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[valiantchong]

Published online 8 December 2009
Haematologica, Vol 95, Issue 6, 900-907 doi:10.3324/haematol.2009.015271
Copyright © 2010 by Ferrata Storti Foundation

http://www.haematolo...t/full/95/6/900

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Chronic Myeloid Leukemia

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

Tom Lenaerts^1,2, Jorge M. Pacheco^3,4, 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: dingli.david@mayo.edu

ABSTRACT

TOP
ABSTRACT
Introduction
Design and Methods
Results
Discussion
References

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.

Introduction

TOP
ABSTRACT
Introduction
Design and Methods
Results
Discussion
References

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

TOP
ABSTRACT
Introduction
Design and Methods
Results
Discussion
References

Normal hematopoiesis
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 r_i that increases exponentially together with compartment size (N_j). Adjacent compartments are related by N_i/N_i-l = y = 1.93 and r_i/r_i-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.

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Figure 1. Hematopoiesis and CML dynamics with and without treatment. Illustration of a typical treatment stage of the hierarchical tree model adopted here (further details provided in the Design and Methods section). Normal, CML and tyrosine kinase inhibitor (TKI)-treated cells (imatinib) co-evolve at each stage of differentiation. Cell differentiation occurs with probability , which depends on cell type, as indicated; otherwise the cell undergoes self-renewal. Because of the relative fitness difference between cell types (inset of Figure 3A), normal cells will out-compete TKI-treated cells (but not CML cells). This leads to the reduction of disease burden achieved with treatment (Figure 5).

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 mechanisms^24,25 (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.

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Figure 2. Moran dynamics within the active stem cell pool. Hematopoietic stem cells (HSC) and LSC (identified on top) undergo a stochastic Moran birth-death process which conserves the population size, consistent with the observed lack of expansion of the stem cell pool in CML.³ In the first step (upper panel, a) one of the N cells is chosen at random to replicate (circled cell in a), producing an additional identical cell and increasing the population by one (. Subsequently one of the N+1 cells is chosen at random to be exported (squared cell in c) - being transformed into one of the downstream cell types bringing the population size back to N (d).

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

Treatment
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

[CallMeLucky]

This seems like wishful thinking to me.  If TKI could cure CML, then I would expect to see more people cured.  If I understand this correctly, they are using a math model to predict the results.  The only problem I see is that in the real world, it doesn't seem to be playing out this way.  Maybe more time will tell, but there have been a lot of people on TKI for a while now and if anything the most recent literature I have read is going in the other direction on this with the concensus among most experts being that TKI does not cure and another approach is needed to eradicate.

[valiantchong]

This paper is a theory, and now more and more in the STIM trial, if the STIM trial on Gleevec 5% of the patients and on second generation about I guess may be double the Gleevec could stop TKIs and survive more than 5 years to 20 years without any issue. I believe this could be it. I believe this is not for everyone, may be 10 -  20 % of the patients. This paper is quite recent only couple of years.

I was wondering if there is any trial using PCRU patient stem cells who are in the STIM trial and transfuse into mice and see if could cause Leukemia, if it could not cause, than this theory may be correct. If not all STIM trial patient may relapse sooner or later....Anyone know if there is any experiment done with this ?  

[Trey]

I agree with Lucky -- in a math model, missing one small variable or over-estimating the effects of one small issue can make the whole model useless.  And the folks who wrote this are not known for their depth of CML research.  They also repeat the theory that CML stem cells die off very quickly after diagnosis, which is not widely accepted as being true.  In fact, the theory does not line up with what is seen in real life.

[valiantchong]

Well, this does not mean it is not true. The backing to this theory is that persent Stop TKIs is presently working on people that reaches MMR and not PCRU. These people are able to stop medication even though not PCRU, which may imply that these LSC could be in control and in disminishing rate. Which is a proof that what the theory may be true... Then again only time will tell.

I also understand that older patient before TKIs, when interferon alpha about 20% had stop therapy and able to stay healthy whithout medication... Presently with second generation of TKIs, eventhough a small group of patient that Stop TKI about 60% higher than Gleevec about 40-50%. This also shows positive results.

However I understand this is only able to apply to only about 10% patients now. Hopefully it could be more people to be able to stay stable and on path to cure.

[Trey]

Actually, by definition, a model is not "true".  It only tries to predict or represent an outcome.  And the more variables, the less likely it will be close to reality.  The reality (people stopping drug therapy) has shown that most are not cured, and the remainder have also not proven a cure, only that they have not relapsed within a certain time period (still rather short).

The part about stopping drug therapy after achieveing MMR does not make sense.  The success rate over a long term would be nearly zero.

[valiantchong]

The present scenario is that there are people who are in the STIM trial was over 5 yrs stoping theraphy and there are also cases of patient on interferon before had been safely off therapy for more than 10 yrs without any issue, Hence I think there is some true in this but only apply to may be 10% or less patients.

Also recently in Australia, Tim Huges CML researhes on the possibility to stop therapy on 50% of patients. If this is not true I dont think any of the patients able to stop therapy for more than 5 yrs.. I still think this could be an initial path to cure.

Pr. Tim Hughes Chronic Myeloid Leukemia CML

''Professor Tim Hughes was promoted to Clinical Professor, University of Adelaide and was also awarded the 2006 Eric Susman Prize from the Royal Australasian College of Physicians for his original and groundbreaking research in chronic myeloid leukaemia (CML). His contributions include defining the importance of molecular monitoring in CML patients receiving kinase inhibitor therapy, showing that the mutation profile helps clinicians to choose the best kinase inhibitor to use and using pre-therapy kinase sensitivity to tailor drug dose for each patients. His work also led to a publication in the journal Nature describing the in-vivo kinetics of a human cancer.''
Extract of http://www.rah.sa.gov.au/cancer/haematology5.php

''Professor Tim Hughes from the Centre for Cancer Biology in Adelaide, who is an internationally renowned expert in CML treatment, presented research partially funded by the Foundation showing the exciting possibility that up to 50% of patients who have received the drug imatinib as treatment for CML may be able to discontinue this therapy and remain disease free. Professor Hughes and his team are undertaking detailed studies to predict which patients can safely stop the treatment and thereby reduce the potential impact of side-effects from long-term drug use. It also represents a potential major cost saving to the health system as imatinib currently costs $60 million to supply annually in Australia.''

Pr. Tim Hughes Chronic Myeloid Leukemia CML

''Professor Tim Hughes was promoted to Clinical Professor, University of Adelaide and was also awarded the 2006 Eric Susman Prize from the Royal Australasian College of Physicians for his original and groundbreaking research in chronic myeloid leukaemia (CML). His contributions include defining the importance of molecular monitoring in CML patients receiving kinase inhibitor therapy, showing that the mutation profile helps clinicians to choose the best kinase inhibitor to use and using pre-therapy kinase sensitivity to tailor drug dose for each patients. His work also led to a publication in the journal Nature describing the in-vivo kinetics of a human cancer.''
Extract of http://www.rah.sa.gov.au/cancer/haematology5.php

''Professor Tim Hughes from the Centre for Cancer Biology in Adelaide, who is an internationally renowned expert in CML treatment, presented research partially funded by the Foundation showing the exciting possibility that up to 50% of patients who have received the drug imatinib as treatment for CML may be able to discontinue this therapy and remain disease free. Professor Hughes and his team are undertaking detailed studies to predict which patients can safely stop the treatment and thereby reduce the potential impact of side-effects from long-term drug use. It also represents a potential major cost saving to the health system as imatinib currently costs $60 million to supply annually in Australia.''

[matt92711]

There are other possible reasons for why in the STIM trial people acheived good responses other than the LSC dying out. Perhaps somehow the body's immune system was able to knock out any remaining CML. Also they are using a mathematical model to explain disease progression which examines events 5 years before anyone has actually observed them. If I had to guess, I would think that the TKI's most likely do not have the ability to hit every CML cell, rather what happens is may be a combination of LSC's dying off naturally or the body's immune system tareting the remaining CML cells. In the non cured people they did not have these factors working right.