Strategic treatment interruptions during imatinib treatment of chronic myelogenous leukemia

Abstract

Although imatinib is an effective treatment for chronic myelogenous leukemia (CML), and nearly all patients treated with imatinib attain some form of remission, imatinib does not completely eliminate leukemia. Moreover, if the imatinib treatment is stopped, most patients eventually relapse (Cortes et al. in Clin. Cancer Res. 11:3425-3432, 2005). In Kim et al. (PLoS Comput. Biol. 4(6):e1000095, 2008), the authors presented a mathematical model for the dynamics of CML under imatinib treatment that incorporates the anti-leukemia immune response. We use the mathematical model in Kim et al. (PLoS Comput. Biol. 4(6):e1000095, 2008) to study and numerically simulate strategic treatment interruptions as a potential therapeutic strategy for CML patients. We present the results of numerous simulated treatment programs in which imatinib treatment is temporarily stopped to stimulate and leverage the anti-leukemia immune response to combat CML. The simulations presented in this paper imply that treatment programs that involve strategic treatment interruptions may prevent leukemia from relapsing and may prevent remission for significantly longer than continuous imatinib treatment. Moreover, in many cases, strategic treatment interruptions may completely eliminate leukemic cells from the body. Thus, strategic treatment interruptions may be a feasible clinical approach to enhancing the effects of imatinib treatment for CML. We study the effects of both the timing and the duration of the treatment interruption on the results of the treatment. We also present a sensitivity analysis of the results to the parameters in the mathematical model.

Fig. 1

Total leukemia concentration without imatinib treatment for 0 ≤ t ≤ 500 days

Fig. 2

The logarithm of the leukemia concentration and the T-cell concentration with continuous imatinib treatment

Fig. 3

Logarithm of the leukemia concentrations and the T-cell concentrations for 0 ≤ t ≤ 1200 days with continuous imatinib treatment (upper left), with a 15-day treatment interruption (STI) from t = 300 to t = 315 days (upper right), and with a 30-day treatment interruption from t = 180 to t = 210 (lower). The treatment interruption is indicated with vertical lines

Fig. 4

Summary of the results of several 15-day and 30-day strategic treatment interruptions. Upper left: The maximum leukemia concentration (k/μL) that occurs after the interruption vs. starting day of the treatment interruption. Upper right: Time (in days) until cytogenetic remission vs. starting day of the treatment interruption. Lower: Time (in days) until complete leukemia elimination vs. starting day of the treatment interruption