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Article ; Online: HLA Haplotypes and Relapse After Hematopoietic Cell Transplantation.

Petersdorf, Effie W / McKallor, Caroline / Malkki, Mari / He, Meilun / Spellman, Stephen R / Gooley, Theodore / Stevenson, Philip

Journal of clinical oncology : official journal of the American Society of Clinical Oncology

2023 Volume 42, Issue 8, Page(s) 886–897

Abstract: Purpose: Recurrence of blood malignancy is the major cause of hematopoietic cell transplant failure. HLA class II molecules play a fundamental role in antitumor responses but the role of class II haplotypes is not known.: Methods: HLA-DR, -DQ, -DM, ... ...

Abstract	Purpose: Recurrence of blood malignancy is the major cause of hematopoietic cell transplant failure. HLA class II molecules play a fundamental role in antitumor responses but the role of class II haplotypes is not known. Methods: HLA-DR, -DQ, -DM, and -DO allele variation was determined in 1,629 related haploidentical transplants to study the clinical significance of individual molecules and haplotypes. Results: Outcome correlated with patient and donor variation for HLA-DRβ residue 86 (Gly/Val), HLA-DQ (G1/G2) heterodimers, and donor HLA-DM (DM11,11/nonDM11,11) molecules, and depended on patient-donor mismatching. Risks of relapse were lower for DRβ-86 GlyGly patients when the donor was GlyVal (hazard ratio [HR], 0.46 [95% CI, 0.30 to 0.68]; Conclusion: HLA class II haplotypes may be functional constituents of the transplantation barrier, and their consideration in patients and donors may improve the success of transplantation.
MeSH term(s)	Humans ; Hematopoietic Stem Cell Transplantation/adverse effects ; Haplotypes ; Neoplasm Recurrence, Local/etiology ; HLA Antigens/genetics ; HLA-DRB1 Chains ; Chronic Disease ; Histocompatibility Testing ; Graft vs Host Disease/etiology
Chemical Substances	HLA Antigens ; HLA-DRB1 Chains
Language	English
Publishing date	2023-12-05
Publishing country	United States
Document type	Journal Article
ZDB-ID	604914-x
ISSN	1527-7755 ; 0732-183X
ISSN (online)	1527-7755
ISSN	0732-183X
DOI	10.1200/JCO.23.01264
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Article ; Online: Role of NKG2D ligands and receptor in haploidentical related donor hematopoietic cell transplantation.

Petersdorf, Effie W / McKallor, Caroline / Malkki, Mari / He, Meilun / Spellman, Stephen R / Hsu, Katharine C / Strong, Roland K / Gooley, Ted / Stevenson, Phil

Blood advances

2023 Volume 7, Issue 12, Page(s) 2888–2896

Abstract: The recurrence of malignancy after hematopoietic cell transplantation (HCT) is the primary cause of transplantation failure. The NKG2D axis is a powerful pathway for antitumor responses, but its role in the control of malignancy after HCT is not well- ... ...

Abstract	The recurrence of malignancy after hematopoietic cell transplantation (HCT) is the primary cause of transplantation failure. The NKG2D axis is a powerful pathway for antitumor responses, but its role in the control of malignancy after HCT is not well-defined. We tested the hypothesis that gene variation of the NKG2D receptor and its ligands MICA and MICB affect relapse and survival in 1629 patients who received a haploidentical HCT for the treatment of a malignant blood disorder. Patients and donors were characterized for MICA residue 129, the exon 5 short tandem repeat (STR), and MICB residues 52, 57, 98, and 189. Donors were additionally defined for the presence of NKG2D residue 72. Mortality was higher in patients with MICB-52Asn relative to those with 52Asp (hazard ratio [HR], 1.83; 95% confidence interval [CI], 1.24-2.71; P = .002) and lower in those with MICA-STR mismatch than in those with STR match (HR, 0.66; 95% CI, 0.54-0.79; P = .00002). Relapse was lower with NKG2D-72Thr donors than with 72Ala donors (relapse HR, 0.57; 95% CI, 0.35-0.91; P = .02). The protective effects of patient MICB-52Asp with donor MICA-STR mismatch and NKG2D-72Thr were enhanced when all 3 features were present. The NKG2D ligand/receptor pathway is a transplantation determinant. The immunobiology of relapse is defined by the concerted effects of MICA, MICB, and NKG2D germ line variation. Consideration of NKG2D ligand/receptor pairings may improve survival for future patients.
MeSH term(s)	Humans ; Ligands ; NK Cell Lectin-Like Receptor Subfamily K/genetics ; NK Cell Lectin-Like Receptor Subfamily K/metabolism ; Histocompatibility Antigens Class I/genetics ; Histocompatibility Antigens Class I/metabolism ; Hematopoietic Stem Cell Transplantation/adverse effects
Chemical Substances	Ligands ; NK Cell Lectin-Like Receptor Subfamily K ; Histocompatibility Antigens Class I
Language	English
Publishing date	2023-02-11
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural
ZDB-ID	2915908-8
ISSN	2473-9537 ; 2473-9529
ISSN (online)	2473-9537
ISSN	2473-9529
DOI	10.1182/bloodadvances.2022008922
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Article ; Online: Impact of the HLA Immunopeptidome on Survival of Leukemia Patients After Unrelated Donor Transplantation.

Crivello, Pietro / Arrieta-Bolaños, Esteban / He, Meilun / Wang, Tao / Fingerson, Stephanie / Gadalla, Shahinaz M / Paczesny, Sophie / Marsh, Steven G E / Lee, Stephanie J / Spellman, Stephen R / Bolon, Yung-Tsi / Fleischhauer, Katharina

Journal of clinical oncology : official journal of the American Society of Clinical Oncology

2023 Volume 41, Issue 13, Page(s) 2416–2427

Abstract: Purpose: Immunopeptidome divergence between mismatched HLA-DP is a determinant of T-cell alloreactivity and clinical tolerability after fully HLA-A, -B, -C, -DRB1, -DQB1 matched unrelated donor hematopoietic cell transplantation (UD-HCT). Here, we ... ...

Abstract	Purpose: Immunopeptidome divergence between mismatched HLA-DP is a determinant of T-cell alloreactivity and clinical tolerability after fully HLA-A, -B, -C, -DRB1, -DQB1 matched unrelated donor hematopoietic cell transplantation (UD-HCT). Here, we tested this concept in HLA-A, -B, and -C disparities after single class I HLA-mismatched UD-HCT. Patients and methods: We studied 2,391 single class I HLA-mismatched and 14,426 fully HLA-matched UD-HCT performed between 2008 and 2018 for acute leukemia or myelodysplastic syndromes. Hierarchical clustering of experimentally determined peptide-binding motifs (PBM) was used as a proxy for immunopeptidome divergence of HLA-A, -B, or -C disparities, allowing us to classify 1,629/2,391 (68.1%) of the HLA-mismatched UD-HCT as PBM-matched or PBM-mismatched. Risks associated with PBM-matching status were assessed by Cox proportional hazards models, with overall survival (OS) as the primary end point. Results: Relative to full matches, bidirectional or unidirectional PBM mismatches in graft-versus-host (GVH) direction (PBM-GVH mismatches, 60.7%) were associated with significantly lower OS (hazard ratio [HR], 1.48; Conclusion: PBM-GVH mismatches inform mortality risks after single class I HLA-mismatched UD-HCT, suggesting that prospective consideration of directional PBM-matching status might improve outcome. These findings highlight immunopeptidome divergence between mismatched HLA as a driver of clinical tolerability in UD-HCT.
MeSH term(s)	Humans ; Unrelated Donors ; Prospective Studies ; Hematopoietic Stem Cell Transplantation ; Leukemia, Myeloid, Acute ; HLA-A Antigens ; Graft vs Host Disease ; Histocompatibility Testing ; Retrospective Studies ; HLA Antigens
Chemical Substances	HLA-A Antigens ; HLA Antigens
Language	English
Publishing date	2023-01-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	604914-x
ISSN	1527-7755 ; 0732-183X
ISSN (online)	1527-7755
ISSN	0732-183X
DOI	10.1200/JCO.22.01229
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Zs.A 1847: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Genetic testing in severe aplastic anemia is required for optimal hematopoietic cell transplant outcomes.

Blood

2024 Volume 140, Issue 8, Page(s) 909–921

Abstract: Patients with severe aplastic anemia (SAA) can have an unrecognized inherited bone marrow failure syndrome (IBMFS) because of phenotypic heterogeneity. We curated germline genetic variants in 104 IBMFS-associated genes from exome sequencing performed on ... ...

Abstract	Patients with severe aplastic anemia (SAA) can have an unrecognized inherited bone marrow failure syndrome (IBMFS) because of phenotypic heterogeneity. We curated germline genetic variants in 104 IBMFS-associated genes from exome sequencing performed on 732 patients who underwent hematopoietic cell transplant (HCT) between 1989 and 2015 for acquired SAA. Patients with pathogenic or likely pathogenic (P/LP) variants fitting known disease zygosity patterns were deemed unrecognized IBMFS. Carriers were defined as patients with a single P/LP variant in an autosomal recessive gene or females with an X-linked recessive P/LP variant. Cox proportional hazard models were used for survival analysis with follow-up until 2017. We identified 113 P/LP single-nucleotide variants or small insertions/deletions and 10 copy number variants across 42 genes in 121 patients. Ninety-one patients had 105 in silico predicted deleterious variants of uncertain significance (dVUS). Forty-eight patients (6.6%) had an unrecognized IBMFS (33% adults), and 73 (10%) were carriers. No survival difference between dVUS and acquired SAA was noted. Compared with acquired SAA (no P/LP variants), patients with unrecognized IBMFS, but not carriers, had worse survival after HCT (IBMFS hazard ratio [HR], 2.13; 95% confidence interval[CI], 1.40-3.24; P = .0004; carriers HR, 0.96; 95% CI, 0.62-1.50; P = .86). Results were similar in analyses restricted to patients receiving reduced-intensity conditioning (n = 448; HR IBMFS = 2.39; P = .01). The excess mortality risk in unrecognized IBMFS attributed to death from organ failure (HR = 4.88; P < .0001). Genetic testing should be part of the diagnostic evaluation for all patients with SAA to tailor therapeutic regimens. Carriers of a pathogenic variant in an IBMFS gene can follow HCT regimens for acquired SAA.
MeSH term(s)	Adult ; Anemia, Aplastic/diagnosis ; Anemia, Aplastic/genetics ; Anemia, Aplastic/therapy ; Congenital Bone Marrow Failure Syndromes ; Female ; Genetic Testing ; Hematopoietic Stem Cell Transplantation/adverse effects ; Humans ; Transplantation Conditioning/methods
Language	English
Publishing date	2024-02-05
Publishing country	United States
Document type	Journal Article
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood.2022016508
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Article ; Online: JAK2 V617F mutation and associated chromosomal alterations in primary and secondary myelofibrosis and post-HCT outcomes.

Rafati, Maryam / Brown, Derek W / Zhou, Weiyin / Jones, Kristine / Luo, Wen / St Martin, Andrew / Wang, Youjin / He, Meilun / Spellman, Stephen R / Wang, Tao / Deeg, H Joachim / Gupta, Vikas / Lee, Stephanie J / Bolon, Yung-Tsi / Chanock, Stephen J / Machiela, Mitchell J / Saber, Wael / Gadalla, Shahinaz M

Blood advances

2023 Volume 7, Issue 24, Page(s) 7506–7515

Abstract: JAK2 V617F is the most common driver mutation in primary or secondary myelofibrosis for which allogeneic hematopoietic cell transplantation (HCT) is the only curative treatment. Knowledge of the prognostic utility of JAK2 alterations in the HCT setting ... ...

Abstract	JAK2 V617F is the most common driver mutation in primary or secondary myelofibrosis for which allogeneic hematopoietic cell transplantation (HCT) is the only curative treatment. Knowledge of the prognostic utility of JAK2 alterations in the HCT setting is limited. We identified all patients with MF who received HCT between 2000 and 2016 and had a pre-HCT blood sample (N = 973) available at the Center of International Blood and Marrow Transplant Research biorepository. PacBio sequencing and single nucleotide polymorphism-array genotyping were used to identify JAK2V617F mutation and associated mosaic chromosomal alterations (mCAs), respectively. Cox proportional hazard models were used for HCT outcome analyses. Genomic testing was complete for 924 patients with MF (634 primary MF [PMF], 135 postpolycythemia vera [PPV-MF], and 155 postessential thrombocytopenia [PET-MF]). JAK2V617F affected 562 patients (57.6% of PMF, 97% of PPV-MF, and 42.6% of PET-MF). Almost all patients with mCAs involving the JAK2 region (97.9%) were JAK2V617-positive. In PMF, JAK2V617F mutation status, allele burden, or identified mCAs were not associated with disease progression/relapse, nonrelapse mortality (NRM), or overall survival. Almost all PPV-MF were JAK2V617F-positive (97%), with no association between HCT outcomes and mutation allele burden or mCAs. In PET-MF, JAK2V617F high mutation allele burden (≥60%) was associated with excess risk of NRM, restricted to transplants received in the era of JAK inhibitors (2013-2016; hazard ratio = 7.65; 95% confidence interval = 2.10-27.82; P = .002). However, allele burden was not associated with post-HCT disease progression/relapse or survival. Our findings support the concept that HCT can mitigate the known negative effect of JAK2V617F in patients with MF, particularly for PMF and PPV-MF.
MeSH term(s)	Humans ; Primary Myelofibrosis/diagnosis ; Primary Myelofibrosis/genetics ; Primary Myelofibrosis/therapy ; Prognosis ; Mutation ; Disease Progression ; Chromosome Aberrations ; Recurrence ; Janus Kinase 2/genetics
Chemical Substances	JAK2 protein, human (EC 2.7.10.2) ; Janus Kinase 2 (EC 2.7.10.2)
Language	English
Publishing date	2023-11-27
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2915908-8
ISSN	2473-9537 ; 2473-9529
ISSN (online)	2473-9537
ISSN	2473-9529
DOI	10.1182/bloodadvances.2023010882
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Article ; Online: A core group of structurally similar HLA-DPB1 alleles drives permissiveness after hematopoietic cell transplantation.

Arrieta-Bolaños, Esteban / Crivello, Pietro / He, Meilun / Wang, Tao / Gadalla, Shahinaz M / Paczesny, Sophie / Marsh, Steven G E / Lee, Stephanie J / Spellman, Stephen R / Bolon, Yung-Tsi / Fleischhauer, Katharina

Blood

2022 Volume 140, Issue 6, Page(s) 659–663

MeSH term(s)	Alleles ; HLA-DP Antigens ; HLA-DP beta-Chains/genetics ; Hematopoietic Stem Cell Transplantation ; Histocompatibility Testing ; Permissiveness
Chemical Substances	HLA-DP Antigens ; HLA-DP beta-Chains ; HLA-DPB1 antigen
Language	English
Publishing date	2022-06-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood.2022015708
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Article ; Online: HLA Class I Genotype Is Associated with Relapse Risk after Allogeneic Stem Cell Transplantation for NPM1-Mutated Acute Myeloid Leukemia.

Narayan, Rupa / Niroula, Abhishek / Wang, Tao / Kuxhausen, Michelle / He, Meilun / Meyer, Everett / Chen, Yi-Bin / Bhatt, Vijaya Raj / Beitinjaneh, Amer / Nishihori, Taiga / Sharma, Akshay / Brown, Valerie I / Kamoun, Malek / Diaz, Miguel A / Abid, Muhammad Bilal / Askar, Medhat / Kanakry, Christopher G / Gragert, Loren / Bolon, Yung-Tsi /

Marsh, Steven G E / Gadalla, Shahinaz M / Paczesny, Sophie / Spellman, Stephen / Lee, Stephanie J

Transplantation and cellular therapy

2023 Volume 29, Issue 7, Page(s) 452.e1–452.e11

Abstract: Mutation-bearing peptide ligands from mutated nucleophosmin-1 (NPM1) protein have been empirically found to be presented by HLA class I in acute myeloid leukemia (AML). We hypothesized that HLA genotype may impact allogeneic hematopoietic stem cell ... ...

Abstract	Mutation-bearing peptide ligands from mutated nucleophosmin-1 (NPM1) protein have been empirically found to be presented by HLA class I in acute myeloid leukemia (AML). We hypothesized that HLA genotype may impact allogeneic hematopoietic stem cell transplantation (allo-HCT) outcomes in NPM1-mutated AML owing to differences in antigen presentation. We evaluated the effect of the variable of predicted strong binding to mutated NPM1 peptides using HLA class I genotypes from matched donor-recipient pairs on transplant recipients' overall survival (OS) and disease-free survival (DFS) as part of the primary objectives and cumulative incidence of relapse and nonrelapse mortality (NRM) as part of secondary objectives. Baseline and outcome data reported to the Center for International Blood and Marrow Transplant Research from a study cohort of adult patients (n = 1020) with NPM1-mutated de novo AML in first (71%) or second (29%) complete remission undergoing 8/8 matched related (18%) or matched unrelated (82%) allo-HCT were analyzed retrospectively. Class I alleles from donor-recipient pairs were analyzed for predicted strong HLA binding to mutated NPM1 using netMHCpan 4.0. A total of 429 (42%) donor-recipient pairs were classified as having predicted strong-binding HLA alleles (SBHAs) to mutated NPM1. In multivariable analyses adjusting for clinical covariates, the presence of predicted SBHAs was associated with a lower risk of relapse (hazard ratio [HR], .72; 95% confidence interval [CI], .55 to .94; P = .015). OS (HR, .81; 95% CI, .67 to .98; P = .028) and DFS (HR, .84; 95% CI, .69 to 1.01; P = .070) showed a suggestion of better outcomes if predicted SBHAs were present but did not meet the prespecified P value of <.025. NRM did not differ (HR, 1.04; P = .740). These hypothesis-generating data support further exploration of HLA genotype-neoantigen interactions in the allo-HCT context.
MeSH term(s)	Adult ; Humans ; Retrospective Studies ; Hematopoietic Stem Cell Transplantation ; Leukemia, Myeloid, Acute/genetics ; Leukemia, Myeloid, Acute/therapy ; Chronic Disease ; Genotype ; Nuclear Proteins/genetics ; Recurrence
Chemical Substances	Nuclear Proteins
Language	English
Publishing date	2023-03-29
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, U.S. Gov't, P.H.S. ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3062231-1
ISSN	2666-6367
ISSN (online)	2666-6367
DOI	10.1016/j.jtct.2023.03.027
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Article ; Online: Donor

Schetelig, Johannes / Baldauf, Henning / Heidenreich, Falk / Hoogenboom, Jorinde D / Spellman, Stephen R / Kulagin, Alexander / Schroeder, Thomas / Sengeloev, Henrik / Dreger, Peter / Forcade, Edouard / Vydra, Jan / Wagner-Drouet, Eva Maria / Choi, Goda / Paneesha, Shankara / Miranda, Nuno A A / Tanase, Alina / de Wreede, Liesbeth C / Lange, Vinzenz / Schmidt, Alexander H /

Sauter, Jürgen / Fein, Joshua A / Bolon, Yung-Tsi / He, Meilun / Marsh, Steven G E / Gadalla, Shahinaz M / Paczesny, Sophie / Ruggeri, Annalisa / Chabannon, Christian / Fleischhauer, Katharina

Frontiers in immunology

2024 Volume 15, Page(s) 1350470

Abstract: Optimizing natural killer (NK) cell alloreactivity could further improve outcome after allogeneic hematopoietic cell transplantation (alloHCT). The donor's Killer-cell Immunoglobulin-like Receptor (KIR) genotype may provide important information in this ... ...

Abstract	Optimizing natural killer (NK) cell alloreactivity could further improve outcome after allogeneic hematopoietic cell transplantation (alloHCT). The donor's Killer-cell Immunoglobulin-like Receptor (KIR) genotype may provide important information in this regard. In the past decade, different models have been proposed aiming at maximizing NK cell activation by activating KIR-ligand interactions or minimizing inhibitory KIR-ligand interactions. Alternative classifications intended predicting outcome after alloHCT by donor KIR-haplotypes. In the present study, we aimed at validating proposed models and exploring more classification approaches. To this end, we analyzed samples stored at the Collaborative Biobank from HLA-compatible unrelated stem cell donors who had donated for patients with acute myeloid leukemia (AML) or myelodysplastic neoplasm (MDS) and whose outcome data had been reported to EBMT or CIBMTR. The donor
MeSH term(s)	Humans ; Middle Aged ; Genotype ; Hematopoietic Stem Cell Transplantation/standards ; Leukemia, Myeloid, Acute/therapy ; Ligands ; Prognosis ; Receptors, KIR/genetics ; Myelodysplastic Syndromes/therapy ; Histocompatibility
Chemical Substances	Ligands ; Receptors, KIR
Language	English
Publishing date	2024-04-02
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2024.1350470
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Article ; Online: Diaphanous 1 (DIAPH1) is Highly Expressed in the Aged Human Medial Temporal Cortex and Upregulated in Myeloid Cells During Alzheimer's Disease.

Derk, Julia / Bermudez Hernandez, Keria / Rodriguez, Moises / He, Meilun / Koh, Hyunwook / Abedini, Andisheh / Li, Huilin / Fenyö, David / Schmidt, Ann Marie

Journal of Alzheimer's disease : JAD

2018 Volume 64, Issue 3, Page(s) 995–1007

Abstract: Background: The receptor for advanced glycation end products (RAGE) is linked to cellular stress and inflammation during Alzheimer's disease (AD). RAGE signals through Diaphanous-1 (DIAPH1); however, the expression of DIAPH1 in the healthy and AD human ... ...

Abstract	Background: The receptor for advanced glycation end products (RAGE) is linked to cellular stress and inflammation during Alzheimer's disease (AD). RAGE signals through Diaphanous-1 (DIAPH1); however, the expression of DIAPH1 in the healthy and AD human brain has yet to be methodically addressed. Objective: To delineate the cell- and disease-state specific expression of DIAPH1 in the human medial temporal cortex during healthy aging and AD. Methods: We used semi-quantitative immunohistochemistry in the human medial temporal cortex paired with widefield and confocal microscopy and automated analyses to determine colocalization and relative expression of DIAPH1 with key cell markers and molecules in the brains of subjects with AD versus age-matched controls. Results: We report robust colocalization of DIAPH1 with myeloid cells and increased expression during AD, which strongly correlated to increased neutral lipids and morphology of inflamed myeloid cells. DIAPH1 moderately colocalized with markers of endothelial cells, astrocytes, neurons, and oligodendrocytes. Discussion: Our findings localize DIAPH1 particularly to myeloid cells in the CNS, especially in AD in the locations of lipid droplet accumulation, thereby implicating RAGE-DIAPH1 signaling in dysregulated lipid metabolism and morphological changes of inflamed myeloid cells in this disorder.
MeSH term(s)	Adaptor Proteins, Signal Transducing/genetics ; Adaptor Proteins, Signal Transducing/metabolism ; Aged ; Aged, 80 and over ; Aging/pathology ; Alzheimer Disease/genetics ; Alzheimer Disease/pathology ; Animals ; Apolipoproteins E/genetics ; Case-Control Studies ; Claudin-1/metabolism ; Female ; Formins ; Glial Fibrillary Acidic Protein/metabolism ; Humans ; Imaging, Three-Dimensional ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Microscopy, Confocal ; Microtubule-Associated Proteins/metabolism ; Myeloid Cells/metabolism ; Receptor for Advanced Glycation End Products/metabolism ; Temporal Lobe/metabolism ; Up-Regulation/physiology
Chemical Substances	Adaptor Proteins, Signal Transducing ; Apolipoproteins E ; Claudin-1 ; DIAPH1 protein, human ; Formins ; Glial Fibrillary Acidic Protein ; MAP2 protein, human ; Microtubule-Associated Proteins ; Receptor for Advanced Glycation End Products
Language	English
Publishing date	2018-06-30
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1440127-7
ISSN	1875-8908 ; 1387-2877
ISSN (online)	1875-8908
ISSN	1387-2877
DOI	10.3233/JAD-180088
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Article ; Online: Number of HLA-Mismatched Eplets Is Not Associated with Major Outcomes in Haploidentical Transplantation with Post-Transplantation Cyclophosphamide: A Center for International Blood and Marrow Transplant Research Study.

Zou, Jun / Wang, Tao / He, Meilun / Bolon, Yung-Tsi / Gadalla, Shahinaz M / Marsh, Steven G E / Kuxhausen, Michelle / Gale, Robert Peter / Sharma, Akshay / Assal, Amer / Prestidge, Tim / Aljurf, Mahmoud / Cerny, Jan / Paczesny, Sophie / Spellman, Stephen R / Lee, Stephanie J / Ciurea, Stefan O

Transplantation and cellular therapy

2021 Volume 28, Issue 2, Page(s) 107.e1–107.e8

Abstract: The number of haploidentical hematopoietic stem cell transplantations (haplo-HSCT) performed has increased substantially in recent years. Previous single-center studies using in silico algorithms to quantitively measure HLA disparity have shown an ... ...

Abstract	The number of haploidentical hematopoietic stem cell transplantations (haplo-HSCT) performed has increased substantially in recent years. Previous single-center studies using in silico algorithms to quantitively measure HLA disparity have shown an association of the number of HLA molecular mismatches with relapse protection and/or increased risk of acute graft-versus-host disease (GVHD) in haplo-HSCT. However, inconsistent results from small studies have made it difficult to understand the full clinical impact of molecular mismatch in haplo-HSCT. In this study, we investigated the potential of the HLA class I and II mismatched eplet (ME) score measured by HLAMatchmaker, as well as ME load at a specific locus to predict outcomes in a registry-based cohort of haplo-HSCT recipients. We analyzed data from 1287 patients who underwent their first haplo-HSCT for acute lymphoblastic leukemia, acute myelogenous leukemia, or myelodysplastic syndrome between 2013 and 2017, as entered in the Center for International Blood and Marrow Transplant Research database. ME load at each HLA locus and total class I and II were scored using the HLAMatchmaker module incorporated in HLA Fusion software v4.3, which identifies predicted eplets based on the crystalized HLA molecule models and identifies ME by comparing donor and recipient eplets. In the study cohort, ME scores derived from total HLA class I or class II loci or individual HLA loci were not associated with overall survival, disease-free survival, nonrelapse mortality, relapse, acute GVHD, or chronic GVHD (P < .01). An unexpected strong association was identified between total class II ME load in the GVH direction and slower neutrophil engraftment (hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.75 to 0.91; P < .0001) and platelet engraftment (HR, 0.80; 95% CI, 0.72 to 0.88; P < .0001). This was likely attributable to ME load at the HLA-DRB1 locus, which was similarly associated with slower neutrophil engraftment (HR, 0.82; 95% CI, 0.73 to 0.92; P = .001) and slower platelet engraftment (HR, 0.76; 95% CI, 0.70 to 0.84; P < .0001). Additional analyses suggested that this effect is attributable to a match versus a mismatch in the graft-versus-host direction and not to ME load, as a dose effect was not identified. These findings contradict those of previous relatively small studies reporting an association between ME load, as quantified by HLAMatchmaker, and haplo-HSCT outcomes. This study failed to demonstrate the predictive value of ME from HLA molecules for major clinical outcomes, and other molecular mismatch algorithms in haplo-HSCT settings should be tested.
MeSH term(s)	Cyclophosphamide/therapeutic use ; Graft vs Host Disease/prevention & control ; Hematopoietic Stem Cell Transplantation/adverse effects ; Humans ; Recurrence ; Transplantation, Haploidentical/adverse effects
Chemical Substances	Cyclophosphamide (8N3DW7272P)
Language	English
Publishing date	2021-11-11
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	3062231-1
ISSN	2666-6367
ISSN (online)	2666-6367
DOI	10.1016/j.jtct.2021.11.001
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