Clinical Utility of the Detection of the Loss of the Mismatched HLA in Relapsed Hematological Patients After Haploidentical Stem Cell Transplantation With High-Dose Cyclophosphamide (original) (raw)
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Leukemia, 2014
Genomic loss of the mismatched human leukocyte antigen (HLA) is a recently described mechanism of leukemia immune escape and relapse after allogeneic hematopoietic stem cell transplantation (HSCT). Here we first evaluated its incidence, risk factors and outcome in 233 consecutive transplants from partially HLA-mismatched related and unrelated donors (MMRD and MMUD, respectively). We documented 84 relapses, 23 of which with HLA loss. All the HLA loss relapses occurred after MMRD HSCT, and 20/23 in patients with acute myeloid leukemia. Upon MMRD HSCT, HLA loss variants accounted for 33% of the relapses (23/69), occurring later than their 'classical' counterparts (median: 307 vs 88 days, P o0.0001). Active disease at HSCT increased the risk of HLA loss (hazard ratio (HR): 10.16; confidence interval (CI): 2.65-38.92; P = 0.001), whereas older patient ages had a protective role (HR: 0.16; CI: 0.05-0.46; P = 0.001). A weaker association with HLA loss was observed for graft T-cell dose and occurrence of chronic graft-versus-host disease. Outcome after 'classical' and HLA loss relapses was similarly poor, and second transplantation from a different donor appeared to provide a slight advantage for survival. In conclusion, HLA loss is a frequent mechanism of evasion from T-cell alloreactivity and relapse in patients with myeloid malignancies transplanted from MMRDs, warranting routine screening in this transplantation setting.
Blood, 2009
The finding that the risk of relapse in hematologic malignancy decreases after allogeneic hematopoietic stem cell transplantation (HSCT) has lead to the concept of a graft-versus-leukemia (GVL) effect. However, this beneficial effect is considered to be frequently offset by graftversus-host disease (GVHD). Thus, improving HSCT outcomes by separating GVL from GVHD is a key clinical issue. This cohort study registered 4643 patients with hematologic malignancies who received transplants from unrelated donors. Six major human leukocyte antigen (HLA) loci were retrospectively genotyped. We identified 4 HLA-Cw and 6 HLA-DPB1 mismatch combinations responsible for a decreased risk of relapse; of these, 8 of 10 combinations were different from those responsible for severe acute GVHD, including all 6 of the HLA-DPB1 combinations. Pairs with these combinations of HLA-DPB1 were associated with a significantly better overall survival than were completely matched pairs. Moreover, several amino acid substitutions on specific positions responsible for a decreased risk of relapse were identified in HLA-Cw, but not in HLA-DPB1. These findings might be crucial to elucidating the mechanism of the decreased risk of relapse on the basis of HLA molecule. Donor selection made in consideration of these results might allow the separation of GVL from acute GVHD, especially in HLA-DPB1 mismatch combinations. (Blood. 2009;113:2851-2858) Methods Patients This study was conducted using clinical data that were collected prospectively at transplant centers participating in the Japan Marrow Donor Program. Patients who received a first transplant of T cell-replete marrow for a hematologic malignancy from a serologically HLA-A,-B, and-DR antigen-matched unrelated donor between January 1993 and December 2005 through the Japan Marrow Donor Program (n ϭ 4643) were registered. Eligible diagnoses included acute lymphoblastic leukemia (ALL); acute myeloid leukemia (AML), which included only de novo AML;
Blood, 2010
We investigated human leukocyte antigen (HLA) expression on leukemic cells derived from patients at diagnosis and relapse after hematopoietic stem cell transplantation (HSCT) using flow cytometry with locus-specific antibodies. Two of 3 patients who relapsed after HLA-haploidentical HSCT demonstrated loss of HLA alleles in leukemic cells at relapse; on the other hand, no loss of HLA alleles was seen in 6 patients who relapsed after HLA-identical HSCT. Single-nucleotide polymorphism array analyses of sorted leukemic cells further revealed the copy number-neutral loss of heterozygosity, namely, acquired uniparental disomy on the short arm of chromosome 6, resulting in the total loss of the mismatched HLA haplotype. These results suggest that the escape from immunosurveillance by the loss of mismatched HLA alleles may be a crucial mechanism of relapse after HLA-haploidentical HSCT. Accordingly, the status of mismatched HLA on relapsed leukemic cells should be checked before donor lymph...
Bone Marrow Transplantation, 2021
Antibodies to HLA are commonly present in hematopoietic cell transplant (HCT) patients and associate with increased risk of graft failure when specific to donor HLA (DSA) (1-4). Increasing trends of mismatched donor HCT, haploidentical HCT (HaploHCT), and reduced-intensity conditioning (RIC) regimens exacerbate these concerns (5, 6). By comparison, HLA antibodies not specific to the donor (third-party antibodies, TPA) are less studied and reported to be innocuous in a matched donor cohort (7). Because high-risk DSA (HR-DSA) is already reported to associate with graft failure (4, 8, 9), we investigated the effects of commonly found low-risk pre-transplant DSA (LR-DSA) and TPA on HaploHCT patients' outcomes, focusing on engraftment, with survival, relapse, and graft vs. host disease as secondary endpoints. We retrospectively analyzed 208 consecutive patients receiving first HaploHCT at City of Hope, Duarte, CA from 04/2014 to 12/2018. HLA test results include HLA antibodies identified within 30 days prior to transplant (cut-off MFI >1000) using Single-Antigen Bead array (One Lambda, West Hills, California), calculated panel reactive antibody (cPRA), lymphocyte crossmatch positivity by Halifaster flow cytometric method (10), and high-resolution HLA typing of patients and donors by NGS (Scisco Genetics, Seattle, Washington). Antibodies requiring desensitization, including DSA > 5000 MFI against highly expressed HLA (i.e., HLA-A, B, or DRB1), were considered high risk; other DSA in the cohort were categorized as low risk (LR-DSA). Patients with high risk antibodies were assessed in antibody prevalence analysis, but excluded from clinical outcome analysis
Haematologica, 2016
Composite endpoints that not only encompass mortality and relapse, but other critical posttransplant events such as graft-versus-host disease, are being increasingly utilized to quantify survival without significant morbidity after allogeneic blood or marrow transplantation. High-dose, posttransplantation cyclophosphamide reduces severe graft-versus-host disease after allogeneic marrow transplantation, making its composite endpoints of particular interest. We retrospectively analyzed 684 adults with hematologic malignancies who received T-cell-replete bone marrows and posttransplantation cyclophosphamide after myeloablative HLA-matched related (n= 192) or unrelated (n=120), or nonmyeloablative HLA-haploidentical (n = 372) donor transplantation; median follow up was 4 (range 0.02-11.4) years. GVHD-free, relapse-free survival was defined as time after transplantation without grade III-IV acute graft-versus-host disease, chronic graft-versus-host disease requiring systemic treatment, r...
Biology of Blood and …, 2007
HLA matching between the donor and recipient improves the success of unrelated hematopoietic stem cell transplantation (HSCT). Because many patients in need of an unrelated transplant have only donors with mismatch, information is needed to evaluate the limits of HLA mismatching. We examined the association of survival, acute graft-versus-host disease (aGVHD) and relapse with HLA-A, -B, -C, -DRB, -DQB1, and -DPB1 mismatching in 334 patients coming from 12 French transplant centers and who received a non-T cell-depleted bone marrow graft from an unrelated donor. All patients were prepared with the use of myeloablative conditioning regimens. Our analyses demonstrate negative effects of HLA mismatching for either HLA-A, -B, -C, -DRB1, or -DQB1 loci on survival. Multivariate Cox analyses showed that a single mismatch was associated with a significant decrement in survival (P ؍ .046, hazard ratio [HR] ؍ 1.41, confidence interval [CI] 95% . The presence of multiple mismatches was worse for survival (P ؍ .003, HR ؍ 1.91, CI 95% 1.26-2.91) and severe aGVHD (grade III-IV) (P ؍ .002, . The cumulative incidences of aGVHD and relapse in those HLA-A, -B, -C, -DRB1, and -DQB1 identical pairs with 2, 1, or 0 DPB1 incompatibilities were 63%, 50%, and 51%, and 12%, 27%, and 20%, respectively, but these differences were not statistically significant. Similar differences of aGVHD and relapse, but not statistically significant, were observed in those HLA-A, -B, -C, -DRB1, and -DQB1 identical pairs with DPB1 disparities classified into permissive or nonpermissive mismatches according to Zino's classification based on a hierarchy of the immunogenicity of the HLA-DP molecules. "Missing killer cell immunoglobulin-like receptor (KIR) ligand" evaluated on the presence of HLA-C1, -C2, and Bw4 groups in the recipients was not associated with aGVHD, survival, and relapse in this cohort of non-T cell-depleted HSCT.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation
Although some reports have found increasing HLA disparity between donor and recipient to be associated with fewer relapses after allogeneic blood or marrow transplantation (BMT), this potential benefit has been offset by more graft-versus-host disease (GVHD) and nonrelapse mortality. However, the type of GVHD prophylaxis could influence the balance between GVHD toxicity and relapse. We analyzed the impact of greater HLA disparity on outcomes of a specific platform for nonmyeloablative, HLA-haploidentical transplantation. A retrospective analysis was performed on 185 patients with hematologic malignancies enrolled on three similar trials of nonmyeloablative, related donor, haploidentical BMT incorporating high-dose posttransplantation cyclophosphamide for GVHD prophylaxis. No significant association was found between the number of HLA mismatches (HLA-A, -B, -Cw, and -DRB1 combined) and risk of acute grade II-IV GVHD (hazard ratio .89, P = .68 for 3-4 versus fewer antigen mismatches). More mismatching also had no detrimental effect on event-free survival (on multivariate analysis, hazard ratio .60, P = .03 for 3-4 versus fewer antigen mismatches; hazard ratio .55, P = .03 for 3-4 versus fewer allele mismatches). Thus, greater HLA disparity does not appear to worsen overall outcomes after nonmyeloablative haploidentical BMT with high-dose posttransplantation cyclophosphamide.
Biology of Blood and Marrow Transplantation, 2007
HLA matching between the donor and recipient improves the success of unrelated hematopoietic stem cell transplantation (HSCT). Because many patients in need of an unrelated transplant have only donors with mismatch, information is needed to evaluate the limits of HLA mismatching. We examined the association of survival, acute graft-versus-host disease (aGVHD) and relapse with HLA-A, -B, -C, -DRB, -DQB1, and -DPB1 mismatching in 334 patients coming from 12 French transplant centers and who received a non-T cell-depleted bone marrow graft from an unrelated donor. All patients were prepared with the use of myeloablative conditioning regimens. Our analyses demonstrate negative effects of HLA mismatching for either HLA-A, -B, -C, -DRB1, or -DQB1 loci on survival. Multivariate Cox analyses showed that a single mismatch was associated with a significant decrement in survival (P ؍ .046, hazard ratio [HR] ؍ 1.41, confidence interval [CI] 95% . The presence of multiple mismatches was worse for survival (P ؍ .003, HR ؍ 1.91, CI 95% 1.26-2.91) and severe aGVHD (grade III-IV) (P ؍ .002, . The cumulative incidences of aGVHD and relapse in those HLA-A, -B, -C, -DRB1, and -DQB1 identical pairs with 2, 1, or 0 DPB1 incompatibilities were 63%, 50%, and 51%, and 12%, 27%, and 20%, respectively, but these differences were not statistically significant. Similar differences of aGVHD and relapse, but not statistically significant, were observed in those HLA-A, -B, -C, -DRB1, and -DQB1 identical pairs with DPB1 disparities classified into permissive or nonpermissive mismatches according to Zino's classification based on a hierarchy of the immunogenicity of the HLA-DP molecules. "Missing killer cell immunoglobulin-like receptor (KIR) ligand" evaluated on the presence of HLA-C1, -C2, and Bw4 groups in the recipients was not associated with aGVHD, survival, and relapse in this cohort of non-T cell-depleted HSCT.