Novel Scoring System for Ranking Hematopoietic Stem Cell Transplantation.

Background: When human leukocyte antigen (HLA)-matched donors are not available for hematopoietic stem cell transplants (HSCT), there are no well-accepted guidelines for ranking 7/8 HLA-matched unrelated donors to achieve optimal transplant outcomes. A novel scoring system for ranking HLA mismatches for these donors was investigated.

Methods: High-resolution HLA types were used to determine amino acid mismatches located in the HLA antigen-recognition domain.

HLA diversity in ethnic populations can affect detection of donor-specific antibodies by single antigen beads.

Introduction: In solid-organ transplantation, human leukocyte antigen (HLA) donor-specific antibodies (DSA) are strongly associated with graft rejection, graft loss, and patient death. The predominant tests used for detecting HLA DSA before and after solid-organ transplantation are HLA single antigen bead (SAB) assays. However, SAB assays may not detect antibodies directed against HLA epitopes that are not represented in the SAB.

Next generation multiplexing for digital PCR using a novel melt-based hairpin probe design.

Digital PCR (dPCR) is a powerful tool for research and diagnostic applications that require absolute quantification of target molecules or detection of rare events, but the number of nucleic acid targets that can be distinguished within an assay has limited its usefulness. For most dPCR systems, one target is detected per optical channel and the total number of targets is limited by the number of optical channels on the platform. Higher-order multiplexing has the potential to dramatically increase the usefulness of dPCR, especially in scenarios with limited sample.

Donor chimerism and immune reconstitution following haploidentical transplantation in sickle cell disease.

Introduction: We previously reported the initial results of a phase II multicenter transplant trial using haploidentical parental donors for children and aolescents with high-risk sickle cell disease achieving excellent survival with exceptionally low rates of graft-versus-host disease and resolution of sickle cell disease symptoms. To investigate human leukocyte antigen (HLA) sensitization, graft characteristics, donor chimerism, and immune reconstitution in these recipients.

Methods: CD34 cells were enriched using the CliniMACS system with a target dose of 10 x 10 CD34 cells/kg with a peripheral blood mononuclear cell (PBMNC) addback dose of 2x10 CD3/kg in the final product.

Cell-free DNA as a solid-organ transplant biomarker: technologies and approaches.

High-quality biomarkers that detect emergent graft damage and/or rejection after solid-organ transplantation offer new opportunities to improve post-transplant monitoring, allow early therapeutic intervention and facilitate personalized patient management. Donor-derived cell-free DNA (DD-cfDNA) is a particularly exciting minimally invasive biomarker because it has the potential to be quantitative, time-sensitive and cost-effective. Increased DD-cfDNA has been associated with graft damage and rejection episodes.

The changing landscape of HLA typing: Understanding how and when HLA typing data can be used with confidence from bench to bedside.

Human leukocyte antigen (HLA) genes are extraordinary for their extreme diversity and widespread impact on human health and disease. More than 30,000 HLA alleles have been officially named and more alleles continue to be discovered at a rapid pace. HLA typing systems which have been developed to detect HLA diversity have advanced rapidly and are revolutionizing our understanding of HLA's clinical importance.

Genetics of HLA Peptide Presentation and Impact on Outcomes in HLA-Matched Allogeneic Hematopoietic Cell Transplantation.

Minor histocompatibility antigens (mHAs), recipient-derived peptide epitopes presented on the cell surface, are known to mediate graft-versus-host disease (GVHD); however, there are no current methods to associate mHA features with GVHD risk. This deficiency is due in part to the lack of technological means to accurately predict, let alone confirm, the tremendous number of potential mHAs in each individual transplant. Previous studies have shown that different HLA molecules present varying fractions of candidate peptide epitopes; however, the genetic "distance" between HLA-matched donors and recipients is relatively constrained.

The discovery of the HLA-B*56:75 allele shows that HLA sequencing is important in all transplant settings.

HLA-B*56:75 has a nonsynonymous C to G substitution in codon 73 compared to HLA-B*56:01:01:02.

Optimal Donor for African Americans with Hematologic Malignancy: HLA-Haploidentical Relative or Umbilical Cord Blood Transplant.

Although hematopoietic cell transplantation from an HLA-matched unrelated donor is potentially curative for hematologic malignancies, survival is lower for African Americans compared with Caucasians. Because only approximately 20% of African Americans will have an HLA-matched unrelated donor, many of these patients undergo HLA-haploidentical relative or umbilical cord blood transplantation. In this study, we analyzed outcomes after HLA-haploidentical related donor (n = 249) and umbilical cord blood (n = 118) transplantations in African American patients with hematologic malignancy between 2008 and 2016.

The clinical impact of donor-specific antibodies on antibody-mediated rejection and long-term prognosis after heart transplantation.

Purpose Of Review: Outcomes after cardiac transplantation have improved over past decades, but long-term graft survival remains limited in part because of uncertainty regarding clinical implications of donor-specific antibodies (DSAs). The purpose of this review is to consolidate recent advances in knowledge on the topic of DSA and their potential to impact long-term prognosis after heart transplantation.

Recent Findings: The presence of persistent DSA increases the risk of poor outcome after heart transplantation, including development of antibody-mediated rejection (AMR), graft failure, cardiac allograft vasculopathy, and mortality.

The safety and efficacy of clofarabine in combination with high-dose cytarabine and total body irradiation myeloablative conditioning and allogeneic stem cell transplantation in children, adolescents, and young adults (CAYA) with poor-risk acute leukemia.

Acute leukemias in children with CR3, refractory relapse, or induction failure (IF) have a poor prognosis. Clofarabine has single agent activity in relapsed leukemia and synergy with cytarabine. We sought to determine the safety and overall survival in a Phase I/II trial of conditioning with clofarabine (doses 40 - 52 mg/m), cytarabine 1000 mg/m, and 1200 cGy TBI followed by alloSCT in children, adolescents, and young adults with poor-risk leukemia.

CPRA for allocation of kidneys in the US: More candidates ≥98% CPRA, lower positive crossmatch rates and improved transplant rates for sensitized patients.

In 2009 calculated panel reactive antibody (CPRA) replaced PRA as the metric for HLA sensitization in the US kidney allocation system. During the next four years, registrants with at least one unacceptable antigen increased (34-40%) and registrants with ≥98% PRA/CPRA increased from 7% to 9% of the waitlist. These changes were accompanied by a reduction in kidney offers refused for positive crossmatch: 14,137 (1.

A Phase I Study of Reduced-Intensity Conditioning and Allogeneic Stem Cell Transplantation Followed by Dose Escalation of Targeted Consolidation Immunotherapy with Gemtuzumab Ozogamicin in Children and Adolescents with CD33+ Acute Myeloid Leukemia.

Myeloablative conditioning and allogeneic hematopoietic stem cell transplant (alloHSCT) in children with acute myeloid leukemia (AML) in first complete remission (CR1) may be associated with significant acute toxicity and late effects. Reduced-intensity conditioning (RIC) and alloHSCT in children is safe, feasible, and may be associated with less adverse effects. Gemtuzumab ozogamicin (GO) induces a response in 30% of patients with CD33+ relapsed/refractory AML.

Pilot trial of risk-adapted cyclophosphamide intensity based conditioning and HLA matched sibling and unrelated cord blood stem cell transplantation in newly diagnosed pediatric and adolescent recipients with acquired severe aplastic anemia.

Background: Cyclophosphamide-based conditioning regimens and allogeneic hematopoietic stem cell transplantation (AlloHSCT) from matched related donors (MRD) has resulted in the highest survival rates in children and adolescents with acquired severe aplastic anemia (SAA). Time to transplant has consistently been associated with decreased overall survival. Reduced toxicity conditioning and AlloHSCT has been used successfully in other pediatric non-malignant diseases.

Impact of allele-level HLA matching on outcomes after myeloablative single unit umbilical cord blood transplantation for hematologic malignancy.

We studied the effect of allele-level matching at human leukocyte antigen (HLA)-A, -B, -C, and -DRB1 in 1568 single umbilical cord blood (UCB) transplantations for hematologic malignancy. The primary end point was nonrelapse mortality (NRM). Only 7% of units were allele matched at HLA-A, -B, -C, and -DRB1; 15% were mismatched at 1, 26% at 2, 30% at 3, 16% at 4, and 5% at 5 alleles.

Amino acid substitution at peptide-binding pockets of HLA class I molecules increases risk of severe acute GVHD and mortality.

HLA disparity has a negative impact on the outcomes of hematopoietic cell transplantation (HCT). We studied the independent impact of amino acid substitution (AAS) at peptide-binding positions 9, 99, 116, and 156, and killer immunoglobulin-like receptor binding position 77 of HLA-A, B, or C, on the risks for grade 3-4 acute graft-versus-host disease (GVHD), chronic GVHD, treatment-related mortality (TRM), relapse, and overall survival. In multivariate analysis, a mismatch at HLA-C position 116 was associated with increased risk for severe acute GVHD (hazard ratio [HR] = 1.

Multiple mismatches at the low expression HLA loci DP, DQ, and DRB3/4/5 associate with adverse outcomes in hematopoietic stem cell transplantation.

A single mismatch in highly expressed HLA-A, -B, -C, and -DRB1 loci (HEL) is associated with worse outcomes in hematopoietic stem cell transplantation, while less is known about the cumulative impact of mismatches in the lesser expressed HLA loci DRB3/4/5, DQ, and DP (LEL). We studied whether accumulation of LEL mismatches is associated with deleterious effects in 3853 unrelated donor transplants stratified according to number of matches in the HEL. In the 8/8 matched HEL group, LEL mismatches were not associated with any adverse outcome.

Transplantation-related mortality, graft failure, and survival after reduced-toxicity conditioning and allogeneic hematopoietic stem cell transplantation in 100 consecutive pediatric recipients.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) with myeloablative conditioning is associated with a 10%-40% risk of day +100 transplantation-related mortality (TRM). We evaluated the feasibility and safety of reduced-toxicity conditioning and allo-HSCT in 100 consecutive children and adolescent recipients (mean age, 9.2 ± 6.