Tyrosine kinase inhibitor therapy can cure chronic myeloid leukemia without hitting leukemic stem cells

Abstract

BackgroundTyrosine kinase inhibitors, such as imatinib, are not considered curative for chronic myeloid leukemia -regardless of the significant reduction of disease burden during treatment -since they do not affect the leukemic stem cells. However, the stochastic nature of hematopoiesis and recent clinical observations suggest that this view must be revisited. Design and MethodsWe studied the natural history of a large cohort of virtual patients with chronic myeloid leukemia under tyrosine kinase inhibitor therapy using a computational model of hematopoiesis and chronic myeloid leukemia that takes into account stochastic dynamics within the hematopoietic stem and early progenitor cell pool. ResultsWe found that in the overwhelming majority of patients the leukemic stem cell population undergoes extinction before disease diagnosis. Hence leukemic progenitors, susceptible to tyrosine kinase inhibitor attack, are the natural target for chronic myeloid leukemia treatment. Response dynamics predicted by the model closely match data from clinical trials. We further predicted that early diagnosis together with administration of tyrosine kinase inhibitor opens the path to eradication of chronic myeloid leukemia, leading to the wash out of the aberrant progenitor cells, ameliorating the patient's condition while lowering the risk of blast transformation and drug resistance. ConclusionsTyrosine kinase inhibitor therapy can cure chronic myeloid leukemia, although it may have to be prolonged. The depth of response increases with time in the vast majority of patients. These results illustrate the importance of stochastic effects on the dynamics of acquired hematopoietic stem cell disorders and have direct relevance for other hematopoietic stem cell-derived diseases.Key words: chronic myeloid leukemia, tyrosine kinase inhibitors, cure, stochastic dynamics. Citation: Lenaerts T, Pacheco JM, Traulsen

Do we have to kill the last CML cell?

“…If the risk of disease progression is as small in imatinib-treated patients as it is in patients in long-term remission after allografting, then a pragmatic response may be that eradication is not necessary. If it is true that stem cell exhaustion is common in CML, as predicted by Lenaerts et al, 36 then perhaps we need only to suppress the disease for long enough and it will burn itself out.…”

“…A second study reached the same conclusion, but for a different reason. 36 The authors incorporated in their model the stochastic process of stem cell exhaustion. Put simply, each time a precursor cell divides it gives rise to two daughter cells and each of these daughter cells will be committed either to differentiation or to self-renewal.…”

Explaining the in vitro and in vivo differences in leukemia therapy

“…In order to understand the differences observed in the response dynamics of CML-ECP under either imatinib or nilotinib therapy, we fitted our model of hematopoiesis 10 to clinical data derived from two patient cohorts treated with either of these agents (Fig. 1A).…”

“…Our fitting further reveals that nilotinib increases the probability of differentiation of CML progenitors ε NIL = 0.932 (0.907-0.946) compared to imatinib, ε IMAT = 0.889 (0.881-0.893). 10 of CD34 + cells. 6 Our results show that only a small fraction of CML cells are responding to therapy (z) at any time:…”

“…10 The difference between the two agents suggests that nilotinib has a higher affinity for Bcr-Abl, leading to a faster response, easier to visualize. This truncation had no impact on the parameter estimation.…”