Unrelated Donor Hematopoietic Stem Cell Research Articles

Recognition of the three deduced probable HLA haplotypes that are associated with HLA-C∗16:04:01 (A∗33:03-B∗44:02-C∗16:04:01-DRB1∗11:04:01 and A∗24-B∗44:02-C∗16:04:01-DRB1∗11:04) and HLA-B∗15:109 (A∗11-B∗15:109-DRB1∗04) in Taiwanese unrelated hematopoietic stem cell donors

ObjectiveHLA-C∗16:04:01 and HLA-B∗15:109 are two uncommon alleles at the HLA-C locus and HLA-B locus, respectively. The objective of this study is to report the deduced probable human leukocyte antigen (HLA) haplotypes associated with HLA-C∗16:04:01 and HLA-B∗15:109 among Taiwanese unrelated bone marrow hematopoietic stem cell donors. Materials and methodsA sequence-based typing method was employed to confirm the two low incidence alleles observed. Polymerase chain reaction was performed to amplify exons 2 and 3 of the HLA-A, and HLA-B loci with group-specific primer sets. Amplicons were sequenced using a BigDye Terminator Cycle Sequencing Ready Reaction Kit in both directions according to the manufacturer's protocols. ResultsThe DNA sequence of C∗16:04:01 is identical to that of C∗16:01:01 in exons 2 and 3, except for two nucleotide substitutions at residues 538 (C->T) and 539 (A->G), which results in a single amino acid replacement at position 156 (glutamine->tryptophan). We deduced two probable HLA haplotypes that are found in association with C∗16:04:01 as A∗33:03-B∗44:02-C∗16:04:01-DRB1∗11:04 and A∗24-B∗44:02-C∗16:04:01-DRB1∗11:04. The DNA sequence of B∗15:109 is identical to B∗15:27:01 in exons 2 and 3 except for one nucleotide substitution at residue 200 (C->T), which results in a single amino acid replacement at position 43 (proline->leucine). A probable HLA haplotype associated with B∗15:109 was deduced to be A∗11-B∗15:109-DRB1∗04. ConclusionInformation on the deduced HLA haplotypes that are found in association with the rare C∗16:04:01 and B∗15:109 alleles that we report here is useful for reference purposes at HLA testing laboratories and will help stem cell transplantation donor search coordinators when they are determining the likelihood of finding a compatible donor for patients bearing these two uncommon HLA alleles from unrelated bone marrow donor registries.

HLA-B*52:33, a variant of HLA-B*52, discovered in a Taiwanese unrelated hematopoietic stem cell donor.

One nucleotide substitution at residue 565 of the human leukocyte antigen HLA‐B*52:01:01:01 results in a new allele, HLA‐B*52:33.

Recognition of the deduced probable HLA haplotypes associated with HLA low incidence alleles B∗13:50 (A∗11:02-B∗13:50-DRB1∗07:01) and B∗51:39 (A∗02-B∗51:39-DRB1∗15; and A∗11-B∗51:39-DRB1∗15) in Taiwanese unrelated hematopoietic stem cell donors

ObjectivesHLA-B∗13:50 and -B∗51:39 are two low incidence alleles in the HLA-B locus. The objective of this study is to report the deduced probable human leukocyte antigen (HLA) haplotypes in association with HLA-B∗13:50 and -B∗51:39 in Taiwanese unrelated bone marrow hematopoietic stem cell donors. Materials and MethodsA sequence-based typing method was used to confirm the two low incidence alleles observed. Polymerase chain reaction was performed to amplify exons 2 and 3 in the HLA-A and HLA-B loci and exon 2 in the HLA-DRB1 locus with group-specific primer sets. Amplicons were sequenced using the BigDye Terminator Cycle Sequencing Ready Reaction Kit in both directions according to the manufacturer's protocols. ResultsThe DNA sequence of B∗13:50 is identical to B∗13:01:01 in exons 2 and 3, except for a one nucleotide substitution at residue 482 (A→T), which results in a one amino acid replacement at position 137 (aspartic acid→valine). We deduced the probable HLA haplotype in association with B∗13:50 in Taiwanese as A∗11:02-B∗13:50-DRB1∗07:01. The DNA sequence of B∗51:39 is identical to B∗51:01:03 in exons 2 and 3 except for two nucleotide exchanges at residue 226 (A→G) and residue 228 (A→G), which result in a one amino acid substitution at position 52 (isoleucine→valine).The probable HLA haplotypes associated with B∗51:39 in Taiwanese may be deduced as A∗02-B∗51:39-DRB1∗15 and A∗11-B∗51:39-DRB1∗15. ConclusionInformation on the deduced HLA haplotypes in association with the low incidence B∗13:50 and B∗51:39 alleles that we report here is valuable for HLA testing laboratories for reference purposes and for stem cell transplantation donor search coordinators, to determine the likelihood of finding compatible donors in unrelated bone marrow donor registries for patients carrying these two uncommon HLA alleles.

HLA‐A*02:466, a variant of HLA‐A*02, discovered in a Taiwanese unrelated hematopoietic stem cell donor

One nucleotide replacement at residue 228 of the human leukocyte antigen HLA-A*02:03:01 results in a novel allele, HLA-A*02:466.

HLA‐A*11:165, a variant of HLA‐A*11, discovered in a Taiwanese unrelated hematopoietic stem cell donor

One nucleotide replacement in codon 145 (CGC>AGC) of the human leukocyte antigen HLA-A*11:01:01 results in a novel allele, HLA-A*11:165.

Cytotoxic T-Lymphocyte Antigen-4 Single Nucleotide Polymorphisms Are Not Associated with Outcomes after Unrelated Donor Transplantation: A Center for International Blood and Marrow Transplant Research Analysis

Cytotoxic T-lymphocyte antigen-4 (CTLA-4) plays an essential role in T cell homeostasis by restraining immune responses. AG and GG genotypes of donor CTLA-4 SNP rs4553808 in patients after unrelated donor hematopoietic stem cell transplantations (HSCT) have been shown to be an independent predictor of inferior relapse-free survival (RFS) and overall survival (OS) compared with those with the AA genotype, in single-center studies. We tested the hypothesis that SNP rs4553808 is associated with RFS, OS, nonrelapse mortality (NRM) and the cumulative incidence of acute graft-versus-host disease (GVHD) and chronic GVHD in adults with acute myeloid leukemia and advanced myelodysplastic syndrome undergoing a first 8/8 or 7/8 HLA-matched unrelated donor HSCT. Multivariable analysis adjusting for relevant donor and recipient characteristics showed no significant association between SNP rs4553808 and OS, RFS, NRM, and incidence of acute and chronic GVHD. An exploratory analysis of other CTLA-4 SNPs, as well as studying the interaction with antithymocyte globulin, also demonstrated no significant associations. Our results indicate that CTLA-4 SNPs are not associated with HSCT outcomes.

Effects of hematopoietic stem cell transplantation on acyl‐CoA oxidase deficiency: a sibling comparison study

Acyl-CoA oxidase (ACOX1) deficiency is a rare disorder of peroxisomal very-long chain fatty acid oxidation. No reports detailing attempted treatment, longitudinal imaging, or neuropathology exist. We describe the natural history of clinical symptoms and brain imaging in two siblings with ACOX1 deficiency, including the younger sibling's response to allogeneic unrelated donor hematopoietic stem cell transplantation (HSCT). We conducted retrospective chart review to obtain clinical history, neuro-imaging, and neuropathology data. ACOX1 genotyping were performed to confirm the disease. In vitro fibroblast and neural stem cell fatty acid oxidation assays were also performed. Both patients experienced a fatal neurodegenerative course, with late-stage cerebellar and cerebral gray matter atrophy. Serial brain magnetic resonance imaging in the younger sibling indicated demyelination began in the medulla and progressed rostrally to include the white matter of the cerebellum, pons, midbrain, and eventually subcortical white matter. The successfully engrafted younger sibling had less brain inflammation, cortical atrophy, and neuronal loss on neuro-imaging and neuropathology compared to the untreated older sister. Fibroblasts and stem cells demonstrated deficient very long chain fatty acid oxidation. Although HSCT did not halt the course of ACOX1 deficiency, it reduced the extent of white matter inflammation in the brain. Demyelination continued because of ongoing neuronal loss, which may be due to inability of transplant to prevent progression of gray matter disease, adverse effects of chronic corticosteroid use to control graft-versus-host disease, or intervention occurring beyond a critical point for therapeutic efficacy.

Injection of G-CSF during leukaphereses reduces the number of aphereses needed for mobilization in unrelated hematopoietic stem cell donors.

This is a single-center, retrospective study in the field of mobilization of hematopoietic stem cell from unrelated donors. We aimed to investigate whether delaying the last G-CSF dose after the start of apheresis influences its results. The medical records of 55 unrelated hematopoietic stem cell donors during the period 2010-2013 were analysed. In this series, 40 received donors the last G-CSF injection prior to the leukapheresis procedure, and 15 received the last injection after apheresis was initiated. In the delayed G-CSF application group, more donors had already reached the requested cell number during first apheresis than in the group treated following the standard procedure (73% vs. 35%, respectively; p<0.01). Also, the average total G-CSF dose needed to mobilize the requested cell number was lower (41 µg/kg vs. 48 µg/kg, respectively, p=0.002). Delayed G-CSF use in donors undergoing stem cell mobilization shows a better efficiency of stem cell mobilization.

Identification and analysis of the rare HLA-A/B/DRB1 allele genes of 10165 bone marrow registry donors in Shaanxi region

This study was purposed to analyze the detected status of rare alleles from HLA-A/B/DRB1 typing of 10165 unrelated hematopoietic stem cell donors in Shaanxi region during 2009-2012. The rare allele distributions of HLA-A/B/DRB1 gene typing of 10165 unrelated-donors from Shaanxi sub-registry of Chinese National Marrow Donor Project (CMDP) were detected and analyzed by PCR-SBT. The results showed that there were 40 rare alleles from 48 donors identified by PCR-SBT in 10165 unrelated-donors of Shaanxi sub-registry. Among them, 10 rare alleles of A*02:04, B*07:10, B*27:09, B*35:11, B*44:29, DRB1*03:04, DRB1*08:18, DRB1*13:05, DRB1*13:14 and DRB1*14:11 from 15 donors were not included in the common alleles and well documented alleles (CWD) of China, but were included in the CWD of American Society for Histocompatibility and Immunogenetics (ASHI). The alleles of A*68:24, B*35:11, B*44:29, DRB1*03:04, DRB1*08:18 and DRB1*13:05 were confirmed in more than two samples. There were totally 21 novel HLA alleles identified by our laboratory and officially assigned by the WHO Nomenclature Committee from 2005 to 2012, and some of them were also detected from multiple donors in other HLA typing laboratories of China. Now the novel alleles of HLA-A*02:90, HLA-B*48:14 and HLA-DRB1*01:14 were added into the Chinese CWD list. It is concluded that to ensure the polymorphism integrity and accurate population distribution of HLA genes and its constant accumulations on CMDP, it is necessary to recognize and submit timely the potential novel alleles in our practical work, as well as to record and statistics the identified rare alleles, which can provide the basis for the modification of Chinese CWD. When CWD list is referred, it should be careful for ambiguous results containing the identified rare alleles in order to avoid the occurrence of false or undiscovered detection, and ensure that the patients carrying rare alleles could find a matching donor with the maximum opportunity.

Comparison of clinical efficacy between HLA-mismatched related and HLA-matched unrelated donor hematopoietic stem cell transplantation for hematopoietic malignancies

ObjectiveTo compare the clinical efficacy of HLA-mismatched related donor (MRD) and HLA-matched unrelated donor (MUD) hematopoietic stem cell transplantation (HSCT) for hematopoietic malignancies, 175 patients with hematopoietic malignancies undergoing allogeneic HSCT (allo-HSCT) (83 from MRD and 92 from MUD) from October 2002 to December 2012 were enrolled in this retrospective study. MethodsOf the 175 patients, 67 were female, and 108 were male. The median age was 27.0 (range 11-53) years. Primary diseases included acute lymphoblastic leukemia (ALL, n=56), acute myelogenous leukemia (AML, n=46), acute leukemias of ambiguous lineage (ALAL, n=13), chronic myeloid leukemia (CML, n=47), myelodysplastic syndrome (MDS, n=7), lymphoma (n=5) and aplastic anemia (AA, n=1). Fifty-seven patients were in the status of no remission (NR), and 118 were complete remission (CR) at the time of transplantation. Genomic molecular typing was used for HLA-A, -B and -DRB in most donors and recipients before May 2008, and then it was used for HLA-A, -B, -DRB, -DRQ and Cw. Hematopoietic engraftment, graft versus host disease (GVHD), relapse, overall survival (OS) and disease-free survival (DFS) were compared between MRD and MUD group. ResultsEighty-three patients received MRD transplantation, including sibling (n=47), parents (n=29), children (n=5) and others (n=2), and 93 received MUD transplantation. Of HLA 6/6 typing, 18 were one allele, 19 two alleles, 1 three alleles-mismatched; of HLA 10/10 typing, 4 were one allele, 17 two alleles, 9 three alleles, 7 four alleles, and 8 five alleles- mismatched in MRD group. Forty-one patients were HLA 6/6 and 51 we HLA 10/10-matched in MUD group. There was no significant difference between MRD and MUD group regarding age, gender, disease type and disease status pre-transplantation (all P>0.05). Except for 4 and 3 patients who died of regimen-related toxicity (RRT), respectively, in MRD and MUD group, other patients obtained hematopoietic engraftment.The median time to neutrophil and platelet engraftment was 11 (range, 9 to 22) days and 13 (range, 10 to 40) days in MRD group, and it was 12 (range, 10 to 29) days and 14 (range, 10 to 60) days in MUD group (P>0.05, P>0.05). The incidence of I-IV0acute GVHD (aGVHD) was 68.7% and 48.9% in MRD and MUD group (P<0.01), but there was no significant difference in the incidence of III-IV0 aGVHD between the two groups (14.5% vs. 8.7%, P>0.05). The incidence of chronic GVHD (cGVHD) was 22.9% and 41.3% in MRD and MUD group (P<0.05), but there was no significant difference in the incidence of extensive cGVHD between the two groups (7.2% vs. 12.0%, P>0.05).The mortality of GVHD was 14.5% and 18.6% in MRD and MUD group (P>0.05).With a median follow up of 51 months (range 1 day-130 months) post-transplantation, the 10- year OS and DFS were 47.2%±6.1% and 42.9%±6.1% in MRD group, compared with 55.1%±5.5% and 45.8%±5.4% in MUD group(P=0.236, P=0.686, respectively). The 10-year cumulative incidence of relapse was 24.8%±6.0% and 39.1%±6.1% in MRD and MUD group (P=0.230). ConclusionsAlthough the incidence of cGVHD was higher in MRD group, there was no significant difference in the incidence of I-IV0aGVHD, III-IV0 aGVHD and extensive cGVHD between MRD and MUD group. Hematopoietic engraftment, cumulative relapse rate, OS and DFS also did not differ significantly between the two groups. These results suggest that MRD is equivalent to MUD in efficacy and safety. Without HLA-matched related donors, MRD is superior to MUD because donor source is unlimited and choice of treatment could be made promptly according to disease status. Disclosures:Liu:It was supported by Science and Technology Program of Guangzhou of China (11A72121174).: Research Funding; It was supported by National Public Health Grand Research Foundation (Grant No. 201202017), National Natural Science Foundation of China (Grant No.81000231, No.81270647).: Research Funding; It was supported by 863 Program (No. 2011AA020105).: Research Funding.

Donor Attrition At The Confirmatory Typing Stage Results In Poorer Transplant Options For Patients Of All Ethnicities

IntroductionIt has been previously recognised that unrelated haematopoietic stem cell donors from certain ethnic minority groups are less likely to be available when called to give a sample for confirmatory (verification) typing (CT), prior to final donor selection. However, a direct impact of such donor attrition on donor selection has not, to date, been shown for patients of any ethnicity. MethodsWe analysed the outcome of CT requests for 303 patients managed by the Anthony Nolan Graft Identification and Advisory Service (GIAS), with the aim of assessing the impact of donor attrition on the speed of donor provision and donor suitability at CT and at transplant. Patient ethnicity was categorised as white Northern European (WNE) or non-white Northern European (non-WNE). A donor was categorised as unavailable if they were unable to return a sample for CT within the timeframe required by the transplant centre, for whatever reason. Requests cancelled by the transplant centre within this timeframe were not categorised as donor attrition. Results235 patients (77.6%) were of white Northern European (WNE) descent, and 68 (22.4%) of non-WNE descent. 43 patients (13.0%) had a high, 141 (42.5%) a medium, 127 (38.3%) a low, and 21 (6.3%) a very low probability of search success (identifying a 10/10 matched donor), based on DRB1 allele and DRB1-DQB1 haplotype frequencies. Donor attrition was more common in those donors requested for CT for non-WNE patients (38.4% vs 24.6%, p<0.001), and more non-WNE patients were affected by at least two incidences of attrition (40.2% vs 29.0%, p=0.059). Patients experiencing two or more incidences of donor attrition had a longer time from first CT request to identifying the donor eventually selected for transplant (median 26 days vs 34.5 days, p<0.001). In addition, donor attrition was associated with fewer patients with at least one 10/10 donor identified at CT (46.5% vs 65.8%, p=0.001), fewer patients with a CMV matched donor at transplant (67.6% vs 80.4%, p=0.044) and fewer patients with a donor aged 30 or less at transplant (44.9% vs 62.8%, p=0.014). When analysing WNE patients alone, similar findings were made. However, the impact of attrition on search outcomes was less for non-WNE patients. Of note, there was only a trend towards a difference in time from first CT request to identifying the donor eventually selected for transplant (29.5 vs 38.5 days, p=0.072), and no impact on number of 10/10 donors identified at CT (22.6% vs 27%, p=0.673). In addition, no impact on CMV status or donor age at transplant was noted for non-WNE patients. Since patients with less common HLA phenotypes are likely to need a greater number of CT requests (and therefore are more exposed to donor attrition), a multivariate analysis was carried out including the probability of search success. For WNE patients, 2 or more episodes of donor attrition remained significantly associated with fewer patients with a 10/10 match at CT (p=0.047), more CMV mismatches at transplant (p=0.043), and fewer donors aged 30 or under (p=0.03). ConclusionWe have shown a significant impact of donor attrition on both search times and the availability of well-matched donors. Donor attrition affects not only the provision of HLA-matched donors, but also those matched for secondary characteristics such as CMV and age. However, despite a higher proportion of non-WNE patients experiencing donor attrition, the overall impact of attrition was less when compared to WNE patients. This may be because non-WNE are already sufficiently disadvantaged by the lack of available HLA-matched donors on international registries that the impact of donor attrition is minor in comparison.Since these variables are strongly associated with survival, donor attrition must be addressed at the donor registry level in order to improve patient outcome following transplant. Disclosures:No relevant conflicts of interest to declare.

Improved Outcomes After Reduced Intensity Conditioning Matched Unrelated Donor Hematopoietic Stem Cell Transplantation In Children With Chronic Granulomatous Disease

BackgroundHematopoietic stem cell transplantation (HSCT) is the only available cure for chronic granulomatous disease (CGD). Preexisting infections tend to put CGD patients at high risk for myeloablative HSCT related complications, making reduced intensity conditioning (RIC) an attractive option for these patients. However, published studies using RIC HSCT in CGD have shown a high rate of graft rejection. ObjectivesTo characterize the clinical features and outcomes of high-risk children with chronic granulomatous disease transplanted at Children's Hospital of Los Angeles with a RIC regimen. MethodsPatients with CGD with pre-existing co-morbidities that precluded the use of myeloablative HSCT and who received RIC HSCT were selected for review. Conditioning regimen consisted of targeted dose Campath (with level monitoring), Fludarabine 30 mg/m2/dose x 3 doses and Total Body Irradiation 200 cGy x 2 doses. Tacrolimus (or cyclosporine) and Mycophenolate Mofetil (MMF) were used for graft-versus-host disease (GVHD) prophylaxis. ResultsFour children (median age 102 months, range 24-180 months) with severe CGD (serious bacterial/fungal infections pretransplantation) and significant comorbidities (Table 1) received RIC matched unrelated donor HSCT. Two patients received a 9/10 HLA allele matched graft, and the other two received a 10/10 HLA allele matched graft. Three patients received peripheral blood stem cells (PBSCs), and the one other patient received a bone marrow (BM) graft. For the PBSC grafts, the mean total nucleated cell (TNC) dose was 24.3 x 10e8/kg (range 11.9-24.5 x 10e8/kg), the mean CD34+ cell dose was 9.4x10e6/kg (range 3.7-11.8 x 10e6/kg), and the mean CD3+ cell dose was 60.3x10e7/kg (range 33.8-77.1 x 10e7/kg). The patient who received a bone marrow graft developed primary graft failure and autologous recovery 4 months after HSCT. Only one patient who was non-compliant with immune-suppressive medications developed grade 4 acute graft-versus-host disease (GVHD) with subsequent extensive chronic GVHD. None of the other patients have any evidence of active GVHD at the most recent follow up. Median follow up of all patients is 23.5 months (range 13-28 months) and three of the four patients are alive with a high donor chimerism (100%). DiscussionPatients with CGD often have multiple co-morbid conditions that lead to an increased risk of transplantation related mortality with myeloablative conditioning regimens. RIC regimens are increasing being used to decrease the short and long term toxicity of transplantation. Previous studies have suggested a high rate of graft rejection with RIC in CGD. Most of the published data on RIC HSCT in CGD patients pertains to the use of bone marrow grafts from HLA-matched siblings. In our series, we demonstrate that RIC (campath, fludarabine, and TBI) matched unrelated donor PBSC transplantation in CGD patients with life threatening infections leads to excellent engraftment, durable donor chimerism, and correction of neutrophil dysfunction, excellent survival and a low incidence of severe graft-vs-host disease. Thus, RIC HSCT represents a possible curative strategy for CGD patients with co-morbidities who are not eligible for myeloablative HSCT. Disclosures:No relevant conflicts of interest to declare.

HLA-B*58:45, a variant ofHLA-B*58, found in a Taiwanese unrelated hematopoietic stem cell donor

A single nucleotide substitution at residue 595 (G→A) of the human leukocyte antigen HLA-B*58:01:01 results in a novel allele, HLA-B*58:45.

Pericardial Constriction Attributable to Graft-Versus-Host Disease

Graft-versus-host disease (GVHD) occurs as a complication of hematopoietic stem cell transplantation when donor immune cells attack host cells identified as immunologically nonself. This is beneficial in completing the eradication of residual malignant cells (the graft versus tumor effect), but detrimental through attack on other host cells and subsequent manifestations of acute and chronic GVHD. Cardiac manifestations of GVHD are rare and include pericardial effusion, coronary artery disease, and conduction abnormalities.1 There are only 2 previously described cases of GVHD-induced pericardial constriction.2,3 Here, we report a case of hematopoietic stem cell transplantation complicated by constrictive pericarditis associated with chronic GVHD of the pericardium, which showed rapid response to systemic corticosteroids. A 44-year-old information technology consultant and keen long-distance cyclist was referred to the cardiac clinic for investigation of dyspnoea. He was diagnosed 4 years previously with Philadelphia-positive acute lymphoblastic leukemia, and was refractory to induction chemotherapy, later achieving morphological remission with imatinib and Ida-FLAG (idarubicin, fludarabine, cytarabine, and granulocyte colony–stimulating factor). He went on to have hematopoietic stem cell transplantation with a regime involving full intensity myeloablation and total body irradiation, followed by infusion of matched unrelated donor hematopoietic stem cells. He made a good initial recovery, complicated only a pleural effusion managed …

Odontoid infiltration and spinal compression in Farber Disease: reversal by haematopoietic stem cell transplantation

Farber disease (FD) is a lysosomal storage disorder caused by accumulation of ceramide in various organs and tissues, most notably the central nervous system, subcutaneous tissues and respiratory tract. We report a girl who developed major destructive bone involvement, which affected the odontoid process and produced spinal compression at 9 years of age. Bone involvement was proven histologically but resolved, as assessed by serial MRI scanning, following matched unrelated donor haematopoietic stem cell transplantation. This transplant resulted in only partial donor chimerism (less than 10 % donor cells in peripheral blood), yet this was sufficient to almost normalize acid ceramidase levels in leukocytes and to produce dramatic improvements in subcutaneous nodules and joint mobility as well as the beneficial effect on the involved bone. Unfortunately, the transplant was rejected after 2 years but the patient was rescued from an aplastic state by successful haploidentical peripheral blood stem cell transplantation and remained a full donor chimera without recurrence of the bone involvement and with steadily improving mobility at the age of 17 years. We describe an FD patient who presented with severe destruction of the odontoid by inflammatory tissue which was reversed after long-term control achieved by allogeneic hematopoietic stem cell transplantation. After extensive literature search, we believe that this is the first report of bony involvement in Farber disease.

An update to the HLA Nomenclature Guidelines of the World Marrow Donor Association, 2012

For more than two decades, international cooperation and information technology have been playing key roles in the identification of suitable unrelated donors and cord blood units for hematopoietic SCT. To ensure consistent coding and interpretation of HLA data among the linked computer systems, the World Marrow Donor Association has standardized the extensions of the World Health Organization (WHO) Nomenclature for factors of the HLA system applied in practice. The first version of this report published in 2007 has become the reference for the technical validation of HLA information on donors and patients in the context of search and matching and is used by registries of volunteer unrelated hematopoietic stem cell donors and umbilical cord blood banks throughout the world. The present update became necessary after the major revision of the WHO HLA nomenclature in April 2010. It now covers issues arising when alleles are withdrawn or renamed because of the continuous updating of the WHO HLA nomenclature. In addition, formal validation and interpretation rules for the so-called 'multiple allele codes' have been added.

Significance of Ethnicity in the Risk of Acute Graft-versus-Host Disease and Leukemia Relapse after Unrelated Donor Hematopoietic Stem Cell Transplantation

The significance of patient and donor ethnicity on risk of acute graft-versus-host disease (GVHD) and disease relapse after unrelated donor hematopoietic cell transplantation (HCT) is not known. A total of 4335 patient–donor pairs from the International Histocompatibility Working Group in HCT met the following 3 criteria: (1) HLA-A, -B, -C, -DRB1, and -DQB1 allele matched donor, (2) diagnosis of leukemia, and (3) non–T cell depleted GVHD prophylaxis. Posttransplantation risks of acute GVHD and leukemia relapse were defined in Asian/Pacific Islander, white, African American, Hispanic, and Native American patients that underwent transplantation from donors with the same self-described background. Asian patients had a significantly lower incidence of acute GVHD (Japanese patients: 40.0% grades II to IV and 15.3% grades III to IV; non-Japanese Asian patients: 42.1% grades II to IV and 15.7% grades III to IV) compared with white patients (56.5% grades II to IV and 22.6% grades III to IV) (P < .001). The hazard ratio of acute GVHD for white patients was significantly higher than for Japanese patients. Unexpectedly, the hazard ratio of leukemia relapse in white patients with early disease status was also significantly higher than that in Japanese patients. These results provide a platform for future investigation into the genetic factors for unrelated donor HCT and clinical implications of diverse ethnic background.

Efficacy analysis of unrelated donor hematopoietic stem cell transplantation for treatment of high risk acute myeloid leukemia

This study was purposed to investigate the therapeutic efficacy of unrelated donor hematopoietic stem cell transplantation (URD-HSCT) for patients with high risk and refractory acute myeloid leukemia (AML). Twenty-two patients with high-risk and refractory AML receive URD-HSCT were enrolled in this study. All the patients received myeloablative preconditioning regimen consisting of busulfan/cyclophosphamide (for 20 cases) or total body irradiation/cyclophosphamide (for 2 cases) before URD-HSCT. The cyclosporin A (CsA)/MTX/MMF/ATG were used to prevent the acute graft versus host disease (aGVHD). The results showed that 21 out of 22 patients acquired engraftment with implantation rate 95.5%. The median time of ANC ≥ 0.5×10(9)/L was 12 (10-19) days, and that of Plt ≥ 20×10(9)/L was 14 (5 - 22) days. The median follow-up time post transplantation was 18 (3 to 135.5) months. The 2-year overall survival (OS) and leukemia-free survival (LFS) were (53.9 ± 12.2) % and (49.1 ± 10.7)% respectively. Eight cases developed aGVHD. The cumulative incidence of aGVHD was (39.1 ± 10.6) %. Six patients developed I-II grade of aGVHD and two patients developed III-IV grade of aGVHD. The chronic graft versus host disease (cGVHD) was occurred in 6 patients (4 patients limited, 2 patients extensive) of the 19 evaluable patients. The cumulative incidence was (28.8 ± 9.6)%. Seven cases relapsed, and the cumulative response rate of 2 years was (35.8 ± 11) %. One of 9 patients died from sepsis before hematopoietic reconstruction, one died from lung infection, Six died from relapse and one relapsed patient died from IV grade of aGVHD post chemotherapy and donor lymphocyte infusion (DLI). The univariate analysis revealed that relapse was the major factor for the OS, and the sex, age, preconditioning regimen, aGVHD and infection didn't significantly influence the efficacy of URD-HSCT. The survival of patients with cGVHD was superior to those who didn't have cGVHD (83.3% vs 37%, P = 0.152). It is concluded that URD-HSCT is a safe and effective therapy for high-risk AML patients without related donor. Notably, patients with cGVHD had a better survival. Relapse is an unfavourable factor for the efficacy of URD-HSCT and adoptive immunotherapy such as DLI can prevent it and improve the prognosis to achieve the long-time survival.

Race and ethnicity in decisions about unrelated hematopoietic stem cell donation

AbstractLarge international registries of potential unrelated hematopoietic stem cell (HSC) donors, including the National Marrow Donor program (NMDP), continue to face difficulties finding matched donors for racial/ethnic minorities. One reason, in addition to the generally less common HLA types among minority patients, is the much higher registry attrition rate of racial/ethnic minorities compared with whites. Reasons for the higher attrition among minority potential donors remain unexplained. The goal of our cross-sectional telephone interview study was to generate a diverse sample of potential HSC donors who have preliminarily matched a patient and to identify factors associated with race/ethnicity and with the decision to continue toward potential donation or to opt out of the registry. Multiple culturally related, psychosocial, and donation-related factors were associated both with race/ethnic group membership and attrition from the registry. The most consistent factor associated with opting out of the registry across all race/ethnic groups was ambivalence about donation: doubts and worries, feeling unsure about donation, wishing someone else would donate in one's place. Our findings suggest that universal donor recruitment and management approaches based on reducing donation-related ambivalence and tailored messages and strategies for each of the individual race/ethnic groups are important.

A one‐step DNA sequencing strategy to HLA type hematopoietic stem cell donors at recruitment – rethinking typing strategies

In order to reduce the time required to identify a match for unrelated donor hematopoietic stem cell transplantation, a one-step DNA sequencing strategy was employed at the time of recruitment. The impact of this strategy on human leukocyte antigen (HLA) typing resolution and the effect of current registry requirements on resolution and coding of assignments were evaluated. Sanger-based DNA sequencing was used to obtain diploid exons 2 and 3 HLA-A, -B and -C assignments of 2747 unrelated African American and 1822 European American volunteers at recruitment. The results demonstrate the high resolution of the approach and challenge several aspects of the current registry typing strategy. Of the 46% of African American and 74% of European American individuals whose HLA typing resulted in alternative genotypes, the majority (≥93%) was predicted to have only a single 'common' genotype among the alternatives. The common practice of adding secondary assays to resolve alternative genotype assignments that include more than two antigen groups was also evaluated. While the percentage of assignments with greater than two antigen groups reached as high as 21% (HLA-A in European Americans), only 1.8% of individuals at most carried two common genotypes encompassing three antigen groups. The assignment of (National Marrow Donor Program) NMDP-designated allele codes to the one-pass results reduced the resolution substantially and introduced genotypes that were not included in the laboratory's assignments. We suggest the alternative strategy of using the exons 2-3 diploid nucleotide sequence as the assignment submitted to the registry with the added benefit of immortalizing the assignment in time regardless of the introduction of novel alleles. To keep pace with current donor selection criteria and with the increasing number of new alleles, it is time to rethink our recruitment typing strategies.