scholarly journals 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

2016 ◽  
Vol 22 (3) ◽  
pp. S420-S421
Author(s):  
Pietro Crivello ◽  
Dietrich W. Beelen ◽  
Andreas Heinold ◽  
Sabine Riebschläger ◽  
Falko Heinemann ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Cell Epitope ◽  
Hematopoietic Cell ◽  
Unrelated Donor ◽  
T Cell Epitope ◽  
Functional Distance

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.

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 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

scholarly journals HLA-DM Mediates Permissiveness of HLA-DPB1 T Cell Epitope Mismatches in Unrelated HCT

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3211-3211
Author(s):  
Maximilian Metzing ◽  
Pietro Crivello ◽  
Thuja Meurer ◽  
Michel G.D. Kester ◽  
Dominik Megger ◽  
...  
Keyword(s):  
T Cell ◽  
Hela Cells ◽  
Hematopoietic Cell Transplantation ◽  
Conflicts Of Interest ◽  
Ex Vivo ◽  
Cell Epitope ◽  
University Hospital ◽  
Unrelated Donor ◽  
T Cell Epitope ◽  
Healthy Individuals

Introduction: In 8/8 matched unrelated donor (UD) hematopoietic cell transplantation (HCT), permissive HLA-DPB1 (DP) mismatches within the same functional T Cell Epitope (TCE) group are associated with better outcomes compared to non-permissive mismatches across different TCE groups (Fleischhauer, Blood 2017). This clinical advantage has been shown to be associated with limited in vitro T cell alloreactivity (Meurer, Front Immunol 2019), which in turn is dependent on polymorphic peptide contact amino acids in the DP molecule (Crivello, Biol Blood Marrow Transplant 2015). The HLA class II immunopeptidome is shaped by the peptide editor HLA-DM (DM), and its natural antagonist HLA-DO (DO). Here we investigated the effect of DM/DO activity on the DP immunopeptidome, the breadth of the overall alloresponse to and immunogenicity of permissive and non-permissive DP mismatches, in healthy individuals and in patients after UD-HCT. Methods: HeLa cells expressing single DP alleles in the presence or absence of DM, or in the presence of DM and DO (Rutten, BBMT 2008), were generated for HLA-DPB1*04:02 (DP4) and *10:01 (DP10) as prototypes for 2 distinct TCE groups. The DP immunopeptidomes were analyzed by mass spectrometry. Alloresponses against DP were quantified by CD137 up-regulation assays after co-culture of irradiated HeLa cells with CD4+ responder T cells from 14 healthy blood donors permissive to DP4 and non-permissive to DP10, or from 2 patients referring to the University Hospital Essen, Germany, the latter alive and well >9 months after 8/8 matched UD-HCT with a permissive DP4 or a non-permissive DP10 mismatch, respectively. The breadth of the responding T cell receptor beta (TCRb) repertoire was determined by immunosequencing (Adaptive Biotechnologies, Seattle, USA). The study was performed under informed consent according to the declaration of Helsinki. Results: Reflecting their association with different TCE groups, DP4 and DP10 presented peptidomes with limited (<4%) overlap and different peptide motifs. These features were not changed by the presence or absence of DM. In contrast, the presence of DM resulted in a significant (>50%) shrinking of the peptide repertoire displayed by the same DP antigen in the absence of DM, with approximately 30% peptides shared by the same allele in the two conditions, both for DP4 and for DP10 (Figure 1A). In the presence of DM, the magnitude of the T cell alloresponse to non-permissive DP10 was significantly higher than to permissive DP4, both in healthy individuals (40.7% vs 16.3%, respectively, p<0.0001) and in the informative transplanted patients (Figure 1B). Neither the absence of DM (40.7% vs 45.3%, p=ns) nor the presence of DM with DO (71.6% vs 77.4%, p=ns) altered the magnitude of the non-permissive alloresponse to DP10. Compellingly, both the absence of DM (16.3% vs 39.0%, p<0.001) and the co-expression of DM and DO (21.6% vs 59.5%, p<0.001) significantly increased the response to permissive DP4, again both in healthy individuals and in the informative transplanted patients. The strength of the overall alloresponse was associated with the breadth of the corresponding TCRb repertoire, with significantly higher diversity (1-clonality) in response to non-permissive DP10 (mean 0.68) compared to permissive DP4 (mean 0.48) in the presence of DM, and similar high diversity against both DP antigens in its absence (mean 0.74 vs 0.75 against DP4 and DP10, respectively) in healthy individuals. In the transplanted patients, the permissive alloresponse to DP4 was dominated by a single TCRb that could be retrieved at high frequency also in ex-vivo follow-up samples from the same patient from day +195 and +363, while the non-permissive alloresponse to DP10 was polyclonal (mean 0.62 and 0.61 in the presence and absence of DM, respectively) (Figure 1C). Conclusion: Permissiveness of HLA-DPB1 TCE mismatches is dependent on the peptide editing by DM, and converted into non-permissiveness in its absence or in the presence of its antagonist DO. Permissiveness is associated with the immunopeptidomes of mismatched HLA-DP alloantigens on the MHC side, and with TCRb diversity on the alloreactive T cell side, both in healthy individuals and in patients after UD-HCT. These new mechanistic insights suggest that expression of DM and DO by leukemia or healthy tissues might modulate graft-versus-leukemia and graft-versus-host disease after permissively DP mismatched UD HCT. Disclosures No relevant conflicts of interest to declare.

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 Effect of T-cell-epitope matching at HLA-DPB1 in recipients of unrelated-donor haemopoietic-cell transplantation: a retrospective study

2012 ◽  
Vol 13 (4) ◽  
pp. 366-374 ◽  
Author(s):  
Katharina Fleischhauer ◽  
Bronwen E Shaw ◽  
Theodore Gooley ◽  
Mari Malkki ◽  
Peter Bardy ◽  
...  
Keyword(s):  
Retrospective Study ◽  
T Cell ◽  
Cell Transplantation ◽  
Cell Epitope ◽  
Unrelated Donor ◽  
T Cell Epitope

scholarly journals Lower Use of DLI Post Relapse of Malignancy May Result in Shorter Post-Relapse Survival (PRS) in Patients Undergoing T Cell Replete Haploidentical Donor Transplantation (HIDT) Versus Matched Related (MRD) or Matched Unrelated Donor (MUD) Hematopoietic Cell Transplantation (HCT)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1967-1967
Author(s):  
Melhem Solh ◽  
Xu Zhang ◽  
Stacey Brown ◽  
Lawrence E. Morris ◽  
H. Kent Holland ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Transplantation ◽  
Median Time ◽  
Hematopoietic Cell Transplantation ◽  
Risk Index ◽  
Hematopoietic Cell ◽  
Unrelated Donor ◽  
Post Transplant ◽  
Comorbidity Index ◽  
Time To Relapse

Abstract Relapse of hematologic malignancies remains a major cause of treatment failure and mortality among patients receiving allogeneic hematopoietic cell transplantation (HCT). Patients relapsing after a matched related or unrelated donor transplantation may benefit from donor lymphocyte infusion (DLI) as part of their post relapse therapy. DLI post-relapse has less frequently been utilized among recipients of HIDT presumably due to the potential for severe GVHD if high T-cell doss are administered without immunosuppression. However, reluctance to administer DLI may limit the possibility of remission following disease relapse in HIDT. We compared the frequency of use of DLI and survival outcomes for patients relapsing after HIDT using post-transplant cyclophosphamide to those relapsing after MRD or MUD HCT at our institution. 195 consecutive HCT recipients with relapse of hematologic malignancy occurring after HIDT (N=35), MUD (N=74) and MRD (N=81) between 1998 and 2014 were included in this analysis. The median age was 50 years (19-77 years) and median time to relapse was 159 days (25-2465 days) post HCT. Patients receiving HIDT had similar median time to relapse (5.1 vs 5.2 vs 5.2 months, p=0.638), Dana-Farber/CIBMTR disease risk index (DRI), comorbidity index (CMI) scores, longer times to neutrophil engraftment (17 vs 14 vs 14 days, p<0.001), and platelet engraftment (28 vs 19 vs 18 days, p<0.001) when compared to MUD and MRD recipients respectively. Post-relapse survival at 1 year was worse among HIDT recipients when compared to MRD (9% versus 41%, p=0.008) and MUD (9% vs 35%, p=0.025). DLI was used in 3 (8%) relapsed HIDT patients, 48 MRD patients (59%) and 28 (38%) MUD recipients. Among patients relapsing post MRD and MUD HCT, use of DLI was associated with a better post relapse survival (p=0.04). In a multivariate analysis, donor type (HIDT), time to relapse (<3 months versus > 3months post-transplant) and comorbidity index (CMI score >= 3) were all predictive of worse post relapse survival. This analysis shows that relapse post HIDT carries a worse prognosis than relapse post MRD and MUD. Efforts such as post-transplant maintenance and haploidentical DLI infusions should be investigated further in the HIDT setting. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures No relevant conflicts of interest to declare.

scholarly journals Pharmacodynamics of mycophenolate mofetil after nonmyeloablative conditioning and unrelated donor hematopoietic cell transplantation

Blood ◽  
2005 ◽  
Vol 106 (13) ◽  
pp. 4381-4388 ◽  
Author(s):  
Luisa Giaccone ◽  
Jeannine S. McCune ◽  
Michael B. Maris ◽  
Theodore A. Gooley ◽  
Brenda M. Sandmaier ◽  
...  
Keyword(s):  
Mycophenolate Mofetil ◽  
T Cell ◽  
Cell Transplantation ◽  
Graft Rejection ◽  
Hematopoietic Cell Transplantation ◽  
Plasma Concentrations ◽  
Hematologic Malignancies ◽  
Immunosuppressive Drug ◽  
Hematopoietic Cell ◽  
Unrelated Donor

The immunosuppressive drug mycophenolate mofetil (MMF) is used after nonmyeloablative hematopoietic cell transplantation (HCT); however, limited pharmacodynamic data are available. We evaluated plasma concentrations of mycophenolic acid (MPA), the active metabolite of MMF, and outcomes in 85 patients with hematologic malignancies conditioned with fludarabine and 2 Gy total body irradiation followed by HLA-matched unrelated-donor HCT and postgrafting cyclosporine and MMF. The first 38 patients received MMF 15 mg/kg twice daily; the next 47 patients received MMF 3 times daily. MPA pharmacokinetics were determined on days 7 and 21. Comparing the twice-daily and 3-times-daily MMF groups, the mean total MPA concentration steady state (Css) was 1.9 and 3.1 μg/mL; the unbound Css was 18 and 36 ng/mL, respectively (P < .001). Sixteen patients with a total MPA Css less than 3 μg/mL had low (< 50%) donor T-cell chimerism (P = .03), and 6 patients with MPA Css less than 2.5 μg/mL had graft rejection. An elevated unbound Css was associated with cytomegalovirus reactivation (P = .03). There were no significant associations between MPA pharmacokinetics and acute graft-versus-host disease (GVHD) or relapse. We conclude that increased MPA Css's predicted higher degrees of donor T-cell chimerism after unrelated donor nonmyeloablative HCT and suggest that targeting MPA Css's greater than 2.5 μg/mL could prevent graft rejection.

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