scholarly journals Directionality of non-permissive HLA-DPB1 T-cell epitope group mismatches does not improve clinical risk stratification in 8/8 matched unrelated donor hematopoietic cell transplantation

2017 ◽  
Vol 52 (9) ◽  
pp. 1280-1287 ◽  
Author(s):  
K Fleischhauer ◽  
K W Ahn ◽  
H L Wang ◽  
L Zito ◽  
P Crivello ◽  
...  
Keyword(s):  
T Cell ◽  
Risk Stratification ◽  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Cell Epitope ◽  
Hematopoietic Cell ◽  
Unrelated Donor ◽  
T Cell Epitope ◽  
Matched Unrelated Donor ◽  
Clinical Risk

scholarly journals Impact of Previously Unrecognized HLA Mismatches Using Ultrahigh Resolution Typing in Unrelated Donor Hematopoietic Cell Transplantation

2021 ◽  
pp. JCO.20.03643
Author(s):  
Neema P. Mayor ◽  
Tao Wang ◽  
Stephanie J. Lee ◽  
Michelle Kuxhausen ◽  
Cynthia Vierra-Green ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Cell Epitope ◽  
Hematopoietic Cell ◽  
Hla Typing ◽  
Unrelated Donor ◽  
T Cell Epitope ◽  
Hla Matching ◽  
Ultrahigh Resolution

PURPOSE Ultrahigh resolution (UHR) HLA matching is reported to result in better outcomes following unrelated donor hematopoietic cell transplantation, improving survival and reducing post-transplant complications. However, most studies included relatively small numbers of patients. Here we report the findings from a large, multicenter validation study. METHODS UHR HLA typing was available on 5,140 conventionally 10 out of 10 HLA-matched patients with malignant disease transplanted between 2008 and 2017. RESULTS After UHR HLA typing, 82% of pairs remained 10 out of 10 UHR-matched; 12.3% of patients were 12 out of 12 UHR HLA-matched. Compared with 12 out of 12 UHR-matched patients, probabilities of grade 2-4 acute graft-versus-host disease (aGVHD) were significantly increased with UHR mismatches (overall P = .0019) and in those patients who were HLA-DPB1 T-cell epitope permissively mismatched or nonpermissively mismatched (overall P = .0011). In the T-cell–depleted subset, the degree of UHR HLA mismatch was only associated with increased transplant-related mortality (TRM) (overall P = .0068). In the T-cell–replete subset, UHR HLA matching was associated with a lower probability of aGVHD (overall P = .0020); 12 out of 12 UHR matching was associated with reduced TRM risk when compared with HLA-DPB1 T-cell epitope permissively mismatched patients, whereas nonpermissive mismatching resulted in a greater risk (overall P = .0003). CONCLUSION This study did not confirm that UHR 12 out of 12 HLA matching increases the probability of overall survival but does demonstrate that aGVHD risk, and in certain settings TRM, is lowest in UHR HLA-matched pairs and thus warrants consideration when multiple 10 out of 10 HLA-matched donors of equivalent age are available.

HLA-matched unrelated donor hematopoietic cell transplantation after nonmyeloablative conditioning for patients with hematologic malignancies

Blood ◽  
2003 ◽  
Vol 102 (6) ◽  
pp. 2021-2030 ◽  
Author(s):  
Michael B. Maris ◽  
Dietger Niederwieser ◽  
Brenda M. Sandmaier ◽  
Barry Storer ◽  
Monic Stuart ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Mononuclear Cells ◽  
Human Leukocyte ◽  
Hematologic Malignancies ◽  
Hematopoietic Cell ◽  
Unrelated Donor ◽  
Matched Unrelated Donor ◽  
Peripheral Blood Mononuclear

Abstract A hematopoietic cell transplantation (HCT) approach was developed for elderly or ill patients with hematologic malignancies that employed nonmyeloablative conditioning to avoid common regimen-related toxicities and relied on graft-versus-tumor effects for control of malignancy. Eighty-nine patients, median age 53 years, were given fludarabine (90 mg/m2) and 2 Gy total body irradiation. Marrow (n = 18) or granulocyte colony-stimulating factor (G-CSF)–stimulated peripheral blood mononuclear cells (G-PBMCs; n = 71) were transplanted from unrelated donors matched for human leukocyte antigen A (HLA-A), -B, -C antigens and -DRB1 and -DQB1 alleles. Postgrafting immunosuppression included mycophenolate mofetil and cyclosporine. Donor T-cell chimerism was higher for G-PBMCs compared with marrow recipients. Durable engraftment was observed in 85% of G-PBMCs and 56% of marrow recipients. Cumulative probabilities of grade II, III, and IV acute graft-versus-host disease (GVHD) were 42%, 8%, and 2%, respectively. Nonrelapse mortality at day 100 and at 1 year was 11% and 16%, respectively. One-year overall survivals and progression-free survivals were 52% and 38%, respectively. G-PBMC recipients had improved survival (57% vs 33%) and progression-free survival (44% vs 17%) compared with marrow recipients. HLA-matched unrelated donor HCT after nonmyeloablative conditioning is feasible in patients ineligible for conventional HCT. G-PBMCs conferred higher donor T-cell chimerism, greater durable engraftment, and better progression-free and overall survivals compared with marrow.

scholarly journals Risk associations between HLA-DPB1 T-cell epitope matching and outcome of unrelated hematopoietic cell transplantation are independent of HLA-DPA1

2014 ◽  
Vol 49 (9) ◽  
pp. 1176-1183 ◽  
Author(s):  
K Fleischhauer ◽  
M A Fernandez-Viña ◽  
T Wang ◽  
M Haagenson ◽  
M Battiwalla ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Cell Epitope ◽  
Hematopoietic Cell ◽  
T Cell Epitope

The Functional Distance Between Mismatched HLA-DPB1 Increases Risks of Relapse and Mortality after Unrelated Donor Hematopoietic Cell Transplantation for AML, ALL and MDS: A Refinement of the T Cell Epitope Group Algorithm for Permissive Mismatches

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4288-4288
Author(s):  
Dietrich W. Beelen ◽  
Pietro Crivello ◽  
Andreas Heinold ◽  
Sabine Riebschläger ◽  
Falko M. Heinemann ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Cell Epitope ◽  
Disease Status ◽  
Marrow Transplant ◽  
Unrelated Donor ◽  
T Cell Epitope ◽  
Functional Distance

Abstract Background: We and others have previously shown that non-permissive T cell epitope (TCE) group mismatches at HLA-DPB1 are associated with the risks of mortality after hematopoietic cell transplantation (HCT) from 10/10 HLA-matched unrelated donors (Fleischhauer et al, Lancet Oncol 2012; Pidala et al, Blood 2014). Moreover, we recently reported that TCE groups are reflected by a numerical score assignable to each HLA-DPB1 allele based on the combined median impact of 12 naturally occurring amino acid substitutions (AAS) on allorecognition of HLA-DPB1*09:01 as reference, termed functional distance (FD) (Crivello et al, Biol Blood Marrow Transplant 2015). Here we studied the association between the Delta in FD scores of HLA-DPB1 alleles present in the patient and in the donor (Delta-FD), and the clinical outcome of unrelated HCT. Methods: 417 consecutive adult patients transplanted from a 10/10 HLA-matched unrelated donor AML (n=302 [72%]), ALL (n=58 [8%]), or MDS (n=57 [14%]) at the University Hospital Essen between the years 2005 and 2014 were included in the analysis. 37 pairs were matched for both HLA-DPB1 alleles (12/12 HLA matches) while the remaining 380 pairs were HLA-DPB1 mismatched. Among the latter, Delta-FD scores were calculated as the absolute number of [FDpatient-FDdonor] on the basis of previously described FD scores for each HLA-DPB1 allele (Crivello et al, Biol Blood Marrow Transplant 2015). Results: The median Delta-FD score of HLA-DPB1 mismatched pairs was 1.64 (0.01-7.46). Receiver Operator Curves indicated stratification into 2 subgroups with Delta-FD scores <=2.665 (n=253 [66%]) and >2.665 (n=127 [34%]) as the best predictor of overall survival (OS). The 2 subgroups showed no significant differences for the distribution of major variables including diagnosis, disease status at transplant, immune prophylaxis and conditioning regimen, except for the percentage of permissive HLA-DPB1 TCE mismatches which was significantly higher in the subgroup with Delta-FD scores <=2.665 (p<0.0001). With a median follow-up of 4 yrs for surviving pts, the 5-yrs OS in the entire HLA-DPB1 mismatched cohort was 48%. In the 2 Delta-FD subgroups, the Kaplan-Meier (KM) probabilities of OS were 52% for Delta-FD <=2.665 and 38% for Delta-FD >2.665 (p<0.008), compared to 50% and 44% (p=0.31) for permissive and non-permissive TCE mismatches, respectively. In multivariate analysis, independent predictors of OS were time-dependent acute GvHD (HR 3.41, p<0.0001) and chronic GvHD (HR 0.41, p<0.0001), the use of anti-thymocyte globulin (HR 0.58, p=0.0006), disease status at transplant (HR 1.27, p<0.007), patient age (HR 1.63 p<0.007), and the stratified Delta-FD score (HR 1.51, p<0.007). Moreover, Delta-FD scores >2.665 were associated with lower probability of event-free survival (HR 1.48, p<0.007), due to significantly higher risks of disease relapse (HR 1.52, p<0.03) and NRM (HR 1.50, p<0.045), but not of acute or chronic GvHD. No significant differences were observed for any of the endpoints between 12/12 HLA-matched and 10/10 HLA-matched pairs with Delta-FD <=2.665. Conclusion: Stratification of HLA-DPB1 mismatches according to Delta-FD scores between donor and recipient represents a refinement of our previously published TCE algorithm of non-permissive mismatches with significant overlaps. In comparison to the latter, Delta-FD scores showed improved associations with the risks of mortality and relapse after 10/10 HLA-matched unrelated HCT in the patient cohort analyzed. If confirmed, these findings could provide a refined tool for donor-recipient matching for HLA-DPB1, and suggest that the combined impact of key AAS on T-cell alloreactivity, rather than AAS at individual positions, are relevant parameters for risk prediction in HLA-DPB1 mismatched HCT. Disclosures No relevant conflicts of interest to declare.

scholarly journals HLA-DRB3/4/5 mismatches are associated with increased risk of acute GVHD in 10/10 matched unrelated donor hematopoietic cell transplantation

2018 ◽  
Vol 93 (8) ◽  
pp. 994-1001
Author(s):  
Stéphanie Ducreux ◽  
Valérie Dubois ◽  
Kahina Amokrane ◽  
Ibrahim Yakoub-Agha ◽  
Myriam Labalette ◽  
...  
Keyword(s):  
Cell Transplantation ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Unrelated Donor ◽  
Matched Unrelated Donor ◽  
Increased Risk
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