Bulletin of Mathematical Biology

, Volume 73, Issue 5, pp 1082–1100 | Cite as

Strategic Treatment Interruptions During Imatinib Treatment of Chronic Myelogenous Leukemia

  • Dana Paquin
  • Peter S. Kim
  • Peter P. Lee
  • Doron Levy
Original Article


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.


Chronic myelogenous leukemia Imatinib Mathematical model Strategic treatment interruptions 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Adams, B. M., Banks, H. T., Kwon, H.-D., & Tran, H. T. (2004). Dynamic multidrug therapies for HIV: optimal and STI control approaches. Math. Biosci. Eng., 1(2), 223–241. MATHMathSciNetGoogle Scholar
  2. Angstreich, G., Smith, B., & Jones, R. (2004). Treatment options for chronic myelogenous leukemia: imatinib versus interferon versus allogeneic transplant. Curr. Opin. Oncol., 16, 95–99. CrossRefGoogle Scholar
  3. Bajaria, S. H., Webb, G., & Kirschner, D. E. (2004). Predicting differential responses to structured treatment interruptions during HAART. Bull. Math. Biol., 66, 1093–1118. CrossRefGoogle Scholar
  4. Chen, C., Maecker, H., & Lee, P. (2008). Development and dynamics of robust T-cell responses to CML. Blood, 111(11), 5342–5349. CrossRefGoogle Scholar
  5. Cortes, J., Talpaz, M., O’Brien, S., Jones, D., Luthra, R. et al. (2005). Molecular responses in patients with chronic myelogenous leukemia in chronic phase treated with imatinib mesylate. Clin. Cancer Res., 11, 3425–3432. CrossRefGoogle Scholar
  6. Dingli, D., & Michor, F. (2006). Successful therapy must eradicate cancer stem cells. Stem Cells, 24, 2603–2610. CrossRefGoogle Scholar
  7. Kim, P., Lee, P., & Levy, D. (2008). Dynamics and potential impact of the immune response to chronic myelogenous leukemia. PLoS Comput. Biol., 4(6), e1000095. CrossRefMathSciNetGoogle Scholar
  8. Komarova, N., & Wodarz, D. (2005). Drug resistance in cancer: Principles of emergence and prevention. Proc. Natl. Acad. Sci., 102, 9714–9719. CrossRefGoogle Scholar
  9. Koup, R. (2004). Reconsidering early HIV treatment and supervised treatment interruptions. PLoS Med., 1(2), e41. CrossRefGoogle Scholar
  10. Lee, S. (2000). Chronic myelogenous leukemia. Br. J. Hematol., 111, 993–1009. CrossRefGoogle Scholar
  11. Lowenberg, B. (2003). Minimal residual disease in chronic myeloid leukemia. N. Engl. J. Med., 349, 1399–1401. CrossRefGoogle Scholar
  12. Maserati, R., Foli, A., Tomasoni, L., Sighinolfi, L., Maggiolo, F., Sacchini, D., DiPietro, M., Bertelli, D., Tinelli, C., & Lori, F. (2007). Effects of structured treatment interruptions on metabolic anthropometric, immunologic, and quality of life outcomes in HIV-positive adults on HAART. Curr. HIV Res., 5(3), 337–343. CrossRefGoogle Scholar
  13. McKay, M. D., Conover, W. J., & Beckman, R. J. (1979). A comparison of three models for selecting values of input variables in the analysis of output from a computer code. Technometrics, 21, 239–245. CrossRefMATHMathSciNetGoogle Scholar
  14. Mahon, F., Rea, D., Guilhot, F., Legros, L., Guilhot, J., Aton, E., Dulucq, S., Reiffers, J., & Rousselot, P. (2009). Persistence of complete molecular remission in chronic myeloid leukemia after imatinib discontinuation: interim analysis of the STIM trial. J. Clin. Oncol., 27, 7084. Google Scholar
  15. Michor, F., Hughes, T., Iwasa, Y., Branford, S., Shah, N., Sawyers, C., & Nowak, M. (2005). Dynamics of chronic myeloid leukemia. Nature, 435, 1267–1270. CrossRefGoogle Scholar
  16. Piazza, R., Magistroni, V., Franceschino, A., Andreoni, F., Tornaghi, L. et al. (2006). The achievement of durable complete cytogenetic remission in late chronic and accelerated phase patients with CML treated with imatinib mesylate predicts for prolonged response at 6 years. Blood Cells Mol. Dis. 37, 111–115. CrossRefGoogle Scholar
  17. Roeder, I., & Glauche, I. (2008). Pathogenesis, treatment effects, and resistance dynamics in chronic myeloid leukemia–insights from mathematical model analyses. J. Mol. Med., 86, 17–27. CrossRefGoogle Scholar
  18. Roeder, I., Horn, M., Glauche, I., Hochhaus, A., Mueller, M. et al. (2006). Dynamic modeling of imatinib-treated chronic myeloid leukemia: functional insights and clinical applications. Nat. Med., 12, 1181–1184. CrossRefGoogle Scholar
  19. Rousselot, P., Huguet, F., Rea, D., Legros, L., Cayuela, J. M. et al. (2007). Imatinib mesylate discontinuation in patients with chronic myelogenous leukemia in complete molecular remission for more than 2 years. Blood, 109, 58–60. CrossRefGoogle Scholar
  20. Sawyers, C. (2000). Chronic myeloid leukemia. N. Engl. J. Med., 340, 1330–1340. CrossRefGoogle Scholar

Copyright information

© Society for Mathematical Biology 2010

Authors and Affiliations

  • Dana Paquin
    • 1
  • Peter S. Kim
    • 2
  • Peter P. Lee
    • 3
  • Doron Levy
    • 4
  1. 1.Department of MathematicsCalifornia Polytechnic State UniversitySan Luis ObispoUSA
  2. 2.Department of MathematicsUniversity of UtahSalt Lake CityUSA
  3. 3.Division of Hematology, Department of MedicineStanford UniversityStanfordUSA
  4. 4.Department of Mathematics and Center for Scientific Computation and Mathematical Modeling (CSCAMM)University of MarylandCollege ParkUSA

Personalised recommendations