Grant Details
Grant Number: |
5R01CA231141-03 Interpret this number |
Primary Investigator: |
Afshar-Kharghan, Vahid |
Organization: |
University Of Tx Md Anderson Can Ctr |
Project Title: |
Genetics of Graft-Versus-Host Disease |
Fiscal Year: |
2020 |
Abstract
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative therapy for many advanced
hematologic malignancies. Allo-HSCT is associated with significant morbidities and mortality, mainly because of
the graft-versus-host disease (GVHD) caused by donor T cells recognizing antigens present in recipient tissues,
and initiating an alloimmune response resulting in damage to many organs including the skin, GI tract, and liver
in recipient. More than half of all allo-HSCT recipients develop different degrees of GVHD (grade I-IV). About
20% of recipients develop severe GVHD (grade III-IV) that is associated with a very high morbidity and mortality.
The most important factor determining the severity of GVHD is the genetic disparities between donors and
recipients, as is reflected in HLA haplotypes that are routinely checked for donor selection. But even when donors
and recipients are HLA-identical many recipients develop severe GVHD. As a result, non-HLA antigens are
important determinants of acute GVHD. An interesting and unique aspect of GVHD is that it is the consequence
of an interaction between antigens present in one individual with the immune system of another individual. As a
result, genotypes of both donor and recipient, and their interactions affect the pathogenesis of GVHD. To
determine the genetic risk factors for GVHD, in the first aim (discovery phase), we will conduct Genome-Wide
Association Studies (GWAS) in 3,000 patients who underwent allo-HSCT and in their respective donors (6000
DNA samples) that are provided to us by the National Marrow Donor Program (NMDP) and the Center for
International Blood and Marrow Transplant Research (CIBMTR). This part of our grant is approved by the Center
for Inherited Disease Research (CIDR) and will be conducted in their sequencing facility. We expect that 3000
recipients will be stratified into 1200 subjects with moderate to severe acute GVHD (grades II-IV) versus 1800
individuals with none to mild GVHD (grade 0-I). We will also include the existing GWAS and clinical outcome
data on 7047 donor/recipient pairs available from two previous studies to augment our cohort with an estimated
2830 pairs with grade II-IV and 4244 pairs with grade 0-I GVHD, and investigate an association between the
severity of acute GVHD and genotypes in donors or recipients, or mismatch of certain genotypes (other than
HLA). In the second aim, we will validate the association between high risk genotypes detected in the aim 1 and
severe GVHD in 1,750 donors and 1,750 recipients of allo-HSCT, and perform the joint analysis with the
discovery samples (an estimated 4730 pairs with grade II-IV vs 7094 pairs with Grade 0-I GVHD). We will
determine the frequency of 5000 single nucleotide polymorphisms (SNP), that GWAS in the aim 1 showed to be
associated with severe GVHD and correlate it to the severity of GVHD. In the third aim, we will investigate the
functional effect of SNPs detected and validated to be significantly correlated with the severity of acute GVHD
in mixed lymphocyte reaction (MLR), as an Ex vivo surrogate for an alloimmune response.
Publications
Clinical characteristics and outcomes of COVID-19 in haematopoietic stem-cell transplantation recipients: an observational cohort study.
Authors: Sharma A.
, Bhatt N.S.
, St Martin A.
, Abid M.B.
, Bloomquist J.
, Chemaly R.F.
, Dandoy C.
, Gauthier J.
, Gowda L.
, Perales M.A.
, et al.
.
Source: The Lancet. Haematology, 2021-01-19; , .
EPub date: 2021-01-19.
PMID: 33482113
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Hematopoietic cell transplantation utilization and outcomes for primary plasma cell leukemia in the current era.
Authors: Dhakal B.
, Patel S.
, Girnius S.
, Bachegowda L.
, Fraser R.
, Davila O.
, Kanate A.S.
, Assal A.
, Hanbali A.
, Bashey A.
, et al.
.
Source: Leukemia, 2020 12; 34(12), p. 3338-3347.
EPub date: 2020-04-20.
PMID: 32313109
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Pediatric HCT in Florida (2014 -2016): A report from the FPBCC.
Authors: Chellapandian D.
, Sunkersett G.
, Oshrine B.
, Galvez Silva J.
, Ziga E.
, Alperstein W.
, Joyce M.
, Katzenstein H.
, Godder K.
, Castillo P.
, et al.
.
Source: Pediatric transplantation, 2020-11-27; , p. e13931.
EPub date: 2020-11-27.
PMID: 33245834
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Genetic factors rather than blast reduction determine outcomes of allogeneic HCT in BCR-ABL-negative MPN in blast phase.
Authors: Gupta V.
, Kennedy J.A.
, Capo-Chichi J.M.
, Kim S.
, Hu Z.H.
, Alyea E.P.
, Popat U.R.
, Sobecks R.M.
, Scott B.L.
, Gerds A.T.
, et al.
.
Source: Blood advances, 2020-11-10; 4(21), p. 5562-5573.
PMID: 33170935
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Real-world evidence of tisagenlecleucel for pediatric acute lymphoblastic leukemia and non-Hodgkin lymphoma.
Authors: Pasquini M.C.
, Hu Z.H.
, Curran K.
, Laetsch T.
, Locke F.
, Rouce R.
, Pulsipher M.A.
, Phillips C.L.
, Keating A.
, Frigault M.J.
, et al.
.
Source: Blood advances, 2020-11-10; 4(21), p. 5414-5424.
PMID: 33147337
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A Personalized Prediction Model for Outcomes after Allogeneic Hematopoietic Cell Transplant in Patients with Myelodysplastic Syndromes.
Authors: Nazha A.
, Hu Z.H.
, Wang T.
, Lindsley R.C.
, Abdel-Azim H.
, Aljurf M.
, Bacher U.
, Bashey A.
, Cahn J.Y.
, Cerny J.
, et al.
.
Source: Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 2020 Nov; 26(11), p. 2139-2146.
EPub date: 2020-08-08.
PMID: 32781289
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Comparison of outcomes of HCT in blast phase of BCR-ABL1- MPN with de novo AML and with AML following MDS.
Authors: Gupta V.
, Kim S.
, Hu Z.H.
, Liu Y.
, Aljurf M.
, Bacher U.
, Beitinjaneh A.
, Cahn J.Y.
, Cerny J.
, Copelan E.
, et al.
.
Source: Blood advances, 2020-10-13; 4(19), p. 4748-4757.
PMID: 33007075
Related Citations
Myeloablative Conditioning for Allogeneic Transplantation Results in Superior Disease-Free Survival for Acute Myelogenous Leukemia and Myelodysplastic Syndromes with Low/Intermediate but not High Disease Risk Index: A Center for International Blood and Marrow Transplant Research Study.
Authors: Bejanyan N.
, Zhang M.
, Bo-Subait K.
, Brunstein C.
, Wang H.
, Warlick E.D.
, Giralt S.
, Nishihori T.
, Martino R.
, Passweg J.
, et al.
.
Source: Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 2020-10-01; , .
EPub date: 2020-10-01.
PMID: 33010430
Related Citations
The interaction between the complement system and hemostatic factors.
Authors: Oncul S.
, Afshar-Kharghan V.
.
Source: Current opinion in hematology, 2020 09; 27(5), p. 341-352.
PMID: 32701617
Related Citations
The Impact of Donor Type on Outcomes and Cost of Allogeneic Hematopoietic Cell Transplantation for Pediatric Leukemia: A Merged Center for International Blood and Marrow Transplant Research and Pediatric Health Information System Analysis.
Authors: Arnold S.D.
, Brazauskas R.
, He N.
, Li Y.
, Hall M.
, Atsuta Y.
, Dalal J.
, Hahn T.
, Khera N.
, Bonfim C.
, et al.
.
Source: Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 2020 09; 26(9), p. 1747-1756.
EPub date: 2020-05-25.
PMID: 32464284
Related Citations
Current Use of and Trends in Hematopoietic Cell Transplantation in the United States.
Authors: D'Souza A.
, Fretham C.
, Lee S.J.
, Arora M.
, Brunner J.
, Chhabra S.
, Devine S.
, Eapen M.
, Hamadani M.
, Hari P.
, et al.
.
Source: Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 2020 08; 26(8), p. e177-e182.
EPub date: 2020-05-11.
PMID: 32438042
Related Citations
Risk Factors for Graft-versus-Host Disease in Haploidentical Hematopoietic Cell Transplantation Using Post-Transplant Cyclophosphamide.
Authors: Im A.
, Rashidi A.
, Wang T.
, Hemmer M.
, MacMillan M.L.
, Pidala J.
, Jagasia M.
, Pavletic S.
, Majhail N.S.
, Weisdorf D.
, et al.
.
Source: Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 2020 08; 26(8), p. 1459-1468.
EPub date: 2020-05-17.
PMID: 32434056
Related Citations
Geriatric assessment in older alloHCT recipients: association of functional and cognitive impairment with outcomes.
Authors: Olin R.L.
, Fretham C.
, Pasquini M.C.
, Arora M.
, Bhatt V.R.
, Derman B.
, Giralt S.A.
, Huang L.W.
, Koll T.
, Lee S.M.
, et al.
.
Source: Blood advances, 2020-06-23; 4(12), p. 2810-2820.
PMID: 32574365
Related Citations
Higher Total Body Irradiation Dose Intensity in Fludarabine/TBI-Based Reduced-Intensity Conditioning Regimen Is Associated with Inferior Survival in Non-Hodgkin Lymphoma Patients Undergoing Allogeneic Transplantation.
Authors: Hamadani M.
, Khanal M.
, Ahn K.W.
, Litovich C.
, Chow V.A.
, Eghtedar A.
, Karmali R.
, Winter A.
, Fenske T.S.
, Sauter C.
, et al.
.
Source: Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 2020 06; 26(6), p. 1099-1105.
EPub date: 2020-03-09.
PMID: 32165327
Related Citations
Prevalence of decisional regret among patients who underwent allogeneic hematopoietic stem cell transplantation and associations with quality of life and clinical outcomes.
Authors: Cusatis R.N.
, Tecca H.R.
, D'Souza A.
, Shaw B.E.
, Flynn K.E.
.
Source: Cancer, 2020-06-01; 126(11), p. 2679-2686.
EPub date: 2020-03-10.
PMID: 32154926
Related Citations
Incidence, Risk Factors for and Outcomes of Transplant-Associated Thrombotic Microangiopathy.
Authors: Epperla N.
, Li A.
, Logan B.
, Fretham C.
, Chhabra S.
, Aljurf M.
, Chee L.
, Copelan E.
, Freytes C.O.
, Hematti P.
, et al.
.
Source: British journal of haematology, 2020 06; 189(6), p. 1171-1181.
EPub date: 2020-03-02.
PMID: 32124435
Related Citations
Outcomes of rituximab-BEAM versus BEAM conditioning regimen in patients with diffuse large B cell lymphoma undergoing autologous transplantation.
Authors: Jagadeesh D.
, Majhail N.S.
, He Y.
, Ahn K.W.
, Litovich C.
, Ahmed S.
, Aljurf M.
, Bacher U.
, Badawy S.M.
, Bejanyan N.
, et al.
.
Source: Cancer, 2020-05-15; 126(10), p. 2279-2287.
EPub date: 2020-02-12.
PMID: 32049359
Related Citations
Subsequent neoplasms and late mortality in children undergoing allogeneic transplantation for nonmalignant diseases.
Authors: Kahn J.M.
, Brazauskas R.
, Tecca H.R.
, Bo-Subait S.
, Buchbinder D.
, Battiwala M.
, Flowers M.E.D.
, Savani B.N.
, Phelan R.
, Broglie L.
, et al.
.
Source: Blood advances, 2020-05-12; 4(9), p. 2084-2094.
PMID: 32396620
Related Citations
Prior Gemtuzumab Ozogamicin Exposure in Adults with Acute Myeloid Leukemia Does Not Increase Hepatic Veno-Occlusive Disease Risk after Allogeneic Hematopoietic Cell Transplantation: A Center for International Blood and Marrow Transplant Research Analysis.
Authors: Ho V.T.
, Martin A.S.
, Pérez W.S.
, Steinert P.
, Zhang M.J.
, Chirnomas D.
, Hoang C.J.
, Loberiza F.R.
, Saber W.
.
Source: Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 2020 05; 26(5), p. 884-892.
EPub date: 2019-12-28.
PMID: 31891815
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African Americans with translocation t(11;14) have superior survival after autologous hematopoietic cell transplantation for multiple myeloma in comparison with Whites in the United States.
Authors: Badar T.
, Hari P.
, Dávila O.
, Fraser R.
, Wirk B.
, Dhakal B.
, Freytes C.O.
, Rodriguez Valdes C.
, Lee C.
, Vesole D.H.
, et al.
.
Source: Cancer, 2020-01-01; 127(1), p. 82-92.
EPub date: 2020-09-23.
PMID: 32966625
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Upfront Therapies and Downstream Effects: Navigating Late Effects in Childhood Cancer Survivors in the Current Era.
Authors: Phelan R.
, Eissa H.
, Becktell K.
, Bhatt N.
, Kudek M.
, Nuechterlein B.
, Pommert L.
, Tanaka R.
, Baker K.S.
.
Source: Current oncology reports, 2019-11-25; 21(12), p. 104.
EPub date: 2019-11-25.
PMID: 31768799
Related Citations
Kidney Injury in Murine Models of Hematopoietic Stem Cell Transplantation.
Authors: Ma Q.
, Li D.
, Vasquez H.G.
, You M.J.
, Afshar-Kharghan V.
.
Source: Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 2019 10; 25(10), p. 1920-1924.
EPub date: 2019-07-02.
PMID: 31271886
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