A mathematical model for reconstitution of granulopoiesis after high dose chemotherapy with autologous stem cell transplantation.
High dose chemotherapy supported with hematopoietic progenitor cells gives a characteristic neutropenic period (blood neutrophils < 0.5 x 10(9) c/l) ranging from 10 to 16 days. The question of a correlation between the CFU-GM content of the transplanted CD34+ cells and time to neutrophil recovery by patients having been given high-dose chemotherapy (HD-CT) with stem cell support was addressed by means of a mathematical model of granulopoiesis. The model utilizes a convection-reaction partial differential equation (PDE) with feedback from a cytokine compartment on proliferation, maturation, and mobilization of granulocytes from bone marrow to blood. The observed number of CFU-GM cells in the transplanted CD34+ cell autograft was used as input to the model. Using this approach, the observed gross relationship between CFU-GM content in the reinfused blood product and engraftment time could be reproduced. At the same time, the effects of assumed physiological mechanisms, especially some of the effects of G-CSF on proliferation rate, maturation rate, mobilization, and cell death, could be investigated and discussed relative to observed engraftment. The model makes it possible to explain how cytokines interfere with progenitor cell mobilization from bone marrow to blood, and it points out the implications of a regulating mechanism for the granulocyte maturation rate.
Østby
Ivar
I
Department of Informatics, University of Oslo, 0316 Oslo, Norway. ivaro@ifi.uio.no
Rusten
Leiv S
LS
Kvalheim
Gunnar
G
Grøttum
Per
P
D000328:Adult; D000465:Algorithms; D018952:Antigens, CD34 / Q000276:immunology / Q000502:physiology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001853:Bone Marrow / Q000502:physiology; D002330:Carmustine / Q000627:therapeutic use*; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D003198:Computer Simulation; D003561:Cytarabine / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology / Q000502:physiology; D006098:Granulocytes / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000502:physiology; D006689:Hodgkin Disease / Q000188:drug therapy / Q000628:therapy*; D006801:Humans; D007700:Kinetics; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000502:physiology; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy / Q000628:therapy*; D008558:Melphalan / Q000627:therapeutic use*; D008875:Middle Aged; D008954:Models, Biological; D038042:Myelopoiesis / Q000502:physiology*; D036102:Peripheral Blood Stem Cell Transplantation; D011034:Podophyllotoxin / Q000627:therapeutic use*; D014182:Transplantation, Autologous
D018952:Antigens, CD34; D003561:Cytarabine; D016179:Granulocyte Colony-Stimulating Factor; D011034:Podophyllotoxin; D008558:Melphalan; D002330:Carmustine