title: Dynamical System Modeling of Immune Reconstitution after Allogeneic Stem Cell Transplantation Identifies Patients at Risk for Adverse Outcomes.
abstract: Systems that evolve over time and follow mathematical laws as they evolve are called dynamical systems. Lymphocyte recovery and clinical outcomes in 41 allograft recipients conditioned using antithymocyte globulin (ATG) and 4.5-Gy total body irradiation were studied to determine if immune reconstitution could be described as a dynamical system. Survival, relapse, and graft-versus-host disease (GVHD) were not significantly different in 2 cohorts of patients receiving different doses of ATG. However, donor-derived CD3(+) cell reconstitution was superior in the lower ATG dose cohort, and there were fewer instances of donor lymphocyte infusion (DLI). Lymphoid recovery was plotted in each individual over time and demonstrated 1 of 3 sigmoid growth patterns: Pattern A (n = 15) had rapid growth with high lymphocyte counts, pattern B (n = 14) had slower growth with intermediate recovery, and pattern C (n = 10) had poor lymphocyte reconstitution. There was a significant association between lymphocyte recovery patterns and both the rate of change of donor-derived CD3(+) at day 30 after stem cell transplantation (SCT) and clinical outcomes. GVHD was observed more frequently with pattern A, relapse and DLI more so with pattern C, with a consequent survival advantage in patients with patterns A and B. We conclude that evaluating immune reconstitution after SCT as a dynamical system may differentiate patients at risk of adverse outcomes and allow early intervention to modulate that risk.
authors: Bone Marrow Transplant Program, Massey Cancer Center, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia. Electronic address: atoor@mcvh-vcu.edu.
authors: Amir A
authors: AA
authors: Toor
authors: Department of Biostatistics, Virginia Commonwealth University, Richmond, Virginia.
authors: Roy T
authors: RT
authors: Sabo
authors: Bone Marrow Transplant Program, Massey Cancer Center, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia.
authors: Catherine H
authors: CH
authors: Roberts
authors: Bone Marrow Transplant Program, Massey Cancer Center, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia.
authors: Bonny L
authors: BL
authors: Moore
authors: Bone Marrow Transplant Program, Massey Cancer Center, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia.
authors: Salman R
authors: SR
authors: Salman
authors: Bone Marrow Transplant Program, Massey Cancer Center, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia.
authors: Allison F
authors: AF
authors: Scalora
authors: Department of Pharmacy and Therapeutics, Virginia Commonwealth University, Richmond, Virginia.
authors: May T
authors: MT
authors: Aziz
authors: Bone Marrow Transplant Program, Massey Cancer Center, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia.
authors: Ali S
authors: AS
authors: Shubar Ali
authors: Bone Marrow Transplant Program, Massey Cancer Center, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia.
authors: Charles E
authors: CE
authors: Hall
authors: Bone Marrow Transplant Program, Massey Cancer Center, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia.
authors: Jeremy
authors: J
authors: Meier
authors: Bone Marrow Transplant Program, Massey Cancer Center, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia.
authors: Radhika M
authors: RM
authors: Thorn
authors: Bone Marrow Transplant Program, Massey Cancer Center, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia.
authors: Elaine
authors: E
authors: Wang
authors: Department of Radiation Oncology, Virginia Commonwealth University, Richmond, Virginia.
authors: Shiyu
authors: S
authors: Song
authors: Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia.
authors: Kristin
authors: K
authors: Miller
authors: Department of Pathology, Virginia Commonwealth University, Richmond, Virginia.
authors: Kathryn
authors: K
authors: Rizzo
authors: Bone Marrow Transplant Program, Massey Cancer Center, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia.
authors: William B
authors: WB
authors: Clark
authors: Bone Marrow Transplant Program, Massey Cancer Center, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia.
authors: John M
authors: JM
authors: McCarty
authors: Bone Marrow Transplant Program, Massey Cancer Center, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia.
authors: Harold M
authors: HM
authors: Chung
authors: Department of Microbiology & Immunology, Virginia Commonwealth University, Richmond, Virginia.
authors: Masoud H
authors: MH
authors: Manjili
authors: Departments of Psychiatry & Human Genetics, Virginia Commonwealth University, Richmond, Virginia.
authors: Michael C
authors: MC
authors: Neale
mesh_terms: D000328:Adult; D000368:Aged; D000961:Antilymphocyte Serum / Q000627:therapeutic use*; D005260:Female; D006086:Graft vs Host Disease / Q000209:etiology / Q000276:immunology / Q000401:mortality / Q000517:prevention & control*; D019337:Hematologic Neoplasms / Q000276:immunology / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D017710:Lymphocyte Transfusion / Q000706:statistics & numerical data; D008297:Male; D008875:Middle Aged; D018448:Models, Immunological; D017711:Nonlinear Dynamics; D011379:Prognosis; D011446:Prospective Studies; D012008:Recurrence; D012306:Risk; D035781:Siblings; D016019:Survival Analysis; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D061349:Unrelated Donors; D014916:Whole-Body Irradiation
chemical_list: D000961:Antilymphocyte Serum; D007166:Immunosuppressive Agents
keywords: Dynamical system; Graft-versus-host disease; Immune reconstitution; Stem cell transplant; T cells