Donor Specific Anti-HLA Antibody and Risk of Graft Failure in Haploidentical Stem Cell Transplantation

Outcomes of allogeneic hematopoietic stem cell transplantation (AHSCT) using HLA-half matched related donors (haploidentical) have recently improved due to better control of alloreactive reactions in both graft-versus-host and host-versus-graft directions. The recognition of the role of humoral rejection in the development of primary graft failure in this setting has broadened our understanding about causes of engraftment failure in these patients, helped us better select donors for patients in need of AHSCT, and developed rational therapeutic measures for HLA sensitized patients to prevent this unfortunate event, which is usually associated with a very high mortality rate. With these recent advances the rate of graft failure in haploidentical transplantation has decreased to less than 5%

Complement-Binding Donor-Specific Anti-HLA Antibodies and Risk of Primary Graft Failure in Hematopoietic Stem Cell Transplantation

AbstractDetection of donor-specific anti-HLA antibodies (DSA) has been associated with graft rejection in all forms of transplantation. The mechanism by which DSA increase the risk of graft failure remains unclear. We hypothesized that complement-binding DSA are associated with engraftment failure in hematopoietic stem cell transplantation (HSCT) and analyzed 122 haploidentical transplant recipients tested prospectively for DSA. Retrospective analysis to detect C1q binding DSA (C1q+DSA) was performed on 22 allosensitized recipients. Twenty-two of 122 patients (18%) had DSA, 19 of which were women (86%). Seven patients with DSA (32%) rejected the graft. Median DSA level at transplant for patients who failed to engraft was 10,055 mean fluorescence intensity (MFI) versus 2065 MFI for those who engrafted (P = .007). Nine patients with DSA were C1q positive in the initial samples with median DSA levels of 15,279 MFI (range, 1554 to 28,615), compared with 7 C1q-negative patients with median DSA levels of 2471 MFI (range, 665 to 12,254) (P = .016). Of 9 patients who were C1q positive in the initial samples, 5 patients remained C1q positive at time of transplant (all with high DSA levels [median, 15,279; range, 6487 to 22,944]) and experienced engraftment failure, whereas 4 patients became C1q negative pretransplant and all engrafted the donor cells (P = .008). In conclusion, patients with high DSA levels (>5000 MFI) and complement-binding DSA antibodies (C1q positive) appear to be at much higher risk of primary graft failure. The presence of C1q+DSA should be assessed in allosensitized patients before HSCT. Reduction of C1q+DSA levels might prevent engraftment failure in HSCT

Haploidentical Hematopoietic Stem Cell Transplantation as a Platform for Post-Transplantation Cellular Therapy.

Haploidentical transplantation can extend the opportunity for transplantation to almost all patients who lack an HLA-matched donor. Advances in the field of haploidentical transplantation have led to a marked decrease in treatment-related mortality, allowing investigators to focus on developing rationale pre- and peri-remission therapies aimed at preventing disease relapse after transplantation. Because of widespread availability, low treatment-related mortality, and cost, haploidentical donors may become the preferred alternative donors for allogeneic hematopoietic stem cell transplantation. One of the major advantages of using a related donor is the possibility of collecting or generating additional cellular products from the same immediately available donor, which will not be rejected. Infusion of these cells in the peri-transplantation period, derived from the same immune system, is opening the possibility of markedly enhancing the antitumor effects of the graft and hastening immunologic reconstitution after transplantation

Adoptive cellular therapy after hematopoietic stem cell transplantation

Effective cellular therapy using CD19 chimeric antigen receptor T-cells for the treatment of advanced B-cell malignancies raises the question of whether the administration of adoptive cellular therapy (ACT) posttransplant could reduce relapse and improve survival. Moreover, several early phase clinical studies have shown the potential beneficial effects of administration of tumor-associated antigen-specific T-cells and natural killer cells posttransplant for high-risk patients, aiming to decrease relapse and possibly improve survival. In this article, we present an in-depth review of ACT after transplantation, which has the potential to significantly improve the efficacy of this procedure and revolutionize this field

OR50 Potential new molecular markers to select donors for bone marrow/hematopoeitic stem cell transplantation

Graft vs Host Disease (GVHD) is a major cause of morbidity and mortality following bone marrow/hematopoietic stem cell transplantation (BMT/HSCT). While HLA-matched biological siblings are the most desired donors, 70% of patients do not have a matching donor in their family and HLA matched unrelated donors (MUD) are the only hope. Regardless, GVHD still occurs in 30% BMT/HSCT, mostly in MUD HSCT. As of now, only the HLA-A, B, C, DR, DQ, and DP located in the, alpha, beta and delta blocks are considered for matching. We stipulated that the gamma block (GB) encoding immune responses could be an additional tool to select the best donor/recipient pair in MUD transplants. Using SNP based molecular assay for GB-typing, we studied 52 recipient/donor pairs who received HSCT at our Institution. Overall 10.1% of related (2/22), 100% haploidentical (4/4) and 65.4% of MUD/recipient pairs (17/22) were GB mismatched showing MUD/recipient pairs as 7 times more likely to harbor GB-mismatch compared to related pairs. A limited clinical outcome study showed that GB-mismatch had a higher incidence of grade 2–4 acute GVHD (p=0.044) and chronic GVHD (p=0.048). Multivariate regression showed GB-mismatch is associated with higher transplant related mortality (p=0.020) and a trend for severe acute GVHD (HR 2.450, 95% CI 0.96−6.22; p=0.060) after controlling for donor type. The 25 GB SNPs we examined span both exons and introns of C4 gene. While 46.7% GB-mismatched MUD/recipient and 50% of the haploidentical recipient/donor pairs had SNPs detected in the exons, 75% of the SNP-mismatches occurred in the introns in related pairs. Since the exons are more relevant to functional proteins and introns are more associated with regulation of expression of genes, this distinction of occurrence of GB SNPs in the exons of MUD and haploidentical cases might have practical significance. All related recipient/donor pairs had ⩽3 GB SNP mismatches; whereas all haploidentical and 11/17 MUD/recipient pairs had ⩾3 GB SNPs. Hence there could be more substance to the SNPs in GB as we proceed with larger studies. Our limited data shows that GB disparity can be an additional marker for donor selection for better BMT/HSCT outcome. More retrospective and prospective studies with long-term follow up are needed

Can a female donor for a male recipient decrease the relapse rate for patients with acute myeloid leukemia treated with allogeneic hematopoietic stem cell transplantation?

The mismatched minor histocompatibility antigens present on Y chromosome (H-Y) in male recipients receiving stem cells from female donors may contribute to the graft-versus-leukemia effect and results in a reduced relapse rate, especially in patients with high-risk disease. We retrospectively compared the outcomes of male patients with acute myeloid leukemia who received an allogeneic hematopoietic stem cell transplant (HSCT) from female donors (F-M) (174 patients) versus other gender combinations (667 patients). Median age was 50 years (range, 18 to 74 years). For the whole group, the 1-year cumulative incidence of relapse was significantly lower in F-M group (34.1% versus 41.3%, P = .044), whereas nonrelapse mortality (NRM) was higher (23.2% versus 15.7%, P = .004). For patients younger than 50 years beyond first complete remission, the F-M group was associated with lower relapse rate (42.5% versus 55.2%, P = .045) whereas NRM was not significantly different (35.8% versus 25.5%, P = .141). Although survival was not significantly improved, transplantation from a female donor for male recipient was associated with a lower relapse rate. When relapse is the most common concern for treatment failure, especially for younger patients, a female donor for a male recipient might be beneficial to decrease relapse rate after transplantation. Future studies are needed to explore how the H-Y mismatch may improve survival after transplantation

Molecular disparity in human leukocyte antigens is associated with outcomes in haploidentical stem cell transplantation

Haploidentical donors are increasingly used for patients requiring hematopoietic stem cell transplantation (HSCT). Although several factors have been associated with transplant outcomes, the impact of HLA disparity in haploidentical HSCT (haplo-HSCT) remains unclear. We investigated the impact of HLA disparity quantified by mismatched eplets (ME) load of each HLA locus on the clinical outcome of 278 consecutive haploidentical transplants. Here, we demonstrated that the degree of HLA molecular mismatches, at individual HLA loci, may be relevant to clinical outcome in the haplo-HSCT. A significantly better overall survival was associated with higher ME load from HLA-A (hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.95-0.99; P = .003) and class I loci (HR, 0.99; 95% CI, 0.97-0.99; P = .045) in the host-versus-graft direction. The apparent survival advantage of HLA-A ME was primarily attributed to reduced risk in relapse associated with an increase in HLA-A ME load (subdistribution HR, 0.95; 95% CI, 0.92-0.98; P = .004). Furthermore, we have identified an association between the risk of grade 3-4 acute graft-versus-host disease (GVHD) and a higher ME load at HLA-B and class I loci in graft-versus-host (GVH) direction. Additionally, GVH nonpermissive HLA-DPB1 mismatch defined by T-cell epitope grouping was significantly associated with relapse protection (subdistribution HR, 0.19; 95% CI, 0.06-0.59; P = .004) without a concurrent increase in GVHD. These findings indicate that alloreactivity generated by HLA disparity at certain HLA loci is associated with transplant outcomes, and ME analysis of individual HLA loci might assist donor selection and risk stratification in haplo-HSCT