Published online 8 December 2009
Haematologica, Vol 95, Issue 6, 900-907 doi:10.3324/haematol.2009.015271
Copyright © 2010 by Ferrata Storti Foundation
Chronic Myeloid Leukemia
Tyrosine kinase inhibitor therapy can cure chronic myeloid leukemia without hitting leukemic stem cells
Tom Lenaerts1,2, Jorge M. Pacheco3,4, Arne Traulsen5, David Dingli6
1 MLG, Département d'Informatique, Université Libre de Bruxelles, Brussels, Belgium
2 Switch, VIB & Vrije Universiteit Brussel, Brussels, Belgium
3 Departamento de Matemática da Universidade do Minho, Braga, Portugal
4 ATP-Group, CFTC, Complexo Interdisciplinar, Lisboa, Portugal
5 Emmy-Noether Group for Evolutionary Dynamics, Max-Planck-Institute for Evolutionary Biology, Plön, Germany and
6 Division of Hematology, Mayo Clinic College of Medicine, Rochester, MN, USA
Correspondence: David Dingli, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905 USA. E-mail: firstname.lastname@example.org
Design and Methods
Background: Tyrosine 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 Methods: We 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.
Results: We 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.
Conclusions: Tyrosine 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.
Design and Methods
Chronic myeloid leukemia (CML) is an acquired hematopoietic stem cell disorder characterized by expression of the BCR-ABL oncoprotein.1-5 Animal models as well as theoretical considerations on the age-specific incidence of CML in human populations suggest that aberrant BCR-ABL expression alone may be enough to explain the chronic phase of the disease.1,5,6 The BCR-ABL oncoprotein interacts with many substrates in the leukemic cell, which ultimately leads to the CML phenotype.7
The introduction of ABL kinase inhibition with imatinib opened a new era in the therapy of CML.2 However, the lack of evidence that this agent has any direct impact on the leukemic stem cell (LSC)8 has led to questions regarding the capacity of imatinib, or the newer tyrosine kinase inhibitors such as dasatinib or nilotinib, to cure CML.9,10 On the other hand, the therapeutic success of tyrosine kinase inhibitors suggests that they efficiently control disease burden in early progenitors and more committed blood cell lineages. In fact, in the absence of acquired resistance to tyrosine kinase inhibition, CML is no longer fatal and the increasing survival of these patients is projected to make the disease one of the most prevalent leukemias. Moreover, there are now reports of patients with CML who, despite stopping tyrosine kinase inhibitor therapy, have remained free of relapse for significant periods of time.11
Previous investigations of CML, including theoretical models,9,12,13 did not take into account the stochastic nature of hematopoiesis.14 Given the small size of the active hematopoietic stem cell pool,15,16 which is not expanded in CML,3 and of which only a very small fraction is constituted by LSC,13,17 stochastic effects should not be overlooked when investigating cell dynamics.14,18 Moreover, the fact that BCR-ABL does not give a fitness advantage to the LSC19 means that expansion of the LSC clone can only occur by neutral drift. In other words, LSC do not benefit and/or are not dependent on BCR-ABL expression, and their expansion is, therefore, independent of oncoprotein expression. Thus, the expansion or elimination of LSC is the same as that of normal hematopoietic stem cells and dependent on chance alone, a feature which is impossible to capture with a deterministic model, in which equal cell division rates imply a constant ratio of LSC and normal hematopoietic stem cell numbers. Here, we argue that LSC should not be considered the main target for CML eradication. Instead, and in accord with the fact that CML is LSC-derived but progenitor cell driven,20 we show how and why progenitor cells, not LSC, are the major cause of problems related to CML. To this end, we developed a model of hematopoiesis which takes explicitly into consideration its stochastic nature and associated effects. In the majority of simulated cases, we found that continued tyrosine kinase inhibitor therapy (assuming it is well tolerated) has the potential to cure CML despite the fact that these agents do not hit LSC. Our results correlate nicely with independent clinical data21 and we employed our model to predict the probability of disease relapse as a function of duration of therapy.
Design and Methods
Normal hematopoiesis can be represented by a hierarchical model in dynamic equilibrium in which cells move along the hematopoietic tree as they become increasingly differentiated.22 In a healthy adult, approximately 400 hematopoietic stem cells, which each replicate on average once per year,15,23 are responsible for the daily marrow output of approximately 3.5x1011 cells. As cells differentiate, they reach new levels of the hematopoietic tree, and we associate a specific compartment to each stage of cell differentiation (Figure 1). Cell divisions contribute to differentiation with a probability and to amplification with a probability of 1- across the hematopoietic tree.22 When a cell in compartment i divides and the two daughter cells differentiate they move to the next compartment (i+l). Cells in compartment i replicate at a rate ri that increases exponentially together with compartment size (Nj). Adjacent compartments are related by Ni/Ni-l = y = 1.93 and ri/ri-l = r = 1.26. From prior work, we have determined that there are 32 compartments (K=32) in the hematopoietic tree and that =0.85 for normal hematopoiesis.22 We capture the dynamics of hematopoiesis combining three different approaches including population dynamics in discrete time, age-structured populations and a continuous model when the cell population is large enough. This is similar to cell dynamics in the colonic crypt as described by Johnston et al.24,25 where these approaches are discussed in detail.
Stem cell dynamics
BCR-ABL expression changes the properties of the progeny of LSC, but not the LSC directly.19,26 The active hematopoietic stem cell pool is not expanded in CML,3 hence the evolutionary dynamics of hematopoietic stem cells and LSC can be described by a neutral Moran process in a population of approximately 400 cells.22,23 Disease dynamics typically starts with the appearance of the first LSC and at a given interval of time, one cell is chosen at random for reproduction and subsequently another cell is chosen for export (differentiation) so that the cell population remains constant under an appropriate feedback mechanisms24,25 (Figure 2). When 400 'selection-reproduction-export' events have occurred, 1 year has passed. Export of a LSC starts the expansion of the CML progenitor pool.
Chronic myeloid leukemia dynamics
The progenitors derived from LSC express BCR-ABL and have a reduced differentiation capacity. Bone marrow expansion concomitant with observations suggests that cells expressing BCR-ABL have a differentiation probability CML = 0.72.13 Besides marrow expansion, this reduced probability of differentiation, compared to normal progenitors (in agreement with what is observed) ultimately also results in an increased hematopoietic output leading to the diagnosis of CML (>1012 cells/day).27
From our prior studies, we have estimated that at any time, imatinib therapy affects approximately 5% of the leukemic cell population.13 This percentage will increase when a higher dose of