matched unrelated HR, 2.33 [95% CI, 1.20-4.51]; mismatched unrelated HR, 1.82 [95% CI, 0.58-5.72]). There was no significant difference in OS among haploidentical, MUD, and mismatched unrelated donor HCTs in the first 3 months. Donor type was not associated with differences in OS beyond 3 months after HCT, relapse, disease-free survival, or OS among patients who underwent HCT within 24 months of diagnosis. Patients who experienced graft failure had more advanced disease and commonly used nonmyeloablative conditioning. Although MSD-HCTs were superior, there is no significant difference in HCT outcomes from haploidentical and MUDs. These results establish haploidentical HCT with posttransplantation cyclophosphamide as a viable option in myelofibrosis, especially for ethnic minorities underrepresented in the donor registries.

Letermovir as secondary prophylaxis of cytomegalovirus infection after allogeneic hematopoietic cell transplantation: A single center experience.

Letermovir, a novel anti-cytomegalovirus (CMV) agent acts by inhibiting the viral terminase complex and is approved for primary prophylaxis in CMV seropositive patients post allogeneic hematopoietic cell transplantation (HCT). The favorable efficacy and safety profile make it an attractive option for use as secondary prophylaxis in patients at high-risk for CMV reactivation. In this study, we report the efficacy and safety of letermovir secondary prophylaxis after at least one treated episode of CMV reactivation in a cohort of 39 high-risk patients. Thirty two (82%) patients received anti-thymocyte globulin (ATG), 27 (69%) received a combination of ATG and post-transplant cyclophosphamide for graft-versus-host disease (GVHD) prophylaxis. Twenty one patients (54%) received CMV seronegative grafts. In addition, 18 (46%) patients had HLA mismatched unrelated or haploidentical donors while 18 (46%) had active GVHD requiring immunosuppression at the time of commencing secondary prophylaxis. Letermovir was initiated at a median of 47 days (range, 41-56) after HCT and was administered for a median duration of 77 days (range, 46-90). A single breakthrough CMV reactivation was noted in this high-risk cohort. Four additional episodes of CMV reactivation occurred at a median of 28 days (range, 23-59 days) after discontinuation of secondary prophylaxis. The drug was well tolerated and 77% of the cohort completed the planned duration of secondary prophylaxis. None of the patients discontinued treatment due to treatment-related adverse effects. In conclusion, letermovir is effective and well tolerated and may be considered for secondary prophylaxis in patients at high risk for CMV reactivation. Prospective studies are required to validate these findings.

Successful Immune Reconstitution in a Patient with a TYK2 Deficiency after Allogeneic Stem Cell Transplantation from Unrelated Donors.

A boy with primary immunodeficiency, caused by a tyrosine kinase 2 (TYK2) mutation, presented with immune defects and a lifelong history of severe infections. Our aim was to determine whether allogeneic hematopoietic stem cell transplantation (HSCT) could restore the patient's immune defenses and reduce susceptibility to infection. In the absence of a suitable HLA-matched blood relative to act as a donor, the patient received an allogeneic HSCT from unrelated donors. The patient's clinical data were analyzed in the Children's Hospital of Chongqing Medical University (Chongqing, China) before transplantation and during the 4-year follow-up period using a combination of western blotting (e.g., TYK2 and STAT levels), qRT-PCR (e.g., T cell receptor rearrangement excision circles, kappa deletion element recombination circles, and TYK2 transcript levels), and flow cytometry (e.g., lymphocyte subpopulations and CD107α secretion). We found that HSCT significantly reduced the incidence of severe infections, restored normal TKY2 levels, and reversed defects such as impaired JAK/STAT signaling in response to interferon-α or interleukin-10 treatment. Although the patient did not develop acute graft-versus-host disease (GVHD) after transplantation, he did experience chronic GVHD symptoms in a number of organs, which were effectively managed. Our findings suggest that HSCT is a feasible strategy for reconstituting the immune system in TYK2-deficient patients; however, the factors associated with GVHD and autoimmune thyroiditis development in TYK2-deficient patients undergoing HSCT warrant further investigation.

NFS-01. EXTREMELY RARE CASE OF CHILDREN WITH NIJMEGEN BREAKAGE SYNDROME AND MEDULLOBLASTOMA – A THERAPEUTIC CHALLENGE

Abstract BACKGROUND Nijmegen Breakage Syndrome (NBS) is an autosomal recessive inherited disorder characterized by DNA repair abnormalities. It manifests with heightened sensitivity to radiotherapy (RT) and predisposes individuals to neoplastic diseases. Antineoplastic treatment in NBS patients is particularly challenging due to concurrent immune disorders, intense toxicities, and contraindications for RT. Hematologic disorders, especially lymphomas, are among the most prevalent malignancies in NBS patients. Solid tumors in NBS are extremely rare, with only two pediatric cases documented in the literature, both succumbing due to severe complications of treatment. METHODS A review and analysis of the medical documentation of a child with NBS and MB treated at the Department of Pediatrics, Hematology, and Oncology, Gdansk, Poland, were conducted. RESULTS A genetically confirmed NBS girl displaying typical phenotypic features presents symptoms at the age of 2 years, such as headaches, reluctance to walk, and drowsiness. Imaging confirmed a tumor in the left cerebellar hemisphere, measuring 40x33x30mm, displaying radiological features consistent with Medulloblastoma (MB). The patient underwent gross total resection of the tumor. The pathology revealed a desmoplastic type of MB with SHH activation, TP53 wild type, and ongoing molecular analysis. Postoperative imaging confirmed clinical remission, and cerebrospinal fluid examination was negative. Considering the substantial toxicities of chemotherapy in NBS patients and the contraindications for RT, the patient received chemotherapy with reduced cytostatic doses. Treatment was complicated by profound and prolonged myelosuppression and infections. Currently, after completing six cycles of chemotherapy, the patient is still in remission. To maintain remission and address NBS, the patient will receive allogeneic bone marrow transplantation from a 9/10 HLA-matched unrelated donor. CONCLUSIONS Managing patients with NBS, complicated by neoplastic diseases, is exceptionally demanding and necessitates an individualized multidisciplinary approach. Modern diagnostic and therapeutic methods enhance the prospects of reducing the toxicity of oncologic treatment, improving quality of life, and extending overall survival.

Does a subset of mature T-cell leukemias with features akin to T-cell prolymphocytic leukemia but lacking rearrangement of the TCL1 represent peripheral T-cell lymphoma, NOS in a leukemic phase?

In the current WHO classification, a T-cell prolymphocytic leukemia (T-PLL) diagnosis requires lymphocytosis of >5 × 109/L, evidence of monoclonality, and TCL1A or MTCP1 rearrangement. However, the 2019 consensus document suggested that in the absence of rearrangement of TCL1-family, the presence of abnormalities involving chromosome 11 (11q22.3; ATM), chromosome 8 (idic(8)(p11), t(8;8), trisomy 8q), 5, 12, 13, 22, or a complex karyotype, as well as involvement specific sites (e.g., splenomegaly, effusions) would suffice for a diagnosis of T-PLL. We present a patient diagnosed with T-PLL with MTCP1 rearrangement who was successfully treated with alemtuzumab followed by consolidative allogeneic unrelated donor stem cell transplantation. Eight years later, the patient presented with inguinal lymphadenopathy with features more akin to peripheral T-cell lymphoma, NOS (PTCL, NOS) of the GATA3 subtype, and there was no evidence of peripheral blood involvement. However, the lymphoma cells were clonally related to those at presentation. Currently, literature on T-PLL-like cases lacking the rearrangement of TCL1A is limited, and the possibility of whether a proportion of such cases could represent PTCL, NOS (with leukemic involvement) needs consideration.

Uncommon HLA Alleles Observed in a Population of Istanbul Province

Objective: New polymorphisms are formed in human leucocyte antigen (HLA) genes with point mutations, gene conversions, and duplication, and the diversity continues to increase. Various new HLA alleles have significant roles in transplantation, and epidemiologic and population studies. The aim of our study was to determine the status of HLA alleles in the Turkish population, which is uncommon, well-defined, and non-defined in the world population according to the international ImMunoGeneTics information system® (IMGT) database. Methods: We performed HLA-A, -B, -C, -DQB1, and DRB1 loci at the four-field resolution level, using Sanger- sequence-based typing (SBT) for 5592 healthy, unrelated bone marrow donor volunteers from Istanbul Province. The uncommon alleles were also confirmed using high-throughput next-generation sequencing (NGS). Results: Uncommon alleles were determined at five loci as follows: HLA-A*01:155, 02:66, 02:90, 02:110, 02:343, 03:82, 24:28, 24:146, 24:276, 24:356, 31:23,33:33, 68:38; HLA-B *07:240, 18:19, 35:193, 40:303, 51:69, 51:169; HLA-C*04:39, 06:40, 07:93, 12:149, 15:73; HLA-DRB1*11:149, 13:14:02 and HLA-DQB1*03:27. All alleles were arranged according to the common and well‐documented (CWD) 3.0.0 catalog. Conclusion: This is the first study to show uncommon alleles in our population. These reported data increase the knowledge of HLA polymorphisms in the Turkish population and provide a basis for further studies in population genetics. This information may also be useful in determining whether a matched, unrelated donor is unlikely to be found so that a mismatch strategy, an extended family search, or alternate therapy, can be pursued, thus saving time and cost for patients.

Haploidentical HSCT in the Treatment of Pediatric Hematological Disorders.

Allogeneic hematopoietic stem cell transplantation has become a treatment option for otherwise non-curative conditions, both malignant and benign, affecting children and adults. Nevertheless, the latest research has been focusing extensively on transplantation from related and unrelated haploidentical donors, suitable for patients requiring emergent hematopoietic stem cell transplantation (HSCT) in the absence of an HLA-matched donor. Haploidentical HSCT (haplo-HSCT) can be an effective treatment for non-malignant pediatric disorders, such as primary immunodeficiencies or hemoglobinopathies, by enabling a much quicker selection of the appropriate donor for virtually all patients, low incidence of graft-versus-host disease (GVHD), and transplant-related mortality (TRM). Moreover, the outcomes of haplo-HSCT among children with hematological malignancies have improved radically. The most demanding tasks for clinicians are minimizing T-cell-mediated alloreactivity as well as early GVHD prevention. As a result, several T-cell depletion approaches, such as ex vivo T-cell depletion (TCD), and T-cell replete approaches, such as a combination of anti-thymocyte globulin (ATG), post-transplantation cyclophosphamide (PTCy), cyclosporine/tacrolimus, mycophenolate mofetil, or methotrexate, have been taken up. As more research is needed to establish the most beneficial form of therapy, haplo-HSCT is currently considered an alternative donor strategy for pediatric and adult patients with complications like viral and bacterial infections, invasive fungal disease, and GVHD.

Vedolizumab for the prevention of intestinal acute GVHD after allogeneic hematopoietic stem cell transplantation: a randomized phase 3 trial

Acute graft-versus-host disease (aGVHD) of the lower gastrointestinal (GI) tract is a major cause of morbidity and mortality in patients receiving allogeneic hematopoietic stem cell transplantation (allo-HSCT). Vedolizumab is a gut-selective anti-α4β7 integrin monoclonal antibody that reduces gut inflammation by inhibiting migration of GI-homing T lymphocytes. The efficacy and safety of vedolizumab added to standard GVHD prophylaxis (calcineurin inhibitor plus methotrexate/mycophenolate mofetil) was evaluated for prevention of lower-GI aGVHD after unrelated donor allo-HSCT in a randomized, double-blind, placebo-controlled phase 3 trial. Enrollment closed early during the COVID-19 pandemic with 343 patients randomized (n = 174 vedolizumab, n = 169 placebo), and 333 received ≥1 intravenous dose of 300 mg vedolizumab (n = 168) or placebo (n = 165) and underwent allo-HSCT. The primary end point was met; Kaplan–Meier (95% confidence interval) estimated rates of lower-GI aGVHD-free survival by day +180 after allo-HSCT were 85.5% (79.2–90.1) with vedolizumab versus 70.9% (63.2–77.2) with placebo (hazard ratio, 0.45; 95% confidence interval, 0.27–0.73; P < 0.001). For the 5 key secondary efficacy end points analyzed by day +180 after allo-HSCT, rates of lower-GI aGVHD-free and relapse-free survival and grade C–D aGVHD-free survival were significantly higher with vedolizumab versus placebo. No significant treatment differences were found for the other key secondary end points of non-relapse mortality, overall survival and grade B–D aGVHD-free survival, respectively. Incidence of treatment-related serious adverse events analyzed in patients receiving ≥1 dose of study treatment (n = 334) was 6.5% (n = 11 of 169) vedolizumab versus 8.5% (n = 14 of 165) placebo. When added to standard calcineurin inhibitor-based GVHD prevention, lower-GI aGVHD-free survival was significantly higher with vedolizumab versus placebo. ClinicalTrials.gov identifier: NCT03657160.

Prognostic factors impacting post-transplant outcomes in adult T-cell acute lymphoblastic leukemia: a registry-based study by the EBMT acute leukemia working party.

T-cell acute lymphoblastic leukemia (T-ALL) predominantly affects individuals in late childhood and young adulthood. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative modality particularly in the setting of poor risk genetics and/or persistent minimal residual disease. Limited studies have directly explored the impact of patient- and transplant-related factors on post-transplant outcomes in T-ALL. Using a large dataset from the European Society for Blood and Marrow Transplantation registry, we identified 1907 adult T-ALL patients (70% male) who underwent their first allo-HSCT in first complete remission (CR1) from matched sibling donors (MSD; 45%), unrelated donors (UD; 43%) or haploidentical donors (12%) between 2010 and 2021. The median age at transplant was 33.4 years (18.1-75). The median follow up was 2.9 years. Most patients underwent total body irradiation (TBI)-based myeloablative conditioning (69%). The 2-year overall survival (OS) was 69.4%, and leukemia -free survival (LFS) was 62.1%. In multivariate analysis, advanced age at transplant negatively affected LFS (for each 10-year increment, HR = 1.11, p = 0.004), GVHD-free, relapse-free survival (GRFS) (HR = 1.06, p = 0.04), OS (HR = 1.12, p = 0.002), and non-relapse mortality (NRM) (HR = 1.23, p < 0.001). More recent years of allo-HSCT were associated with improved GFRS (For each 3-year increment, HR = 0.89, p < 0.001), OS (HR = 0.9, p = 0.02), and decreased NRM (HR = 0.82, p = 0.008). TBI improved LFS. (HR = 0.79, p = 0.02), GRFS (HR = 0.83, p = 0.04), and relapse incidence (RI) (HR = 0.65, p < 0.001). Female-to-male transplant negatively affected GRFS (HR = 1.21, p = 0.02) and OS (HR = 1.23, p = 0.048). In vivo T-cell depletion significantly improved GFRS (HR = 0.74, p < 0.001). This large study identified prognostic factors, such as age at transplant conditioning regimen, in influencing post-transplant in adult T-ALL patients undergoing allo-HSCT. Importantly, a significant improvement over time was noted. These findings hold great promise for new adapted treatment strategies and can serve as a benchmark for future studies in that setting.

Facilitating the ethical sourcing of donor hematopoietic stem cells for cell and gene therapy research and development.

Aim: Unrelated stem cell donor registries (DRs) are increasingly engaging in the field of cell and gene therapy (CGT). This study aims to explore the values, concerns, needs and expectations of donors and members of the public on donating hematopoietic stem cells (HSCs) for CGT.Methods: Seven focus groups were conducted in 2019 with members of the public, prospective donors and donors on the Anthony Nolan DR in the UK.Results: Participants expressed concerns over increased frequency of donation and incidental findings and required more information on the type of research including the purpose and possible outcomes.Conclusion: Addressing donors' concerns, needs and expectations on donating cellular materials for CGT research and development is essential to maintaining the highest standards for donor care and safety within this rapidly emerging field.