Donor Selection For Hematopoietic Cell Transplantation Research Articles

Donor Selection for Allogeneic Hematopoietic Cell Transplantation.

In Germany, each year over 3000 patients with malignant and non-malignant hematologic and systemic diseases are treated by allogeneic hematopoietic cell transplantation (HCT). Genetic donor-recipient disparities, especially those concerning variable human leukocyte antigens (HLA), mediate both an immunotherapeutic effect and the risk of damage to healthy tissues ("graft-versus-host disease"). The adoption of evidence-based strategies for donor selection has been crucial for the continuous improvement of survival rates after allogeneic HCT, with over 50% of patients transplanted for standard indications-such as early-stage acute myeloid leukemia-alive at three years post-transplant. The PubMed database was selectively searched for literature on immunogenetic and clinical factors relevant to allogeneic HCT, as part of the process of establishing a German consensus statement on HCT donor selection. The most important factor in donor selection is a match for the five major HLA loci (HLA-A, -B, -C, -DR, -DQ), either in genetically HLA-identical siblings or in unrelated but fully HLA-compatible donors from international registries. Additional selection criteria for the latter include compatibility for the HLA-DP locus, donor age and sex, cytomegalovirus serostatus, and blood group. Related donors identical for only 50% of the HLA genes (haploidentical donors) as well as unrelated donors with a single HLA mismatch are both valid alternatives although they are associated with an up to 10% higher risk of mortality. The refinement of donor selection strategies has been instrumental for the continuous improvement of patient survival rates after allogeneic HCT witnessed over the past decades. An interdisciplinary approach to donor selection based on up-to-date scientific evidence is crucial for optimizing patient outcomes.

KIR genotype and haplotype repertoire in Kuwaiti healthy donors, hematopoietic cell transplant recipients and healthy family members.

The gene complex located on chromosome 19q13.4 encodes the Killer-cell Immunoglobulin-like Receptors (KIRs), which exhibit remarkable polymorphism in both gene content and sequences. Further, the repertoire of KIR genes varies within and between populations, creating a diverse pool of KIR genotypes. This study was carried out to characterize KIR genotypes and haplotypes among 379 Arab Kuwaiti individuals including 60 subjects from 20 trio families, 49 hematopoietic cell transplantation (HCT) recipients and 270 healthy Kuwaiti volunteer HCT donors. KIR Genotyping was performed by a combination of reverse sequence specific oligonucleotide probes (rSSO) and/or Real Time PCR. The frequencies of KIR genes in 270 healthy Kuwaiti volunteer donors were compared to previously reported frequencies in other populations. In addition, we compared the differences in KIR repertoire of patients and healthy donors to investigate the reproducibility of previously reported significant differences between patients with hematological malignancies and healthy donors. The observed frequencies in our cohort volunteer HCT donors was comparable to those reported in neighboring Arab populations. The activating genes KIR2DS1, KIR2DS5 and KIR3DS1 and the inhibitory gene KIR2DL5 were significantly more frequent in patients compared to healthy donors, however, none of the previously reported differences were reproducible in our Kuwaiti cohort. This report is the first description of KIR gene carrier frequency and haplotype characterization in a fairly large cohort of the Kuwaiti population, which may have implications in KIR based HCT donor selection strategies.

Hematopoietic Cell Transplantation Donor Selection Reimagined: KIR-KIR Ligand Interactions and a Formalized Donor Risk Index Effective at Predicting Survival

When selecting a human leukocyte antigen (HLA) matched unrelated donor (URD) for hematopoietic cell transplantation (HCT) it is generally accepted that donor age, sex, ABO blood group and viral serologic status should be considered. However, the inter-relationship among these variables is not well established and a consensus on how strongly to consider each variable has not been reached. Selection of the optimal donor gets more complicated as new donor recipient pair (DRP) selection parameters, including killer immunoglobulin-like receptors (KIR) haplotypes are included. In this study we seek to develop a logic-based method to reduce the inconsistencies in donor selection in the HLA matched HCT. Retrospective review of eligible adults with known KIR genotyping receiving HLA-A, B, C & DRB1 allelically matched URD HCT for hematologic malignancy. Donor recipient pairs were selected based on donor age, sex match, CMV sero-status match, and ABO compatibility when possible; KIR genotype was not considered in DRP selection. KIR-KIR ligand interactions were calculated for each DR pair and interaction unit values were ascribed as previously described and each DRP IM KIR score (eq. 1) was calculated. IM KIR Score = |iKIR| + |mKIRL| [1] Weights of each donor risk variable (age, sex, CMV & ABO match) contribution were ascribed using Cox regression methods and summed up to determine donor risk parameter. Donor risk parameters and reciprocal-IM-KIR were finally combined into a donor risk index. Ninety-eight DRP with known HLA & KIR genotyping were studied. A higher IM-KIR score describes a DRP with increased iKIR-KIR ligand interactions and missing KIR ligand interactions; which was associated with a favorable survival after HCT, HR of 0.44 (95%CI: 0.26 to 0.73; P=0.002). Univariate analysis of overall survival for donor age, sex match, ABO compatibility and CMV status were all statistically insignificant (p>0.05). Donor risk parameter was predictive of mortality with a hazard ratio (HR) of 2.76 (95% CI: 1.22-6.18, p=0.014). Combining the two into a donor risk index was predictive of survival with a HR of 2.38 (1.44-3.92, p=0.001). ROC-AUC comparison of survival for IM-KIR score and donor risk parameter showed AUCs of 0.63 and 0.67 respectively. Further, the combined donor risk index shows improved sensitivity and specificity over the donor risk parameter with AUCs of 0.72 and 0.67 respectively. A novel IM-KIR score independently predicts survival in HLA matched DRP, as does a formalized donor risk parameter which includes non-HLA donor characteristics. Moreover, their addition enhanced the specificity and sensitivity of predicting survival in these patients. If validated in a larger exploration and validation cohort this method of donor selection may improve the donor selection process, decreasing variability in clinical outcomes and improve overall survival.

Hematopoietic Cell Transplantation Donor Selection Reimagined: KIR-KIR Ligand Interactions and a Formalized Donor Risk Index Effective at Predicting Survival

Background When selecting a human leukocyte antigen (HLA) matched unrelated donor (URD) for hematopoietic cell transplantation (HCT) it is generally accepted that donor age, sex, ABO blood group and viral serologic status should be considered. However, the inter-relationship among these variables is not well established and a consensus on how strongly to consider each variable has not been reached. Selection of the optimal donor gets more complicated as new donor recipient pair (DRP) selection parameters, including killer immunoglobulin-like receptors (KIR) haplotypes are included. In this study we seek to develop a logic-based method to reduce the inconsistencies in donor selection in the HLA matched HCT. Methods VCU IRB approval was obtained for a retrospective review of eligible subjects who were adults with known KIR genotyping receiving HLA-A, B, C & DRB1 allelically matched URD HCT for hematologic malignancy between 2014 and 2017. Donor recipient pairs were selected based on donor age, sex match, CMV sero-status match, and ABO compatibility when possible; KIR genotype was not considered in DRP selection. KIR-KIR ligand interactions were calculated for each DR pair and interaction unit values were ascribed as follows; -1, when the donor possessed an inhibitory KIR (iKIR) and the recipient the corresponding HLA; +1, when the donor possessed iKIR and recipient lacked corresponding HLA (mKIR score, missing ligand). A novel inhibitory-missing KIR (IM-KIR) score was calculated for each HLA matched DRP by summing the interaction values as in equation 1. IM KIR Score = |iKIR| + |mKIRL| ………. [1] Univariate and multivariate analysis using Cox regression methods were utilized to evaluate donor parameters associated with overall survival. Weights of each donor risk variable (age, sex, CMV & ABO match) contribution were ascribed and summed up to determine donor risk parameter. Donor risk parameters and reciprocal-IM-KIR were finally combined into a donor risk index. Receiver operating characteristic curve- area under the curve (ROC-AUC) analysis was utilized to compare indices. Results Ninety-eight DRP with known HLA & KIR genotyping were studied. Median follow up at the time of analysis was 583 days. A higher IM-KIR score describes a DRP with increased iKIR-KIR ligand interactions and missing KIR ligand interactions; which was associated with a favorable survival after HCT, HR of 0.44 (95%CI: 0.26 to 0.73; P=0.002). Further analyses were performed using a reciprocal of this score. Univariate analysis of overall survival for donor age, sex match, ABO compatibility and CMV status were all statistically insignificant (p>0.05). However, the donor risk parameter was predictive of mortality with a hazard ratio (HR) of 2.76 (95% CI: 1.22-6.18, p=0.014). Covariate analysis of the donor risk parameter and reciprocal IM-KIR score were both predictive of survival independent of each other with HR 2.41 (1.05-5.54, p=0.038) and 2.35 (1.18-4.70, p=0.016) respectively. Combining the two into a donor risk index was predictive of survival with a HR of 2.38 (1.44-3.92, p=0.001). ROC-AUC comparison of survival for IM-KIR score and donor risk parameter showed statistically significant AUCs of 0.63 and 0.67 respectively. Further, the combined donor risk index shows improved sensitivity and specificity over the donor risk parameter with AUCs of 0.72 and 0.67 respectively. Conclusions A novel KIR-HLA interaction score, the IM-KIR score independently predicts survival in HLA matched DRP, as does a formalized donor risk parameter which includes non-HLA donor characteristics. Moreover, the addition of IM-KIR score to the donor risk parameter enhanced the specificity and sensitivity of predicting survival in these patients. If validated in a larger exploration and validation cohort this method of donor selection may improve the donor selection process, decreasing variability in clinical outcomes and improve overall survival. Disclosures No relevant conflicts of interest to declare.

Direct HLA Genetic Comparisons Identify Highly Matched Unrelated Donor-Recipient Pairs with Improved Transplantation Outcome.

HLA matching by allele-level genotyping is largely based on genetic similarity between a few exons that encode the antigen recognition domain (ARD) of the HLA protein. Next-generation sequencing (NGS) can identify HLA genetic polymorphisms in non-ARD-encoding exons, introns, and untranslated regions, but the impact of these polymorphisms on hematopoietic cell transplantation (HCT) outcome is unclear. We performed NGS-based sequencing of 11 HLA loci on a well-characterized retrospective cohort of 166 unrelated donor-recipient HCT pairs. Genetic differences between HCT pairs were identified and visualized using a novel bioinformatics approach that directly compares phased full-length HLA sequences. Our approach was able to correctly classify HCT pairs without known HLA allele-level mismatches and also to identify a subset of HLA allele-matched HCT pairs with very few to no genetic differences in the sequenced HLA regions. This highly HLA genetically matched unrelated HCT group shows improved overall survival and reduced acute graft-versus-host disease compared with HCT pairs with HLA allele-level mismatches. These results suggest that direct genetic matching of HLA loci may offer an additional means of HCT donor selection beyond traditional HLA allele comparisons and suggests that genetic similarity as defined by HLA sequencing may have a novel role in unrelated HCT donor selection. Finally, our approach can enable larger cohort studies with adequate power to detect differences in other HCT outcomes based on genetic similarity within the HLA loci.

Evaluation of a Machine Learning-Based Prognostic Model for Unrelated Hematopoietic Cell Transplantation Donor Selection

The survival of patients undergoing hematopoietic cell transplantation (HCT) from unrelated donors for acute leukemia exhibits considerable variation, even after stringent genetic matching. To improve the donor selection process, we attempted to create an algorithm to quantify the likelihood of survival to 5 years after unrelated donor HCT for acute leukemia, based on the clinical characteristics of the donor selected. All standard clinical variables were included in the model, which also included average leukocyte telomere length of the donor based on its association with recipient survival in severe aplastic anemia, and links to multiple malignancies. We developed a multivariate classifier that assigned a Preferred or NotPreferred label to each prospective donor based on the survival of the recipient. In a previous analysis using a resampling method, recipients with donors labeled Preferred experienced clinically compelling better survival compared with those labeled NotPreferred by the test. However, in a pivotal validation study in an independent cohort of 522 patients, the overall survival of the Preferred and NotPreferred donor groups was not significantly different. Although machine learning approaches have successfully modeled other biological phenomena and have led to accurate predictive models, our attempt to predict HCT outcomes after unrelated donor transplantation was not successful.

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Complications of allogeneic hematopoietic cell transplantation (HCT), mainly graft-vs-host disease (GVHD) are substantial and severely limit the survival and quality of life of HCT recipients. Cytokines act as chief mediators/regulators of allo-immune responses. Genetic control of cytokine production is evidenced by polymorphisms in cytokine gene regulatory regions resulting in low, moderate, or high cytokine production profiles. Here, we investigated the impact of cytokine gene variants on significant GVHD (defined as grade 2-4 acute GVHD and/or chronic GVHD requiring systemic therapy). A total of 139 first allogeneic HCT donors were analyzed for 22 single nucleotide variants located in the regulatory and/or exonic regions of 13 cytokine/cytokine receptor genes. The panel of genes includes TNF-a, IFN-g, IL-1a, IL-1b, IL-1R, IL-1Ra, IL-2, IL-4, IL-4Ra, IL-6, IL-12, IL-10 , and TGF-b . Genotyping was performed by SSP based method. Binary logistic regression analysis was performed. Allogeneic HCT donors carrying low producing genotype of IL-10 promoter region variants (-1082G/A, -819C/T, -592C/A) were strongly associated with significant GVHD. 28% vs 76% of HCT recipients developed significant GVHD when they received graft from donors carrying high vs low IL10 producing genotypes (IL10 -1082 AA) respectively (p = 0.02, OR = 8.167). The cumulative analysis of all three IL-10 gene variants showed a higher (∼13 fold) risk for significant GVHD in donors carrying low IL-10 producing hapotypes (p = 0.01, OR = 13.12). Genetic predisposition to low IL-10 production is a strong predictor of GVHD. Low IL-10 production may contribute to a deficient regulatory milieu culminating in stronger allo-immune responses involved in the pathogenesis of GVHD. The findings of this study may contribute in developing a new algorithm for improved allogeneic HCT donor selection - where selecting HLA matched donors that carry high IL-10 producing genotypes will result in a low likelihood of GVHD.

Is allergic disease curable or transferable with allogeneic hematopoietic cell transplantation?

AbstractIn the pathogenesis of allergic asthma/rhinitis, 2 main types of cells play a role: hematolymphatic cells (mast cells, eosinophils, T cells, B cells) and nonhematolymphatic cells (airway smooth muscle cells, epithelial cells). It is not known which one of the 2 cell types plays the primary role. Here we review the literature on allergic disease transfer and potential cure with allogeneic hematopoietic cell transplantation (HCT), as transferability and curability would support a primary role of hematolymphatic cells and have implications for donor selection for HCT and possible future treatment of severe allergic disease with HCT. A total of 18 nonallergic recipients were reported to develop allergic disease after transplantation; however, conclusive information for transfer was available for only 5 cases. Allergic disease was reported to abate in 3 allergic recipients; however, conclusive information for “cure” was available for only 2 cases. Problems in interpreting the reports include incomplete data on allergic disease in the donor or recipient before transplantation, not knowing the denominator, and the lack of controls. In summary, review of the literature generates the hypothesis that allergic disease is transferable and curable with HCT. A prospective study, including appropriate controls, is needed to evaluate this hypothesis.

Tissue typing for hematopoietic cell transplantation: Newer techniques and newer antigens for which cross‐matching is helpful

Refinements in human leukocyte antigen (HLA) typing techniques for hematopoietic cell transplantation (HCT) have permitted a more precise assessment of donor-recipient histocompatibility, which has impacted transplantation outcomes. More recently, differences in transplant outcomes associated with killer immunoglobulin-like receptor compatibility have emphasized the potential importance of natural killer (NK) cell typing in HCT. This article reviews the current state of the art for HCT donor selection based on both HLA and NK cell typing.