Phylogenetic landscape of peptide-binding domains of classical HLA alleles reported in the Indian population: Plausible implications for stem cell transplantation

Bloodstream infection (BSI) is a common and serious complication after hematopoietic stem cell transplantation (HSCT). An investigation of the characteristics of pre-engraftment BSI after haploidentical HSCT compared with human leukocyte antigen (HLA)-identical sibling HSCT has not been conducted. A single-center cohort representing 1847 consecutive patients undergoing haploidentical or HLA-identical sibling HSCT from 2013 to 2016 was selected. We investigated the characteristics of pre-engraftment BSI after haploidentical HSCT and its impact on patient outcome, and we compared it with HLA-identical sibling HSCT. After haploidentical HSCT, the cumulative incidence of pre-engraftment BSI was higher (30-day: 9.2% [7.6, 10.8] vs 1.7% [0.5, 2.9], P < .0001) and median onset of BSI was earlier (day +3 vs day +9, P = .001) than HLA-identical sibling HSCT. Escherichia coli, Klebsiella pneumoniae, and coagulase-negative staphylococci were the most common isolates after haploidentical HSCT. However, Enterococcus faecium was the most common isolate after HLA-identical sibling HSCT. A multivariate analysis suggested that variables associated with BSI after haploidentical HSCT included a diagnosis of myelodysplastic syndrome (MDS), an interval from diagnosis to HSCT ≥190 days, carbapenem therapy, and grade 3-4 intestinal mucositis. The same variables, except MDS, were also associated with BSI after HLA-identical sibling HSCT. The multivariate analysis also suggested that BSI was a risk factor for increased all-cause mortality at 3 months after haploidentical HSCT (hazard ratio = 2.281; 95% confidence interval: 1.334, 3.900; P = .003). Pre-engraftment BSI was more common after haploidentical HSCT than HLA-identical sibling HSCT. It was an independent factor associated with increased all-cause mortality at 3 months after haploidentical HSCT.

Graft-versus-host disease (GVHD) in its acute (aGVHD) and chronic (cGVHD) form remains one of the most serious complications of allogeneic haematopoietic stem cell transplantation (allo-HSCT). There are several risk factors known to be associated with GVHD development. Some reports suggest that certain human leukocyte antigen (HLA) variants may influence the incidence of GVHD. The aim of our study was to analyse possible association between individual HLA alleles and the occurrence of aGVHD and cGVHD in patients following allo-HSCT from HLA-identical sibling donors. We have retrospectively reviewed medical records of 96 patients who received a transplant in the years 1994–2008. Cumulative incidence of acute GVHD was 31.3% and that of chronic GVHD was 26.0%. Recipients carrying the HLA-A*01, -DRB1*03 and -DQB1*03 alleles showed a statistically significantly lower incidence of aGVHD. Furthermore, the HLA-DQB1*06 allele was associated with a higher incidence of cGVHD. Each of these alleles was confirmed by logistic regression analysis as an independent factor with impact on GVHD development. Our results support findings of authors showing an association between certain HLA variants and GVHD appearance. However, other authors assume that there is no convincing evidence for such an association. Therefore, when taking into account limitations of our study design and the significant inconsistency in the results of the previous reports, a careful approach in judgement is required. To conclude, in our view, the prognostic value of individual HLA variants for GVHD development in a setting of HLA-identical allo-HSCT does not seem to be of great clinical relevance.

Analysis of the Impact of KIR B Haplotype Donors on Outcomes after Haploidentical (HI) and Matched Related (MR) Hematopoietic Stem Cell Transplantation (HSCT)

Advances in HLA: Practical Implications for Selecting Adult Donors and Cord Blood Units

Genomic Loss of the Mismatched HLA Locus in Leukemia Is a Major Mechanism of in Vivo Escape from T Cell Immunosurveillance Following Haploidentical HSCT

The Presence of Recipient CMV Immunodominant Human Leukocyte Antigen (HLA) Alleles Affect Outcomes after Haploidentical (HI) Hematopoietic Stem Cell Transplantation (HSCT)

At present, haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is one of important treatment of malignant hematological diseases, and solve the problem for patients who need allogeneic hematopoietic stem cell transplantation (allo-HSCT), but don′t have suitable donors. However, graft rejection, graft versus host disease (GVHD), graft failure (GF), and implant dysfunction are haplo-HSCT related adverse events. Currently, factors which aren′t associated with human leukocyte antigen (HLA) matching, such as donor′s gender, age, donor specific HLA antibody (DSA) and killer cell immunoglobulin like receptor (KIR), receive more and more attention in donor selection in haplo-HSCT from researchers. KIR3DL1 is one of important inhibitory receptors on the surface of natural killer (NK) cells, and plays an important role in inducing heterologous responsive NK cells. In order to optimize the process of donor selection in haplo-HSCT, authors summarize the role of DSA and KIR matching in haplo-HSCT donor selection. Key words: Hematopoietic stem cell transplantation; Recepters, KIR; Donor selection; Graft rejection; Graft vs host reaction; Donor specific human leukocyte antigen antibodies

Outcomes after Bone Marrow Versus Peripheral Blood Haploidentical Hematopoietic Stem Cell Transplantation Using Post-Transplant Cyclophosphamide-Based Gvhd Prophylaxis

An Examination of Cytomegalovirus, Socioeconomic Status, Race, and Ethnicity on Outcomes after Haploidentical Hematopoietic Transplantation

Primary plasma cell leukaemia (PCL) is a rare, aggressive neoplasm of plasma cell dyscrasia. Conventional chemotherapy is usually ineffective, with an overall survival of only 8 months. Here, we describe a 42-year-old man with primary PCL, who was successfully treated with haploidentical (2-HLA loci mismatched) haematopoietic stem-cell transplantation (HSCT). To overcome the human leukocyte antigen (HLA) disparity, in vivo T-cell purging by the pre-transplant administration of antithymocyte globulin followed by a conventional prophylactic treatment against graft-versus-host disease (GVHD) resulted in an avoidance of severe GVHD as well as infectious complications. The patient has maintained complete remission for 13 months after haploidentical HSCT, indicating that a graft-versus-PCL effect might be preserved. Haploidentical HSCT can be a potentially curative treatment for patients with primary PCL who do not have an HLA-identical donor.

Introduction. Hematopoietic stem cell transplantation (HSCT) from an alternative donor is the main treatment option for patients with severe acquired aplastic anemia (AAA) refractory to combined immunosuppressive therapy with anti-thymocyte globulin and cyclosporine A. Although the outcomes of unrelated and haploidentical HSCTs have improved over the years, graft-versus-host disease (GVHD) continues to pose a major clinical challenge associated with significant morbidity and mortality. Aim: to present the outcomes of unrelated and haploidentical HSCTs with TCRαβ-depleted grafts in patients with AAA. Materials and methods. Eighty patients (42 males and 38 females) with AAA underwent HSCT between September 2012 and February 2022. The median age at transplantation was 10 (2.3–22.7) years. Seventy-eight patients received HSCT after relapse or refractory disease after one (n = 14) or two (n = 18) courses of immunosuppressive therapy. Two patients underwent HSCT as first-line treatment. The median time from diagnosis to transplantation was 1 (0.1–11.8) year. Conditioning regimen included cyclophosphamide (100–150 mg/kg), fludarabine (150 mg/kg), antithymocyte globulin (ATGAM (100 mg/kg) or thymoglobulin (5–10 mg/kg)), and thoracoabdominal irradiation (2–6 Gy). In some cases, additional medications such as melphalan (140 mg/m2), thiophosphamide (5–10 mg/kg), and rituximab (200 mg/m2) were used. Patients with paroxysmal nocturnal hemoglobinuria (n = 6) received eculizumab at a dose of 600 mg from day –7 to day +14 (every 7 days). Post-transplant GVHD prophylaxis included calcineurin inhibitors. TCRαβ/CD19 depletion was performed using a CliniMACS Plus system (Miltenyi Biotec, Bergish Gladbach, Germany). The median CD34+ cell dose in the graft was 10 (2.7–23.0) × 10⁶/kg, and the median TCRαβ+ cell dose was 26.6 (0.85–316.00) × 10³/kg. Results. The cumulative incidence of engraftment was 0,95 (95% confidence interval (CI) 0.9–1.0) with the median time to neutrophil recovery being 13 (9–24) days and to platelet recovery – 12 (7–25) days. Graft rejection occurred in 9 patients, the cumulative incidence of rejection was 0,11 (95% CI 0.06–0.20). Three of these patients underwent successful retransplantation. The cumulative incidence of grade II–III acute GVHD was 0,12 (95% CI 0.05–0.27) in the patients who had undergone unrelated donor HSCT versus 0,42 (95% CI 0.29–0.61) in the haploidentical HSCT recipients (p = 0.003). The cumulative incidence of chronic GVHD was 0,5 (95% CI 0.01–0.20) in the unrelated donor HSCT group and 0,21 (95% CI 0.12–0.38) in the haploidentical HSCT group (p = 0.02). The median follow-up was 6.4 years. Twenty-two (27.5%) patients died. Sixteen of them died of complications after the first HSCT; 4 deaths occurred due to complications associated with repeat HSCT. Two patients died after graft rejection due to infectious complications. The overall survival was 0,79 (95% CI 66–91) in the unrelated donor HSCT group and 0,66 (95% CI 51–81) in the haploidentical donor HSCT group. Conclusion. The use of TCRαβ/CD19-depleted HSCT from alternative donors ensured high engraftment rates and reduced the incidence of severe GVHD. However, there were no significant improvements in graft rejection or mortality.

Trial in Progress: Cureaa - a Clinical Trial of Upfront Haploidentical or Unrelated Donor BMT to Restore Normal Hematopoiesis in Aplastic Anemia, Blood and Marrow Transplant Clinical Trials Network (BMT CTN) #2207

Natural Killer Cell Killing of Acute Myelogenous Leukemia and Acute Lymphoblastic Leukemia Blasts by Killer Cell Immunoglobulin-Like Receptor–Negative Natural Killer Cells after NKG2A and LIR-1 Blockade

High degree of variability in human leukocyte antigens (HLAs) system restricts availability of histocompatible HLA-matched-related donors, thus increasing reliance on worldwide bone marrow registries network. Nevertheless, due to limited coverage/accessibility/affordability of some ethnicities in these registries, haploidentical haematopoietic stem cell transplantation (HSCT) emerged as an alternative option, though with allorecognition-mediated graft versus host disease (GvHD) (>40% cases). A dimorphism [-21 methionine (M) or threonine (T)] in HLA-B leader peptide (exon 1) which differentially influences its HLA-E binding, plausibly regulates natural killer cell functionality, affecting GvHD vulnerability and clinically in practice for donor selection. Here, we analysed population-specific influence of this functionally relevant dimorphism on post HSCT GvHD occurrence and clinical utility (if any) towards defining donor permissibility. High resolution HLA-B genotyping data were analysed in 178 study participants, including 89 HSCT patient-donor pairs, for the frequency distribution of -21 leader dimorphism. Distribution of HLA-Bw4/Bw6 was deduced with killer cell immunoglobulin receptor ligand calculator tool in IPD-IMGT/HLA database. Though -21T (∼85%) was over represented in the study participants, no significant influence is observed for this variant between HLA-identical v/s haplo HSCT either with or without GvHD, at allelic and genotypic levels as well as in BLEAT (HLA-B Leader Assessment Tool)-based donor-recipient matching. Stratified analysis of -21M/T into Bw4/Bw6 groups revealed a higher frequency of -21T+Bw4 in GvHD (+) group compared to GvHD (-) (p<0.05), plausibly linking this haplotype with occurrence of GvHD post HSCT and importance of HLA class I-mediated NK cell functionality in GvHD.

Superior Graft-versus-Leukemia Effect Associated with Transplantation of Haploidentical Compared with HLA-Identical Sibling Donor Grafts for High-Risk Acute Leukemia: An Historic Comparison