Incomplete chimerism following myeloablative and anti-thymocyte globulin-conditioned hematopoietic cell transplantation is a risk factor for relapse and chronic graft-versus-host disease |
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| Affiliation: | 1. Department of Medicine, University of Calgary, Calgary, Canada, T2N 4N1;2. Department of Laboratory Medicine and Pathology, University of Calgary, Calgary, Canada, T2N 4N1;3. Alberta Precision Laboratories, Calgary, Canada, T2N 4N1;4. Alberta Health Services, Calgary, Canada, T2N 4N1;1. Department of Regenerative Medicine Research, Texas Heart Institute, Houston, Texas, USA;2. Department of Dermatology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA;3. Department of Chemistry, Rice University, Houston, Texas, USA;4. Chemistry–Biology Interface Predoctoral Training Program, Stanford University, Stanford, California, USA;5. Department of Molecular and Human Genetics, Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute, Texas Children''s Hospital, Houston, Texas, USA;6. Center for Cell and Gene Therapy, Baylor College of Medicine, Houston Methodist Hospital and Texas Children''s Hospital, Houston, Texas, USA;7. Department of Pathology and Laboratory Medicine, McGovern Medical School, University of Texas Health Science Center, Houston, Texas, USA;8. Center for Clinical Research, Texas Heart Institute, Houston, Texas, USA;1. First Clinical Medical College of Lanzhou University, Lanzhou, China;2. Chengren Institute of Traditional Chinese Medicine, Lanzhou, China;3. Department of Spine, Changzheng Hospital, Naval Medical University, Shanghai, China;4. Gansu University of Chinese Medicine, Lanzhou, China;5. The Second Hospital of Lanzhou University, Lanzhou, China;1. Laboratory of Pulmonary Investigation, Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil;2. Toxicology Laboratory, Oswaldo Cruz Institute, Rio de Janeiro, Brazil;3. Center for Technological Development in Health, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil;4. National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro, Brazil;5. Rio de Janeiro Innovation Network in Nanosystems for Health–NanoSaúde, Research Support Foundation of the State of Rio de Janeiro, Rio de Janeiro, Brazil;1. Immunobiology Laboratory, Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi, India;2. Cellular Immunology Laboratory, Department of Zoology, The University of Burdwan, PurbaBardhhaman, India;3. Chittaranjan National Cancer Institute, Kolkata, India;1. Regenerative Medicine Institute, National University of Ireland Galway, Galway, Ireland;2. Centre for Cell Manufacturing Ireland, National University of Ireland Galway, Galway, Ireland;3. HRB Clinical Research Facility, National University of Ireland Galway, Galway, Ireland;4. Galway Blood and Tissue Establishment, National University of Ireland Galway, Galway, Ireland;5. School of Medicine, National University of Ireland Galway, Galway, Ireland;6. Department of Vascular Surgery, University Hospital Galway, Galway, Ireland |
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| Abstract: | Background aimsThe value of routine chimerism determination after myeloablative hematopoietic cell transplantation (HCT) is unclear, particularly in the setting of anti-thymocyte globulin (ATG)-based graft-versus-host disease (GVHD) prophylaxis.MethodsBlood samples were collected at 3 months post-HCT from 558 patients who received myeloablative conditioning and ATG-based GVHD prophylaxis. Chimerism was assessed using multiplex polymerase chain reaction of short tandem repeats in sorted T cells (CD3+) and leukemia lineage cells (CD13+CD33+ for myeloid malignancies and CD19+ for B-lymphoid malignancies). ATG exposure was determined using a flow cytometry-based assay. The primary outcomes of interest were relapse and chronic GVHD (cGVHD).ResultsIncomplete (<95%) T-cell chimerism and leukemia lineage chimerism were present in 17% and 4% of patients, respectively. Patients with incomplete T-cell chimerism had a significantly greater incidence of relapse (36% versus 22%, subhazard ratio [SHR] = 2.03, P = 0.001) and lower incidence of cGVHD (8% versus 25%, SHR = 0.29, P < 0.001) compared with patients with complete chimerism. In multivariate modeling, patients with high post-transplant ATG area under the curve and any cytomegalovirus (CMV) serostatus other than donor/recipient seropositivity (non-D+R+) had an increased likelihood of incomplete T-cell chimerism. Patients with incomplete leukemia lineage chimerism had a significantly greater incidence of relapse (50% versus 23%, SHR = 2.70, P = 0.011) and, surprisingly, a greater incidence of cGVHD (45% versus 20%, SHR = 2.64, P = 0.003).ConclusionsHigh post-transplant ATG exposure and non-D+R+ CMV serostatus predispose patients to incomplete T-cell chimerism, which is associated with an increased risk of relapse. The increased risk of cGVHD with incomplete B-cell/myeloid chimerism is a novel finding that suggests an important role for recipient antigen-presenting cells in cGVHD pathogenesis. |
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