In contrast with monotherapy, sequential use of dasatinib and nilotinib may prolong survival of patients with chronic myeloid leukemia (CML), according to a modeling study published in PLoS Computational Biology.1
CML is highly treatable with tyrosine kinase inhibitors that target the aberrant BCR-ABL fusion protein. The development of resistance to these agents is, however, common, which may be due to the presence of mutations in BCR-ABL. A proportion of patients harbor a subset of resistance-promoting mutations prior to the initiation of therapy, which has been associated with eventual treatment failure. It has been observed, furthermore, that mutations in BCR-ABL result in unique dynamics during treatment. The purpose of this modeling study was to determine an optimal treatment schedule based on CML mutant strains.
“There has been a significant amount of work done in the past to mathematically model CML. We focus on understanding the optimal administration schedule of multiple therapies to prevent resistance,” write the authors.
The mathematical model used a differentiation hierarchy of hematopoietic cells to produce CML with different BCR-ABL variants. The treatment portion utilizes an optimal treatment plan problem and includes equations to account for the objective of treatment, cell dynamics based on treatment, and the time period of treatment. The model does not, however, account for acquired resistance during therapy. For toxicity, the dynamics of absolute neutrophil count (ANC) was modeled for each treatment regimen, including drug holiday, as well as the need for a drug holiday if the ANC fell below an acceptable threshold (1,000/mm3). The initial ANC was defined as 3,000/mm3.
The model suggests that monotherapy with imatinib (400 mg once daily), dasatinib (100 mg once daily), or nilotinib (300 mg twice daily) over 120 months resulted in good disease control for CML with the wild-type BCR-ABL variant. Dasatinib provided only modest improvement over no treatment for CML with the BCR-ABL F317L mutation. All 3 agents were effective against the BCR-ABL M351T mutation, although nilotinib had greater efficacy than dasatinib. Nilotinib, however, had a negative effect on the healthy cell population.
According to the authors: “This suggests that some trade-offs between these drugs exist, and these trade-offs may be exploited in designing combination therapies.”
Sequential combination therapy was evaluated, and the model suggested that the optimal regimen was dasatinib followed by nilotinib. Interestingly, over about 30 months, dasatinib and nilotinib monotherapy perform similarly to the sequential combination in reducing leukemic cell burden. By 36 months, however, the combination resulted in a greater than 50% reduction in leukemic cell abundance compared with the monotherapies.