Relapse in chronic myeloid leukemia after bone marrow transplantation: Biomathematical modeling as a new approach to understanding pathogenesis

A biomathematical model was developed to simulate relapse development in pa tients with chronic myeloid leukemia (CML) following bone marrow transplant ation (BMT), The purpose of this study was to better understand the pathoph ysiology of the time evolution of CML relapse and to provide means whereby the outcomes of patients with CML relapse can be projected and treatment mo dified accordingly. The model consists of three parallel series of catenate d compartments representing granulopoiesis in normal (donor) cells from the marrow, in CML cells from the marrow, and in CML cells from extramedullary sites. It was assumed that CML stem cells were resistant to feedback contr ol and that CML-derived neutrophils, as well as normal neutrophils, exercis ed feedback regulation of normal stem cells. The known longer generation ti mes for CML neutrophil precursors compared with normal neutrophil precursor s were used, and it was assumed that 10(7) pluripotential stem cells were i nfused with BMT, The model was evaluated for its ability to simulate the reappearance of CML (Philadelphia chromosome positive) metaphases in the marrow and the recove ry pattern in the blood neutrophil count in six patients who had relapsed f ollowing BMT (allogeneic in three patients, allogeneic with T-cell depletio n in two patients, and syngeneic in one patient). The variables tested incl uded the site of origin of the CML stem cells responsible for relapse (marr ow alone versus marrow and extramedullary sites), the minimum number of CML stem cells responsible for relapse, and the time delay between BMT and the onset of relapse. Model profiles based on the observed values were obtained in each case. The simulations pointed to the fact that relapse began from a small number of CML cells in medullary and extramedullary sites. The time delay between BMT and the onset of relapse varied from 15 to 240 days, We suggest that this biomathematical model should be further investigated a s a possible means of predicting outcome and guiding the treatment for pati ents with CML relapsing after BMT.