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1
Buhler, Stéphane, Helen Baldomero, Sylvie Ferrari-Lacraz, Anne-Claire Mamez, Stavroula Masouridi-Levrat, Dominik Heim, Jörg Halter, et al. "Analysis of biological models to predict clinical outcomes based on HLA-DPB1 disparities in unrelated transplantation." Blood Advances 5, no. 17 (September 3, 2021): 3377–86. http://dx.doi.org/10.1182/bloodadvances.2020003998.
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Abstract HLA compatibility is a key factor for survival after unrelated hematopoietic stem cell transplantation (HSCT). HLA-A, -B, -C, -DRB1, and -DQB1 are usually matched between donor and recipient. By contrast, HLA-DPB1 mismatches are frequent, although it is feasible to optimize donor selection and DPB1 matching with prospective typing. Because classical DPB1 allele mismatches are often unavoidable, however, several biological models have been developed to predict the optimal DPB1 mismatch combination for less graft-versus-host disease (GVHD) and better overall survival. In 909 recipient/donor pairs, we analyzed the role of 3 biological models: T-cell epitopes (TCEs) based on the immunogenicity of DPB1, cell surface expression of DPB1 molecules based on a single-nucleotide polymorphism located in the 3′ untranslated region, and the Predicted Indirectly ReCognizable HLA Epitopes (PIRCHE) model based on the presentation of allogeneic peptides derived from mismatched HLA, compared with the classical allele mismatch. Matching for both DPB1 alleles remains the best option to prevent acute GVHD. In the situation of one DPB1 allele mismatch, the donor associated with the lowest acute GVHD risks is mismatched for an allele with a low expression profile in the recipient, followed by a permissive TCE3/4 mismatch and/or the absence of PIRCHE II potential against the recipient. In the context of 2 DPB1 mismatches, the same considerations apply for a permissive TCE3/4 mismatch and no PIRCHE II. By combining the biological models, the most favorable DPB1 constellation can be defined. This approach will help optimize donor selection and improve post-HSCT complications and patient prognosis.
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Chiusolo, Patrizia, Teresa Lamparelli, Giuseppe Sapienza, Alida Dominietto, Anna Maria Raiola, Carmen Di Grazia, Sabrina Giammarco, et al. "The Impact of Aminoacid Substitution at Position 116 Class I HLA, in Unrelated Donor Transplants." Blood 134, Supplement_1 (November 13, 2019): 4620. http://dx.doi.org/10.1182/blood-2019-130614.
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Background : The role of aminoacid substitution at position 116 of class I HLA antigens, has been the subject of several contributions, suggesting the possibility of permissive or non permissive mismatches. Hypothesis. Permissive mismatched at position AA116, yield outcomes comparable to 10/10 matched grafts and superior to AA116 non permissive mismatches. Patients: We have analyzed 358 unrelated donor transplants (UD) to test this hypothesis. All donors were matched at class II for DRB1 and DQ alleles; 226 were also matched at high resolution for A,B and C alleles; 84 had 1 permissive AA116 mismatch (Pmm), and 48 had 1 non permissive mismatch (NPmm). The 3 groups were comparable for patients age (p=0.5), donors age (p=0.9), diagnosis (p=0.2) and intensity of the conditioning regimen (p=0.4); both NPmm and Pmm had more patients with advanced disease, as compared to matched patients. The stem cell source was peripjheral blood for the large majority of patients. Results. The cumulative incidence (CI) of acute GvHD grade II-IV (p=0.01) and III-IV (p=0.001) was greater in patients with 1 allele mismatch, compared to matched patients, irrespective of AA116 permissive substitution. The CI of non relapse mortality (NRM) at 5 years 29%, 35%, 50% respectively in patients grafted from 10/10 matched donors, 1 allele Pmm donors and 1 allele NPmm donors (p=0.005). GvHD with or without infections, as a cause of death was recorded in 19%, 23% and 33% of the three groups respectively (p=0.1). The CI of relapse was respectively 18%, 30%, 20% (p=0.1). The actuarial survival at 5 years was 68% for 10/10 matched patients, 63% for 1 allele Pmm patients and 47% for 1 allele NPmm patients. Conclusions. We confirm that aminoacid substitution at position 116 of class I HLA antigens, is a risk factor for non relapse mortality and survival. Patients with permissive mismatched AA116 donors have outcome comparable to patients grafted from matched donors. Figure Disclosures Angelucci: Novatis: Honoraria, Other: Chair Steering Committee TELESTO protocol; Celgene: Honoraria, Other: Participation in DMC; BlueBirdBio: Other: Local advisory board; Jazz Pharmaceuticals: Other: Local advisory board; Roche: Other: Local advisory board; Vertex Pharmaceuticals Incorp., and CRISPR Therapeutics: Other: Participation in DMC.
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Stevens, Cladd E., Carmelita Carrier, Carol Carpenter, Dorothy Sung, and Andromachi Scaradavou. "HLA mismatch direction in cord blood transplantation: impact on outcome and implications for cord blood unit selection." Blood 118, no. 14 (October 6, 2011): 3969–78. http://dx.doi.org/10.1182/blood-2010-11-317271.
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AbstractDonor-recipient human leukocyte antigen mismatch level affects the outcome of unrelated cord blood (CB) transplantation. To identify possible “permissive” mismatches, we examined the relationship between direction of human leukocyte antigen mismatch (“vector”) and transplantation outcomes in 1202 recipients of single CB units from the New York Blood Center National Cord Blood Program treated in United States Centers from 1993-2006. Altogether, 98 donor/patient pairs had only unidirectional mismatches: 58 in the graft-versus-host (GVH) direction only (GVH-O) and 40 in the host-versus-graft or rejection direction only (R-O). Engraftment was faster in patients with GVH-O mismatches compared with those with 1 bidirectional mismatch (hazard ratio [HR] = 1.6, P = .003). In addition, patients with hematologic malignancies given GVH-O grafts had lower transplantation-related mortality (HR = 0.5, P = .062), overall mortality (HR = 0.5, P = .019), and treatment failure (HR = 0.5, P = .016), resulting in outcomes similar to those of matched CB grafts. In contrast, R-O mismatches had slower engraftment, higher graft failure, and higher relapse rates (HR = 2.4, P = .010). Based on our findings, CB search algorithms should be modified to identify unidirectional mismatches. We recommend that transplant centers give priority to GVH-O-mismatched units over other mismatches and avoid selecting R-O mismatches, if possible.
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Jucaud, Vadim. "The Immunogenicity of HLA Class II Mismatches: The Predicted Presentation of Nonself Allo-HLA-Derived Peptide by the HLA-DR Phenotype of the Recipient Is Associated with the Formation of DSA." Journal of Immunology Research 2017 (2017): 1–12. http://dx.doi.org/10.1155/2017/2748614.
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The identification of permissible HLA class II mismatches can prevent DSA in mismatched transplantation. The HLA-DR phenotype of recipients contributes to DSA formation by presenting allo-HLA-derived peptides to T-helper cells, which induces the differentiation of B cells into plasma cells. Comparing the binding affinity of self and nonself allo-HLA-derived peptides for recipients’ HLA class II antigens may distinguish immunogenic HLA mismatches from nonimmunogenic ones. The binding affinities of allo-HLA-derived peptides to recipients’ HLA-DR and HLA-DQ antigens were predicted using the NetMHCIIpan 3.1 server. HLA class II mismatches were classified based on whether they induced DSA and whether self or nonself peptide was predicted to bind with highest affinity to recipients’ HLA-DR and HLA-DQ. Other mismatch characteristics (eplet, hydrophobic, electrostatic, and amino acid mismatch scores and PIRCHE-II) were evaluated. A significant association occurred between DSA formation and the predicted HLA-DR presentation of nonself peptides (P=0.0169; accuracy = 80%; sensitivity = 88%; specificity = 63%). In contrast, mismatch characteristics did not differ significantly between mismatches that induced DSA and the ones that did not, except for PIRCHE-II (P=0.0094). This methodology predicts DSA formation based on HLA mismatches and recipients’ HLA-DR phenotype and may identify permissible HLA mismatches to help optimize HLA matching and guide donor selection.
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Shaw, Bronwen E., Katharina Fleischhauer, Mari Malkki, Theodore Gooley, Elisabetta Zino, Stephen Spellman, Yasuo Morishima, et al. "Permissive HLA-DPB1 Mismatching Compared to a Non-Permissive Mismatching Significantly Improves Overall Survival Following Allogeneic Transplantation In Patients with Both 10/10 and 9/10 Matched Unrelated Donors." Blood 116, no. 21 (November 19, 2010): 227. http://dx.doi.org/10.1182/blood.v116.21.227.227.
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Abstract Abstract 227 It is well established that the use of a donor matched for 9–10/10 alleles at HLA-A,-B,-C,-DRB1,-DQB1 significantly improves overall survival (OS) after unrelated donor (UD) haematopoietic stem cell transplantation (HSCT). Whilst the matching status for HLA-DPB1 alleles has been shown to influence transplant complications (relapse and graft-versus-host disease (GVHD), its impact on survival has not been well defined. The current unmet need in clinical practice is an approach to stratify selection criteria when a clinician is confronted with the choice between several 10/10 or 9/10 matched unrelated donors. There is now considerable interest in exploring different types of matching criteria to define permissive HLA-DPB1 mismatches which may be associated with an improved outcome. We have previously shown that HLA-DPB1 permissiveness can be functionally defined by the characterization of shared T cell epitopes (TCE) recognized by alloreactive T cells. In this model, allelic HLA mismatches are classified as permissive if they do not involve TCE disparities, and as non-permissive if they do. Using this concept, we developed two overlapping algorithms of permissivity for allelic HLA-DPB1 mismatches, on the basis of 3 (TCE3) or 4 (TCE4) groups of DPB1 alleles encoding immunogenic TCE. Data from relatively small prospective studies has shown a worse outcome to be associated with non-permissive DPB1 TCE disparities. Here, we present outcomes in 9123 UD-HSCT pairs, collected through the International Histocompatibility Working Group (IHWG). The cohort was comprised of 5809 10/10 matched transplant pairs and 3314 9/10 matched pairs. Within the 10/10 and 9/10 matched pairs three groups of patients were identified: 1. Zero DPB1 mismatches (i.e. allele matched), 2. Permissive DPB1 mismatch, 3. Non-permissive DPB1 mismatch. The model was adjusted for disease severity, source of stem cells, conditioning regimen, use of T-cell depletion, patient/donor gender and patient age. In line with DPB1 allele frequencies in worldwide populations, the number of transplants scored as permissive was higher for TCE3 (4398/7270 [60.4%]) than for TCE4 (2577/7270 [35.4%]). Using the DPB1 permissive mismatch transplants as the reference group (either 10/10 or 9/10 matched), we showed that DPB1 allelic matches resulted in similar survivals to DPB1 permissive mismatches, both in the 10/10 (HR 0.96, p=0.498 for TCE3 and HR 0.99, p=0.85 for TCE4) and the 9/10 setting (HR 0.97, p=0.70 for TCE3 and HR 0.99, p=0.96 for TCE4). In contrast, survival was significantly worse in the presence of a non-permissive TCE3 or TCE4 mismatch, both in the 10/10 (HR 1.15, p=0.0005 for TCE3 and HR 1.13, p=0.0035 for TCE4) and in the 9/10 matched setting (HR 1.13, p=0.0140 for TCE3 and HR 1.11, p=0.0448 for TCE4). The survival detriment appeared to be due to a significantly increased non-relapse mortality (TCE3: 10/10 HR 1.27, p<0.001 and 9/10 HR 1.21, p=0.0001; TCE4: 10/10 HR 1.24, p<0.001 and 9/10 HR 1.13, p=0.0514), as well as an increase in grades II-IV acute GVHD (TCE3: 10/10 HR 1.17, p<0.001 and 9/10 HR 1.29, p<0.001; TCE4: 10/10 HR 1.12, p=0.0035 and 9/10 HR 1.19, p<0.0001). There was no significant difference in disease relapse between permissive and non-permissive mismatched pairs. Finally, using the 10/10 DPB1 permissive mismatched group as a reference, we found survival to be similar for 10/10 DPB1 non-permissive (HR 1.15) and 9/10 DPB1 permissive (HR 1.20) or DPB1 allele matched (HR 1.17) transplants. In conclusion, our results suggest that extending donor selection to include HLA-DPB1 both allelic and functional TCE matching may result in better prediction of survival for patients. These findings provide an attractive new algorithm to stratify donor choice when several well-matched UD are identified. Disclosures: No relevant conflicts of interest to declare.
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Ruggeri, Annalisa, Carlheinz Mueller, Liesbeth C. de Wreede, Junfeng Wang, Lotte Wieten, Luca Vago, Jorinde Hoogenboom, et al. "Association of Donor-Recipient HLA Matching with Outcome of Unrelated Donor Hematopoietic Stem Cell Transplantation: A Study from the Cellular Therapy and Immunobiology Working Party (CTIWP) of the European Society for Blood and Marrow Transplantation (EBMT)." Blood 134, Supplement_1 (November 13, 2019): 3281. http://dx.doi.org/10.1182/blood-2019-125369.
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Introduction: Optimal HLA matching is associated with clinical outcome of unrelated donor (UD) hematopoietic cell transplantation (HCT)(Pidala, Blood2014, Morishima, Blood2015, Fürst, Blood2013), but a comprehensive analysis addressing this question in European transplant centers has not yet been performed. Within the CTIWP of EBMT, we have addressed this issue in adultsreceiving an UD-HCT from 2000 to 2015. Methods: All consecutive cases of UC-HCT with available 6-loci high resolution (2nd field) HLA-A, -B, -C, -DRB1, -DQB1, -DPB1 typing for both patient and donor and ARD-level matching for at least 7/8 HLA-A,B,C,DRB1 alleles reported to the EBMT were selected. Further inclusion criteria were first allogeneic HCT for hematological malignancies, patient age >=18 years, availability of donor age and use of either bone marrow or peripheral blood (PB) as stem cell source. Overall, 9575 patient-donor pairs were included from 29 countries and 198 transplant centers. Median follow-up was of 28.3 months, main diagnosis was acute leukemia (AL)(51.5%), disease stage was early in 44.1% of cases. UD-HCT were performed with PB in 84.7%, in vivo T cell depletion (TCD) in 64.4% and reduced intensity conditioning regimen in 57.3% of cases, and mostly standard graft-versus-host-disease (GvHD) prophylaxis with calcineurin inhibitors. HLA data were validated using the HLAcore library and a haplotype based probability check from the German Donor Registry. Pairs were stratified by: 1) In the overall cohort, according to HLA-A, -B, -C, -DRB1 matching status (8/8 N=7724 and 7/8 N=1851) and 2) in informative 8/8 matched pairs (N=7480), according to HLA-DPB1 matching status as identical (23.7%), permissive (26.6%) or non-permissive (32.9%) by the 3-group T Cell Epitope (TCE3) model, or by the 4-group TCE4 model (Fleischhauer, Blood2017). Primary endpoint was overall survival (OS), secondary endpoints were non-relapse mortality (NRM), relapse and acute GvHD grade II-IV, and relapse free survival (RFS). Results: At 5 years, OS and RFS in the entire cohort were 47% and 40.5%. The cumulative incidence of 5-y NRM, relapse and 1-y grade II-IV aGvHD was 28.1%, 31.4% and 19.4%, respectively. In multivariate analysis, a single mismatch at HLA-A, -B, -C, -DRB1 (7/8) was associated with a significantly higher risk of death compared to full match (8/8; HR 1.16, p<0.001). Other variables significantly associated with OS were patient (HR 1.14, p<0.001) and donor age (HR 1.08, p<0.001) per decade, CMV serostatus (HR 1.10, p=0.007), diagnosis of AL (HR 1.14, p<0.001), disease status (HR 1.22, p<0.001) and year of HCT (HR 0.98, p<0.001). The hazards of NRM, grade II-IV aGvHD and RFS were also significantly higher in 7/8 compared to 8/8 group (HR 1.34, p<0.001, HR 1.18, p<0.001 and HR 1.13, p<0.001, respectively) but not with lower risks of relapse (HR 0.96, p=0.51). In 8/8 matched HCT, when comparing with the HLA-DPB1 TCE3 permissive group, NRM were significantly higher in the non-permissive but not in the allele matched group (HR 1.17, p<0.001 and HR 0.90, p=0.15). Permissive HLA-DPB1 mismatches were associated with significantly lower relapse risks compared to allele matches but not compared to non-permissive mismatches (HR 0.85, p<0.01 and HR 0.96, p=0.433, respectively). OS was not significantly different between permissively HLA-DPB1 mismatched and allele matched pairs (HR 0.98, p=0.678.) or non-permissively mismatched pairs (HR 1.07, p=0.08). RFS was similar between the 3 groups. Stratification according to the TCE4 group model resulted in similar outcome associations. Conclusion: In this large independent cohort of UD-HCT from EBMT performed mostly from PB with in vivo TCD, a single allele mismatch at HLA-A, -B, -C, -DRB1 was independently associated with lower OS, and RFS, higher risk of NRM and aGvHD and no difference in relapse. The latter outcome was improved by permissive HLA-DPB1 mismatches in the 8/8 setting, which carried a significantly lower risk of NRM compared to non-permissive mismatches. The results from this new dataset validate current paradigms in donor selection and provide an important new platform for donor selection and HCT immunobiology. Figure: OS and RI relapse in UD-HCT. Pairs were stratified according to A) 8/8 (N=7724) and 7/8 (N=1851) HLA-A,B,C,DRB1 allele mismatches, or B) HLA-DPB1 allele matches (N=2045), TCE3 permissive mismatches (N=3743) and TCE3 non-permissive mismatches (N=2838) in the 8/8. Figure Disclosures Vago: Moderna Therapeutics: Research Funding; GenDx: Research Funding. Socie:Alexion: Consultancy. Kröger:Celgene: Honoraria, Research Funding; DKMS: Research Funding; JAZZ: Honoraria; Medac: Honoraria; Neovii: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Riemser: Research Funding; Sanofi-Aventis: Research Funding. Leleu:Takeda: Honoraria; Oncopeptide: Honoraria; Karyopharm: Honoraria; Amgen: Honoraria; Carsgen: Honoraria; Incyte: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Janssen: Honoraria; BMS: Honoraria; Merck: Honoraria; Sanofi: Honoraria. Bonini:Novartis: Consultancy; -: Patents & Royalties: Adoptive T cell therapy field; Intellia Therapeutics: Research Funding; Molmed: Consultancy; Intellia Therapeutics: Consultancy; TxCell: Consultancy; GSK: Consultancy; Allogene: Consultancy; Kite/Gilead: Consultancy. Chabannon:EBMT: Other: Working Party Chair, Board member; Fresenius Kabi: Other: research support; Miltenyi Biotech: Other: research support; Terumo BCT: Other: speaker's fees; Celgene: Other: speaker's fees; Novartis: Other: speaker's fees; Gilead: Other: speaker's fees, hospitalities; Sanofi SA: Other: research support, speaker's fees, hospitalities.
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Michallet, Mauricette, Mohamad Sobh, Hélène Labussière-wallet, Marie Balsat, Caroline Lejeune, Sophie Ducastelle-Leprêtre, Xavier Thomas, et al. "Allogeneic Hematopoietic Stem Cell Transplantation from Unrelated Peripheral Blood or Bone Marrow Donors: The Impact of HLA Matching Including HLA-DPB1 Allele in a Multivariable Risk Model." Blood 126, no. 23 (December 3, 2015): 3213. http://dx.doi.org/10.1182/blood.v126.23.3213.3213.
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Abstract Introduction Allogeneic hematopoietic stem cell transplantation (allo-HSCT) from unrelated donors has been increasingly used worldwide in the last decade in patients with hematological malignancies when HLA-identical sibling donors are unavailable. Identification of the HLA locus matching at the allele level is important in optimizing transplantation outcomes by minimizing non-relapse mortality (NRM) as well as in enhancing the graft-versus-leukemia effect. It has been demonstrated that patients with HSC donors matched on HLA-A, -B, -C, -DRB1, and -DQB1 alleles can have different outcomes if considering matching on HLA-DPB1 allele. HLA-DPB1 mismatches based on T-cell-epitope groups could identify mismatches that might be tolerated (permissive) and those that would negatively impact transplantation outcomes (non-permissive). We conducted this study to evaluate the impact of HLA matching degree between patient and HSC donor including HLA-DPB1, taking into account the other impacting variables in the allo-HSCT settings. Material and methods A total of 235 patients who received allo-HSCT at our center between January 2005 and December 2014 with a full donor/recipient HLA class I and II locus available data were included, 131 (56%) were males, the median age at allo-HSCT was 50 years (range: 18-69). There was 123 (53%) acute leukemia (93 AML, 30 ALL), 24 (10%) MDS, 35 (15%) multiple myeloma, 20 (8%) NHL, 7 (3%) Hodgkin's disease, 10 (4%) myeloproliferative neoplasms, 13 (6%) CML, and 3 (1%) CLL. One hundred and nineteen patients (51%) received myeloablative conditioning (MAC) and 116 (49%) received reduced intensity conditioning (RIC). Disease status at allo-HSCT was complete remission (CR) in 144 (61%) patients and less than CR in 91 (39%). HSC donor was 10/10 HLA matched unrelated (MUD) for 162 (69%) (80 PBSC and 93 BM), among them 21 (9%) were matched for HLA-DPB1, 41 (18%) had permissive mismatch and 100 (42%) had non-permissive mismatch; while 73 (31%) had 9/10 HLA mismatched donor MMUD (48 PBSC and 25 BM), among them, 7 (3%) were matched for HLA-DPB1, 12 (5%) had permissive mismatch and 54 (23%) had non-permissive mismatch; 110 (47%) were ABO compatible, 58 (24%) had minor incompatibility and 67 (29%) had major incompatibility. For sex mismatching, in 33 (14%) cases, it was female donor to a male patient. Results After a median follow-up for surviving patients of 29 months (range: 4-108), patients with 10/10 HLA MUD had better overall survival (OS) than those with 9/10 MMUD without considering the HLA-DPB1 matching, with 2 years OS probability of 51% vs 35% respectively (p=0.09), which was reflected by a lower NRM at 2 years of 29% vs 42% (p=0.07). When considering the HLA-DPB1 matching, we found comparable outcomes in terms of OS and NRM for: 1) 10/10 HLA MUD - DPB1 matched vs 10/10 HLA MUD - DPB1 permissive mismatched, 2) 10/10 HLA MUD - non-permissive DPB1 mismatched vs 9/10 HLA MMUD - DPB1 matched, 3) 9/10 HLA MMUD - DPB1 matched vs 9/10 HLA MMUD - DPB1 permissive mismatched; all these 3 groups were not significantly different between each other expect for a last group which included 9/10 HLA MMUD with non-permissive DPB1 mismatch, this group had worse OS and NRM compared to all others with 2 years rates of 34% vs 49% (p=0.05) and 47% vs 29% (p=0.04) respectively. In multivariate analysis, patient age (>50 years), disease status (less than CR), HLA matching (9/10 HLA MUD non-permissive DPB1) and sex mismatching (female donor to male patient) were significantly impacting OS and NRM. We included all these variables in a risk score: age < 50 years= 0, > 50 years= 1; CR= 0, less than CR= 1; HLA 10/10 (matched on DPB1) or HLA 10/10 with permissive MM on DPB1= 0; HLA 10/10 with non-permissive MM on DPB1 or HLA 9/10 (matched on DPB1 or with permissive MM on DPB1)=1; HLA 9/10 with non-permissive MM on DPB1=2; for sex matching, female donor to male patient=1, all other= 0. The risk score distinguished low risk patients (total score=0), intermediate (total score=1 or 2) and high risk (total score >2) with 2 years OS and NRM rates of 66%, 52%, 30% (p=0.003) and 22%, 29% 48% (p=0.004) respectively. Conclusion MMUD with non-permissive T-cell-epitope mismatch at HLA-DPB1 should be avoided due to increased rates of NRM. The risk score combining HLA matching with age, disease status and sex matching is very helpful for daily clinical practice offering patients better treatment strategy. Figure 1. Figure 1. Disclosures Nicolini: Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ariad Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.
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Oran, Betul, Rima M. Saliba, Yudith Carmazzi, Elizabeth J. Shpall, Katayoun Rezvani, Marcos De Lima, Marcelo Fernández-Viña, Richard E. Champlin, and Kai Cao. "Increased Disease Progression in HLA-a, -B, -C, -DRB1 and -DBP1 Matched Recipients of Unrelated Donor Transplants with Peripheral Blood Is Independent of Risk Groups By Disease Risk Index." Blood 126, no. 23 (December 3, 2015): 2005. http://dx.doi.org/10.1182/blood.v126.23.2005.2005.
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Abstract The use of unrelated donors matched in all alleles of HLA-A, -B, -C, and -DRB1 loci has been associated with superior outcomes compared with those having 1 or more mismatches. Recent studies showed increased transplant-related mortality (TRM) with the use of HLA-DPB1 mismatched donors supporting the notion that the ideal volunteer unrelated donor should fully match at HLA-A, -B, -C, and -DRB1 and lack -DPB1 mismatches. The issue of the effect of HLA-DPB1 mismatch on the disease progression rate is still controversial and we aimed to investigate the impact of HLA-DPB1 mismatch in the graft versus host direction on transplant outcomes in patients categorized according to the recently defined disease risk index (DRI) for disease risk classification. Our study cohort included 1,211 transplant patients with hematological malignancies whohave received an hematopoietic stem cell transplant (HSCT) from an unrelated HLA-A, -B, -C,-DRB1 matched donor by high resolution typing (8/8 matched) after 2005 through 2014. The study cohort had a median age of 55 (range, 19-77); the hematopoietic stem cell source was peripheral blood (PB) in 698 and bone marrow (BM) in 513 patients. Disease risk index (DRI) at HSCT was high or very high in 382 (33%), intermediate in 598 (51%), low in 185 (16%) patients. Of the pairs, 1,154 (95%) were matched atHLA-DQB1 and 1,116 (92%) at HLA- DRB3/4/5 by high resolution testing. However, 633 (52%) had mismatch at one of the DPB1 alleles and 208 (17%) had two mismatches. There was association between matching for DPB1and matching for DRB3/4/5 (p=0.002) but not with DQB1. In PB recipients, there was a highly significant decreaseof disease progression in DPB1 mismatched pairs (one and two allele; HR=0.7, p=0.01 and HR=0.6, p=0.01 respectively) as compared tothose pairs with DPB1 matched. The impact of mismatches at one or two alleles were not different on disease progression (HR=1.2, p=0.4). However, the impact of DPB1 mismatch on disease progression was not uniform in different disease risk groups by DRI. Mismatch at DPB1 significantly decreased disease progression only in the intermediate risk group (HR=0.5, p=0.002) but not in low risk and high/very high disease groups by DRI (HR=0.9, p=0.8 and HR=0.7, p=0.1 respectively) (Figure 1a-c). In BM recipients, increasing number of DPB1 incompatibilities decreased disease progression (HR=0.9, p=0.4 and HR=0.6, p=0.1 for 1 and 2 allele mismatches respectively) but did not reach significance. Mismatches at HLA-DQB1 and -DRB3/4/5 had no impact on disease progression in both PB and BM recipients. Pairs with one or two allele-level DPB1 mismatches increased TRM compared with DPB1 matched pairs in PB (HR=1.5, p=0.04 and HR=1.9, p=0.006 respectively) and BM recipients (HR=1.8, p=0.03 and HR=1.9, p=0.05). There was no difference between two and one allele DPB1 mismatched for TRM in PB and BM recipients. Multivariate analyses revealed that the negative impact of DPB1 mismatch on TRM was not uniform in younger or (?) older patients. Interestingly, DPB1 mismatches increased TRM only in younger (aged<55) patients (HR=2.3, p=0.02) if they were PB recipients but only in older patients (HR=2.03, p=0.046) if they were BM recipients. We next analyzed the impact of DPB1 matching on progression free survival (PFS) and did not observe any impact of DPB1 mismatches on PFS in PB (HR=0.9, p=0.9) and BM (HR=1.12, p=0.6) recipients. Subgroup analyses by DRI to identify a specific risk group that the use of HLA-A, -B, -C and -DRB1 matched but DPB1 mismatched unrelated donor might lead to improved PFS did not reveal any particular risk group in both PB and BM recipients. Thus, in recipients of HLA-A, -B-C and DRB1 allele-level matched unrelated donors a mismatch for DPB1 is associated with a significantlydecreased risk of disease progression with no impact on PFS in intermediate risk group by DRI. Further analysis permissive vs. non-permissive DPB1 mismatches would be warranted. Figure 1. The cumulative incidence of disease progression by DPB1 mismatch and Disease Risk Index in peripheral blood recipients. Figure 1. The cumulative incidence of disease progression by DPB1 mismatch and Disease Risk Index in peripheral blood recipients. Disclosures No relevant conflicts of interest to declare.
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Arrieta-Bolanos, Esteban, Pietro Crivello, Meilun He, Tao Wang, Shahinaz M. Gadalla, Sophie Paczesny, Steven G. E. Marsh, et al. "A Refined Model of HLA-DP Permissiveness Improves Stratification of Acute Graft-Versus-Host Disease Risks after Unrelated Hematopoietic Cell Transplantation: A Retrospective Study from the CIBMTR." Blood 138, Supplement 1 (November 5, 2021): 2890. http://dx.doi.org/10.1182/blood-2021-146957.
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Abstract Introduction: Permissive HLA-DPB1 mismatches defined by the T-cell epitope (TCE) model are an established selection criterion for unrelated donors in allogeneic hematopoietic cell transplantation (alloHCT) (Dehn et al. Blood 2019). Based on biological evidence, the TCE model has classified HLA-DPB1 alleles into at least three functional groups, one of which (TCE group 3; TCE3) houses a large number of alleles with different structural and functional characteristics. We have recently shown that structurally close HLA-DP allotypes have similar peptide-binding motifs and share a significant proportion of their immunopeptidomes, the latter being fundamental for permissiveness (Meurer & Crivello et al. Blood 2021). Hence, we hypothesized that HLA-DPB1 mismatches involving alleles that encode structurally distant allotypes within TCE3 could be less permissive than those involving alleles that encode structurally closer allotypes, and thus have a differential impact on clinical outcomes. Methods: Multidimensional scaling techniques were used to compare 28 polymorphic positions (amino acids 8-215) among 51 alleles present in a cohort of 5,140 10/10 matched patient-donor pairs who received a first alloHCT for AML, ALL, or MDS between 2008-2017. Based on these analyses, TCE3-permissive mismatches (N=2,216) were further stratified into those involving structurally close or more distant combinations and compared with HLA-DPB1-matched (N=785) and non-permissively mismatched (N=2,023) pairs. These models were tested in parallel to the "classical" TCE model considering permissive mismatches (N=2,332) as a whole, to determine their association with overall survival (OS), disease-free survival (DFS), treatment-related mortality (TRM), primary disease relapse, and acute (a) and chronic (c)GVHD. Kaplan-Meier analysis and log-rank testing were used to compare the median OS and DFS. The incidences of GVHD, relapse and TRM were compared using competing risks and Gray's test. The effect of HLA-DPB1 mismatch on time-to-event outcomes was modelled by Cox regression after adjusting for confounders and testing for the proportional hazards assumption. Results: Within TCE3, we identified a subgroup of 4 frequent and structurally as well as functionally closely related alleles (i.e. DPB1*02:01, 04:01, 04:02, 23:01) that form a separate cluster (Figure 1A). These "core" alleles have similar bound-peptide motifs (van Balen et al. J Immunol 2020) and can be distinguished from other alleles in TCE3 in terms of the strength of in vitro alloreactive responses elicited from permissive responders (Meurer et al. Front Immunol 2018). Moreover, principal component analysis identified the HLA-DP 84-87 DEAV/GGMP motif as a major factor driving structural variability among TCE3 alleles (not shown). We used these observations to stratify TCE3 permissive mismatches in the allo-HCT cohort into "core" (N=930) and "non-core" (N=1,286) or into DEAV/GGPM-matched (N=1,209) and mismatched (N=1,007) pairs (Figure 1B). Multivariable analysis confirmed the association of aGVHD2-4 for the classical TCE model of non-permissive mismatching (p<.0001) and revealed a trend in DEAV/GGPM and "core"/"non-core" TCE3-permissive models. When compared to HLA-DPB1 allele matched pairs the risks of aGVHD2-4 increased progressively with "core" TCE3-permissive (HR 1.12 [0.98-1.28]; p=0.1012), "non-core" TCE3-permissive (HR 1.24 [1.06-1.46]; p= 0.0082), and non-permissive mismatches (HR 1.32 [1.16-1.50]; p<.0001) (Figure 1C, "core" vs. "non-core" HR 0.90 [0.80-1.01]; p=0.062). Similar albeit less significant results were obtained with the DEAV/GGPM model. The "core"/"non-core" TCE3 model was also associated with TRM with alloHCT from "core" TCE3-permissive donors showing lower risks of TRM than "non-core" TCE3-permissive (HR 0.82 [0.70-0.96]; p=0.0118) and non-permissive donors (HR 0.78 [0.68-0.88]; p=0.0002). Conclusion: Our results suggest that structural differences within TCE3 that reflect functional divergence and differential immunogenicity of alleles in this group associate with the risks of aGVHD and TRM after alloHCT. Hence, within the population of 10/10 matched donors, selection of "core" TCE3-permissive donors might reduce patient morbidity after transplantation. Figure 1 Figure 1. Disclosures Paczesny: Medical University of South Carolina: Patents & Royalties: inventor on the ST2 bispecific antibody patent application. Lee: AstraZeneca: Research Funding; Incyte: Research Funding; Janssen: Other; Kadmon: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Syndax: Research Funding; Takeda: Research Funding; National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding.
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Metzing, Maximilian, Pietro Crivello, Thuja Meurer, Michel G. D. Kester, Dominik Megger, Weiqiang Chen, Peter Van Balen, et al. "HLA-DM Mediates Permissiveness of HLA-DPB1 T Cell Epitope Mismatches in Unrelated HCT." Blood 134, Supplement_1 (November 13, 2019): 3211. http://dx.doi.org/10.1182/blood-2019-129921.
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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.
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Fernandez-Viña, Marcelo A., Tao Wang, Stephanie J. Lee, Michael Haagenson, Mahmoud Aljurf, Medhat Askar, Minoo Battiwalla, et al. "Identification of a permissible HLA mismatch in hematopoietic stem cell transplantation." Blood 123, no. 8 (February 20, 2014): 1270–78. http://dx.doi.org/10.1182/blood-2013-10-532671.
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Key Points Mismatches in alleles C*03:03/C*03:04 were most frequent (68.7%) among the transplants with a single allele level mismatch in HLA-C. The 7/8 C*03:03/C*03:04 mismatch group was not significantly different from the 8/8 HLA matched transplants in any transplant outcome.
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Lee, Yoo Jin, Joon Ho Moon, In Hee Lee, Jae-Ho Yoon, Byung-Sik Cho, Jae-Sook Ahn, Hyeoung Joon Kim, et al. "Killer Cell Immunoglobulin-like Receptor Ligand Matching Determines the Post-Transplant High Risk Groups Among Patients with Permissive HLA Mismatch in Unrelated Donor Hematopoietic Cell Transplantation." Blood 128, no. 22 (December 2, 2016): 4566. http://dx.doi.org/10.1182/blood.v128.22.4566.4566.
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Abstract Background: Human leukocyte antigen (HLA) matching between donor and recipient is a key part of successful allogeneic hematopoietic cell transplantation (allo-HCT). The HCT from the unrelated donor (UD) with one allele/antigen mismatch (MM) can be as beneficial as HCT from perfectly matched donor. For the remaining patients, the donors with permissive mismatches may be the option. In HLA-mismatched transplantation, the patient and donor can also be mismatched for their killer cell immunoglobulin-like receptor (KIR) ligands that recognize allotypic determinants shared by certain HLA class I allele groups. Recent research has accumulated evidence of the role of each HLA locus and KIR ligand MM on clinical outcomes for UD-HCT. However, HCT outcomes of the patients with permissive MM depending on KIR ligand MM (KIR-L-MM) status remain obscure in UD-HCT. In the current study, we identified permissive and nonpermissive MM allele combinations and analyzed the effects of these mismatches in combination of KIR ligand mismatches in patients with acute myeloid leukemia (AML). Methods: A total of 438 patients with AML who underwent allo-HCT from UD from 2007 to 2014 were analyzed. Alleles of patients and donors at the HLA-A, -B, -C, and -DRB1 loci were identified by the high resolution DNA typing. Nonpermissive HLA allele combinations were defined as a significant HLA risk factor for severe acute graft-versus-host disease (aGVHD). KIR-L-MM among patient-donor pairs were searched in the Immuno Polymorphism Database available at www.ebi.ac.uk/ipd/kir. Results: Median age of the patients was 45 (range 15-60) years and 117 patients (40.4%) were female. Eighty-five (19.4%) patients were high risk at the time of HCT. Reduced intensity conditioning was performed in 131 patients (29.9%) and anti-thymocyte globulin was used in 324 patients (74.0%). Primary graft source was peripheral blood stem cells (n=369, 84.2%) and median 6.0 x 106/kg cells were infused. Severe aGVDH occurred in 43 patients (9.8%) and chronic GVHD (cGVHD) in 193 (44.1%). With median follow-up duration of 19 (range, 2-96) months, treatment-related mortality (TRM) occurred in 111 patients (25.3%), relapse in 119 (27.2%) and death in 214 (48.9%). Two-hundred sixty-four patients (60.3%) were HLA full matched in the 4 loci. Mismatches in HLA-A loci observed in 64 patients, HLA-B in 35, HLA-C in 98, and HLA-DRB1 in 60. Five nonpermissive MM pairs in 33 patients were identified as donor/patient pair: A*02:06/A*02:01, C*03:03/C*08:01, C*08:01/C03:04, C*08:01/C*15:02, and DRB1*04:03/DRB1*04:05. Among 98 patients with HLA-C loci MM, 16 patients showed KIR ligand MM (KIR-L-MM) as GvH direction, which was observed in the permissive MM group. Severe aGVHD occurred in 30.4%, 22.4%, 13.4%, and 10.8% in nonpermissive, permissive MM and KIR-L-MM, permissive MM and KIR-L-M, and full match group, respectively (p=0.003). The 3-year overall survival (OS) rate was inferior in permissive MM and KIR-L-MM group (30.0%) compared to full match (53.5%), permissive MM and KIR-L-M (51.8%), and nonpermissive (42.4%) group (p=0.067). The 3-year TRM was higher in permissive MM and KIR-L-MM group (57.5%) than full match (21.0%), permissive MM and KIR-L-M (27.7%), and nonpermissive (33.3%) group (p=0.006). In the multivariate analysis, high risk at HCT (HR 2.087, p<0.001), severe aGVHD (HR 3.851, p<0.001), and cGVHD (HR 0.321, p<0.001) were identified as variables affecting the OS. The following variables adversely affected on TRM: permissive MM and KIR-L-MM group (HR 2.699, p=0.007), severe aGVDH (HR 2.204, p=0.001), and cGVHD (HR 2.052, p<0.001). Non-permissive MM (HR 7.487, p=0.001) and CD34+ cells >6x106/kg (HR 4.113, p=0.017) were high risk factors on severe aGVHD. Conclusion: Permissive MM for HLA could be further classified into high risk groups with regard to TRM by KIR-L matching in UD-HCT. The evaluation of KIR-L matching is warranted to reduce unfavorable outcomes among the patients with permissive MM in UD-HCT. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.
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Anasetti, Claudio. "The Ever Elusive Permissive Mismatch." Biology of Blood and Marrow Transplantation 18, no. 5 (May 2012): 657–58. http://dx.doi.org/10.1016/j.bbmt.2012.03.006.
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Sandhu, Karamjeet S., Ketevan Gendzekhadze, Dongyun Yang, Ryotaro Nakamura, Sally Mokhtari, Monzr M. Al Malki, Haris Ali, et al. "Prediction of Graft-Versus-Host Disease in Recipients of Single Mismatched Unrelated Hematopoietic Cell Transplantation Donor Using a Highly Multiplexed Proteomic Assay, MHC-Pepseq." Blood 138, Supplement 1 (November 5, 2021): 1808. http://dx.doi.org/10.1182/blood-2021-153597.
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Abstract Graft-versus-host disease (GVHD) remains a major cause of treatment failure after allogeneic hematopoietic cell transplantation (alloHCT). In HLA-mismatched donor setting, indirect presentation of allogeneic peptides from recipient's mismatched HLA class I or II proteins by donor or recipient antigen presenting cells can be an immunogenic driver of GVHD. However, the potential diversity of such antigens is large, and predicting them in a systematic manner has proven challenging. Using a novel, highly-multiplexed peptide-MHC binding assay (MHC-PepSeq) we sought to 1) identify allogeneic peptides derived from mismatched HLA protein that can be efficiently presented by HLA-DR, and 2) explore the possibility that the frequency of these HLA-DRB1 binding allopeptides may be predictive of clinical GVHD in HLA-DPB1 mismatched donor/recipient pairs. Using publicly-available population allele frequency data (allelefrequencies.net), we identified a set of class I and II sequences that cover >95% of alleles at each of 9 human HLA-loci (-A, -B, -C, -DRA1,-DRB1, -DQA1, -DQB1, -DPA1, -DPB1) in 3 major US populations (European Caucasian, African American, Mexican Chicano). When represented in the form of densely overlapping tiled 15-mer peptides, 7,744 unique 15mers were identified. We encoded these peptides into DNA oligonucleotides and used the PepSeq parallel synthesis protocol to generate a library of the corresponding DNA-barcoded peptides. The library was incubated with recombinantly-expressed full-length HLA proteins, washed, eluted, amplified, and sequenced to identify the various HLA-derived peptides that bind to the assayed HLA proteins (Figure 1). In the current study, DPB1-derived allopeptides in the setting of HLA-A, B, C, DRB1, and DQB1 (10/10) matched unrelated (MUD) HCT donors with a mismatch in DPB1 were investigated. The peptide library was assayed for binding to the DRB1*07:01 protein, selected since it was the common allele in this cohort. We identified 327 patients who were transplanted at our center and met these criteria. For each case, we used comprehensive in silico tiling to identify HLA-DPA and DPB-derived peptides present in the recipient but absent in the donor. This set was intersected with the peptides identified as binders to HLA-DRB1*07:01 in the 7,744-plex MHC-PepSeq assay, to arrive at a donor-recipient pair-specific set of 'allopeptides' Overall, we identified such allopeptide at the median of 0 (range: 0-8) across the 327 cases. Next, we examined an association between the number of allopeptides and acute GVHD in the cohort of 94 patients with positive HLA-DRB1*07:01. Median age at alloHCT was 60 years (range: 19-78), 53% males, 1.% bone marrow graft and only 7% female to male donors. Ablative (TBI) conditioning was delivered to 34%) pts. 83% received Tacrolimus/Sirolimus-based, and 9% received post-transplant cyclophosphamide-based GVHD prophylaxis. Patient/HCT characteristics are summarized in Table 1. In this cohort, 18% had no DPB1 mismatch, 54% had a single and 28% had double mismatches, with 21% pts carrying non-permissive DPB1 mismatches. Allopeptide score was 0 in 75% of pts. Non-permissive mismatch 9 (39%) vs. 11 (16%) were more likely to have allopeptide score ≥1 and similarly double mismatches 11 (48%) vs. 15 (21%) were more likely to have allopeptide score of ≥1. Among pts with ≥1 allopeptide score 14 (61%) had DPB1 matched or permissive mismatch. The cumulative incidence of grade 2-4 acute GVHD was 40.8% (range: 29-52) in pts with no allopeptides from DPB1 compared with 56% (range: 34-74) in those with ≥1 allopeptides (p=0.259) (Figure 2). The cumulative incidence of grade 3-4 acute GVHD and chronic GVHD were similar between allopeptide 0 vs. ≥1. Together, we show that the "MHC-PepSeq" assay can identify novel candidate HLA-derived allopeptides in 10/10 MUD HCTs. The number of such peptides are relatively low - with a majority having no allopeptide. In an exploratory analysis in a selected cohort of patients with HLA-DRB1*0701 in the setting of 10/10 MUD HCT, the number of allopeptides in our assay may be predictive of GVHD. The expanded analyses on other HLA-DRB1 restriction elements are underway. Figure 1 Figure 1. Disclosures Al Malki: CareDx: Consultancy; Hansa Biopharma: Consultancy; Neximmune: Consultancy; Jazz Pharmaceuticals, Inc.: Consultancy; Rigel Pharma: Consultancy. Ali: BMS: Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees. Forman: Mustang Bio: Consultancy, Current holder of individual stocks in a privately-held company; Lixte Biotechnology: Consultancy, Current holder of individual stocks in a privately-held company; Allogene: Consultancy.
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Mayor, Neema P., Tao Wang, Stephanie J. Lee, Michelle Kuxhausen, Cynthia Vierra-Green, Dominic J. Barker, Jeffrey Auletta, et al. "Impact of Previously Unrecognized HLA Mismatches Using Ultrahigh Resolution Typing in Unrelated Donor Hematopoietic Cell Transplantation." Journal of Clinical Oncology 39, no. 21 (July 20, 2021): 2397–409. http://dx.doi.org/10.1200/jco.20.03643.
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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.
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Walz, Juliane Sarah. "The immunopeptidome guides permissive HLA mismatch." Blood 137, no. 7 (February 18, 2021): 864–65. http://dx.doi.org/10.1182/blood.2020009266.
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Iwasaki, Makoto, Junya Kanda, Hidenori Tanaka, Takero Shindo, Noriko Doki, Takahiro Fukuda, Yukiyasu Ozawa, et al. "Impact of Human Leukocyte Antigen Epitope Matching on Outcomes after Unrelated Bone Marrow Transplantation." Blood 138, Supplement 1 (November 5, 2021): 3914. http://dx.doi.org/10.1182/blood-2021-145686.
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Abstract Background The immunological effect of human leukocyte antigen (HLA) disparity has not been fully elucidated by the number and locus of HLA antigens or alleles. Several methods to predict epitopes recognized by the immune system have been developed to understand the immunogenicity of amino acid sequences in mismatched HLA pairs. We investigated the association between mismatching of HLA antibody-identified epitopes and hematopoietic stem cell transplantation (HSCT) outcomes. Patients and Methods This was a retrospective cohort study with 9,991 patients who underwent their first HSCT for hematologic malignancies from unrelated bone marrow donors in the Transplant Registry Unified Management Program (TRUMP). HLA epitope mismatches (EMM) were quantified using HLA-matchmaker (HLAMM). We conducted a multivariate analysis using Cox proportional hazard regression for the overall survival and the Fine-Gray regression model for competing risks. Statistical analyses were performed with Stata version 15.1 and R version 4.0.2. Results The median follow-up period for survivors was 6.3 years (interquartile range [IQR], 2.5-9.2 years). The most common indication for HSCT was acute myeloid leukemia (n=3,917, 39.2%), followed by acute lymphoblastic leukemia (n=1,913, 19.2%), and mature lymphoid malignancies (n=1,906, 19.1%). HSCT from HLA-matched, HLA 1 allele mismatched, and HLA 2 or more allele mismatched donors was received by 6,200, 2660, and 1131 patients, respectively. The number of EMM in recipient-donor pairs in our study population ranged from 0 to 37 in HLA class I (median, 0) and 0 to 60 in HLA class II (median, 1). Patients were categorized into two groups, low and high EMM, using the median value for each epitope matching as the threshold. Higher HLA class I EMM in the graft-versus-host (GVH) direction was associated with a significantly higher risk of grade III-IV acute GVHD (aGVHD) (hazard ratio [HR] 1.69, 95% confidence interval [CI] 1.21-2.36). Higher EMM for both class I and class II in the host-versus-graft (HVG) direction was associated with a significantly longer time to neutrophil engraftment (HR 0.78, 95% CI 0.65-0.95). In subgroup analysis limited to HLA 1 allele mismatch, class I high EMM group in the GVH direction had a significant association with higher risk for grade II-IV and grade III-IV aGVHD compared with both class I and class II low-EMM group (HR 1.69, 95% CI 1.16-2.47). Patients with HLA-C EMM accounted for 94.5% (n=1,603) of patients with HLA class I EMM. We further investigated the impact of HLA-C on severe aGVHD in relation to other known high-risk mismatch patterns. All killer immunoglobulin-like receptor (KIR)-ligand mismatched recipient-donor pairs (n=376) had HLA-C EMM. In multivariate analysis, patients with KIR-ligand mismatches and EMM did not show a higher incidence of grade III-IV aGVHD compared with KIR-ligand-matched patients with EMM (HR 0.96, 95% CI 0.74-1.25). In addition to the known high-risk mismatch patterns in the Japanese cohort (Kawase et al. Blood. 2007, Morishima et al. Haematologica. 2016), EMM was associated with a higher risk for grade III-IV aGVHD (Figure 1A, compared with HLA-C allele-matched patients (Match), HLA-C allele-mismatched patients without antigen mismatches, and EMM (group A): HR 0.78, 95% CI 0.41-1.48; HLA-C antigen-mismatched patients without EMM (group B): HR 0.56, 95% CI 0.28-1.15; HLA-C epitope-mismatched patients without high-risk mismatches (group C): HR 1.67, 95% CI 1.44-1.95; Patients with high-risk mismatches other than patient mismatched HLA-C*14:02 (group D): HR 2.01, 95% CI 1.50-2.69; Patients with patient mismatched HLA-C*14:02 (group E): HR 3.38, 95% CI 2.39-4.78). HLA-C epitope-mismatched patients without high-risk mismatches also showed a higher incidence of non-relapse mortality (NRM) and lower overall survival (OS) than HLA-C allele-matched patients (NRM (Figure 1B): HR 1.39, 95% CI 1.25-1.54; OS (Figure 1C): HR 1.20, 95% CI 1.10-1.30). Conclusion HLAMM-based epitope matching might be useful for identifying high-risk groups who can develop serious complications after HSCT from HLA-mismatched unrelated donors. In the HLA-C locus, epitope-mismatched recipient-donor pairs are non-permissive mismatched patterns along with known high-risk amino acid substitutions. Our findings might be helpful for clinicians in selecting permissive donors from alternative donor options. Figure 1 Figure 1. Disclosures Iwasaki: Amgen Astellas BioPharma: Honoraria; Astellas Pharma Inc.: Consultancy, Honoraria; Bristol-Myers Squibb Co: Honoraria; CHUGAI PHARMACEUTICAL Co., Ltd.: Honoraria; DAIICHI SANKYO Co., Ltd.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Eisai: Research Funding; Janssen Pharmaceutical K.K.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kyowa Kirin Co., Ltd.: Honoraria; Megakaryon Co: Honoraria, Membership on an entity's Board of Directors or advisory committees; NextGeM Inc: Patents & Royalties; Novartis Pharma K.K.: Honoraria; Ono Pharma Inc.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Sanofi K.K.: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; SymBio Pharmaceuticals, Ltd.: Membership on an entity's Board of Directors or advisory committees; Takeda Pharmaceutical Company Limited: Honoraria, Membership on an entity's Board of Directors or advisory committees; TEIJIN PHARMA LIMTED.: Honoraria. Uchida: Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Astellas Pharma Inc.: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Novartis Pharma Inc.: Honoraria. Kataoka: Ono Pharmaceutical: Honoraria, Research Funding; Celgene: Honoraria; Eisai: Honoraria, Research Funding; Astellas Pharma: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Chugai Pharmaceutical: Honoraria, Research Funding; AstraZeneca: Honoraria; Sumitomo Dainippon Pharma: Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; Janssen Pharmaceutical: Honoraria; Takeda Pharmaceutical: Honoraria, Research Funding; Otsuka Pharmaceutical: Honoraria, Research Funding; Asahi Genomics: Current holder of individual stocks in a privately-held company; Shionogi: Research Funding; Teijin Pharma: Research Funding; Japan Blood Products Organization: Research Funding; Bristol-Myers Squibb: Research Funding; Mochida Pharmaceutical: Research Funding; JCR Pharmaceuticals: Research Funding; MSD: Research Funding. Kanda: MSD: Honoraria; Sanofi: Research Funding; Otsuka Pharmaceutical: Honoraria, Research Funding. Ichinohe: Daiichi Sankyo: Research Funding; Bristol-Myers Squibb: Honoraria; Chugai Pharmaceutical: Research Funding; CSL Behring: Honoraria, Research Funding; Eisai Co.: Honoraria, Research Funding; FUJIFILM Wako Chemicals.: Honoraria, Research Funding; Kyowa Kirin Co.: Honoraria, Research Funding; Ono Pharmaceutical Co.: Honoraria, Research Funding; Nippon Shinyaku Co: Research Funding; Otsuka Pharmaceutical Co.: Research Funding; Sumitomo Dainippon Pharma Co.: Honoraria, Research Funding; Taiho Pharmaceutical Co.: Research Funding; Takara Bio Inc.: Research Funding; Zenyaku Kogyo Co.: Research Funding; Celgene: Honoraria; Novartis Pharma K.K.: Honoraria; Repertoire Genesis Inc.: Honoraria, Research Funding; AbbVie Pharma: Research Funding; Astellas Pharma: Honoraria, Research Funding; Takeda Pharmaceutical Co.: Honoraria. Atsuta: Mochida Pharmaceutical Co., Ltd.: Speakers Bureau; Astellas Pharma Inc.: Speakers Bureau; AbbVie GK: Speakers Bureau; Kyowa Kirin Co., Ltd: Honoraria; Meiji Seika Pharma Co, Ltd.: Honoraria.
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Beelen, Dietrich W., Pietro Crivello, Andreas Heinold, Sabine Riebschläger, Falko M. Heinemann, Vera Rebmann, Monika Lindemann, Hellmut Ottinger, Peter Horn, and Katharina Fleischhauer. "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 126, no. 23 (December 3, 2015): 4288. http://dx.doi.org/10.1182/blood.v126.23.4288.4288.
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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.
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Szabolcs, Paul. "Permissive mismatches for blood and marrow transplantation." Lancet Oncology 13, no. 4 (April 2012): 323–24. http://dx.doi.org/10.1016/s1470-2045(12)70071-2.
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Bacigalupo, Andrea. "A closer look at permissive HLA mismatch." Blood 122, no. 22 (November 21, 2013): 3555–56. http://dx.doi.org/10.1182/blood-2013-09-525469.
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Fleischhauer, Katharina, and Bronwen E. Shaw. "HLA-DP in unrelated hematopoietic cell transplantation revisited: challenges and opportunities." Blood 130, no. 9 (August 31, 2017): 1089–96. http://dx.doi.org/10.1182/blood-2017-03-742346.
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Abstract When considering HLA-matched hematopoietic cell transplantation (HCT), sibling and unrelated donors (UDs) are biologically different because UD-HCT is typically performed across HLA-DP disparities absent in sibling HCT. Mismatched HLA-DP is targeted by direct alloreactive T cell responses with important implications for graft-versus-host disease and graft-versus-leukemia. This concise review details special features of HLA-DP as model antigens for clinically permissive mismatches mediating limited T-cell alloreactivity with minimal toxicity, and describes future avenues for their exploitation in cellular immunotherapy of malignant blood disorders.
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Fleischhauer, Katharina. "Selection of matched unrelated donors moving forward: from HLA allele counting to functional matching." Hematology 2019, no. 1 (December 6, 2019): 532–38. http://dx.doi.org/10.1182/hematology.2019000057.
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Abstract Matched unrelated donors (URD) are the most frequent source of stem cells for allogeneic hematopoietic cell transplantation (HCT) to date, with HCT performed mainly under conventional immunosuppression by methotrexate and cyclosporine. In this setting, every single allelic donor–recipient mismatch for HLA-A, -B, -C, -DRB1 (8/8), but not for HLA-DQB1, -DPB1, has a significant negative effect on overall survival (OS). When several 8/8 HLA-matched URD are available, donor age is the most important factor impacting OS. Moving forward from the traditional way of counting the number of donor–recipient HLA allele mismatches to biology-driven algorithms for functional matching has led to the unraveling of an association between permissive, low-risk HLA-DPB1 mismatches and improved outcome after URD HCT for malignant disease but not for nonmalignant disease. Functional HLA matching might prove to have increasing importance for URD selection in the era of new immunosuppressive regimens that have the potential to substantially reshuffle the role of HLA mismatches in URD HCT.
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Marino, Susana R., Sang M. Lee, T. Andrew Binkowski, Michael D. Haagenson, Martin Maiers, Stephen Spellman, Koen van Besien, Stephanie J. Lee, Theodore Karrison, and Andrew Artz. "Identification of High Risk HLA Class I Amino Acid Substitutions in Hematopoietic Stem Cell Transplantation." Blood 120, no. 21 (November 16, 2012): 3050. http://dx.doi.org/10.1182/blood.v120.21.3050.3050.
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Abstract Abstract 3050 Approximately 30% of Caucasian and 70% of African-American hematopoietic stem cell transplant (HCT) patients are unable to find an 8/8 HLA matched unrelated donor. Mismatches at HLA-A, B, C, or DRB1 alleles reduce survival. Therefore, identification and avoidance of high-risk allele combinations and the associated amino acid substitutions (AAS) that negatively impact HCT outcomes may increase access to this treatment option and allow safer utilization of HLA mismatched donors. Using random forest (RF) analysis, our group has previously reported the AAS associated with 100 day survival (D100S) in single HLA class I mismatched, DRB1 matched recipient-donor pairs. We now extend that analysis to one year outcomes of overall survival (1y OS), disease free survival (1y DFS), transplant related mortality (1y TRM), and acute graft-versus-host disease (aGvHD) grades III-IV using the same clinical variables (recipient age, disease type, disease status, and gender match) and 389 AAS position and types (AASPT). The AASPT were defined by the HLA locus, amino acid position in the HLA class I protein and the actual AAS, e.g. locus: HLA-C, position: 97, type: tryptophan to arginine = C97_WR. Patients (n=2107) received myeloablative (99%) HCT as treatment for ALL, AML, CML, and MDS in early and intermediate stage of disease between 1988 and 2003. RF analysis, a tree-based method for classification was used to assign an importance score (IS), reflecting the association of each potential predictor variable with the outcome of interest. Logistic regression analyses were performed to determine the magnitude of the effect of each individual AASPT (n=600) relative to 8/8 matched cases (n=1507), adjusted for the four clinical variables. Using the criteria of n≥10, a relatively high IS (≥5) and a highly statistically significant odds ratio (p<0.01), C 97_WR has a deleterious effect on all outcomes. HLA-C156_RW has a deleterious effect on all outcomes except on 1y DFS. HLA-C80_NK and C77_SN affects 1y OS and 1y DFS; HLA-C11_SA, C116_YS, and C24_AS affect 1y TRM and aGvHD III-IV. Eighteen additional AASPT were associated with a single outcome each. No AASPT at the HLA -B loci met the above criteria, which could be due to the small number of HLA-B mismatched cases (n=88) compared to HLA-A (n=179) and HLA-C (n=333) mismatched cases. Other AASPT conferred high point estimates of relative risk but the number of patients with a mismatch was too small to yield statistical significance. The most common alleles associated with all of the AASPT listed above are: HLA-C*01:02/02:02; 01:02/15:02; 02:02/01:02; 03:03/04:01; 04:01/16:01; 14:02/15:02; and HLA-A*02:01/02:05; 24:02/24:03; 29:02/30:01; 30:01/30:02; 30:01/32:01. To understand the potential biological significance of mismatched allele pairs in the molecular context of peptide antigen binding, computational models were constructed for the 10 most important AASPT. In silico screening of ∼500 unique peptides was conducted against each pair to determine differences in the peptide repertoire capable of binding to each mismatched molecule. We found that the mismatched pairs identified by RF as less permissive displayed greater loss in their ability to bind identical peptides compared to other mismatches in the binding groove predicted to be more permissive by RF analysis. Overall, the computational modeling suggests a different affinity and peptide binding repertoire between mismatched HLA molecules. Results from these analyses indicate that only a small number (6.4%) of AASPT clearly confer adverse outcomes in HCT patients with single HLA class I mismatched unrelated donors, and it is likely that these AASPT are responsible for differential binding of immunogenic peptides. Validation studies in an independent dataset are in progress. Additional prospective studies should be performed to refine HLA matching algorithms in the mismatched setting that may increase donor availability and minimize the adverse effects of donor HLA mismatching. Disclosures: No relevant conflicts of interest to declare.
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Crivello, Pietro, Esteban Arrieta-Bolanos, Meilun He, Tao Wang, Shahinaz M. Gadalla, Sophie Paczesny, Steven G. E. Marsh, et al. "Single HLA Class I Mismatches with High Peptide Divergence in the Graft-Versus-Host Direction Are Associated with Inferior Survival after 9/10 HLA-Matched UD-HCT: A Retrospective Study from the CIBMTR." Blood 138, Supplement 1 (November 5, 2021): 97. http://dx.doi.org/10.1182/blood-2021-152792.
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Abstract Introduction Unrelated donor (UD)-recipient disparity for human leukocyte antigen (HLA) class I adversely affects outcome of hematopoietic cell transplantation (UD-HCT). HLA polymorphisms in the peptide antigen binding groove can affect the repertoire of presented peptides. We have recently shown that the degree of peptide divergence between mismatched HLA-DP allotypes is related to T-cell alloreactivity and clinical permissiveness after UD-HCT (Meurer et al Blood 2021). Here, we hypothesized that the clinical tolerability also of HLA class I mismatches in UD-HCT might depend on the divergence of their respective peptide repertoires. Methods We studied 2,562 patients after 9/10 HLA-A, -B, -C, -DRB1, -DQB1-matched UD-HCT for acute myeloid or lymphocytic leukemia, or myelodysplastic syndrome, between 2008 and 2018, and 14,426 10/10 HLA-matched UD-HCT with similar characteristics. Peptide divergence of the mismatched HLA allotypes was predicted based on hierarchical clustering of experimentally determined peptide binding motifs (PBM) (Bassani-Sternberg et al Front Immunol 2018), with 21 different PBM groups identified in 122 HLA class I allotypes (44, 63 and 18 for HLA-A, -B and -C, respectively). The mismatched cohort was stratified into PBM-matches or PBM-mismatches, and within the latter into host-versus-graft (HvG), graft-versus-host (GvH) or bidirectional PBM-mismatches (Figure 1A). The primary study endpoint was overall survival (OS); secondary endpoints included treatment-related mortality (TRM), GVHD and relapse. P-value<0.01 was considered statistically significant. Results The available PBM data allowed us to classify 1,629/2,562 (63.6%) of our pairs. Of these, 386 (23.7%) were PBM-matched and 1,243 (76.3%) were PBM-mismatched, and in the latter, 254 (20.5%), 238 (19.1%) and 751 (60.4%) had HvG, GvH or bidirectional PBM-mismatches, respectively. Transplants were performed mainly with peripheral blood stem cells (78%), myeloablative conditioning (65%) and tacrolimus-based graft-versus-host disease (GvHD) prophylaxis (74%). About half of the 9/10 HLA-matched HCT were performed using in vivo T-cell depletion by anti-thymocyte globulin or Campath, and none used post-transplant cyclophosphamide. Multivariable analyses showed that 10/10 HLA-matched transplants had significantly higher OS, lower TRM and aGvHD 3-4 compared to 9/10 HLA-matched transplants but relapse was similar (Figure 1B,C). There were no significant differences between the PBM-matched and aggregate PBM-mismatched group (Figure 1B). In further analysis, pairs with a bidirectional or only GvH PBM-mismatch had significantly worse OS, compared to pairs in the PBM-matched group or with only a unidirectional HvG (hazards ratio [HR] 0.76, 95% confidence interval [CI] 0.63-0.92, P = 0.0036; Figure 1C). The hazards of TRM and aGvHD 3-4 were lower for the HvG or PBM-matched group compared to the reference (HR 0.78, 95% CI 0.65-0.95, P = 0.0135 and HR 0.79, 95% CI 0.65-0.95, P = 0.0126, respectively), although these were not statistically significant (Figure 1C). Conclusion We show that single HLA class I PBM-mismatches with high peptide divergence in the unidirectional or bidirectional GvH directions are significantly associated with worse survival after 9/10 HLA-matched UD-HCT compared to PBM-matched or unidirectional mismatching in the HvG direction. These data suggest that the mechanistic role of peptide-diversity for T-cell alloreactivity we previously observed for HLA-DPB1 disparity (Meurer et al., Blood 2021), is also a relevant to class I mismatches, providing a new rationale for selecting permissive donors in the setting of 9/10 HLA-matched UD-HCT. Avoiding class I PBM mismatches in the GvH direction is associated with better survival. Figure 1 Figure 1. Disclosures Paczesny: Medical University of South Carolina: Patents & Royalties: inventor on the ST2 bispecific antibody patent application. Lee: Amgen: Research Funding; AstraZeneca: Research Funding; Incyte: Research Funding; Janssen: Other; Kadmon: Research Funding; National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Syndax: Research Funding; Takeda: Research Funding.
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Doxiadis, I. I. N., E. Maruya, J. Thorogood, S. Takemoto, G. M. Th Schreuder, G. G. Persijn, P. I. Terasaki, and J. J. van Rood. "Permissible HLA mismatches for kidney transplants." Human Immunology 39, no. 2 (February 1994): 130. http://dx.doi.org/10.1016/0198-8859(94)90148-1.
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Wujciak, T., and G. Opelz. "Evaluation of the permissible mismatch concept." Transplant International 9, s1 (August 1996): S8—S10. http://dx.doi.org/10.1111/j.1432-2277.1996.tb01692.x.
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Geneugelijk, Kirsten, Kirsten Anne Thus, and Eric Spierings. "Predicting Alloreactivity in Transplantation." Journal of Immunology Research 2014 (2014): 1–12. http://dx.doi.org/10.1155/2014/159479.
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Human leukocyte Antigen (HLA) mismatching leads to severe complications after solid-organ transplantation and hematopoietic stem-cell transplantation. The alloreactive responses underlying the posttransplantation complications include both direct recognition of allogeneic HLA by HLA-specific alloantibodies and T cells and indirect T-cell recognition. However, the immunogenicity of HLA mismatches is highly variable; some HLA mismatches lead to severe clinical B-cell- and T-cell-mediated alloreactivity, whereas others are well tolerated. Definition of the permissibility of HLA mismatches prior to transplantation allows selection of donor-recipient combinations that will have a reduced chance to develop deleterious host-versus-graft responses after solid-organ transplantation and graft-versus-host responses after hematopoietic stem-cell transplantation. Therefore, several methods have been developed to predict permissible HLA-mismatch combinations. In this review we aim to give a comprehensive overview about the current knowledge regarding HLA-directed alloreactivity and several developedin vitroandin silicotools that aim to predict direct and indirect alloreactivity.
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He, Jun, Zi-Xing Chen, Xiaojing Bao, Qiaocheng Qiu, Xiaoni Yuan, and Yang Li. "The Effect of High-Resolution Donor-Recipient HLA Matching and Mismatching Frequencies On Choosing Donor in Chinese Population for Unrelated Allo-HSCT." Blood 114, no. 22 (November 20, 2009): 4503. http://dx.doi.org/10.1182/blood.v114.22.4503.4503.
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Abstract Abstract 4503 The relative importance of various human leukocyte antigen (HLA) loci and the resolution level at which they are matched has not been fully defined for unrelated donor (URDs) transplantation. Hematopoietic stem cell transplantation (HCT) from volunteer URDs may give a chance of cure for patients with malignant hematological diseases. Although donor-recipient HLA matching is associated with better outcomes, many are not able to identify an HLA-A, -B, -C, -DRB1, DQB1 matched URD and are faced with choosing the closest matching among the available donors. The Chinese Marrow Donor Program (CMDP) has completed a retrospective high-resolution HLA typing on sufficient patient-donor pairs to analyze high resolution matching and mismatches probability at specific loci. These data are critical for selecting the best available partially HLA-matched donor for patients undergoing HLA-mismatched URD HCT. We have performed high-resolution typing for HLA-A,-B,-C,-DRB1,-DQB1 by using SBT, SSOP and SSP techniques on 1092 donors and 931 patients from the data base of CMDP. Among 1092 donors, the allele with highest frequency were HLA-A*1101, A*0201, A*2402, A*0207, A*3303, A*0206 and A*3001; HLA-B*4001, B*4601, B*5801, B*1302, B*1501, B*5101and B*1301; HLA-Cw*0102, Cw*0702, Cw*0304, Cw*0801, Cw*0602, Cw*0303, Cw*0302 and Cw*0401; HLA-DRB1*0901, DRB1*1501, DRB1*1202, DRB1*0701, DRB1*0803, DRB1*0405, DRB1*0301 and DRB1*1101; HLA-DQB1*0301, DQB1*0303, DQB1*0601, DQB1*0202, DQB1*0602, DQB1*0302, DQB1*0401, DQB1*0201 and DQB1*0502. The probability of HLA high-resolution DNA matching between 1092 donors and 931 patients(10/10 match) was 16.7%. Mismatching at a single HLA-A, -B, -C, -DRB1 or DQB1 locus (9/10) was 17.7%. A single mismatch at each locus of HLA-A, -Cw,- DRB1,- DQB1,- B was 6.8%, 6.3%, 2.0%, 1.7%, and 0.8%, respectively. Double mismatch (8/10) was 18.4%, such as loci A+ Cw(5.0%), DRB1+DQB1(4.6%) and B+ Cw(3.8%). The donor/patient pairs mismatched between allele of A*0201 and A*0206, A*0201 and A*0207, A*1101 and A*1102, B*4006 and B*4002, B*1501 and B*1527, Cw*0304 and Cw*0302, Cw*0304 and Cw*0303, DRB1*1501 and DRB1*1502, DRB1*1202 and DRB1*1201, DRB1*0406 and DRB1*0403, DRB1*1401 and DRB1*1454, DQB1*0303 and DQB1*0302, respectively, were statistically associated with lower-risk Allo-HSCT. These results suggested that high-resolution DNA matching or mismatching for HLA-A, -B, -C, -DRB1 and DQB1 alleles could be associated with better clinical outcome and higher survival. Furthermore, the identification of high risk mismatch and permissive mismatch would be beneficial for the selection of a suitable donor. Disclosures: No relevant conflicts of interest to declare.
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Park, Meerim, and Jong Jin Seo. "Role of HLA in Hematopoietic Stem Cell Transplantation." Bone Marrow Research 2012 (October 2, 2012): 1–7. http://dx.doi.org/10.1155/2012/680841.
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The selection of hematopoietic stem cell transplantation (HSCT) donors includes a rigorous assessment of the availability and human leukocyte antigen (HLA) match status of donors. HLA plays a critical role in HSCT, but its involvement in HSCT is constantly in flux because of changing technologies and variations in clinical transplantation results. The increased availability of HSCT through the use of HLA-mismatched related and unrelated donors is feasible with a more complete understanding of permissible HLA mismatches and the role of killer-cell immunoglobulin-like receptor (KIR) genes in HSCT. The influence of nongenetic factors on the tolerability of HLA mismatching has recently become evident, demonstrating a need for the integration of both genetic and nongenetic variables in donor selection.
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Ayuk, Francis, Martin Bornhäuser, Matthias Stelljes, Tatjana Zabelina, Eva-Maria Wagner, Christoph Schmid, Maximilian Christopeit, Martina Guellstorf, Nicolaus Kröger, and Wolfgang Bethge. "Predicted Indirectly ReCognizable HLA Epitopes (PIRCHE) Are Associated with Poorer Outcome after Single Mismatch Unrelated Donor Stem Cell Transplantation: A Study of the Cooperative Transplant Study Group (KTS) of the German Group for Bone Marrow and Stem Cell Transplantation (DAG-KBT)." Transfusion Medicine and Hemotherapy 46, no. 5 (2019): 370–75. http://dx.doi.org/10.1159/000502389.
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There is no established standard for selection of mismatched unrelated donors. Indirect recognition of HLA mismatches can be predicted using the model of “Predicted Indirectly ReCognizable HLA Epitopes” (PIRCHE). We performed a multicenter retrospective study evaluating the impact PIRCHE on outcome after allogeneic stem cell transplantation (allo-HSCT) from single mismatched (HLA 9/10 matched) unrelated donors. The study cohort included 424 adult recipients of HLA 9/10 matched unrelated donor transplants (9/10 MUD), treated for AML or MDS at 6 transplant centers across Germany. Detection of PIRCHE was associated with lower overall survival (OS) (47 vs. 57%, p = 0.04), higher non-relapse mortality (NRM) (32 vs. 20%, p = 0.05), and higher incidence of chronic graft-versus-host disease (GVHD) (49 vs. 31%, p = 0.04) at 2 years. Cumulative incidence of acute GVHD grade 2–4 at 6 months was not significantly different (30 vs. 23%, p = 0.2). OS for 9/10 MUD with no PIRCHE was similar to 10/10 MUD (57 vs. 55%). In multivariate analysis, PIRCHE retained negative impact on OS (RR 1.5, 95% CI 1.0–2.1, p = 0.03) and NRM (RR 1.7, 95% CI 1.0–2.9, p = 0.03). To the best of our knowledge, for the first time, we show the association of PIRCHE and survival outcome after allo-HSCT. The PIRCHE model, if validated in an independent cohort, may allow selection of permissible HLA mismatches that enable improved transplant outcome.
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Suchyta, Marissa, Richard Sharp, Hatem Amer, Elizabeth Bradley, and Samir Mardini. "4364 Ethicists’ Viewpoints on Face Transplant: A survey study to guide clinical practice." Journal of Clinical and Translational Science 4, s1 (June 2020): 131. http://dx.doi.org/10.1017/cts.2020.388.
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OBJECTIVES/GOALS: Face transplant can offer functional and aesthetic restoration to patients who have exhausted reconstructive options. Ethical issues in face transplant still abound, including that of patient selection. The goal of this study was to assess ethicists’ viewpoints on face transplant. METHODS/STUDY POPULATION: A large-scale online survey of attendees of the International Conference on Clinical Ethics Consultation (N = 401) was performed to assess ethicists’ opinions on issues in face transplant. Questions were asked regarding the risk-benefit ratio of immunosuppression, permissibility of face transplant for more recipient subpopulations (including children and blind patients), donor-recipient age, gender, and ethnicity mismatches, and ethics committee make-up. RESULTS/ANTICIPATED RESULTS: Among 84 respondents, 84% agreed it is permissible to perform a face transplant on an adult with no medical contraindications. The majority of respondents agreed that it is permissible to perform a face transplant on a child or blind recipient. An issue of continued concern was risk of immunosuppression. Respondents had a high threshold of permissibility for ethnic mismatches between donor and recipient, and 43% reported it is permissible to have a gender mismatch. A 10 year age difference between donor and recipient was the most commonly accepted. Questions regarding the ideal composition of a face transplant ethics committee demonstrated consensus on the roles that should be represented. DISCUSSION/SIGNIFICANCE OF IMPACT: This study provides insight into ethicists’ viewpoints on face transplant, which demonstrates a high level of permissibility towards the procedure. This may be due to the early success of face transplants and the shifting ethical issues in the field to practical aspects of the procedure. This research also provides guidance to programs regarding questions of donor and recipient selection, ethics committee composition, and offers insight into strengthening the ethical framework of the field.
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Petersdorf, Effie W., Theodore A. Gooley, Mari Malkki, Andrea P. Bacigalupo, Anne Cesbron, Ernette Du Toit, Gerhard Ehninger, et al. "HLA-C expression levels define permissible mismatches in hematopoietic cell transplantation." Blood 124, no. 26 (December 18, 2014): 3996–4003. http://dx.doi.org/10.1182/blood-2014-09-599969.
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Key Points The expression level of patient HLA-C allotypes affects GVHD and mortality after HCT from HLA-C-mismatched unrelated donors. Transplant outcome can be improved by avoiding high-risk HLA-C-mismatched donors when no matched stem cell source is available.
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Takemoto, S., J. M. Cecka, and P. I. Terasaki. "Permissible class I mismatches identified from 7-year kidney transplant successes with 4 AB mismatches." Human Immunology 40 (January 1994): 17. http://dx.doi.org/10.1016/0198-8859(94)91692-6.
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Fleischhauer, Katharina. "Immunogenetics of HLA-DP — A New View of Permissible Mismatches." New England Journal of Medicine 373, no. 7 (August 13, 2015): 669–72. http://dx.doi.org/10.1056/nejme1505539.
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Lorentino, Francesca, Nicoletta Sacchi, Elena Oldani, Valeria Miotti, Alessandra Picardi, Anna Maria Gallina, Paolo Bernasconi, et al. "Permissive HLA-DPB1 Mismatch and Survival after Unrelated Donor Allogeneic Stem Cell Transplantation for Hematological Malignancies: A Comparative Analysis of Different Immunogenetic Models on 422 Patients from GITMO and IBMDR." Blood 132, Supplement 1 (November 29, 2018): 482. http://dx.doi.org/10.1182/blood-2018-99-115216.
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Abstract Introduction: Hematopoietic Stem Cell Transplantation (HSCT) from unrelated donors (UD) is a curative therapy for many hematologic malignancies. HLA matching plays a major role in determining HSCT outcome but the relative role of incompatibilities at the different HLA loci is still debated. In particular, over 80% of UD-HSCT are performed across HLA-DPB1 mismatches (mm): a number of previous studies have devised immunogenetic models to elucidate the impact of HLA-DPB1 mm on HSCT outcome, but a comparative analysis of these models in a recent and well-characterized cohort is lacking. Methods: We selected 422 adult patients (pts) who received an 8/8 (HLA-A, B, -C and -DRB1) allele level-matched UD-HSCT from 2012 to 2015: of them, 382 (90%) had a mm at one or both HLA-DPB1 alleles. We classified functional HLA-DPB1 matching by four models, on the basis of: I) differential immunogenicity of alleles belonging to 3 groups of T-cell epitopes (TCE), as defined by functional studies (Zino, Blood, 2004) and refined by in silico prediction (Crivello, BBMT 2015); II) a similar model subdividing allelles in 4 TCE groups (TCE4, Crocchiolo, Blood 2009); III) differences in "delta functional distance" scores between the alleles of donor and pt, based on 12 polymorphic AA in HLA-DPB1 exon 2 (Crivello, Blood 2016); IV) mismatches in the rs9277534 single-nucleotide polymorphism in the HLA-DPB1 3′ UTR region, predicted on the basis of the DPB1 genotype (Schöne, Hum Immunol 2018), and previously shown to be associated to the expression levels of HLA-DPB1 molecules (HLAexp, Petersdorf, NEJM 2015). Indication for HSCT was acute leukemia (55%), lymphoma and multiple myeloma (29%), myelodysplastic and myeloproliferative syndromes (16%). According to EBMT score definition, 45% of pts were in early, 26% in intermediate, and 29% in advanced disease status. Conditioning regimens were myeloablative (64%) or reduced intensity (36%). Peripheral blood was the preferred stem cell source (81%). Graft-versus-host disease (GvHD) prophylaxis was based on anti-thymocyte globulin (ATG) in 91% of pts, mostly associated with cyclosporine and methotrexate (81%). Median follow-up was 3.2 y. Results: Among the four models adopted to classify functional HLA-DPB1 matching, the TCE4 provided the best results in predicting mm that were permissive (P) or non permissive (NP) for HSCT outcomes. By this model, P mismatched pairs (N=135) had a significantly superior 3-y overall survival (OS) and Graft-versus host disease and Relapse-Free Survival (GRFS) compared to NP pairs (N=247) (60±8% vs 49±7%, p .05; and 36±8% vs 29±5%, p .04). This was associated with a higher transplant-related mortality (TRM), 30±6% in NP mm and 21±6% in P mm, p .09 and a higher 3-y CI of extensive cGvHD in NP mm (12±4%) compared to P (4±2%), p .01 (Figure 1). No effect was found for relapse incidence. Cox multivariate analysis (adjusted for pt age, donor/host gender and CMV, disease status, Sorror score, conditioning intensity, stem cell source, ATG use, HLA matching on 5 loci, center effect), showed that a NP mm compared to P mm was associated with higher hazards for OS (HR 1.6, p .01), GRFS (HR 1.4, p .02), TRM (HR 1.9, p .01), cGvHD (HR 1.6, p .03) and extensive cGvHD (HR 3.6, p <.01). No interaction was found between HLA matching on 5 loci and HLA-DPB1 permissivity predicted by TCE4. Directionality of NP mm did not impact on clinical risk stratification. Of the 382 transplants with HLA-DPB1 mismatches, 229 had unidirectional mismatches in GvH direction and thus could be classified by the HLAexp model. The predicted expression level of the mismatched allele in the patient was associated with 100-d CI of grade≥2 aGvHD: 32±10% in high expression (N=76) versus 16±6% in low expression (N=153) mismatched alleles, p <.01. This was also confirmed in adjusted Cox multivariate analysis for grade≥2 aGvHD (HR 2.2, p <.01). However, this did not have a significant impact on severe aGvHD, TRM and OS. No significant associations with clinical outcomes were found for the "delta functional distance" or the TCE3 model, respectively. Conclusions: Our study provides further proof that functional HLA-DPB1 matching is crucially associated to UD-HSCT outcome also in recent transplants, and suggest that, at least in the cohort under analysis, mainly composed of Italian pts transplanted using an ATG-based prophylaxis, the TCE4 model appears superior to other models in stratifying risk groups and predicting survival. Figure. Figure. Disclosures Patriarca: Medac: Other: Travel, accommodations, expenses; Jazz: Other: Travel, accommodations, expenses; Celgene: Other: Advisory Role; Travel, accommodations, expenses; Janssen: Other: Advisory role; MSD Italy: Other: Advisory Role. Rambaldi:Italfarmaco: Consultancy; Roche: Consultancy; Omeros: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Amgen Inc.: Consultancy. Fleischhauer:GENDX: Research Funding. Vago:GENDX: Research Funding; Moderna TX: Research Funding.
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Green, E. K., S. C. Bain, P. J. Day, A. H. Barnett, F. Charleson, A. F. Jones, and M. R. Walker. "Detection of human apolipoprotein E3, E2, and E4 genotypes by an allele-specific oligonucleotide-primed polymerase chain reaction assay: development and validation." Clinical Chemistry 37, no. 7 (July 1, 1991): 1263–68. http://dx.doi.org/10.1093/clinchem/37.7.1263.
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Abstract A polymerase chain reaction (PCR) assay has been developed and validated by using allele-specific oligonucleotide (ASO) primers to specifically amplify E3, E2, and E4 polymorphic sequences of the human apolipoprotein E (apo E) genes. Degenerate ASOs containing one or two additional 3' mismatches provided greater specificity than did ASOs containing a single mid-sequence or 3' allele-specific mismatch with plasmid pEB4 or genomic DNA as template. Optimal specificity and efficiency of amplification did not correlate with primer annealing conditions, whether determined theoretically or via oligo-melting experiments. Pre-cycling denaturation times and high cycling denaturation temperatures were also required for optimal amplification, presumably because of the high G:C content (75-85%) of apo E gene sequences. Conditions permissive for amplification and discrimination with plasmid DNA did not transpose favorably to amplification from human genomic DNA from peripheral blood leukocytes; the latter required nested primer reactions. These data may be valuable in predicting PCR assay conditions for other G:C-rich sequences containing polymorphic sequence differences. The assay described is both more accurate and rapid (24 h) than previously described methods for phenotyping or genotyping human apo E from blood specimens.
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Crocchiolo, Roberto, Elisabetta Zino, Nicoletta Sacchi, Jessica Marcon, Simona Pollichieni, Rosi Oneto, Giuseppe Bandini, Andrea Bacigalupo, Fabio Ciceri, and Katharina Fleischhauer. "NON-Permissive HLA-DPB1 T CELL Epitope Disparities Correlate with Engraftment and Survival after Unrelated Stem Cell Transplantation." Blood 112, no. 11 (November 16, 2008): 562. http://dx.doi.org/10.1182/blood.v112.11.562.562.
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Abstract Over 80% of stem cell transplantations (SCT) from unrelated donors (UD) are performed across allelic HLA-DPB1 disparities which have been associated with acute graft-versus-host disease (aGvHD) and, in 10/10 matched pairs, protection from disease relapse, while no significant correlation with overall survival (OS) could be revealed so far. We have previously developed an algorithm for non-permissive HLA-DP disparities involving an immunogenic T cell epitope (TCE) encoded by DPB1*0901, *1001 and *1701 (group 1), and, in a weaker form, by DPB1*0301, *1401 and *4501 (group 2) (Zino et al, Blood 2004). Here we report on the analysis of this algorithm in 627 UD SCT facilitated through the Italian Bone Marrow Donor Registry (IBMDR) and the Gruppo Italiano Trapianto di Midollo Osseo (GITMO) between 1999 and 2006, performed for malignant disorders including acute myeloid or lymphoid leukaemia (n=320; 51%) and Hodgkin’s or non-Hodgkin’s lymphoma (n=86; 13.7%). 242 pairs (38.5%) were matched at the allelic level for HLA-A, B, C, DRB1 and DQB1 (10/10 allele-matched pairs), while the remaining 385 pairs (61.5%) presented at least one mismatch at either of these loci (<10/10 matched pairs). Non-permissive DPB1 TCE disparities were determined by either considering both group 1 and group 2 DPB1 alleles (“2-group model”), or group 1 alleles only (“1-group model”). In line with DPB1 allelic frequencies in the Italian population, non-permissive DPB1 TCE disparities were present in 40% of pairs according to the 2-group model, and in 16% of pairs according to the 1-group model. In the 10/10 matched pairs, the Cox regression probability of engraftment was significantly reduced by the presence of non-permissive TCE disparities in the 2-group model (HR=0.23; C.I. 0.07–0.70, p=0.01) and in the 1-group model (HR=0.25; C.I. 0.08–0.75, p=0.01). Importantly, in the 10/10 matched pairs, the adjusted Cox regression hazards of transplant related mortality (TRM) were significantly increased by the presence of non-permissive TCE disparities in the 2-group model (HR=1.72; C.I. 1.09–2.70, p=0.02) and in the 1-group model (HR=1.71; C.I. 1.01–2.92, p=0.05), resulting in a significant increase in the hazards of overall mortality in the 1-group model (HR=1.66; C.I. 1.07–2.58, p=0.02) which was marked but not statistically significant in the 2-group model (HR=1.38; C.I. 0.96–1.98, p=0.08). These effects of non-permissive TCE DPB1 disparities were completely abrogated by the additional presence of one or more mismatches at either of the other five HLA loci in the <10/10 matched group. Interestingly, the estimated cumulative incidence probability of TRM and OS was similar in the 10/10 matched pairs with non-permissive DPB1 TCE disparities according to the 2-group model and in the <10/10 matched pairs regardless of DPB1 matching status, and worse in the presence of DPB1 TCE disparities according to the 1-group model. No impact of non-permissive DPB1 disparities on the hazards of aGvHD grade 2–4 or disease relapse were observed in neither of the two models. Taken together, our data show, for the first time, a significant association between HLA-DP matching status and survival in UD SCT, suggesting that the avoidance of non-permissive DPB1 TCE disparities according to the 2-group model and, even more so, according to the 1-group model, could significantly improve the clinical success of this treatment by reducing transplant mortality.
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Solomon, Scott R., Michael A. Aubrey, Xu Zhang, Allison Piluso, Brian M. Freed, Stacey Brown, Katelin C. Jackson, et al. "Selecting the Best Donor for T Cell-Replete Haploidentical Transplantation: Importance of HLA Disparity, NK Alloreactivity, and Other Clinical Variables." Blood 130, Suppl_1 (December 7, 2017): 670. http://dx.doi.org/10.1182/blood.v130.suppl_1.670.670.
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Abstract Lack of a matched sibling or unrelated donor can be a significant barrier to allogeneic hematopoietic cell transplantation (HCT). Haploidentical (haplo) donors are readily available for nearly all such patients. However, donor selection criteria to determine the optimal haplo donor are not readily available. In order to determine which donor characteristics are most important in predicting transplant success, we retrospectively analyzed 208 consecutive donor-recipient pairs receiving haplo HCT with post-transplant cyclophosphamide for hematologic malignancy. Donor characteristics were evaluated by multivariate Cox analysis and correlated with overall survival (OS), disease-free survival (DFS), relapse/progression, and non-relapse mortality (NRM), while controlling for significant patient and transplant-related factors. Donor variables analyzed included age, sex, relationship to recipient, CMV status, ABO compatibility, HLA disparity and several NK alloreactivity models (KIR receptor-ligand, ligand-ligand, haplotype, B content, activating KIR-based education systems, Sekine donor licensing model). Median (range) recipient and donor age was 52 (19-75) and 38 (15-73) years respectively, and 41% of donor-recipient pairs were non-Caucasian. Patients were transplanted for AML (34%), MDS/MPS/CML (20%), ALL (17%), NHL/HD/CLL (25%). PBSC was used as the stem cell source in 66% of patients, and conditioning intensity was myeloablative in 41%. The donor was a child, sibling, or parent in 47%, 38%, and 14% respectively. Median (range) follow-up for surviving patients was 33 (7-130) months. In multivariate Cox analysis, patient/transplant characteristics associated with improved OS and DFS included recipient age <55 years, black race, CMV seronegativity, low/intermediate disease risk index (DRI), and more recent transplant year. When adjusting for significant patient/transplant variables, donor characteristics independently associated with improved overall survival included presence of HLA-DR mismatch [GVH direction] (HR 0.35, p=0.010), the presence of HLA DP non-permissive mismatch [GVH direction] (HR 0.51, p=0.033), KIR receptor-ligand mismatch (HR 0.56, p=0.023), the presence of KIR B/x haplotype with KIR2DS2 (HR 0.38, p=0.005 vs. B/x without KIR2DS2; HR 0.47, p=0.013 vs. A/A), donor CMV positivity (HR 0.49, p=0.009) and donor relation (child vs. parent - HR 0.31, p=0.016; sibling vs. parent - HR 0.48, p=0.087). Donor characteristics independently associated with reduced risk of disease relapse/progression included the presence of KIR receptor-ligand mismatch (HR 0.39, p=0.001), KIR B/x haplotype with KIR2DS2 (HR 0.43, p=0.023 vs. B/x without KIR2DS2), the presence of ≥4 (out of 10) HLA allelic mismatches [GVH direction] (HR 0.29, p=0.001), the presence of a non-permissive HLA-DP mismatch (HR 0.25, p<0.001) and the use of a non-parental donor (child vs. parent - HR 0.26, p=0.010; sibling vs. parent - HR 0.37, p=0.039). Donor characteristics associated with increased NRM included higher HLA disparity (HR 7.86, p=0.016), HLA-DR match (HR 15.99, p<0.001), absence of KIR B/x haplotype with KIR2DS2 (A/A haplotype - HR 5.03, p=0.003; B/x without KIR2DS2 - HR 3.92, p=0.034), CMV seronegativity (HR 2.99, p=0.026), and female donor-male recipient (HR 2.35, p=0.071). Adjusted 3-yr OS was improved in patients with the presence of KIR R-L mm (66% vs 50%, p=0.013), KIR B/x with KIR2DS2 (69% vs. 55% [A/A] or 43% [B/x without KIR2DS2, p=0.052 and 0.007, respectively]), HLA-DR mm (64% vs. 45%, p=0.071), and HLA-DP non-permissive mm (72% vs. 56%, p=0.026), emphasizing the importance of donor HLA and KIR typing for optimal donor selection (see figure). This large, single institution analysis demonstrates the significance of HLA-DR/HLA-DP disparity, NK alloreactivity, and other clinical variables in the donor selection process for haplo HCT. These results suggest that HLA-DP and donor KIR typing should be performed routinely in T cell-replete haplo HCT to assist in donor selection and risk stratification. Disclosures Solh: ADC Therapeutics: Research Funding; Amgen: Speakers Bureau; Celgene: Speakers Bureau.
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Arrieta-Bolaños, Esteban, Maryam Mohamaddokht, Thuja Meurer, Pietro Crivello, Amin T. Turki, Peter A. Horn, Dietrich W. Beelen, J. H. Frederik Falkenburg, and Katharina Fleischhauer. "Relative Contribution of Naïve and Memory T Cells to Alloreactivity in Hematopoietic Cell Transplantation." Blood 134, Supplement_1 (November 13, 2019): 1923. http://dx.doi.org/10.1182/blood-2019-130273.
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Introduction: Graft-versus-host disease (GvHD) is a major impediment to the cure of blood disorders by hematopoietic cell transplantation (HCT). GvHD is mediated by alloreactive T cells recognizing histocompatibility antigen (HAg) mismatches between patient and donor. Naïve T cells are thought to be the main mediators of alloreactive responses since, theoretically, memory T cells would have never been exposed to and selected by alloantigens, except in multiparous women or transfused individuals. Accordingly, clinical trials using naïve T cell-depleted allografts are being conducted with the aim to reduce GvHD after human leukocyte antigen (HLA)-matched HCT. However, several groups have shown that memory T cells can also mediate alloreactive responses, in particular against mismatched HLA. We hypothesized that the relative importance of naïve vs. memory T cell alloreactivity depends on the matching status of the patient-donor pair. Specifically, we reasoned that naïve-depletion strategies will be most efficient in HLA-identical sibling HCT, where minor (m)HAg presented by self-HLA are the only targets of T cell alloreactivity, but less so in HLA-matched unrelated HCT, where HLA-DPB1 mismatches (mmDPB1) are frequent and potentially recognized through molecular mimicry by both naïve and memory T cells. Methods: In order to model T cell alloreactivity to mHAg and to major HLA mismatches post HCT, we used a quantitative in vitro assay based on co-culture of responder and stimulating cells. Naïve (CD45RA+CD45RO-) and memory (CD45RA-CD45RO+) CD4+ T cells were enriched from peripheral blood mononuclear cells from healthy individuals using microbead technology to >95% purity and used as responders. Irradiated transduced HeLa cells engineered to express single HLA-DP antigens and the necessary machinery for HLA class II antigen presentation were used to stimulate CD4+ T cells. HeLa transductants expressing the autologous (i.e. DP-matched, response restricted to mHAg) or an allogeneic (mmDPB1) DP antigen were used to challenge naïve and memory CD4+ cells from each responder. After 14 days of culture, T cells were restimulated overnight and the levels of T cell response were quantified by cell surface expression of the activation marker CD137. Results: In 36 independent T cell cultures from 8 different individuals, the overall levels of alloreactivity against mHAg were significantly lower than those against mmDPB1 (mean 50.3% vs 20.7%, p<0.0001) (Figure 1A). Consistent with current concepts, alloreactivity to mHAg was significantly higher in the naïve than in the memory subset (mean 27.7% vs 10.5%, p=0.015) (Figure 1B). This was most evident in 5/8 responders (mean 38.4% vs 13.3%, p=0.016), in particular in females under 40 years of age. In 3 of the 8 responders, mHAg alloreactivity was generally low and not significantly different between the naïve and the memory subsets (mean 10.3% vs 12.9%, p=0.73). In contrast, alloreactivity against mmDPB1 was evenly distributed between the naïve and the memory subset (mean 52.1% vs 48.5%, p=0.62) in all responders, independent of age, sex or cytomegalovirus serostatus of the responder (Figure 1C). Interestingly, naïve DPB1*04:01-restricted mHAg alloreactive CD4+ T cells were able to cross-recognize the structurally similar (i.e. permissive) DPB1*04:02 (mean 43.3%) but not the dissimilar (i.e. non-permissive) DPB1*09:01 (mean 14.1%) (Figure 1D). Moreover, when purified CD4+ cells from self-DPB1*04:01 homozygous donors were challenged with DPB1*04:02 or DPB1*09:01, naïve CD4+ T cells were the main source of alloreactive responses against the permissive mmDPB1 (mean 25.0% vs 7.4% for naïve and memory cells, respectively), while both memory (mean 50.0%) and naïve (mean 46.0%) CD4+ cells elicited strong alloresponses against the non-permissive mmDPB1. Conclusion: Our data provide the first direct experimental evidence that alloreactivity against mmDPB1 is stronger than against mHAg, and importantly that it is mediated equally by naïve and memory CD4+ T cells while the mHAg response is mediated mainly by the naïve subset. However, our data also suggests that some mmDPB1 involving structurally (and hence functionally) similar alleles (in general permissive) might behave similarly to DPB1 matches. These observations should be taken into account in clinical trials aimed at improving the outcome of unrelated HCT by selective depletion of naïve T cells. Disclosures Turki: Jazz Pharmaceuticals, CSL Behring, MSD.: Consultancy; Neovii Biotech, all outside the submitted work: Other: Travel subsidies. Beelen:Medac GmbH Wedel Germany: Consultancy, Honoraria.
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Reddy, Manjula, and J. Gowrishankar. "A Genetic Strategy to Demonstrate the Occurrence of Spontaneous Mutations in Nondividing Cells Within Colonies of Escherichia coli." Genetics 147, no. 3 (November 1, 1997): 991–1001. http://dx.doi.org/10.1093/genetics/147.3.991.
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A genetic strategy was designed to examine the occurrence of mutations in stationary-phase populations. In this strategy, a parental population of cells is able to survive under both permissive and restrictive conditions whereas mutants at a particular target locus exhibit a conditional-lethal phenotype. Thus, by growing the population to stationary phase under restrictive conditions and then shifting it to permissive conditions, mutations that had arisen in stationary phase can be studied without confounding effects caused by the occurrence of similar mutations during growth of the population. In two different applications of this strategy, we have studied the reversion to Lac+ in stationary phase of several Lac– mutations in Escherichia coli. Our results indicate that a variety of spontaneous point mutations and deletions, particularly those that are sensitive to the mechanisms of replication slippage (for their generation) and methyl-directed mismatch repair (for their correction), can arise in nondividing populations of cells within a colony. The frequency of their occurrence was also elevated in mutS strains, which are defective in such mismatch repair. These data have relevance to the ongoing debate on adaptive or directed mutations in bacteria.
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Rutten, Caroline E., Simone A. P. van Luxemburg-Heijs, Edith D. van der Meijden, Marieke Griffioen, Roelof Willemze, and J. H. Frederik Falkenburg. "HLA-DPB1 Mismatching Results in the Generation of a Full Repertoire of HLA-DPB1 Specific T Cell Responses Showing Immunogenicity of All HLA-DPB1 Alleles." Blood 112, no. 11 (November 16, 2008): 3504. http://dx.doi.org/10.1182/blood.v112.11.3504.3504.
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Abstract In unrelated donor hematopoietic stem cell transplantation (URD-SCT) patients are preferably transplanted with stem cells from a fully HLA matched donor, usually defined as identical for HLA-class I, -DR and -DQ. Since HLA-DPB1 is often not taken into consideration in donor selection, 80–90% of URD-SCTs are mismatched for HLA-DPB1. The role of HLA-DPB1 as transplantation antigen has been unclear, since clinical reports on the impact of matching for HLA-DPB1 on transplant outcome showed conflicting results. HLA-DPB1 mismatching has been associated with an increased risk of graft versus host disease (GVHD). However, we recently demonstrated that HLA-DPB1 specific T cells can mediate a potent graft versus leukemia effect without inducing GVHD. It has been suggested that the controversial effects of matching for HLA-DPB1 in URD-SCT could partly be explained by the assumption that not all HLA-DPB1 differences are immunogenic. This theory was based on the cross-reactive recognition of two HLA-DPB1* 09 specific T cell clones that recognized other HLA-DPB1 alleles sharing amino acids (aa) in position 8–11 of HLA-DPB1 (Zino et al, blood 2004). It was hypothesized that there would be no induction of T cell responses between individuals expressing HLA-DPB1 molecules sharing this aa sequence. This was translated into a classification of permissive and non-permissive HLA-DPB1 mismatches in order to allow a broader donor selection. To investigate whether cross-reactive recognition of other HLA-DPB1 molecules by our previously generated HLA-DPB1*02 or *03 specific CD4+ T cell clones depended on the presence of specific aa sequences we tested recognition of a panel of 14 EBV-LCL expressing 9 different HLA-DPB1 molecules. All HLA-DPB1*02 as well as all *03 specific T cell clones showed cross-reactivity with other HLA-DPB1 alleles and each T cell clone exhibited its own pattern of cross-reactivity. Two HLA-DPB1*0201 specific T cell clones with different TCR-Vβ showed also recognition of EBV-LCL expressing HLA-DPB1*1001 and *1701 or HLA-DPB1*1001, *0901 and *1601 respectively. Five HLA-DPB1*03 reactive T cells clones with different TCR-Vβ showed differential cross-recognition of EBV-LCL expressing HLA-DPB1*0101, *0601, *1101, *1301 and *1401. To identify immunogenic differences the aa sequences of the HLA-DPB1 molecules recognized by the various T cell clones were compared. The HLA-DPB1 molecules recognized by the HLA-DPB1*02 specific T cell clones shared an aa substitution at position 69 compared to the responder cell. However, HLA-DPB1*0601,*0901 and *1901 with the same substitution were not recognized by both T cell clones. This phenomenon was also observed for the HLA-DPB1*03 specific T cell clones, indicating that the cross-reactive recognition of HLA-DPB1 could not be predicted by aa sequences. Next, we analyzed the immunogenicity of various HLA-DPB1 alleles in different stimulator/responder combinations to verify the classification of permissive and non-permissive mismatches. We developed a model to generate allo-HLA-DP responses by transducing HLA-class II negative HELA cells with various HLA-DP molecules and used these cells to stimulate purified CD4+ T cells from HLA-DPB1 homozygous donors. HELA cells transduced with HLA-DPB1*0101, *0201, *0301, *0401, *0402, *0501, *0601, *0901, *1101, *1301, *1401 or *1701 were used as stimulator cells. Responder CD4+ T cells were typed HLA-DPB1* 0201, *0301, *0401 or *0402. 14 days after stimulation, CD4+ T cells were tested for recognition of the stimulator cells and of HELA cells transduced with the responder HLA-DPB1 molecule as a negative control. For these 4 responders, stimulation with 12 different HLA-DP transduced HELA cell lines resulted in specific IFN-γ production in response to the stimulator cells in 47 out of 48 stimulations. 28 CD4+ T cell lines also showed cross-reactive recognition of HELA cells transduced with at least one other HLA-DPB1 molecule. In conclusion, we showed that cross-reactive recognition of various HLA-DPB1 molecules by HLA-DPB1 specific T cells is a common observation. However, we demonstrated that cross-reactivity between HLA-DPB1 molecules by allo-HLA-DPB1 specific T cells does not exclude the generation of immune response between individuals expressing these HLA-DPB1 molecules. By generating multiple allo-HLA-DP specific T cell lines, we showed that all HLA-DPB1 mismatch combinations are immunogenic.
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Pingel, Julia, Camila J. Hernandez Frederick, Tao Wang, Emmanuelle Polge, Michael D. Haagenson, Stephanie J. Lee, Mohamad Mohty, et al. "Evaluation of the Impact of Non-Inherited Maternal Antigens on the Outcome of HLA Mismatched Unrelated Donor Hematopoietic Stem Cell Transplantation for Hematological Malignancies on Behalf of the ALWP of the EBMT and the CIBMTR." Blood 126, no. 23 (December 3, 2015): 3226. http://dx.doi.org/10.1182/blood.v126.23.3226.3226.
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Abstract Allogeneic hematopoietic stem cell transplantation (HSCT) offers a potential cure for a variety of hematological malignancies. Patients without an HLA matched sibling donor can turn to unrelated donor registries to identify a suitably HLA matched donor. In the case where a fully HLA-A, -B, -C, -DRB1 and -DQB1 (10/10) matched donor is unavailable, there are often multiple 9/10 matched donors to select from. However, the prioritization and identification of permissive HLA mismatches in the 9/10 matched setting have proven elusive. Fetal exposure to non-inherited maternal antigens (NIMA) imparts lifelong immune modulating effects leading to tolerance to these antigens. Prior studies have found that matching for non-inherited maternal antigens (NIMA) can lead to lower rates of acute graft versus host disease (aGVHD) and lower treatment-related mortality (TRM) in cord blood HSCT (J.J. van Rood et al., Blood 2002; J. J. van Rood et al., PNAS, 2009; V. Rocha et al., BBMT, 2012). Patients undergoing mismatched HSCT with adult unrelated donors could benefit from NIMA matching by introducing maternal HLA testing during confirmatory typing of the donor and using NIMA matching as a criterion for mismatched donor selection. This joint EBMT-CIBMTR retrospective analysis was designed to evaluate the influence of NIMA matching in HSCT with mismatched adult unrelated donors. Matching criteria were based on HLA-A, -B, -C, -DRB1, -DQB1 at high resolution. Included donor-recipient pairs had 5 loci HLA typing and a minimum of one year follow-up recorded at EBMT or CIBMTR and donors were registered with DKMS German Bone Marrow Donor Center. To obtain maternal HLA typing information, DKMS contacted the respective donors by mail to inform about the study and to provide detailed information, a buccal swab kit and an informed consent form to the donor's mother that the donor could send on. SBT-based HLA typing was performed at the DKMS Life Science Lab, Dresden, Germany once signed informed consent and samples were received. A total of 1735 donors were contacted and maternal samples could be retrieved for 803 cases (46%). A total of 50 NIMA matches (6%) were found reflecting the rate expected from previous studies. Multivariate analyses were performed using Cox proportional hazards models adjusting for significant co-variates for overall survival (OS), disease free survival (DFS), relapse, TRM and acute and chronic GVHD comparing NIMA matched to NIMA mismatched cases. The final analysis population was restricted to 9/10 matched cases (N=452) transplanted for acute myeloid leukemia (N=307) and acute lymphoblastic leukemia (N=145) using myeloablative (N=307) or reduced intensity (N=145) conditioning from 1999-2013. The NIMA matched (N=32) and mismatched (N=420) groups were well balanced for all disease, patient, transplant and donor characteristics. The groups differed by mismatched HLA locus with the NIMA matched group skewed towards more HLA-C mismatches (66% vs. 35%). Univariate analyses did not find any significant differences between the NIMA matched and mismatched groups for any outcomes. TRM rates were similar between the groups at 1 year with 23% (95% CI: 10-40%) and 23% (95% CI: 19-28%) in the NIMA matched and mismatched groups, respectively. No significant associations were observed in multivariate analyses of the NIMA matched versus mismatched groups (Table). In contrast to prior studies of NIMA matched HSCT, no significant associations were found between NIMA matching and any outcomes. However, our findings may be due to the fact that the current study was underpowered to detect the expected difference in TRM observed in prior studies. Investigation on a larger cohort or a prospective trial would be needed. We thank Carlheinz Müller from the German unrelated donor registry ZKRD for providing additional HLA information and the donors and their mothers for their cooperation in this study. Table. Multivariate analysis results of NIMA matched versus mismatched (used as reference) HSCT Table 1.OutcomeHR95% CIp-valueOS0.890.54-1.480.653DFS0.880.53-1.430.598TRM0.740.35-1.600.447Relapse0.890.45-1.750.737aGVHD II-IV0.970.53-1.800.935aGVHD III-IV0.590.19-1.910.382cGVHD1.770.99-3.160.053 Disclosures Lee: Bristol-Myers Squibb: Consultancy; Kadmon: Consultancy. Nagler:Biokine LTD: Consultancy.
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Petersdorf, Effie W. "Genetics of Graft-Versus-Host Disease." Blood 118, no. 21 (November 18, 2011): SCI—49—SCI—49. http://dx.doi.org/10.1182/blood.v118.21.sci-49.sci-49.
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Abstract Abstract SCI-49 The HLA barrier remains the primary roadblock to hematopoietic cell transplantation from alternative donors for the treatment of blood disorders. Currently over 18 million unrelated donors are represented by registries worldwide and they serve as a critically important resource for patients in need of a transplant. The basis for the selection of unrelated donors has evolved with advances in HLA typing technology. The demonstration that serologically identical HLA phenotypes have DNA-defined allelic variants that can provoke graft-versus-host reactions has served as the basis for the current criteria for the selection of donors. Although donor HLA matching lowers morbidity and mortality from graft-versus-host disease (GVHD), matching does not guarantee that the patient will not experience life-threatening GVHD and require prolonged immunosuppression after transplantation. Furthermore, the risks of acute and chronic GVHD associated with transplantation from HLA mismatched donors has lead to a reluctance to use mismatched donors for some patients. In 2011, the unmet need is two-fold. First, the vast majority of patients in need of a transplant have no HLA matched unrelated donor. To permit these patients the opportunity for a life-saving transplant, more information on the rules that govern permissible donor-recipient HLA mismatches is needed. Second, information is needed on the extent of non-HLA genetic variation that resides within the major histocompatibility complex (MHC) region and the manner in which such variation contributes to the transplantation barrier. Several research strategies have been applied to identify HLA mismatch combinations that can be used safely, including but not limited to analysis of individual amino acid residues that define the peptide binding repertoire of HLA class I and II alleles and antigens, and computational approaches that relate the sequence to structure of HLA molecules. The availability of a dense map of over 36,000 single nucleotide polymorphisms and complete sequence information for common HLA haplotypes has recently provided new information on the extent of human genetic variation and its organization on haplotypes. These data serve as a rich resource for mapping novel MHC resident variation associated with GVHD risk and transplant outcome. New information is emerging on the diversity of the MHC among transplant patient-donor pairs, the organization of simple and complex genetic variation relative to the classical HLA loci, and the putative regions within the MHC that are amenable to fine mapping. Future investigation of the genetic basis of GVHD will be enhanced with more complete information on MHC region variation in diverse human populations, haplotype content, and robust tools for both querying and analyzing complex variation. Disclosures: No relevant conflicts of interest to declare.
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Jordan, William J., Paul A. Brookes, Richard M. Szydlo, John M. Goldman, Robert I. Lechler, and Mary A. Ritter. "IL-13 production by donor T cells is prognostic of acute graft-versus-host disease following unrelated donor stem cell transplantation." Blood 103, no. 2 (January 15, 2004): 717–24. http://dx.doi.org/10.1182/blood-2003-01-0192.
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Abstract Despite the success of human leukocyte antigen (HLA) typing in allogeneic stem cell transplantation (SCT) it is rare to find an unrelated donor that is perfectly matched, making identification of “permissive” mismatches of paramount importance. Here, we describe novel associations between donor T-cell cytokine production during donor-antipatient mixed lymphocyte reactions (MLRs) and acute graft-versus-host disease (aGVHD). The data reveal positive correlations between both Th1-type and Th2-type cytokine production and GVHD and the assay established could potentially represent a useful tool for identification of permissible unrelated SCT donors. Associations between interleukin 13 (IL-13) levels and aGVHD were by far the strongest predictor of a GVHD (P = .0002). All patients suffering severe (grade III) aGVHD following SCT had donors who produced very high pretransplantation IL-13 responses, while those developing little or no aGVHD (grades 0-I) produced no IL-13 at all. IL-13 levels were independent of all other cytokines measured as well as cytotoxic T-lymphocyte precursor (CTLp) frequencies. The cytokines IL-5, interferon γ (IFN-γ), and tumor necrosis factor α (TNF-α) also predicted development of aGVHD (P < .05 for all 3), appearing to be coproduced in the assay and correlating with estimated CTLp frequencies. The data challenge the notion that aGVHD is purely a Th1-type cytokine-driven response, high-lighting a novel and highly significant link between the Th2-type cytokine IL-13 and aGVHD.
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Fuchs, Ephraim J., Shannon R. McCurdy, Scott R. Solomon, Tao Wang, Michelle Kuxhausen, Yvette L. Kasamon, MHD Monzr Al Malki, et al. "Improving Donor Selection for Haploidentical Stem Cell Transplantation with Post-Transplant Cyclophosphamide through Selective HLA-Mis/Matching." Blood 136, Supplement 1 (November 5, 2020): 24–26. http://dx.doi.org/10.1182/blood-2020-140433.
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Background HLA-haploidentical (haplo) blood or marrow transplantation (BMT) with post-transplantation cyclophosphamide (PTCy) is widely used, but few factors that inform donor selection have been identified. Based on prior observations for HLA-B leader (EW Petersdorf et al. Lancet Haematol 2020), HLA-DRB1 (YL Kasamon et al. BBMT 2010), and HLA-DPB1 (SR Solomon et al. BBMT 2018), we hypothesized that mismatching at individual HLA loci may influence BMT outcomes, but single and additive HLA gene effects have not been evaluated systematically in the context of haploBMT with PTCy. Methods The Center for International Blood and Marrow Transplant Research (CIBMTR) identified 1,434 patients who underwent T-cell-replete haploBMT with PTCy for acute leukemia or myelodysplastic syndrome (MDS) between 2008-2017. Multivariable models assessed transplant outcomes associated with 3 HLA-factors: (1) B-leader dimorphism (MM, MT, TT) matching; (2) HLA-DRB1 mismatching in the graft-versus-host (GVH) direction; and (3) nonpermissive HLA-DPB1 mismatching in the GVH direction using the T-cell epitope-3 model, which classifies HLA-DPB1 mismatches into permissive or non-permissive. All final models contained the HLA factors and adjusted for other significant clinical covariates at p<.05 in univariate analysis. P-values were not adjusted for multiple testing. Results Diagnoses were 58% AML, 23% ALL, 19% MDS. 22% of AML patients were in advanced disease stage (relevant analyses were stratified for disease stage for both acute leukemia and MDS). Median recipient age was 54 (range 1-78) years. Median follow up among survivors was 12 (range 2-119) months. Marrow was the graft source in 43% of recipients. Myeloablative conditioning was used in 45% of recipients. Fifty percent of recipients had hematopoietic cell transplantation-comorbidity index (HCT-CI) scores of ≥3. HLA-DP typing was missing in 52% of cases and thus all models had a "missing" category for HLA-DP. Mismatching in the GVH direction at HLA-A, HLA-C, or HLA-DQ was not associated with study outcomes [overall survival (OS), disease-free survival (DFS), relapse, nonrelapse mortality (NRM), or grade II-IV acute, grade III-IV acute, or chronic graft-versus-host disease (gr2-4a or cGVHD)]. When compared to leader-matched patients, HLA-B leader-mismatching was associated with worse OS and DFS (hazard ratio [HR] 1.25 [95% CI, 1.09 to 1.44]; P=.002, and HR 1.18 [95% CI, 1.03 to 1.34]; P=.01, respectively), and higher risk of NRM (HR 1.38 [95% CI, 1.10 to 1.74]; P=.005), but was not associated gr2-4a or cGVHD, or relapse. In contrast, when compared to matching at HLA-DRB1, the presence of any GVH direction mismatch at HLA-DRB1 was associated with improved DFS (HR 0.80 [95% CI, 0.68 to 0.94]; P=.007) and lower risk of relapse (HR 0.69 [95% CI, 0.56 to 0.86]; P=.0008), but with no effect on OS, gr2-4a or cGVHD, or NRM. Similarly, any nonpermissive GVH mismatching at HLA-DPB1 was also associated with improved DFS (HR 0.72 [95% CI, 0.55-0.94], p=.015) and OS (HR 0.59 [95% CI, 0.43-0.82], p=.002), with a tendency towards lower relapse (HR 0.75 [95% CI, 0.54-1.05], p=.09), but with no effect on gr2-4a or cGVHD, or NRM. When combining the effects of leader matching at HLA-B and mismatching at HLA-DRB1 there was an additive improvement in both DFS and OS (Figure 1 A and B) with significantly lower NRM (p=0.03) and relapse (p=0.008) when compared to other groups. Within this unselected large cohort, favorable haplo donors based on B-leader matching and HLA-DRB1 mismatching were used for 48.5% of recipients and had improved DFS (HR 0.68 [95% CI, 0.52 to 0.88], p=.004) when compared to B-leader mismatched and HLA-DRB1 matched pairs, suggesting that with intentional selection of donors based on these factors, even more could receive a favorable combination. Conclusion HLA-B leader mismatching is a risk factor for NRM and worse OS and DFS, whereas either HLA-DRB1 or nonpermissive HLA-DPB1 mismatch is associated with reduced relapse and improved DFS, after haploBMT with PTCy. PTCy dissociates the graft-versus-leukemia effect of HLA-DRB1 and nonpermissive HLA-DPB1 mismatching from GVHD. The best outcomes after haploBMT with PTCy are seen when a donor is HLA-B leader matched and HLA-DRB1 mismatched. When there is more than one potential haplo donor for an acute leukemia or MDS patient, selection based on HLA considerations may improve DFS and OS. Figure Disclosures Shaw: Orca Bio: Consultancy. Lee:Takeda: Research Funding; AstraZeneca: Research Funding; Novartis: Research Funding; Incyte: Consultancy, Research Funding; Syndax: Research Funding; Pfizer: Consultancy, Research Funding; Amgen: Research Funding; Kadmon: Research Funding.
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Morishima, Yasuo, Takakazu Kawase, Keitaro Matsuo, Koichi Kashiwase, Hidetoshi Inoko, Hiroh Saji, Shunichi Kato, Takeo Juji, Yoshihisa Kodera, and Takehiko Sasazuki. "Identification of Non-Permissive HLA Allele Mismatch Combinations and Amino Acid Substitution Responsible for Acute Graft-Versus-Host Disease in Unrelated Allogeneic Bone Marrow Transplantation." Blood 108, no. 11 (November 16, 2006): 170. http://dx.doi.org/10.1182/blood.v108.11.170.170.
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Abstract Background: In the allogenic hematopoietic stem cell transplantation from unrelated donors (UR-HSCT), an effect of HLA locus mismatch in allele level on clinical outcome has been clarified. However, the effect of each HLA allele mismatch combinations is little known, and its molecular mechanism to induce acute graft versus host disease (aGVHD) remained to be elucidated. Methods: Consecutive 4866 patients transplanted with T cell replete marrow from a serologically HLA-A, -B and -DR antigen-matched donor through Japan Marrow Donor Program were registered in this cohort study. All HLA-A, -B, -C, -DRB1, -DQB1 and -DPB1 alleles were retrospectively typed in 2171 pairs, and partly in the other pairs. The impact of the HLA allele mismatch combinations in HLA six loci and amino acid substitution positions in HLA-C and HLA-DPB1 locus on aGVHD and survival was analyzed using a multivariable Cox regression model. Results: Significant high-risk HLA allele mismatch combinations compared with match for severe aGVHD were identified; four in HLA-A allele (donor A*0206- patient A*0201 (n=108) hazard ratio (HR): 1.77, A*0206-A*0207 (n=20) : 3.24, A*2601-A*2603 (n=32): 1.96, A*2602-A*2601 (n=24): 2.18), six in HLA-B (B*1507-B*1501 (n=14): 2.95, B*4002-B*4003 (n=14): 2.44, B*4002-B*4006 (n=85): 1.69, B*4003-B*4006 (n=7): 3.85, B*4006-B*4002 (n=60): 1.62, B*4403-B*4402 (n=4) : 5.78), 11 in HLA-C, six in HLA-DRB1, zero in HLA-DQB1 and two in HLA-DPB1. Amino acid substitutions of position 80 of HLA-C at which donor had Asp80 and patient Lys80 (Asp80-Lys80) and Ser77-Asp77 were first elucidated as significant risk factors for severe aGVHD. These two amino acid substitutions were completely linked, and HR for severe aGVHD was 1.49 (1.01–2.21). As position 80 is ligand for NK cell receptor KIR2DL as a result, further analysis was performed in the KIR2DL ligand match in the GVH vector population. Notably, particular amino acid substitution at positions 95, 156 and 163 of HLA-C was a significant risk factor for severe aGVHD. HR of Leu95-Ile95, Arg156-Leu156, Leu156-Trp156, Trp156-Leu156 and Thr163-Leu163 substitutions were 1.74 (95%CI: 1.06–2.86), 2.10 (1.16–3.81), 5.22 (1.65–16.4), 4.64 (1.04–20.7) and 1.82 (1.11–2.99), respectively. The amplitude of hydropathy scales were 0.7, 8.3, 4.7, 4.7 and 4.7, respectively. Amino acid substitutions of any other positions of HLA-C were not significant risk factors. When analyzing the location of amino acid substitution in HLA-C, residues located in the T-cell receptor contact have marginal impact on severe aGVHD (HR: 1.45 trend P=0.096), and no other locations were significant. In HLA-DPB1 mismatch combinations, there was no obvious tendency to associate the positons of amino acid substitutions with severe aGVHD and grades 2–4 aGVHD. Conclusion: These findings provide evidences to elucidate the mechanism of aGVHD on the base of HLA molecule. Furthermore, the identification of non-permissive and possible permissive mismatch would be beneficial for the selection of suitable donor and international donor exchange for UR-HSCT.
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Solomon, Scott R., Michael T. Aubrey, Xu Zhang, Melhem Solh, Lawrence E. Morris, H. Kent Holland, Katelin C. Jackson, Brian M. Freed, Christina L. Roark, and Asad Bashey. "Optimizing Donor Selection for Haploidentical Transplantation Utilizing the Four-Group T Cell Epitope (TCE-4) Algorithm for Prediction of HLA-DPB1 Non-Permissive Mismatches." Blood 138, Supplement 1 (November 5, 2021): 420. http://dx.doi.org/10.1182/blood-2021-149289.
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Abstract An HLA-DPB1 non-permissive mismatch (npmm) has been associated with higher risks of acute graft-versus-host disease and non-relapse mortality after matched unrelated donor transplantation (MUDT) and thus avoiding HLA-DPB1 npmm is important in unrelated donor selection. In contrast, HLA-DPB1 npmm by the 3-group T cell epitope algorithm (TCE-3) has been shown to be protective in the context of haploidentical donor transplantation (HIDT) using post-transplant cyclophosphamide (PTCy) (Solomon et al. BBMT 2018). Additional HLA-DPB1 "permissiveness" models, also based on cross-reactive patterns of alloreactive T cells against HLA-DPB1 alleles, include the TCE-4 (based on 4 TCE groups) and functional distance (FD, based on net difference in distance between key amino acid polymorphisms) algorithms. Lastly, an expression model is based on the surface expression of the recipient mismatched HLA-DPB1 (RDP) allele according to variants of a biallelic SNP. The present analysis had 2 major aims: to 1) determine which HLA-DPB1 permissiveness model (TCE-3, TCE-4, FD, expression) provides the best tool for haploidentical donor selection and 2) analyze the role of vector (GVH vs. HVG direction) on the effect of an HLA-DPB1 npmm. A total of 322 patients with acute leukemia, MDS, lymphoma, CLL or CML, receiving a HIDT-PTCy from a single institution were evaluated with a median follow-up time of 45 months [range 6, 184]. Baseline characteristics included a median age of 50 years [19, 80], 47% non-white, HCT-CI ≥3 in 50%, PBSC graft in 80%, and myeloablative conditioning in 49%. The number of donor-recipient pairs having an HLA-DPB1 npmm according to the TCE-3, TCE-4, FD and expression was 82 (25%), 130 (40%), 54 (17%) and 99 (31%) respectively. In univariate analysis, HLA-DPB1 npmm identified by the TCE-3 and TCE-4 models were statistically associated with improved overall survival (OS) (p=0.041 and p=0.004 respectively), whereas FD risk and RDP expression were not (see figure). For disease-free survival (DFS), only the TCE-4 model showed a statistically significant association (p=0.022). Directionality of the HLA-DP npmm (GVH vs. HVG vector) had no significant impact on survival following HIDT-PTCy, a finding similar to the context of MUDT (Fleischhauer BMT 2017). In multivariate Cox analysis, adjusting for patient/donor age, gender, race, HLA-DR mismatch and transplant year, HLA-DPB1 npmm by the TCE-4 model had the most significant association with improved OS (HR 0.59, p=0.012), with TCE-3 being less predictive (HR 0.65, p=0.07) (see figure). Furthermore, HLA-DPB1 npmm by TCE-4 led to improved DFS (HR 0.69, p=0.046) and trends for lower cumulative incidences of relapse/progression (HR 0.73, p=0.16) and NRM (HR 0.54, p=0.09). In summary, the presence of an HLA-DP npmm in either the GVH or HVG direction continues to be associated with improved survival following HIDT-PTCy in a large single institution retrospective analysis with extended follow-up. Compared to the original TCE-3 model, a TCE-4-predicted HLA-DPB1 npmm is more strongly associated with overall survival. This fact, combined with the larger number of HLA-DPB1 npmm donors identified by the TCE-4 model, suggests that it may be a better selection tool for optimal haploidentical donor identification. Figure 1 Figure 1. Disclosures Solh: Partner Therapeutics: Research Funding; Jazz Pharmaceuticals: Consultancy; BMS: Consultancy; ADCT Therapeutics: Consultancy, Research Funding.
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Powley, L., C. Brown, A. Melis, Y. Li, G. Parkes, and C. V. Navarrete. "Consideration of noninherited maternal Ags as permissible HLA mismatches in cord blood donor selection." Bone Marrow Transplantation 51, no. 5 (January 25, 2016): 675–79. http://dx.doi.org/10.1038/bmt.2015.344.
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Geneugelijk, Kirsten, Matthias Niemann, Julia Drylewicz, Arjan van Zuilen, Irma Joosten, Wil Allebes, Arnold van der Meer, et al. "OR41 PIRCHE-II: A novel tool to identify permissible HLA mismatches in kidney transplantation." Human Immunology 78 (September 2017): 39. http://dx.doi.org/10.1016/j.humimm.2017.06.047.
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Roelen, Dave L., Inge Stobbe, Neil T. Young, Simone P. M. J. van Bree, Ilias I. N. Doxiadis, M. Oudshoorn, Peter J. Morris, Kathryn J. Wood, and Frans H. J. Claas. "Permissible and immunogenic HLA-A mismatches: cytotoxic T-cell precursor frequencies reflect graft survival data." Human Immunology 62, no. 7 (July 2001): 661–67. http://dx.doi.org/10.1016/s0198-8859(01)00263-4.
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