Search For Unrelated Bone Marrow Donors Research Articles

High-resolution HLA phased haplotype frequencies to predict the success of unrelated donor searches and clinical outcome following hematopoietic stem cell transplantation

HLA matching is a critical factor for successful allogeneic hematopoietic stem cell transplantation. For unrelated donor searches, matching is usually based on high-resolution typing at five HLA loci, looking for a 10/10 match. Some studies have proposed that further matching at the haplotype level could be beneficial for clinical outcome. In this study, we determined the phased haplotypes of 291 patients using family members and segregation analysis. The sum of ranks of the haplotypes carried by patients was used as a surrogate predictor of a successful unrelated donor search. The putative impact of haplotypes was then analyzed in a cohort of 211 recipients transplanted with 10/10 matched unrelated donors. A logistic regression analysis showed a highly significant effect of the haplotypes in the outcome of a search, but we did not find any significant effect on overall survival, graft versus host disease or relapse/progression following HSCT. This study provides useful data for the optimization of unrelated bone marrow donor searches, but does not confirm previous reports that matching at the haplotype level has a clinical impact following HSCT. Due to the extreme polymorphism of HLA genes, further studies are warranted to better understand the many factors at play.

HLA class I null alleles and new alleles affect unrelated bone marrow donor searches

Unrecognized HLA null alleles or new alleles may affect the outcome of bone marrow transplants using unrelated donors. Some reports suggest that null alleles occur in the range of 0.003-0.07% (1, 2), which has led some transplant programs to stop performing serologic typing. We describe nine cases involving expression variants or new alleles. Three cases involved expression variants, including two null alleles and A*24020102L. One of the null alleles was a new variant of A*02. Seven cases involved new alleles. In five cases, there where discrepancies between HLA typing by serology and PCR-SSP. These included the three expression variants, one new B40 allele that typed serologically as B41 and one new B*07 allele that typed serologically as B42. Eight of these cases were found in the course of typing bone marrow transplant patients or potential unrelated donors since May of 2001 (total tested, 710 patients, 1914 donors). Thus, the incidence of null alleles was two in 2,624 (0.08%). Sequence-based typing (SBT) was performed on 676 of these samples. The decision to perform SBT was influenced by finding a serologic typing discrepancy in two cases. In one of those cases, SBT would probably have been performed at a later time, prior to final selection of a donor. Thus, the incidence of new alleles was between 4 and 6 of 676 (0.59-0.89%). We conclude that new HLA alleles and null alleles are uncommon but not extremely rare, and they continue to affect a significant number of unrelated donor searches.

New HLA class I alleles and null alleles effect unrelated bone marrow donor searches: Do we still need serologic typing?

New HLA class I alleles and null alleles effect unrelated bone marrow donor searches: Do we still need serologic typing?

Bone marrow transplantation with unrelated donors: what is the probability of identifying an HLA-A/B/Cw/DRB1/B3/B5/DQB1-matched donor?

Patients transplanted with marrow from an HLA-ABDR serologically matched unrelated donor suffer from more post-transplant complications than those who are transplanted with marrow from an HLA-identical sibling. This is most likely due to either HLA-ABDR incompatibilities not resolved by standard techniques and/or HLA polymorphisms not tested for by routine tissue typing (HLA-Cw,-DQ). By resolving these incompatibilities by molecular techniques combined with the in vitro cytotoxic T lymphocyte precursor frequency (CTLpf) test, we have shown that a high degree of HLA compatibility is associated with increased patient survival. However, higher requirements for HLA matching decrease the number of available donors. We have estimated the probability of finding an HLA-A/B/Cw/DRB1/DRB3/DRB5/DQB1 compatible donor based on 104 consecutive unrelated bone marrow donor searches initiated between January 1995 and December 1997, with December 1998 as the endpoint. For 96 patients (92.3%), one or more ABDR-identical donors were listed in the Bone Marrow Donor Worldwide Registry (BMDW). After contacting the registries, we obtained at least one (mean, 5.36; range, 1-20; total, 461) blood sample for 86 patients. A highly compatible donor was identified for 33/86 patients (38.4%), after testing an average number of 4.5 donors/patients (range, 1-13). However, by accepting an HLA-DRB3 or -DQB1 or -Cw incompatibility, this number would be as high as 68.6%. Approximately half of the patients (n = 40) for whom a search had been initiated have been transplanted: 22 patients with a perfectly matched donor, 15 patients with an HLA-DRB3 or -DQB1 or -Cw mismatch and three with other mismatches. The average time needed to identify the most compatible donor was 4 months. Extremely long searches seemed to be less useful, because after testing the first seven, a more compatible donor was seldom found. These results show that even when requirements for compatibility are high, the chances of finding a donor remain considerably low.

Outcome of unrelated bone marrow donor searches in 174 children resulting in 45 patients transplanted in the HLA-matched and -mismatched situation.

The aim of the study was to evaluate the outcome of unrelated bone marrow donor (UBMD) searches initiated for 174 children between 1986 and 1997. Seven patients were registered twice so that a total of 181 UBMD searches took place. At the time of registration, patients suffered from hematological malignancies (n = 121), non-malignant hemopathies (n = 26) and inborn errors (n = 34). Forty-five of the patients (26%) were given transplants from unrelated donors of whom 26 (58%) were HLA-mismatched transplants. Our strategy accepted HLA mismatches at the time of donor selection, using Thymoglobuline as part of the conditioning regimen. Of the 45 patients given unrelated donor transplants, overall survival was 60% at 3 years and concerned 27 patients of whom 14 were from HLA-mismatched donors. Disease-free survival for hematological malignancies was 65% in HLA-matched transplants and 50% in HLA-mismatched transplants. For some patients (16%) urgency led us to use alternative options: non-identical related donor (n = 14), autograft (n = 10), related cord blood transplant (n = 4). For others, UBMD searches were stopped because of favorable evolution (n = 29), death (n = 24), disease progression (n = 22) or other reasons (n = 21). By the end of the follow-up period, 88 patients had died (50%), 75 (43%) are currently alive with or without being transplanted of whom eight are still having active searches and 11 are no longer contactable. In conclusion, in severe disease in children, an immediate transplant from a partially matched donor might be preferable to a prolonged search for a full match. Consequently, this strategy increases the number of patients for whom a suitable donor can be found. We have chosen this option in order not to delay BMT; in so doing we have obtained encouraging results which include high overall survival, low incidence of acute GVHD grade III-IV and low percentage of relapse even in mismatched pairs.

Sequencing of two HLA-A blank alleles: implications in unrelated bone marrow donor matching.

DNA-based methods can type for HLA antigens with no or very low cell surface expression. The role of such serological blank antigens in bone marrow donor selection is unknown. HLA-A serological blank antigens detected in two leukemic patients were cloned and sequenced from genomic DNA. mRNA expression and exon 3 splicing were determined by reverse transcriptase-polymerase chain reaction (PCR). Two patients typed A2/x and A3/x by serology were revealed to be A*01/A*0201 and A*03/A*24 by DNA typing. The HLA-A*O1 blank antigen was identified as the A*0104N allele with a C insertion in exon 4, which results in a stop codon. The HLA-A*24 blank antigen was identified as the A*2402102L allele characterized by a mutation in intron 2 leading to impaired splicing of mainly exon 3. As a consequence, functional A24 mRNA was reduced to less than 5% compared with the other HLA-A allele. For both patients, a search for an unrelated donor was initiated on the basis of the functional absence of the serologically blank allele. The second patient with the A*24 blank antigen could undergo transplantation with marrow from a "fully A/B/C/DRB1/DRB5/DQB1-compatible" donor, homozygous for the A antigen. Donor T cells did not react against the patient in a pretransplantation cytotoxic T lymphocyte precursor frequency test known to detect all class I incompatibilities. However, despite this functional pretransplantation compatibility, the patient died 44 days after bone marrow transplantation, suffering from graft-versus-host disease grade IV. The presence of potentially functional A*2402 mRNA could be demonstrated by reverse transcriptase-PCR and sequencing: 50% of the A24 mRNA molecules were estimated to contain exon 3 with a correct splice site. These findings show that serological blank antigens with low mRNA expression might still be recognized after bone marrow transplantation. The determination of such alleles by molecular methods and the assessment of mRNA expression should therefore be included in the unrelated bone marrow donor search protocol.

OUTCOME OF 158 CHILDREN REGISTERED ON UNRELATED BONE MARROW DONORS FILES. 145

From `86 to `96, 163 unrelated bone marrow donor (UBMD) searches for 158 children were performed in our institution. the 79 male and 79 female (pts) aged from 1 month (m) to 18 years (y) (mean: 7.2 y) at time of registration suffered from Severe Haematological Malignancies (n=108) including 69 ALL, 15 AML, 5 CML, 18 Myelodysplastic Syndroms, 1 Lymphoma; Non Malignant Hemopathies(n=23): 17 Aplastic Anaemia, 6 Fanconi; Metabolic Diseases/ID (n=27): 13 Hurler, 1 Gaucher, 2 Mucolipidosis, 1 Osteopetrosis, 6 FLH, 2 ID, 1 WA, 1 Kossman. They were eligible for a transplant procedure but the lack of family-member donor attempted us to search UBMD on international registries. The mean duration of searches was 16 m (range 9 days to 85 m). In `93, we speed the procedure to short the donor location delay reduced from 7 to 2 m(median). Eleven searches remain active today. For other pts, causes of cancellation are classified as follows: Complete Remission (CR): n=25 (17%), Deceased: n=23 (15%), Clinical status/disease progression: n=17 (11%), Allograft unrelated: n+35 (24%), Non identical Allograft Familiar: n=12 (8%), Cord blood transplantation: n=4 (3%), Autograft: n=10 (7%), Therapeutic failure/relapse (n=3), Other Causes (transfer, parents request, SAL/GCSF): n=17 (11%. All pts canceled because of disease progression died except 2 (1/2 autografted). When searches were stopped because of prolonged CR, evolution was favourable in 22/25 cases: 1 pt alive after autograft, 1 after transplant with geno id sib. born in the meantime, 1 pt died of relapse after prolonged CR of 7 y. Sixty-two patients were transplanted (39%): 35 from UBMD (3 pts transplanted twice with same UBMD), 12 from non id. familiar donor, 2 from geno-id. sibling (born in the meantime), 4 from familiar cord blood, 10 were autografted. The overall survival for unrelated BMT concerns 20/35 pts (57%): 7 ALL, 1 AML, 2 RAEBt, 1 JCML, 1 CML, 1 AA, 4 Hurler, 1 mucolip., 2 FLH. The event free survival for the 17 pts in CR with functional graft is of 59%. Among the 12 pts transplanted from non id. familiar donor, 2 are alive (1 ID/PNP, 1 FLH) but with graft failure. One patient (Hurler) transplanted with cord blood cells (HLA ½ id.) is alive but without engraftment. Four of 10 pts are alive in CR (40%). The 2 pts transplanted with geno-id brother are alive in CR. Among the 158 pts registered, 80 died (50%), 66 are alive with or without being transplanted (42%) of whom the 11 activated searches (2 BMT in progress) and 12 are lost of sight. For 3 pts who died, 1 IBMD was located too late for BMT. For 7 pts in prolonged CR, 1 or more UBMD are identified. For all high risk pts, BMT is the only therapeutic alternative and UBMD search is capital in their management.

Progress of unrelated bone marrow donor search at the University Hospital of Essen (1991–1994)

The development of unrelated bone marrow donor search (UMDS) was analyzed in a retrospective single-center study covering the period from 1991 to 1994. The data files of the 285 enrolled UMDS patients were evaluated for the patients' underlying disease, HLA phenotype frequency, year of search start, UMDS duration/outcome, and the origin of identified donors. Within 3 months after UMDS start, a donor was found in 5%, 10%, 19%, and 49% of the searches started in 1991 (n = 57), 1992 (n = 73), 1993 (n = 77), and 1994 (n = 78, until September), respectively. The total UMDS success rate increased from 53% (1991 group) to 67% (1994 group), with 5% and 54%, respectively, of the accepted donors being supplied by German registries. Thus, the current UMDS procedure provides a suitable donor for the majority of the patients lacking a related donor, and the majority of the donors are now facilitated by national donor centers.

Progress of unrelated bone marrow donor search at the University Hospital of Essen (1991?1994)

Progress of unrelated bone marrow donor search at the University Hospital of Essen (1991?1994)