Investigation of KIR/HLA relationship and other clinical variables after T-cell-replete haploidentical bone marrow transplantation in patients with acute myeloid leukemia (AML).

BACKGROUND: KIR/HLA mismatch in hematopoietic stem cell transplantation (HSCT), particularly in patients with acute myeloid leukemia (AML), was related to decreased recurrence rates, improved engraftment, and a reduction in graft-versus-host disease, according to recent research (GVHD). Uncertainty exists about the impact of KIR/HLA mismatch on haploidentical-HSCTs treated with post-transplant cyclophosphamide (PTCy). We attempted to analyze the effects of KIR/HLA mismatch on clinical outcomes on transplant outcomes using the cohort of 54 AML patients who received a haplo-HSCT with PTCy. RESULTS: In contrast to KIR/HLA match, our findings showed that donor KIR/HLA mismatch was substantially associated with superior OS (HR, 2.92; (P = 0.04)). Moreover, donor KIR/HLA mismatch (KIR2DS1D/C2+ R and KIR2DS2D/C1+ R mismatch versus KIR2DL1D/C2- R mm, KIR2DL2/3D/C1- R mm and KIR3DL1D/Bw4- mm) was correlated with the improvements in OS (HR, 0.74; P = 0.085) and activating. KIR/HLA mismatch versus KIR/HLA match was significantly correlated with improvements in OS (HR, .46; P = 0.03) and inhibitory. KIR/HLA mismatch versus KIR/HLA match was enhancement in the OS (HR, .93; P = 0.06). Despite a higher rate of aGvHD (grade I-IV) in the patients with KIR/HLA mismatch compared to KIR/HLA matched (57% vs. 33% (p = 0.04). However, the KIR/HLA mismatch group saw a decreased relapse rate (3.2% vs. 23%, p = 0.04). CONCLUSION: This analysis shows the significance of KIR/HLA Incompatibility, other clinical variables like CMV, the relationship between donor/recipient and donor age, and the relationship between donor/recipient and donor age in the haplo-donor selection process. It also suggests that KIR and HLA mismatching between donor and recipient could be routinely performed for haplo-donor selection and may improve clinical outcomes after haplo-HSCTs with PTCy.

Early progression of chronic histologic lesions in kidney transplant biopsies is not associated with HLA histocompatibility.

BACKGROUND: Early progression of chronic histologic lesions in kidney allografts represents the main finding in graft attrition. The objective of this retrospective cohort study was to elucidate whether HLA histocompatibility is associated with progression of chronic histologic lesions in the first year post-transplant. Established associations of de novo donor-specific antibody (dnDSA) formation with HLA mismatch and microvascular inflammation (MVI) were calculated to allow for comparability with other study cohorts. METHODS: We included 117 adult kidney transplant recipients, transplanted between 2016 and 2020 from predominantly deceased donors, who had surveillance biopsies at three and twelve months. Histologic lesion scores were assessed according to the Banff classification. HLA mismatch scores (i.e. eplet, predicted indirectly recognizable HLA-epitopes algorithm (PIRCHE-II), HLA epitope mismatch algorithm (HLA-EMMA), HLA whole antigen A/B/DR) were calculated for all transplant pairs. Formation of dnDSAs was quantified by single antigen beads. RESULTS: More than one third of patients exhibited a progression of chronic lesion scores by at least one Banff grade in tubular atrophy (ct), interstitial fibrosis (ci), arteriolar hyalinosis (ah) and inflammation in the area of interstitial fibrosis and tubular atrophy (i-IFTA) from the three to the twelve-month biopsy. Multivariable proportional odds logistic regression models revealed no association of HLA mismatch scores with progression of histologic lesions, except for ah and especially HLA-EMMA DRB1 (OR = 1.10, 95%-CI: 1.03-1.18). Furthermore, the established associations of dnDSA formation with HLA mismatch and MVI (OR = 5.31, 95-% CI: 1.19-22.57) could be confirmed in our cohort. CONCLUSIONS: These data support the association of HLA mismatch and alloimmune response, while suggesting that other factors contribute to early progression of chronic histologic lesions.

Impact of human leukocyte antigen mismatch on outcomes after unrelated bone marrow transplantation in paediatric patients: A retrospective analysis by the JSTCT HLA working group.

The impact of human leukocyte antigen (HLA) mismatching at the HLA-A, -B, -C, and -DRB1 loci after unrelated bone marrow transplantation in paediatric patients with haematological malignancies has not been fully examined. Here, we analysed patients with haematological malignancies (all aged ≤15 years; n = 1330) who underwent a first unrelated bone marrow transplantation between 1993 and 2017 in Japan. The results show that although an HLA mismatch was significantly associated with a low relapse rate, it was also associated with higher non-relapse mortality. There was a significant association between HLA mismatch and low overall survival. Locus mismatch analysis revealed that, as in adults, an HLA-C mismatch had a significant negative impact on survival; however, in paediatric patients, an HLA-DRB1 mismatch did not have a negative impact, although these HLA mismatch effects are weakened in recent cases. Taken together, the results suggest that an HLA-matched donor should be the first candidate for paediatric patients; however, for patients without a matched sibling or matched unrelated donor, we can select an unrelated donor with a mismatch at HLA-DRB1 if available.

Association of Predicted HLA T-Cell Epitope Targets and T-Cell-Mediated Rejection After Kidney Transplantation.

RATIONALE & OBJECTIVE: The relationship between human leukocyte antigen (HLA) molecular mismatches and T-cell-mediated rejection (TCMR) is unknown. We investigated the associations between the different donor HLA-derived T-cell targets and the occurrence of TCMR and borderline histologic changes suggestive of TCMR after kidney transplantation. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: All kidney transplant recipients at a single center between 2004 and 2013 with available biopsy data and a DNA sample for high-resolution HLA donor/recipient typing (N = 893). EXPOSURE: Scores calculated by the HLA matching algorithm PIRCHE-II and HLA eplet mismatches. OUTCOME: TCMR, borderline changes suggestive of TCMR, and allograft failure. ANALYTICAL APPROACH: Multivariable cause-specific hazards models were fit to characterize the association between HLA epitopes targets and study outcomes. RESULTS: We found 277 patients developed TCMR, and 134 developed only borderline changes suggestive of TCMR on at least 1 biopsy. In multivariable analyses, only the PIRCHE-II scores for HLA-DRB1 and HLA-DQB1 were independently associated with the occurrence of TCMR and with allograft failure; this was not the case for HLA class I molecules. If restricted to rejection episodes within the first 3 months after transplantation, only the T-cell epitope targets originating from the donor's HLA-DRB1 and HLA-DQB1, but not class I molecules, were associated with the early acute TCMR. Also, the median PIRCHE-II score for HLA class II was statistically different between the patients with TCMR compared to the patients without TCMR (129 [IQR, 60-240] vs 201 [IQR, 96-298], respectively; P < 0.0001). These differences were not observed for class I PIRCHE-II scores. LIMITATIONS: Observational clinical data and residual confounding. CONCLUSIONS: In the absence of HLA-DSA, HLA class II but not class I mismatches are associated with early episodes of acute TCMR and allograft failure. This suggests that current immunosuppressive therapies are largely able to abort the most deleterious HLA class I-directed alloimmune processes; however, alloresponses against HLA-DRB1 and HLA-DQB1 molecular mismatches remain insufficiently suppressed. PLAIN-LANGUAGE SUMMARY: Genetic differences in the human leukocyte antigen (HLA) complex between kidney transplant donors and recipients play a central role in T-cell-mediated rejection (TCMR), which can lead to failure of the transplanted kidney. Evaluating this genetic disparity (mismatch) in the HLA complex at the molecular (epitope) level could contribute to better prediction of the immune response to the donor organ posttransplantation. We investigated the associations of the different donor HLA-derived T-cell epitope targets and scores obtained from virtual crossmatch algorithms with the occurrence of TCMR, borderline TCMR, and graft failure after kidney transplantation after taking into account the influence of donor-specific anti-HLA antibodies. This study illustrates the greater importance of the molecular mismatches in class II molecules compared to class I HLA molecules.

Alloimmune Risk Stratification for Kidney Transplant Rejection.

Different types of kidney transplantations are performed worldwide, including biologically diverse donor/recipient combinations, which entail distinct patient/graft outcomes. Thus, proper immunological and non-immunological risk stratification should be considered, especially for patients included in interventional randomized clinical trials. This paper was prepared by a working group within the European Society for Organ Transplantation, which submitted a Broad Scientific Advice request to the European Medicines Agency (EMA) relating to clinical trial endpoints in kidney transplantation. After collaborative interactions, the EMA sent its final response in December 2020, highlighting the following: 1) transplantations performed between human leukocyte antigen (HLA)-identical donors and recipients carry significantly lower immunological risk than those from HLA-mismatched donors; 2) for the same allogeneic molecular HLA mismatch load, kidney grafts from living donors carry significantly lower immunological risk because they are better preserved and therefore less immunogenic than grafts from deceased donors; 3) single-antigen bead testing is the gold standard to establish the repertoire of serological sensitization and is used to define the presence of a recipient's circulating donor-specific antibodies (HLA-DSA); 4) molecular HLA mismatch analysis should help to further improve organ allocation compatibility and stratify immunological risk for primary alloimmune activation, but without consensus regarding which algorithm and cut-off to use it is difficult to integrate information into clinical practice/study design; 5) further clinical validation of other immune assays, such as those measuring anti-donor cellular memory (T/B cell ELISpot assays) and non-HLA-DSA, is needed; 6) routine clinical tests that reliably measure innate immune alloreactivity are lacking.

Association of human leukocyte antigen mismatches between donor-recipient and donor-donor in pancreas after kidney transplant recipients.

The effects of HLA mismatching on pancreas outcomes among pancreas after kidney (PAK) recipients are undefined. Outcomes might potentially differ depending on whether there is a mismatch between pancreas donor and recipient (PD-R) or pancreas donor and kidney donor(PD-KD). All primary PAK at our centre were included in this study. Patients were divided into two groups based on the degree of HLA mismatching: low (L-MM) as 0-4 and high (H-MM) as 5-6. We analysed all (N = 73) PAK for PD-R mismatch and the subset of PAK for PD-KD mismatch (N = 71). Comparing PD-R L-MM (n = 39) and H-MM (n = 34) PAKs, we observed no difference in the rate of pancreas graft failure. There was also no difference in the rate of rejection (L-MM 33% vs. H-MM 41%) or the severity of rejection. However, we observed a significantly (P < 0.01) shorter time to acute pancreas rejection in the H-MM group (6.8 ± 8.7 mo) versus the L-MM cohort (29.0 ± 36.2 mo) (P < 0.001). Similar to the PD-R mismatched cohort, we did not observe a detrimental effect of HLA mismatching on graft outcomes in the PD-KD cohort; time to rejection was again shorter in the H-MM subset. In this study, we found no impact of HLA mismatch on either pancreas graft survival or rejection rates, though rejection occurred earlier in high mismatched PAK transplants.

Human leukocyte antigen disparities reduce relapse after hematopoietic stem cell transplantation in children with juvenile myelomonocytic leukemia: A single-center retrospective study from China.

BACKGROUND: HSCT is the only proven curative therapy for JMML. Matching donor and recipient HLA alleles is considered optimal to reduce the risk of GVHD after HSCT but is not always possible. Only a limited number of studies have compared the influence of HLA disparities on HSCT outcomes for patients with JMML. METHODS: We conducted a retrospective study among 47 children with JMML who received related or unrelated unmanipulated HSCT (March 2010-October 2018). Among our participants, 27 (57.4%) donor-recipient pairs had 0-1 HLA disparities (Group 1: HLA-matched or ≤1 allele/antigen mismatch donor) and 20 (42.6%) had ≥2 HLA disparities (Group 2: 2-3 mismatched/haploidentical donors). RESULTS: The median follow-up period was 26.0 months (range: 1-105 months), and the 5-year probabilities of DFS and RI for the whole cohort were 54.6 ± 7.7% and 34.8 ± 15.0%, respectively. Compared to Group 1, Group 2 patients had a significantly lower RI (5.3 ± 10.5% vs 55.5 ± 20.9%, P Ë‚ .001), though similar rates of grade II-IV acute GVHD (60.0 ± 22.4% vs 33.3 ± 18.2%, P = .08), grade III-IV acute GVHD (25.0 ± 19.5% vs 7.4 ± 10.1%, P = .08), chronic GVHD (30.0 ± 20.9% vs 34.9 ± 18.8%, P = .85), NRM (20.0 ± 18.0% vs 3.9 ± 7.7%, P = .07), and DFS (74.4 ± 9.9% vs 41.3 ± 10.0%, P = .08). CONCLUSIONS: Disease relapse remains the major cause of treatment failure in JMML patients, especially in patients receiving HLA-matched and limited HLA-mismatched HSCT. Our findings suggest that donor-recipient HLA disparities may improve the outcome of HSCT in children with JMML.

[Optimal selection of alternative donors for allogeneic hematopoietic stem cell transplantation].

A human leukocyte antigen (HLA)-matched related donor is considered as the first donor candidate in case of allogenic hematopoietic stem cell transplantation (allo-HSCT). Given the declining birthrate and aging population in Japan, the number of sibling donors is also decreasing. Hence, candidates other than HLA-matched siblings, named "alternative donors," have attracted increasing attention. Improved graft-versus-host disease (GvHD) prophylaxis with posttransplant cyclophosphamide or pretransplant antithymocyte globulin represented a major breakthrough in allo-HSCT with alternative donors by overcoming the barriers of HLA mismatch. In addition, there have been improved outcomes of unrelated cord blood transplantation, owing to better unit selection along with improved GvHD prophylaxis and supporting strategies. These changes have expanded the range of donor options and consequently, increased donor availability at the critical moment for allo-HSCT. The next challenge that warrants further investigation is the development of personalized strategies to select the best donor from the available multiple options according to the status of each patient.

Transforming growth factor beta 1 levels in the blood of pediatric liver recipients: Clinical and biochemical correlations.

TGF-ß1 is a cytokine with profibrogenic and immunosuppressive activities, which suggest the clinical significance of TGF-ß1 for the assessment of graft function after LT. We analyzed the dynamics of TGF-ß1 levels in the blood after LDLT in 135 pediatric liver recipients and examined the relationship between the cytokine levels and the laboratory and clinical variables. We found that TGF-ß1 levels in the blood of patients with ESLD were lower than that in healthy children of the same age, P = .001. Moreover, blood levels of TGF-ß1 were associated with liver disease etiology (r = .23) and hepatic fibrosis severity (r = .33). Before LDLT, TGF-ß1 levels were significantly higher in children with good outcomes than in recipients who developed graft dysfunction early in the post-transplant period, P = .047. One month after LDLT, TGF-ß1 levels in blood plasma increased in pediatric recipients, P = .002. Cytokine levels were significantly correlated with gender (r = .21) and HLA (r = -.24) mismatches, as well as with TAC dosage (r = -.32) later in the post-transplant period. One year after LDLT, TGF-ß1 plasma levels were higher (P = .01) than those before LDLT and did not correlate with most of the investigated biochemical and clinical variables. Conclusion: Blood levels of TGF-ß1 are associated with hepatic fibrosis severity, graft dysfunction development, and TAC dosage and can be regarded as a potential prognostic biomarker for the assessment of graft function and the optimization of immunosuppressant dosage in pediatric recipients after LDLT.

Evaluation of HistoCheck as a Predictor of Clinical Outcomes after Haploidentical Hematopoietic Stem Cell Transplantation.

Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is available for nearly all patients without matching HLA-related or -unrelated donors. There was not a valid evaluation system to predict the most proper donor. HistoCheck was based on the functional similarity of amino acids to estimate the allogenicity of HLA mismatches with a sequence similarity matching (SSM) score. We investigated whether HistoCheck could predict clinical outcomes in 500 patients with acute leukemia or myelodysplastic syndrome receiving haplo-HSCT. The total SSM score of the 5 loci (HLA-A, -B, -C, -DRB1, and -DQB1) had no association with clinical outcomes. HLA-C SSM score was significantly associated with transplant-related mortality (TRM) (hazard ratio [HR], .in691; 95% confidence interval [CI], .520 to .917; P = .011), disease-free survival (DFS) (HR, .714; 95% CI, .586 to .869; P = .001), and overall survival (OS) (HR, .711; 95% CI, .574 to .881; P = .002) by multivariate analysis. No significant associations were observed between other single-locus SSM score and clinical outcomes. In summary, our data demonstrate that a high HLA-C HistoCheck SSM score may lead to lower TRM and improved DFS and OS after haplo-HSCT and inclusion of HLA-C HistoCheck in donor selection criteria may need to be further confirmed in prospective studies.

[Impact of mismatched HLA on graft-versus-host disease in unrelated stem cell transplantation].

Graft-versus-host disease (GVHD) caused by patient and donor human leukocyte antigen (HLA) mismatch is a complication of unrelated hematopoietic stem cell transplantation (UR-HSCT) that leads to reduced success rates. To date, studies on HLA alleles in transplant have provided important information on unrelated donor selection. In this study on the effects of specific HLA alleles on acute GVHD in UR-HSCT, HLA-C＊14:02 was found to be significantly associated with an increased risk of acute GVHD. Patient HLA-C＊14:02 and donor HLA-C＊15:02 mismatch was usually KIR2DL-ligand mismatch in the GVH direction in Japanese UR-HSCT cohort, and the higher risk of severe acute GVHD for KIR2DL-ligand mismatch in GVH direction demonstrated in previous Japanese UR-HSCT study was attributable to this particular mismatch combination. Recently, the risk of acute GVHD after UR-HSCT was reported to be associated with the HLA-DP expression level, which is associated with the variant rs9277534 located in the 3'untranslated region (UTR) of the HLA-DPB1 gene. We constructed phylogenetic trees of HLA-DPB1 alleles using next-generation sequencing (NGS) HLA typing data that included introns and 3'UTRs. Results reported that rs9277534 represented a highly conserved region from exon 3 to the 3'UTR, which may lead to acute GVHD via a mechanism different from that observed using T-cell epitope mismatching algorithms, perhaps reflecting exon 2 polymorphisms. The usage of innovative technologies such as NGS in genetic analysis and HLA typing thus has profound implications in this field.

Impact of Human Leukocyte Antigen Allele Mismatch in Unrelated Bone Marrow Transplantation with Reduced-Intensity Conditioning Regimen.

The impact of HLA mismatch in hematopoietic stem cell transplantation with reduced-intensity conditioning (RIC) has not been fully examined. We analyzed a total of 1130 cases to examine the effects of HLA allele mismatch in unrelated bone marrow transplantation (BMT) with RIC in the Japan Marrow Donor Program registry cohort. Compared with HLA 8/8-allele match (n = 720, 8/8 match), both 1 (n = 295, 7/8 match) and 2 allele mismatches (n = 115, 6/8 match) were associated with significant reduction of overall survival (OS) (hazard ratio [HR], 1.34; P = .0024 and HR, 1.33; P = .035 for 7/8 and 6/8 match, respectively). The incidence of grades 2 to 4 acute graft-versus-host disease (aGVHD) increased with increasing number of mismatched alleles (HR, 1.36 and HR, 2.08 for 7/8 and 6/8 match, respectively). Nonrelapse mortality showed a similar tendency to aGVHD (HR, 1.35 for 7/8 and HR, 1.63 for 6/8). One-allele mismatches at the HLA-A or -B and HLA-C loci were significantly associated with inferior OS compared with 8/8 match (HR, 1.64 for A or B mismatch and HR, 1.41 for C mismatch), whereas HLA-DRB1 allele mismatch was not (HR, 1.16; P = .30). However, the effect of HLA-A or -B and -C mismatch on OS was not observed in those who received RIC BMT since 2010, in contrast to recipients before 2010. These results suggested that in unrelated RIC BMT, 1-allele mismatch is associated with poorer outcome, and the impact of HLA mismatch may differ depending on the HLA locus, although these HLA mismatch effects may be different in recent cases.

No effect of HLA-C mismatch after allogeneic hematopoietic stem cell transplantation with unrelated donors and T-cell depletion in patients with hematological malignancies.

HLA-C mismatch in unrelated donor's hematopoietic stem cell transplantation (HSCT) has been associated with poor patient outcome. However, the impact of HLA-C mismatch in the context of HSCT combined with in vivo T-cell depletion remains unclear. We therefore performed a single-center, retrospective analysis of the clinical outcome on patients with hematological malignancies treated with allo-HSCT, who underwent T-cell depletion. The majority of the patients (n=276) received a HLA-A, HLA-B, HLA-DRB1-matched graft that were either also HLA-C matched (n=260), or patients with the permissive HLA-C*03:03/03:04 mismatch (n=16), while the remaining patients (n=95) received a HLA-C-mismatched graft (excluding HLA-C*03:03/03:04 mismatches). We did not observe any significant differences between the HLA-C-matched patients (including the permissive HLA-C*03:03/03:04 mismatch) and the HLA-C-mismatched patients regarding cumulative proportion surviving, graft failure, relapse-free survival, relapse, or acute graft-versus-host disease. Our data suggest that in the context of high dose T lymphocyte-depleting agents, HLA-C matching is not essential for patients with hematological malignancies.

[Impact of HLA mismatch on transplant outcomes].

Human leukocyte antigen (HLA) mismatch increases the risk of severe graft-versus-host disease (GVHD) and transplant-related mortality. However, the variety of stem cell sources such as cord blood units or the improvements in GVHD prophylaxis makes the interpretation of HLA mismatch more complex. In unrelated transplantation, the locus of HLA mismatch has a great impact on the donor candidate selection, whereas in related transplantation, it has an impact on the intensity of GVHD prophylaxis because donor availability is limited. Anti-thymocyte globulin and post-transplant cyclophosphamide are attractive GVHD prophylactic agents to reduce the risk of immune-associated complications in HLA-mismatched transplantations. HLA mismatch has a reduced impact in adult cord blood transplantation. In this review article, the impact of HLA mismatch based on graft sources is discussed.

Haploidentical and Matched Sibling Donor Hematopoietic Cell Transplantation for Patients with HLA-Homozygous Haplotypes.

More than 1% of the Japanese population has HLA-homozygous haplotypes. For patients with such haplotypes, HLA-haploidentical family members who have no HLA mismatch in the graft-versus-host direction are readily available donor candidates for hematopoietic cell transplantation (HCT). In this study, the outcomes of patients with homozygous HLA-A, -B, and -DRB1 antigens who received HCT without T cell depletion from a haploidentical related donor with mismatches in the host-versus-graft direction only (hetero-to-homo, n = 78) or from an HLA-matched sibling donor (MSD) (MSD-homo, n = 153) were compared with those in patients with heterozygous haplotypes who received HCT from an MSD (MSD-hetero, n = 7242). Transplant outcomes in the hetero-to-homo group were similar to those in the MSD-hetero group regarding neutrophil engraftment, grades III to IV acute graft-versus-host disease (aGVHD), nonrelapse mortality (NRM), relapse, and overall survival. On the other hand, the incidences of severe aGVHD and NRM in the MSD-homo group were significantly lower than those in the MSD-hetero group (grades III to IV aGVHD: aHR .50, P = .034; NRM: aHR .48, P = .004). In conclusion, patients with HLA-homozygous haplotypes achieved lower GVHD and NRM rates for MSD transplantation than those with HLA-heterozygous haplotypes. When an MSD or an appropriate alternative donor is not available for patients with HLA-homozygous haplotypes who need immediate transplantation, transplantation from a haploidentical donor without T cell depletion is a viable option, given the comparable transplant outcomes for hetero-to-homo HCT and MSD-hetero HCT.

A Bortezomib-Based Regimen Offers Promising Survival and Graft-versus-Host Disease Prophylaxis in Myeloablative HLA-Mismatched and Unrelated Donor Transplantation: A Phase II Trial.

Hematopoietic stem cell transplantation (HSCT) recipients lacking HLA-matched related donors have increased graft-versus-host disease (GVHD) and nonrelapse mortality (NRM). Bortezomib added to reduced-intensity conditioning can offer benefit in T cell-replete HLA-mismatched HSCT and may also benefit myeloablative conditioning (MAC) transplants. We conducted a phase II trial of short-course bortezomib plus standard tacrolimus/methotrexate after busulfan/fludarabine MAC in 34 patients with predominantly myeloid malignancies. Fourteen (41%) received 8/8 HLA-matched unrelated donor (MUD) and 20 (59%) received 7/8 HLA-mismatched related/unrelated donor peripheral blood stem cell grafts. Median age was 49 years (range, 21 to 60), and median follow-up was 25 months (range, 11 to 36). The regimen was well tolerated. No dose modifications were required. Neutrophil and platelet engraftment occurred at a median of 14 (range, 10 to 33) and 17 (range, 10 to 54) days, respectively. Median 30-day donor chimerism was 99% (range, 90 to 100), and 100-day grades II to IV and III to IV acute GVHD incidence was 32% and 12% respectively. One-year chronic GVHD incidence was 50%. Two-year cumulative incidence of both NRM and relapse was 16%. Two-year progression-free and overall survival rates were 70% and 71%, respectively. Outcomes were comparable to an 8/8 MUD MAC cohort (n = 45). Immune reconstitution was robust. Bortezomib-based MAC HSCT is well tolerated, with HLA-mismatched outcomes comparable with 8/8 MUD MAC HSCT, and is suitable for randomized evaluation. (clinicaltrials.gov: NCT01323920.).

Impact of HLA mismatch direction on the outcome of unrelated bone marrow transplantation: a retrospective analysis from the Japan Society for Hematopoietic Cell Transplantation.

The relative desirability of an unrelated donor with a bidirectional 1-locus mismatch (1MM-Bi), a 1-locus mismatch only in the graft-versus-host direction (1MM-GVH), or a 1-locus mismatch only in the host-versus-graft direction (1MM-HVG) is not yet clear. We analyzed adult patients with leukemia or myelodysplastic syndrome who received a first allogeneic stem cell transplant from an HLA-A, -B, -C, and -DRB1 matched or 1-allele mismatched unrelated donor in Japan. The effects of 1MM-Bi (n = 1020), 1MM-GVH (n = 83), and 1MM-HVG (n = 83) compared with a zero mismatch (0MM) (n = 2570) were analyzed after adjusting for other significant variables. The risk of grades III to IV acute graft-versus-host disease (GVHD) was higher with marginal significance in the 1MM-GVH group than in the 0MM group (hazard ratio, 1.85; P = .014). However, there was no significant difference in overall or nonrelapse mortality between the 1MM-GVH and 0MM groups. There was no significant difference in acute GVHD or overall or nonrelapse mortality between the 1MM-HVG and 0MM groups. The risks of acute GVHD and overall mortality were significantly higher in the 1MM-Bi group than in the 0MM group. These findings indicate that unrelated donors with 1MM-GVH and 1MM-HVG are both good candidates for patients without an HLA-matched unrelated donor in a Japanese cohort.

Graft and patient outcomes of zero-human leucocyte-antigen-mismatched deceased and live donor kidney transplant recipients.

Greater compatibility of human leucocyte antigen (HLA) alleles between kidney donors and recipients may lead to improved graft outcomes. This study aimed to compare the incidence of acute rejection and graft failure in zero-HLA-mismatched recipients of living-related (LD) and deceased donor (DD) kidney transplants. Using data from the Australia and New Zealand Dialysis and Transplant Registry, we compared the risk of any acute rejection and biopsy-proven acute rejection (BPAR) and graft failure in recipients of zero-HLA-mismatched kidneys between LD and DD using logistic and Cox regression models. Of the 931 zero-HLA-mismatched recipients transplanted between 1990 and 2012, 19 (2.0%) received kidneys from monozygotic/dizygotic twins (twin), 500 (53.7%) from nontwin LD and 412 (44.3%) from DD. Twin kidney transplant recipients did not experience rejection. Compared to DD transplant recipients, the risk of any acute rejection (adjusted odds ratio 0.52, 95%CI 0.34-0.79, P = 0.002) and overall graft failure (adjusted hazard ratio 0.55, 95%CI 0.41-0.73, P < 0.001) was significantly lower in LD recipients independent of initial immunosuppression, but not for BPAR (adjusted odds ratio 0.52, 95%CI 0.16-1.64, P = 0.263). Zero-HLA-mismatched DD kidney transplant recipients have a significantly higher risk of any acute rejection episodes and graft loss compared to zero-HLA-mismatched LD kidney transplant recipients. A cautious and careful approach in reducing immunosuppression appears to be warranted in this group of transplant recipients.

The rationale behind grafting haploidentical hematopoietic stem cells.

The ability to perform hematopoietic cell transplant across major histocompatibility complex barriers can dramatically increase the availability of donors and allow more patients across the world to pursue curative transplant procedures for underlying hematologic disorders. Early attempts at haploidentical transplantation using broadly reactive T-cell depletion approaches were compromised by graft rejection, graft-versus-host disease and prolonged immune deficiency. The evolution of haploidentical transplantation focused on expanding transplanted hematopoietic progenitors as well as using less broadly reactive T-cell depletion. Significant outcome improvements were identified with technology advances allowing selective depletion of donor allospecific T cells, initially ex-vivo with evolution to its current in-vivo approach with the infusion of the highly immunosuppressive chemotherapy agent, cyclophosphamide after transplantation procedure. Current approaches are facile and portable, allowing expansion of allogeneic hematopoietic cell transplantation for patients across the world, including previously underserved populations.

The impact of pretransplant suspected HLA antibody on the long-term outcome of the graft kidney: A retrospective cohort study.

INTRODUCTION: The preoperative examination of kidney transplantation includes HLA antibody screening to initially determine the presence of preexisting donor-specific antibody (DSA) that mediates hyperacute rejection. Recipients with positive HLA antibodies require further HLA specificity analysis to type the antigen and determine the antigen mismatches between the donor and recipient. However, recipients with suspected antibodies would have no further HLA specificity analysis. It is unclear whether suspected HLA antibodies would affect renal graft function. This study aimed to explore the impact of pretransplant suspected HLA antibody on the long-term outcome of the graft kidney and thus determine the necessity of routinely performing the HLA specificity analysis in recipients with suspected HLA antibodies preoperatively. METHODS: This is a single-center retrospective cohort study. 179 kidney transplant recipients (KTRs) were included and further divided into HLA antibody-negative group (Group 1) and HLA antibody-suspected groups (Group 2) based on the result of the pretransplant HLA antibody screen test. And the antibody-suspected group was further divided into a low-mismatched group (Group A) and a high-mismatched group (Group B) according to the HLA specificity analysis. We tracked the renal function indexes, biochemical indexes, and posttransplant adverse events within 5 years after transplantation and explored the necessity of further HLA specificity analysis in recipients with pretransplant suspected HLA antibodies. RESULTS: There was no statistically significant difference in demographics between HLA antibody-negative group and HLA antibody-suspected groups. At 5 years of follow-up, the KTRs in HLA antibody-negative group had significantly higher eGFR levels, lower serum creatinine levels, and less urinary protein compared to those in antibody-suspected group. Meanwhile, the KTRs in low-mismatched group also had significantly higher eGFR levels, lower serum creatinine levels, and less proteinuria compared to those in high-mismatched group. Correlation analysis showed that the age of KTRs, urinary protein levels and the load capacity of HLA mismatches were associated with eGFR levels of KTRs at 5 year posttransplant. CONCLUSION: KTRs with suspected HLA antibodies before kidney transplantation have worse graft function than the preoperative HLA antibody-negative recipients in the long-term posttransplant follow-up. The specific load capacity of HLA mismatches, the age of the recipient and the urinary protein was found to be negatively correlated with long-term posttransplant renal outcomes. It is necessary to undergo further HLA specificity analysis for recipients with suspected HLA antibodies in HLA antibody screen test to explicit HLA mismatches and improve long-term posttransplant outcomes.