High-resolution HLA Matching Research Articles

Existence of HLA-Mismatched Unrelated Donors Closes the Gap in Donor Availability Regardless of Recipient Ancestry

In patients without a matched sibling donor (MSD) or well-matched unrelated donor (MUD), hematopoietic cell transplantation (HCT) can still be successful when using an HLA-mismatched unrelated donor (MMUD) in combination with post-transplantation cyclophosphamide (PTCy), abatacept, or other novel approaches. This may allow clinicians to choose a suitable donor from a wide range of donor options while optimizing other donor selection characteristics, including donor age. We hypothesized that allowing for a 5/8 HLA match level considering high-resolution matching at HLA-A, -B, -C and -DRB1, there is a potential to close the donor availability gap for all patients regardless of their race/ethnicity. In this work, we estimate the likelihood of matching for all racial/ethnic groups at different HLA match thresholds. Our study aimed to assess the potential for identifying an available MUD or MMUD in the National Marrow Donor Program (NMDP)/Be The Match (BTM) donor registry for 21 detailed and 5 broad racial/ethnic groups, using high-resolution HLA matching for HLA-A, -B, -C, and -DRB1 at various levels (8/8, 7/8, 6/8, and 5/8). We used donor registry population data from the NMDP/BTM in 2020 and redistributed the donor registry data according to existing population ratios, accounting for demonstrated donor availability. Finally, we used a genetic model at the population level to estimate the match likelihood for detailed and broad racial/ethnic groups. Likelihood of 8/8 HLA match ranging from 16% to 74% were obtained for various detailed racial/ethnic groups with available donors age ≤35 years. When considering more mismatches in the HLA loci, registry coverage became >99% with a 5/8 HLA match level for donors of all ages or those age ≤35 years, with HLA-DPB1 T cell epitope permissive matching, or when searching for donors outside of their racial/ethnic group. Our registry models demonstrate the potential for using MMUDs at various HLA match levels to study whether this will expand access to HCT across racial/ethnic groups. Expanded donor options may erase the donor availability gap for all patients while allowing for selection of MMUDs with favorable characteristics, such as younger age.

Third party CMV viral specific T-cells for refractory CMV viremia and disease after hematopoietic transplant.

Refractory CMV viremia and disease are associated with significant morbidity and mortality in recipients of hematopoietic stem cell transplant (HCT). In Phase I/II trials, we treated 67 subjects for CMV viremia or disease arising after allogeneic hematopoietic cell transplant with adoptive transfer of banked off-the-shelf, 3rd party, CMVpp65-sensitized T cells (CMVpp65-VSTs). All were evaluable for toxicity and 59 for response. Evaluable subjects had CMV disease or persisting viremia that had failed at least two weeks of induction therapy with a median of 3 antiviral drugs; 84.7% had >3/11 high risk features. CMVpp65-VSTs were specific for 1-3 CMVpp65 epitopes, presented by a limited set of HLA class I or II alleles, and were selected based on high resolution HLA matching at 2/10 HLA alleles and matching for subject and subject's HCT donor for ≥1 allele through which the CMVpp65-VSTs were restricted. T-cell infusions were well tolerated. Of 59 subjects evaluable for response, 38 (64%) achieved complete or durable partial responses. Recipients responding to CMVpp65VSTs experienced an improved overall survival. Of the risk factors evaluated, transplant type, recipient CD4+ and CD8+ T-cell levels prior to adoptive therapy, and the HLA-restriction of CMVpp65-VSTs infused each significantly affected responses. In addition, CMVpp65-specific T cells of HCT donor or recipient origin contribute to the durability of both complete and partial responses. The trials describe were registered with the NIH as follows: NCT00674648, NCT01646645 and NCT02136797. They were single center investigator-initiated trials and were not industry sponsored. This study was supported by funding from the National Institute of Health (P01 CA23766, R21 CA162002 and P30 CA008748), the Aubrey Fund, Claire Tow Foundation, Major Family Foundation, "Rick" Eisemann Pediatric Research Fund, Banbury Foundation, Edith Robertson Foundation, and Larry Smead Foundation.

Eplet mismatch scores and de novo donor-specific antibody development in simultaneous pancreas-kidney transplantation

Antibody-mediated rejection is the principal cause of allotransplant graft failure. Available studies differ on the impact of de novo donor specific antibody (dnDSA) in pancreas transplants but are limited by patient sample size and sera sample collection. High-resolution HLA incompatibility scoring algorithms are able to more accurately predict dnDSA development. We hypothesized that HLA incompatibility scores as determined by the HLA-Matchmaker, HLA-EMMA, and PIRCHE-II algorithms would serve as a predictor of de novo donor specific antibody (dnDSA) development and clarify the role dnDSA as detrimental to simultaneous pancreas-kidney graft survival.Our results show that female sex and race were significantly associated with dnDSA development and dnDSA development resulted in worse kidney and pancreas graft survival. The majority of individuals who developed dnDSA (88%), developed anti-HLA-DQ antibody in some combination with anti-HLA class I or -DR. A multivariate analysis of the incompatibility scores showed that both HLA-Matchmaker and PIRCHE-II scores predicted anti-DQ dnDSA development. An optimal cutoff threshold for incompatibility matching was obtained for these scores and demonstrated statistical significance when predicting freedom from anti-DQ DSA development.In conclusion, increased scores from high-resolution HLA matching predict dnDSA development, and dnDSA is associated with antibody-mediated rejection and worse pancreas and kidney graft outcomes.

IFNL4 and donor selection for matched unrelated donor haematopoietic stem-cell transplantation

IFNL4 and donor selection for matched unrelated donor haematopoietic stem-cell transplantation

The value of high-resolution HLA in the perioperative period of non-sensitized lung transplant recipients.

The importance of HLA antigen matching is widely recognized and accepted worldwide. With the improvement of diagnostic methods, recent studies have shown that eplet mismatched for organ transplantation is essential. In the field of lung transplantation, eplet mismatch (MM) is closely related to chronic rejection after lung transplantation. To further investigate the relationship between early graft failure and acute rejection, we performed high-resolution HLA analysis on 59 patients in our center. We conduct high-resolution HLA matching and Donor specific antibody (DSA) monitoring on 59 lung transplantation donors and recipients from April 1, 2018, to June 30, 2019. Baseline data were collected composed of both recipient characteristics and transplant-related features. Clinical outcomes were primary graft dysfunction (PGD) and acute rejection (AR). Overall, for these 59 patients, HLA antigen mismatch is 7.19±1.61, eplet mismatch is 8.31±1.75 (P=0.0005). As the number of mismatch sites increases, the severity of PGD increased significantly, especially when presented both eplet mismatch and HLA-DQ mismatch. In this group of patients, 2 cases of antibody-mediated rejection (AMR) occurred after transplantation, eplet MM 9 (HLA-DQ MM 2) and eplet MM 5 (HLA-DQ MM1). Both patients developed DSA after operation, and they are DQB1 06:01 and C07:02, respectively. There were 9 cases of death during the perioperative period. Five of them died of severe PGD, and 4 died of severe infection. All these 9 patients were with high-level eplet MM and HLA-DQ MM. Perioperative PGD and AR closely related to HLA mismatches, especially eplet and HLA-DQ MM. It might be noteworthy to do complementary detection of eplet matching and DSA in lung transplant donors and recipients, to predict the risk of early PGD and acute rejection after lung transplantation.

Evaluation of Cord Blood Total Nucleated and CD34+ Cell Content, Cell Dose, and 8-Allele HLA Match by Patient Ancestry.

How cord blood (CB) CD34+ cell content and dose and 8-allele HLA match vary by patient ancestry is unknown. We analyzed cell content, dose, and high-resolution HLA-match of units selected for CB transplantation (CBT) by recipient ancestry. Of 544 units (286 infused, 258 next-best backups) chosen for 144 racially diverse adult patients (median weight, 81 kg), the median total nucleated cell (TNC) and CD34+cell +contents were higher for Europeans than for non-Europeans: 216 × 107versus 197×107 (P=.002) and 160 × 105 versus 132 × 105 (P=.007), respectively. There were marked cell content disparities among ancestry groups, with units selected for Africans having the lowest TNC (189×107) and CD34+ cell (122×105) contents. Units for non-Europeans were also more HLA-mismatched (P=.017). When only the 286 transplanted units were analyzed, the adverse effect of reduced cell content was exacerbated by the higher weights in some groups. For example, northwestern Europeans (high patient weight, high unit cell content) had the best-dosed units, and Africans (high weight, low unit cell content) had the lowest. In Asians, low cell content was partially compensated for by lower weight. Marked differences in 8-allele HLA-match distribution were also observed by ancestry group; for example, 23% of units for northwestern Europeans were 3/8 to 4/8 HLA-matched, compared with 40% for southern Europeans, 46% for white Hispanics, and 51% for Africans. During the study period, 20 additional patients (17 non-Europeans; median weight, 98 kg) did not undergo CBT owing to the lack of a suitable graft. CB extends transplantation access to most patients, but racial disparities exist in cell content, dose, and HLA match.

Confirmation of High Resolution Antiviral HLA Restrictions Correlates with Antiviral Responses Following Virus-Specific T-Cell Therapy

Background Adoptive immunotherapy using virus-specific T-lymphocytes (VSTs) have been successful in treating viral infections in immunocompromised patients, and use of VSTs from healthy third-party donors have improved the accessibility and timeliness of this therapy. However, best methods of donor/recipient matching of HLA-mismatched VST products remain unclear. Objective To determine the factors influencing the chances of antiviral responses following VST therapy between HLA-mismatched donor/recipient pairs. Design/Methods Patients who received HLA-mismatched VST infusions for active infections with CMV, Epstein-Barr virus, or adenovirus were analyzed for response. Antiviral response was defined as >1 log decrease in viral load within 3 months of VST infusion. Degree of high and low resolution HLA match was determined, and presence of confirmed antiviral HLA restrictions in the utilized VST products was recorded. Unpaired, 2-tailed T-tests were performed for group comparisons. Results Twenty one patients received 30 VST infusions with 27 T-cell products (20 from third-party donors, and 7 from mismatched related donors). Eleven patients were treated for CMV, 8 for adenovirus, and 2 for EBV infection. All patients had persistent viral infections in spite of standard antiviral therapy prior to study enrollment. Seven patients were admitted to intensive care units due to severe viral disease and received VSTs under expanded access for emergency treatment. Overall, of this poor prognosis patient cohort, 12 achieved antiviral responses within 3 months of infusion (2 of 7 patients who received VST derived from MMRD, and 10 of 20 patients who received third-party VSTs). Of 25 evaluable infusions, chances of antiviral response following VST infusion were greater when utilizing a VST product with a confirmed antiviral HLA restriction that is shared at high resolution with the recipient (p=0.02). There was no difference in overall degree of HLA match between responders and non-responders (p=0.83). Conclusions VST matching based on sharing of high resolution HLA alleles that mediate target antiviral restrictions is more successful than overall degree of HLA match. Further testing of this methodology for VST therapy is ongoing in a current phase II trial (PBMTC SUP1701).

The effect of NIMA matching in adult unrelated mismatched hematopoietic stem cell transplantation - a joint study of the Acute Leukemia Working Party of the EBMT and the CIBMTR.

Hematological malignancies can be cured by unrelated donor allogeneic HSCT and outcomes are optimized by high-resolution HLA matching at HLA-A, -B, -C, -DRB1 and -DQB1 (10/10 match). If a 10/10 match is unavailable, 9/10 matches may be suitable. Fetal exposure to non-inherited maternal antigens (NIMA) may impart lifelong NIMA tolerance modulating the immune response, as shown in adult haploidentical transplantation. In cord blood transplantation, NIMA matching lowered rates of aGvHD and TRM; in haploidentical transplantation, sibling donors with non-shared maternal antigens showed less grade II-IV aGvHD. This retrospective analysis examined if 9/10 matched unrelated donor HSCT benefits from NIMA matching. DKMS contacted 1,735 donors and obtained 733 (42%) maternal samples. NIMA-matched and -mismatched cases with a minimum follow-up of 1 year were compared by univariate and multivariate analyses adjusted for co-variates for OS, DFS, relapse, TRM and a/cGvHD. The study population (N = 445) comprised 31 NIMA-matched and 414 NIMA-mismatched cases. No significant differences between NIMA-matched and NIMA-mismatched groups were found for any outcomes with similar OS and TRM rates within both groups. This study provides the proof of principle that NIMA matching is possible in the unrelated donor HSCT setting; larger studies may be able to provide significant results.

East Meets West—Impact of Ethnicity on Donor Match Rates in the Ezer Mizion Bone Marrow Donor Registry

HLA haplotype frequencies in a volunteer bone marrow donor registry should reflect the frequencies of potential transplant recipients served by that registry, a challenge in a country with diverse subethnicities of immigrants from Eastern and Western cultures, such as Israel. We evaluated the likelihood of finding suitable donors for hypothetical patients drawn from defined subethnicities in the Ezer Mizion Bone Marrow Donor Registry (EM BMDR) from donors both within and outside the registry now and during the coming decade. On average, bioinformatics modeling predicts that, given current donor recruitment trends, 6/6 high-resolution HLA match rates for Israelis, which currently stand at 40% to 55% for most subethnicities, will rise by up to 1% per year over the next decade. Subethnicities with historically lower rates of interethnic admixture are less likely to find matches outside of their designated group but will benefit from expansion of the registry, whereas ethnically directed drives will enhance matching rates for currently underrepresented subethnicities. Donor searches for the same cohort using a large extramural registry was of only slight benefit for most of the 19 EM BMDR subethnicities evaluated, confirming that local donor registries that reflect the ethnic diversity of the community being served are best equipped to serve the needs of their respective communities. Contemporary trends of an increasingly multiethnic admixture in Israel may impact the effect of ethnic profiling in assessing future match rates for EM BMDR.

Better High Resolution HLA-Matching Is Associated with Lower Transplant Related Mortality after Cord Blood Transplantation

Background: For patients lacking a suitable related or unrelated stem cell donor, cord blood (CB) as the source of stem cells is being increasingly utilized both in pediatric and adult patients. A CB graft is attractive due to the increased level of HLA disparity that can be tolerated, allowing nearly all patients to find a donor. HLA-typing is performed minimally at the antigen level for HLA-A and -B (low resolution LR), and high resolution (HR) HLA-typing is performed for HLA-DRB1 alleles. More recently, many centers are turning to HR HLA-typing as the standard; however the impact on outcomes of HLA disparity using HR typing has not been clearly determined.Methods: The impact of HR HLA matching was retrospectively analyzed on 202 patients with hematologic malignancies receiving either a single or double cord blood transplant (CBT) between 2007-2014 at the Hutchinson Center. 135 patients (67%) had HR typing for HLA-A, -B, -C, and -DRB1. For double CBT, the HR HLA typing of the predominant cord was used in the outcome analysis. Patients with mixed chimerism (n=2) or graft failure (n=9) were excluded leaving a total of 124 patients (61%) in the final analysis. HR typing at 4 loci revealed that the median HLA match was 5/8 (range 2-7/8). The cause-specific hazards of failure for each endpoint were compared between patients with worse HR typing (≤ 4/8 HR HLA match, n=46) and patients with better HR typing (≥5/8 HLA match, n=78). These models were adjusted for various factors: patient age, weight, risk of disease, presence of minimal residual disease (MRD), patient CMV serostatus, conditioning regimen (myeloablative vs. non-myeloablative), and grades III-IV acute graft-vs.-host disease (aGVHD).Results: The median patient age and weight were 43 years and 76 kg and 33 years and 69 kg for the ≤ 4/8 and ≥5/8 groups respectively (p=0.03, p=0.06). The two groups were similar with respect to conditioning intensity, sex, race, CMV serostatus, MRD status, and diagnosis (Fig. 1). The median pre-thaw TNC/kg x107 and pre-thaw CD 34 cells/kgx106 values (Fig. 1) indicated that there was no difference between the two HR HLA groups in regards to both CB unit size or stem cell content (p=0.25). Median time of neutrophil recovery was 20 days for ≤ 4/8 group and 19 days for ≥5/8 group with a cumulative incidence of engraftment of 93% and 98% respectively (p=0.20). The median time to platelet recovery (>20 x 109/L) was also similar between the two groups: 34 days for the ≤ 4/8 group and 35 days for the ≥5/8 group (p=0.12). The probability of 4-year DFS was 34% and 62%, respectively (p=0.04) (Fig. 2A). The cumulative incidence of transplant related mortality (TRM) at 4 years was 41% for the ≤ 4/8 group and 15% for the ≥5/8 group (p=0.002) (Fig. 2B). In multivariable analysis the association between worse HLA-matching and higher TRM remained statistically significant [HR=3.22, 95% CI: 1.25-8.20, p=0.01]. The most common causes of death were pulmonary failure (27%), bacterial or fungal infection (24%), and multi-system organ failure (21%). Interestingly, worse HLA matching did not reduce the risk of relapse [HR=0.87, 95% CI: 0.32-2.4, p=0.80] or increase the risk of grades III-IV aGVHD (p=0.45).Conclusion: Our study demonstrates that TRM was significantly lower in patients receiving a ≥5/8 HR HLA engrafting CB unit leading to a better DFS. The increased incidence of TRM in the less HLA-matched group was not due to an increased risk of aGVHD. Our results support that the use of ≥5/8 allele-matched HLA-units is associated with better outcomes; however how to select CB units based on HLA-allele match in the setting of double CBT still needs to be confirmed in larger studies analyzing how HLA-mismatch at different loci (patient vs. units and unit vs. unit) can impact CB unit selection and dominance. [Display omitted] [Display omitted] DisclosuresDelaney:Novartis: Other: Chair, DSMB; Biolife Solutions: Membership on an entity's Board of Directors or advisory committees; medac: Research Funding.

High-resolution HLA matching in unrelated donor transplantation in Switzerland: differential impact of class I and class II mismatches may reflect selection of nonimmunogenic or weakly immunogenic DRB1/DQB1 disparities.

Unrelated donor searches in Switzerland require high-resolution HLA typing for HLA-A/B/C/DRB1/DRB3,4/DQB1 loci. We evaluated this strategy accepting donors with ⩾9/10 match. Of 802 unrelated donor transplants in 2000-2013, 570 were 10/10 matched, 31 were DRB3/4 mismatched, 261 were single-allele mismatched and 13 had 2 allele mismatches. Of the 261 single-allele disparities, 60 concerned HLA-A/-B, 55 HLA-C and 73 HLA-DRB1/-DQB1 loci. Transplants were reduced intensity conditioning (289, 36%), marrow (187, 23%), EBMT risk score was low in 39, intermediate I in 331, intermediate II in 333 and high in 99 patients. Five-year survival was 48±4%. HLA affected survival in the multivariate model adjusted for risk score. HLA-A/-B and HLA-C mismatches had twice the mortality risks, whereas HLA-DRB1/-DQB1 mismatches were similar to matched transplants. HLA-DRB3/4 mismatches were associated with a nonsignificant increased mortality risk. HLA-DRB3/4 mismatches had higher graft-versus-host disease and transplant-related mortality risks and lower relapse rates compared with matched transplants. We show significant effects of HLA class I, but not HLA class II, mismatches. The lack of impact of DRB1 disparities may be related to the lower immunogenicity of the DRB1*11:01/11:04 and DRB1*14:01/14:54 mismatches, representing 46% of DRB1 incompatibilities. These results support a matching algorithm that prioritizes mismatches considered as more permissive.

Non-HLA genomics: does it have a role in predicting haematopoietic stem cell transplantation outcome?

Haematopoietic stem cell transplantation (HSCT) remains the only cure for many haematological neoplasms; however, the mortality rate remains high, at around 30-80%. Complications after HSCT include relapse, graft-versus-host disease, graft rejection and infection. High-resolution HLA matching has improved survival in HSCT over recent years; however, GVHD still remains a serious complication. Single nucleotide polymorphisms (SNPS) within genes that are involved with an individual's capability to mount an immune response to infectious pathogens, residual leukaemia, alloantigens or genes involved in drug metabolism have been studied for their association with HSCT outcome. Indeed, over the last 15 years, several groups, including ourselves, have demonstrated that non-HLA gene polymorphisms can be predictive of HSCT outcome. Can genetic characteristics of the patient and donor be used in the future to tailor HSCT protocols and determine GVHD prophylaxis? This review summarizes some of the recent SNP association studies in HSCT and highlights some of the disparities therein, discussing the integral problems of performing genetic association studies on diseases with complex outcomes using heterogeneous cohorts. The review will comment on recent genomewide association studies (GWAS) and discuss their relevance in this field, and it will also comment on recent meta-analysis combining GWAS studies with other studies such as gene expression micro array data in the field of autoimmune disease and solid organ transplantation. It will mention possible novel candidate gene polymorphisms, for example SNPS in microRNAs. In addition, it will discuss some of the inherent problems associated with gene association studies including the GRIPs (genetic risk prediction studies) recommendations. In summary, this review will assess the usefulness of non-HLA genomic studies in HSCT with regard to predicting outcome and modifying therapy.

P068 : ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATIONS WITH KILLER IMMUNOGLOBULIN-LIKE RECEPTOR GENOTYPE MATCHED DONORS HAVE REDUCED INCIDENCE OF GRAFT VERSUS HOST DISEASE WITH NO EFFECT ON THE RISK OF DISEASE RELAPSE

Background Complications of allogeneic hematopoietic cell transplantation (HCT), primarily graft versus host disease (GVHD) and relapse of the underlying disease are substantial. In spite of high resolution HLA matching incidences of clinically significant GVHD and disease relapse among Albertan HCT recipients remain as high as 35% and 20%, respectively. Unfortunately, strategies/treatments aiming to control GVHD in most cases lead to increase in the rate of disease relapse and infections. In the recent years, the natural killer (NK) cell genetic system, regulated by the activating and inhibitory Killer Immunoglobulin-like Receptors (KIR) has garnered substantial research interest as a modifier of HCT outcomes. Here we set out to determine the influence of KIR matching between HCT donor and recipient pairs on allogeneic HCT complications. Study design KIR gene repertoires of 200 allo-HCT pairs were obtained by a Luminex-based rSSO method. Donor (D) and recipients (R) were ‘matched’ for KIR genotypes when both carried either AA (two copies of group A haplotypes) or B/x (at least one copy of group B haplotype) genotypes. Effect of KIR matching on significant GVHD (described as grade 2–4 acute GVHD or chronic GVHD needing systemic therapy) as well as disease relapse was analyzed using competing-risks regression and Cox proportional hazard statistics. Results A significant protection against GVHD was conferred upon when both the donor and recipient were matched for the KIR genotypes (HR = 1.7; p = 0.03) without any effect on disease relapse (HR = 1.2; p = 0.57). Recipients of a KIR genotype matched graft appeared to have an improved survival. Conclusions Since GVHD is concomitant with graft-vs-leukemia (GVL) reaction, strategies to decrease GVHD in most cases have resulted in increased relapse. Matching donor and recipients for KIR genotypes can offer a significant protection against GVHD without increasing the risk of disease relapse.

Donor-recipient allele-level HLA matching of unrelated cord blood units reveals high degrees of mismatch and alters graft selection.

The feasibility of selecting cord blood (CB) units at high-resolution HLA match has not been investigated. We analyzed the high-resolution donor-recipient HLA match of 100 double-unit 4-6/6 HLA-A,-B antigen, -DRB1 allele-matched CB grafts (units 1a and 1b) and their back-up units (n=377 units in total). The median cryopreserved graft dose was 2.9 × 10(7)/kg/unit, and at high resolution these units had a median donor-recipient HLA-allele match of 5/8 (range 2-8/8) and 6/10 (range 2-9/10), respectively. We then evaluated how often use of high-resolution HLA-match criteria would change the original graft selection to substitute one or both of the back-up units for units 1a and/or 1b. On using a model in which both a higher eight-allele HLA match and a cell dose ⩾ 2.0 × 10(7)/kg/unit were required, graft selection changed in 33% of transplants with minimal effect on cell dose (8.3% reduction). In summary, while units chosen based on HLA-A,-B antigen and -DRB1 allele match have substantial mismatch at higher resolution, CB selection based on high-resolution HLA match is possible in a significant proportion of patients without compromise in cell dose.

Application of high resolution HLA typing in unrelated umbilical cord blood transplantation

This study was purposed to investigate the clinical value of HLA matching(low and high resolution) and its effect on outcome of the patients received umbilical cord blood transplantation(UCBT). Sequence-specific oligonucleotide probe (SSOP) , sequence-based typing (SBT) and sequence-specific primers(SSP) were used to perform high resolution HLA matching for HLA-A, -B, -Cw, -DRB1, -DQB1 and low resolution for HLA-A, B, DRB1 among 34 patients with hematologic malignancies who received unrelated UCB transplantation and grafts. The effects of HLA matching (low or high resolution ) on leading engraftment, hematopoietic reconstitution, graft-versus-host disease (GVHD) and infection after UCB transplantation were analyzed by comparison. The results showed that the median of total nucleated cells (TNC) of transplanted cord blood was 6.0×10(7)/kg, The time of neutrophil recovery was significantly shortened when more than 5×10(7)/kg TNC were transplanted (P < 0.05). The HLA-(6-10)/10 group of high resolution HLA matching was better than the HLA (4-5)/10 group in the respect of leading engraftment, the time of platelet recovery and the rate of acute GVHD (P < 0.05). In contrast, HLA-I+II locus, HLA-DRB1 or HLA-DQB1 locus mismatch could prolong the platelet engraftment time (P < 0.05). There was statistical difference in the time of platelet recovery, the rate of acute GVHD between the HLA (5-6)/6 group of low resolution HLA matching and the HLA (3-4)/6 group after UCB transplantation (P < 0.05), but the mismatch locus of HLA with low resolution did not correlate with the time of platelet recovery (P > 0.05). It is concluded that the high resolution HLA matching between patients received unrelated UCB transplantation and grafts may contribute to select the better UCB, that has important clinical value to promote hematopoietic reconstitution and to reduce the complications after UCB transplantation.

High-Resolution Donor-Recipient HLA Matching Does Not Influence Acute or Chronic Gvhd in Umbilical Cord Blood Transplantation

The degree of antigen-level (HLA-A, -B) and allele-level HLA-DRB1 matching has been correlated with the risk of acute GVHD (aGVHD) in prior studies of umbilical cord blood transplantation (UCBT), however no impact of HLA matching on development of chronic GVHD (cGVHD) has been reported for ≥4/6-matched UCBT. To understand the impact of high-resolution HLA allele matching at -A, -B, -C, -DRB1 and -DQ loci on GVHD we studied 404 recipients of single- (n=129) and double-unit (n=275, based on the predominating unit) UCBT from 2000 to 2010. Overall cumulative incidence of grade II-IV aGVHD, grade III-IV aGVHD, and cGVHD was 47%, 18%, and 20%, respectively. HLA allele-matched recipients, grouped as 9-10/10 (17%), 6-8/10 (61%), and <6/10 (22%), had a similar cumulative incidence of grade II-IV (43% vs. 47% vs. 52%, p=0.5) or grade III-IV (17% vs. 16% vs. 22%, p=0.4) aGVHD, respectively. In multivariable analysis HLA matching did not influence grade II-IV and III-IV aGVHD (all p>0.5) after adjustment for the number of units, CD3, CD34 dose, age, gender match, conditioning, recipient CMV status, ATG use, and the year of transplant (Table). Use of ATG was independently associated with a lower risk of grade II-IV aGVHD (relative risk [RR]=0.5, p<0.01). Univariate difference in cumulative incidence of cGVHD for 9-10/10 (17%), 6-8/10 (17%), and <6/10 (29%) HLA match was confounded by age (RR=3.4 for ≥18 years, p<0.01) and prior aGVHD (RR=2.3, p<0.01) in multivariable analysis adjusted for CD34, CD3 dose, and the number of cord units. No other factors influenced cGVHD or modified the risk of HLA matching on cGVHD. Similar results were found in a multivariable analysis for stratified single- and double-unit UCBT. We conclude that stringent high-resolution HLA matching at -A, -B, -C, -DRB1 and -DQ loci does not influence the incidence of acute or chronic GVHD among recipients of UCBT.Tabled 1Relative risk* of acute and chronic GVHD based on degree of high-resolution HLA matchingFactorRR of aGVHD (95% CI)RR of cGVHD (95% CI) (n=79)Grade II-IV (n=191)Grade III-IV (n=72)HLA match**9-10/10 (n=69)1.01.01.06-8/10 (n=246)1.1 (0.7-1.8)1.1 (0.5-2.5)0.7 (0.3-1.5)<6/10 (n=89)1.1 (0.7-2.0)1.4 (0.6-3.3)1.1 (0.1-2.5)*Adjusted for age, gender match, year of transplant, number of units, CD3, CD34 dose, ATG use, conditioning, recipient CMV status, prior aGVHD as appropriate; **High-resolution allele match at HLA-A, -B, -C, -DRB1, and -DQ loci; RR, relative risk; CI, confidence interval Open table in a new tab *Adjusted for age, gender match, year of transplant, number of units, CD3, CD34 dose, ATG use, conditioning, recipient CMV status, prior aGVHD as appropriate; **High-resolution allele match at HLA-A, -B, -C, -DRB1, and -DQ loci; RR, relative risk; CI, confidence interval

HLA-A, -B, -C and –DRB1 High Resolution Matching Can Improve Patient' Outcome After Double Umbilical Allogeneic Stem Cell Transplantation (allo-SCT)

BackgroundUnrelated umbilical cord blood cells (UCB) have emerged as an alternative stem cell source for allo-SCT for patients who lack a matched-related or unrelated donor. In BM or PBSC unrelated transplantation, high resolution (HR) matching at HLA-A, -B, -C and –DRB1 loci is crucial. Whereas, in UCB allo-SCT, HLA typing is usually performed at low resolution (LR) for HLA-A and -B loci and HR for HLA-DRB1 locus. Also in many centres, priority is often given to cell dose over donor-recipient HLA matching for UCB selection. Development of double UCB allo-SCT allows achieving higher cell doses. However, in the setting of double UCB allo-SCT, data regarding the effect of HR HLA matching between patient and UCB are scarcer. With this background, this retrospective analysis assessed whether HR matching at HLA-A, -B, -C and –DRB1 loci could be associated with improved outcome after allo-SCT using double UCB. Patients and MethodsThis analysis was performed in a series of 46 consecutive adult patients treated for hematological diseases. 25 patients were males (54%) and the median age at time of allo-SCT was 49 years (range, 16-68). Diagnoses included 20 AML (43%), è MDS/MPN (15%) 13 NHL (28%), 2 HD (4%), 4 ALL (9%) and 1 severe aplastic anaemia (2%). 9 patients (20%) had standard risk disease and 36 patients (78%) presented with high risk disease. 6 patients (13%) received a myeloablative conditioning (cyclophosphamide and high dose TBI) and 40 patients (87%) received a reduced intensity conditioning (fludarabine, cyclophosphamide and low dose TBI). 9 patients (20%) received ATG. HLA-A, -B, -C and -DRB1 HR typing was retrospectively performed by sequencing on both UCB units. We compared patient' outcome according to the donor recipient HLA-A, -B, -C and -DRB1 HR matching. We defined 2 groups, a group of 27 patients with high HLA matching, group “high” (24 UCB-recipient pair were matched at 5/8 or higher for both UCB, 3 dUCB-recipient were matched at 4/8 for one UCB and at 6/8 or 7/8 for the second UCB) and a group of 19 patients with low HLA matching, group “low” (UCB-recipient pair were matched at 5/8 and 4/8 or less for both UCB). ResultsWith a median follow-up of 30.0 months (range, 6.5-83.0), there is a trend towards improved better overall survival (OS) at 2 years in group “high” [69% (95%CI, 47-83%) versus 42% (95%CI, 18-64%) in group “low” P=0.07]. The estimate of progression-free survival (PFS) at 2 years was significantly higher in group “high” [62% (95%CI, 41-78%) versus 30% (95%CI, 11-51%) in group “low” P=0.02]. Also, there was a trend towards a lower cumulative incidence of NRM in group “high” [12%, versus 39% in group “low” P=0.06]. Grade 3-4 acute GVHD and extensive chronic GVHD incidences were 11% versus 10% (P=0.99), and 4% versus 15% (P=0.25), in group “high” versus group “low”, respectively. The cumulative incidence of relapse was 23% in the group high versus 37% in the group low (P=0.07). The cumulative incidence of neutrophil recovery at day 42 and platelet recovery at 6 months were 78% versus 89% (P=0.38) and 78% versus 84% (P=0.54) in group “high” versus group “low”, respectively. In multivariable analysis including the most important parameters associated with outcome (patient's age at transplantation, patient's gender, disease status, conditioning regimen, TNC), HLA matching (high versus low) was the only parameter with a significant impact on OS (HR=0.31 (95% CI, 0.12-0.80); P=0.02). Regarding impact of HLA matching at HLA-A,-B LR and –DRB1 HR, both UCB-recipient pairs were matched at 5/6 or higher in 22 cases and in 24 cases at least one UCB-recipient pair was matched at 4/6 or less, both groups were comparable regarding OS [62% (95%CI, 40-78%) in group high versus 57% (95%CI, 32-75%) in group low, P=0.41] and PFS [54% (95%CI, 33-71%) in group high versus 45% (95%CI, 24-64%) in group low, P=0.26]. ConclusionThese preliminary data suggest that in contrast to standard HLA matching, HR HLA matching at HLA-A, -B, -C and –DRB1 loci affect patients outcome after double UCB allo-SCT. Furthermore HR HLA matching overcome impact of cell doses regarding OS in multivariate analysis. This highlight the need to reassess the curent strategy for UCB unit selection in the setting of double UCB allo-SCT, where HLA-A and -B typing should be performed at the allele level and matching at HLA-C should be included. Prospective randomized studies are needed to confirm these results and analyze the impact of each HLA locus at the allele level. Disclosures:Moreau:CELGENE: Honoraria, Speakers Bureau; JANSSEN: Honoraria, Speakers Bureau.

7/8 High-Resolution Unrelated Donor HLA Match Rate: Caucasian, African American, Hispanic, and Asian-Pacific Islander

AimEstimation of the National Marrow Donor Program's Be The Match Registry (BTMR) 8/8 (HLA-A, B, C, DRB1) high resolution (HR) unrelated donor (URD) match rate was determined in a 2009 study for each of the four most frequent patient race/ethnic groups in the United States- Caucasian (CAU), African American (AFA), Hispanic (HIS), and Asian Pacific Islander (API) (Dehn et al, ASBMT/CIBMTR abstract 2011). For patients without an 8/8 matched URD, a 7/8 match is often the minimum acceptable mismatch used by many transplant centers. A follow up to the 8/8 study was designed to determine the 7/8 or better match rate among the 4 major race/ethnic groups, using the same study cohort. Methods1344 previously high resolution tested URD in the BTMR were randomly selected and treated as pseudopatients (PP) where HR testing was performed to identify an 8/8 matched URD. Following 8/8 potential URD testing, a search was performed on each PP to determine the 7/8 match rate, regardless of whether an 8/8 match was previously identified. The searches used a fixed BTMR file from January of 2012, composed of over 8.6 million URD. The BTMR race/ethnic diversity breakdown for 2012 was 65% CAU, 7% AFA, 10% HIS, 7% API, and 11% miscellaneous categories such as Multiple, Unknown, American Indian- Alaska Native, and Declined to answer. Search results from CAU (N=377), AFA (N=390), HIS (N=307), and API (N=270) PP were evaluated and classified as follow:1) 7/8 HR matched donor exists on BTMR2) Potential 7/8 HR donors exist on BTMR3) No 7/8 potential donors exist on BTMRPP searches falling into category 2 had an HLA search strategy expert rank potential URD within BTMR in order of their matching likelihood. URD samples were HR HLA tested in order of ranking and evaluated to determine match status. Consecutive rounds of URD sample testing were performed until either a 7/8 matched URD was identified, no potential URD with stored samples remained, or a patient maximum number of URD testing was reached.Since many PP searches had greater than 100 potential 7/8 matched URD, it was not possible to type every URD. In these cases, up to 35 URD with sample were tested per patient. For analysis of the 7/8 match rate, PP with no 7/8 match identified after URD testing were considered as having no HR match. Results98% of CAU and over 80% of the non-CAU race/ethnic groups- AFA, HIS, and API- had at least a 7/8 match identified (Table 1). For cases where an 8/8 matched donor had been previously identified, all but 8 PP also had a 7/8 match (CAU= 1, AFA= 3, API= 3, HIS= 1). Only three PP cases had no 7/8 potential donors on the search prior to URD testing. The range of donors tested for the cases resulting in a match was larger for the non-CAU race groups. The maximum number of URD tested before a 7/8 match was identified was 24 for AFA, 6 for HIS, and 10 for API, while for CAU the maximum number of URD tested was 2 (Table 2). A median of 1 URD was typed for cases resulting in a 7/8 match for each of the four race/ethnic groups. HLA expert review of cases where no 7/8 match was identified but additional 7/8 potential URD remained suggests that few additional cases would likely yield HR matches.Table 2Number of 7/8 URD Tested by Race/Ethnic Group and HR Match OutcomeCAU PPAFA PPHIS PPAPI PP7/8 HR MatchNo 7/8 HR Match7/8 HR MatchNo 7/8 HR Match7/8 HR MatchNo 7/8 HR Match7/8 HR MatchNo 7/8 HR MatchMedian # URD tested112115127135Range of URDtested1-21-351-240-351-60-351-101-35 ConclusionsThis study estimates a 7/8 or better HR match rate for the BTMR of over 80% for all four broad race/ethnic group categories. These results show that in the majority of cases, after first testing to identify an 8/8 matched URD, a 7/8 matched URD was identified after typing just one URD. However, particularly with non-CAU patients, testing additional URD may be needed to identify a 7/8 match. This study provides a baseline match rate that can be further supplemented using the additional worldwide URD inventory. Disclosures:No relevant conflicts of interest to declare.

High-resolution HLA matching in hematopoietic stem cell transplantation: a retrospective collaborative analysis

AbstractTo validate current donor selection strategies based on previous international studies, we retrospectively analyzed 2646 transplantations performed for hematologic malignancies in 28 German transplant centers. Donors and recipients were high resolution typed for HLA-A, -B, -C, -DRB1, and -DQB1. The highest mortality in overall survival analysis was seen for HLA-A, -B, and DRB1 mismatches. HLA-DQB1 mismatched cases showed a trend toward higher mortality, mostly due to HLA-DQB1 antigen disparities. HLA incompatibilities at >1 locus showed additive detrimental effects. HLA mismatching had no significant effect on relapse incidence and primary graft failure. Graft source had no impact on survival end points, neither in univariate nor in multivariate analysis. Higher patient age, advanced disease, transplantations before 2004, patient C2C2 killer cell immunoglobulin-like receptor (KIR)-ligand phenotype, and unavailability of a national donor adversely influenced outcomes in multivariate analysis. Our study confirms the association of HLA-A, -B, -C, and -DRB1 incompatibilities with adverse outcome in hematopoietic stem cell transplantation (HSCT). The relevance of HLA-DQB1 disparities in single mismatched transplantations remains unclear. Similar hazard ratios for allele and antigen mismatches (possibly with an exception for HLA-DQB1) highlight the importance of allele level typing and matching in HSCT. The number of incompatibilities and their type significantly impact survival.

Recent decrease in non-relapse mortality due to GVHD and infection after allogeneic hematopoietic cell transplantation in non-remission acute leukemia

Although recent improvements have been indicated in the outcome after allogeneic hematopoietic cell transplantation (allo-HCT), little information is available on how changes in transplant modalities have affected the outcomes after allo-HCT in non-remission, based on patient age, donor source and disease type. We compared the incidence and causes of non-relapse mortality (NRM) after allo-HCT in non-remission among three consecutive four-year periods using a nationwide transplant outcome registry database. A total of 3308 patients with acute leukemia in non-remission were analyzed. The risk of NRM decreased over the three periods, and the hazard ratios (HRs) in 2001-2004 and 2005-2008 compared with 1997-2000 were 0.86 (95% CI, 0.70-1.06; P=0.16) and 0.65 (95% CI, 0.53-0.80; P<0.01), respectively. A significant decrease in the HR for overall mortality was also observed in 2005-2008 (HR 0.85; 95% CI, 0.75-0.97; P=0.02). We found that a decrease in the incidences of death due to GVHD and infection contributed to the reduction in NRM, to which high-resolution donor-recipient HLA matching and other improvements may have contributed. As none of the subgroups showed improved survival without a reduction in NRM, the effective prevention of transplant-related complications appears to be necessary for improving outcomes after allo-HCT in non-remission.