Chemotherapy drug scheduling for the induction treatment of patients with acute myeloid leukemia

Abstract

Leukemia is an immediately life-threatening cancer wherein immature blood cells are overproduced, accumulate in the bone marrow (BM) and blood and causes immune and blood system failure. Treatment with chemotherapy can be intensive or nonintensive and can also be life-threatening since only relatively few patient-specific and leukemia-specific factors are considered in current protocols. We have already presented a mathematical model for one intensive chemotherapy cycle with intravenous (IV) daunorubicin (DNR), and cytarabine (Ara-C) [1]. This model is now extended to nonintensive subcutaneous (SC) Ara-C and for a standard intensive chemotherapy course (four cycles), consistent with clinical practice. Model parameters mainly consist of physio- logical patient data, indicators of tumor burden and characteristics of cell cycle kinetics. A sensitivity analysis problem is solved and cell cycle parameters are identified to control treatment outcome. Simulation results using published cell cycle data from two acute myeloid leukemia patients [2] are presented for a course of stan- dard treatment using intensive and nonintensive protocols. The aim of remission–induction therapy is to debulk the tumor and achieve normal BM function; by treatment completion, the total leukemic population should be reduced to at most 109 cells, at which point BM hypoplasia is achieved. The normal cell number should be higher than that of the leukemic, and a 3-log reduction is the maximum permissible level of population reduction. This optimization problem is formulated and solved for the two patient case studies. The results clearly present the benefits from the use of optimization as an advisory tool for treatment design.