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Dynamics of chronic myeloid leukemia response to long-term targeted therapy reveal treatment effects on leukemic stem cells. Estimated Gleevec daily 1st phase BCR-ABL reduction rate at -0.05 = - 5%

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#1 valiantchong


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Posted 06 September 2011 - 09:06 PM

Dynamics of chronic myeloid leukemia response to long-term targeted therapy reveal

treatment effects on leukemic stem cells

  1. Min Tang1,
  2. Mithat Gonen2,
  3. Alfonso Quintas-Cardama3,
  4. Jorge Cortes3,
  5. Hagop Kantarjian3,
  6. Chani Field4,
  7. Timothy P. Hughes4,
  8. Susan Branford4, and
  9. Franziska Michor1
+ Author Affiliations

  1. 1Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, and Department of Biostatistics, Harvard School of Public Health, Boston, MA;

  2. 2Department of Biostatistics and Epidemiology, Memorial Sloan-Kettering Cancer Center, New York, NY;

  3. 3Department of Leukemia, University of Texas M. D. Anderson Cancer Center, Houston, TX; and

  4. 4Department of Genetics and Molecular Pathology, SA Pathology, and University of Adelaide, Adelaide, Australia


Treatment of chronic myeloid leukemia (CML) with the tyrosine kinase inhibitors (TKIs) imatinib mesylate and nilotinib represents a successful application of molecularly targeted anticancer therapy. However, the effect of TKIs on leukemic stem cells remains incompletely understood. On the basis of a statistical modeling approach that used the 10-year imatinib mesylate treatment response of patients with CML and a patient cohort receiving first-line nilotinib therapy, we found that successful long-term therapy results in a triphasic exponential decline of BCR-ABL1 transcripts in many patients. Within our framework, the first slope of ?0.052 ± 0.018 (imatinib mesylate) and?0.042 ± 0.015 (nilotinib) per day represents the turnover rate of leukemic differentiated cells, whereas the second slope of ?0.0057 ± 0.0038 (imatinib mesylate) and ?0.0019 ± 0.0013 (nilotinib) per day represents the turnover rate of leukemic progenitor cells. The third slope allows an inference of the behavior of immature leukemic cells, potentially stem cells. This third slope is negative in most patients, positive in others, and not observable in some patients. This variability in response may be because of insufficient follow-up, missing data, disease heterogeneity, inconsistent compliance to drug, or acquired resistance. Our approach suggests that long-term TKI therapy may reduce the abundance of leukemic stem cells in some patients.

#2 GerryL


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Posted 06 September 2011 - 09:43 PM

Interesting they don't really appear to be saying anything. 

#3 valiantchong


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Posted 06 September 2011 - 10:13 PM

This study conclude long term TKIs treatment is actually divided in 2 or 3 phase. The 1st where slope is steep is the TKIs effect on Leukemic differentiated cells, 2 nd phase treatment slope is effect of drugs on progenitor Leukemic cells and finaly 3 rd phase where the treatment slope is almost flat or slightly negative (sometime positive) is the TKIs effect possibly effect on the Leukemic stem cells. However this is a postulate base on the empirical mathematic model. If this is true then the patients that went into the 3rd phase has a chance of curing.

This wa taken from the Blood 2011 write up.

It has been suggested that it is impossible to cure CML using targeted therapy because
leukemic stem cells cannot be eradicated.20 For months or years after achieving a
complete cytogenetic response, the majority of CML patients treated with imatinib has
measurable disease by RQ-PCR and would relapse if imatinib therapy was
discontinued.21-22 However, in the majority of patients who respond to imatinib, there is
a progressive decline in the BCR-ABL1 counts over time, such that after several years
of treatment an increasing number of patients achieve a complete molecular response
within the limitations of the assay. Whether all CML cells have been eradicated in any of
these patients is a question of significant clinical and scientific importance. Furthermore,
the dynamics of responses to second-generation inhibitors have not yet been
In this paper, we performed statistical analyses of both short- and long-term imatinib as
well as nilotinib treatment responses, encompassing patients who were treated with
600mg of imatinib and followed for 12 months, patients who were treated with 400mg of
imatinib with a follow-up of up to 10 years, and patients who were treated with first-line
nilotinib (400mg BID) with a follow-up of up to 66 months. Based upon these data and
our mathematical framework,11,13 we concluded that the leukemic treatment response
displays three phases: during the first phase, the abundance of leukemic cells
decreases with a slope of -0.052 ± 0.018 (imatinib) or -0.042 ± 0.015 (nilotinib) per day,
representing a depletion of differentiated leukemic cells by treatment. During the second
phase, the leukemic burden declines with a slope of -0.0057 ± 0.0038 (imatinib) or -
0.0019 ± 0.0013 (nilotinib) per day, signifying a decrease of the abundance of leukemic
progenitors. Both the first and second slopes are significantly different between the
imatinib and nilotinib patient cohorts, signifying variability due to differences in follow-up,
missing data, pharmacokinetic effects or potentially due to different effects of imatinib
versus nilotinib on the death rates of leukemic cells during therapy. During the third
phase, the leukemic cell number decreases in a subset of imatinib-treated patients
(mean -0.0008 ± 0.0003) and three nilotinib-treated patients (-0.00028, -0.00002 and -
0.00697) while increasing in one imatinib-treated patient (0.0014). In a few patients, this
third slope could not be observed, probably due to insufficient follow-up or missing data.
The number of patients with a third slope was smaller in the nilotinib as compared to the
imatinib cohort, since the follow-up of patients treated with first-line nilotinib was much
shorter than the follow-up of imatinib-treated patients. Importantly, this third slope has
never before been described in TKI response data and offers novel insights into the
biology of the disease.
The existence of a third slope suggests that it may be possible to infer the kinetics of a
population of immature leukemic cells, possibly stem cells, from long-term TKI response
data. Our findings support the hypothesis that targeted therapy is capable of depleting
leukemic stem cells at a very slow rate in a subset of patients. In a few patients,
however, the third slope was positive or could not be identified with statistical
significance. The variability in response to long-term targeted therapy may be due to
inconsistent patient adherence to drug; indeed, poor adherence was hypothesized to be
the predominant reason for the inability of some CML patients to obtain and/or maintain
adequate molecular responses to imatinib therapy23. Alternatively, this variability in
patient response may be caused by the presence of low-level resistance in some
patients and/or by heterogeneity in the disease characteristics among CML patients. In
many situations, there is marked heterogeneity in phenotype even if genetically, cells
are identical24-27. Similarly, different patients may present with leukemic cell phenotypes
with disparate growth and differentiation kinetics. This hypothesis is supported by
experimental evidence suggesting that both the amount of BCR-ABL mRNA and second
site mutations alter the fitness of leukemic cells28-29. Furthermore, even leukemic stem
cells within one patient may be highly heterogeneous, harboring clones with different
growth kinetics30-31. Inclusion of such intra-patient variability into our framework would
not alter the results, since the mathematical framework describes the behavior of the
dominant clone in each differentiation stage (see SI). Finally, this variability in the third
slope observed among patients may be due to the limitations in the sensitivity of the
RQ-PCR assay to detect BCR-ABL1 transcripts at such low levels (SI).
Note that the long-term TKI treatment follow-up data used for our analyses represents a
strongly selected population of patients who were not only able to tolerate TKI therapy
for a decade, but also achieved at least a complete cytogenetic response. Therefore,
the conclusions based upon this patient group may not apply in general to all CML
patients. Furthermore, the shape of the imatinib treatment response curve was identified
based upon converted BCR-ABL1 transcript values (see SI); as long as the shape of the
curve using converted values accurately represents the shape of the curve of true
values, this data can be used to identify the behavior of immature CML cells during
imatinib therapy. However, the majority of patients (over 93%) had at least one positive
(non-converted) value after their specific turning points between the second and third
slopes, and over 79% of those patients had multiple positive measurements thereafter.
Therefore, the estimation of the third slope is not purely based on converted values.
Furthermore, a subset of nilotinib-treated patients, who did not have any converted data
points, also displayed a tri-phasic decline of the leukemic cell burden.
Our results stand in contrast to extensive in vitro studies of CML stem cells suggesting
that these cells are intrinsically resistant to TKIs.32 Such studies identified multiple
pathways contributing to stem cell resistance, including decreased intracellular uptake
and retention of cytotoxic drugs and tyrosine kinase inhibitors32 and resistance to
apoptosis.33-34 A lower expression of human leukocyte antigen co-stimulatory molecules
and targets of adaptive immunity may also protect stem cells from immune
surveillance.35-36 Furthermore, treatment with TKIs in vitro results in an increase in
quiescent immature CML cells that retain proliferative capacity after treatment is
withdrawn.37-38 Finally, human CML stem cell survival was recently found to be
independent of BCR-ABL activity39, and although short-term in vitro imatinib treatment
reduced the expansion of CML stem/progenitors, cytokine support permitted growth and
survival in the absence of BCR-ABL activity that was comparable to that of normal
stem/progenitor counterparts. These data suggest that stem cells may not be inhibited
by imatinib therapy. These observations can be reconciled with our findings by the fact
that in vitro studies may not predict the in vivo behavior of CML stem cells, that in vitro
settings arguably utilize a more differentiated cell population than the most primitive
leukemic stem cells present in patients, and that our study population represents a very
selected group of patients which may not display the same disease characteristics and
long-term response to TKIs as those patients from whom samples for in vitro studies
were obtained. Furthermore, the possibility remains that the third slope represents the
behavior not of leukemic stem cells, but of an immature subpopulation that is more
differentiated than stem cells; in that case we would predict the existence of another
slope signifying the behavior of leukemic stem cells.
Our findings provide a fresh perspective for the discussion of whether TKIs are capable
of curing CML. The identification of a bi-phasic depletion of leukemic cells in response
to imatinib therapy11 led to the design of several computational models; while our
framework predicted that there would be three phases of BCR-ABL1 depletion in CML
patients,12-13 representing the behavior of differentiated cells, progenitors and potentially
leukemic stem cells, other models suggested that there are only two slopes, caused by
a decline of cycling and quiescent leukemic stem cells,12 or by a decline of leukemic
progenitors and stem cells.40 The validity of any of these interpretations of the bi-phasic
depletion of leukemic cells11-12,40 and thus the inferred effect of TKIs on leukemic stem
cells remains unresolved. However, these computational models led to distinct
predictions of the long-term imatinib response. Our analyses thus contribute to the
discussion of the applicability of these alternative interpretations to long-term treatment
response data.
Our findings are consistent with the results of imatinib discontinuation trials14-16, which
found that the majority of patients relapsed a few months after discontinuation of
imatinib while about 40% of patients remained BCR-ABL1-negative for the duration of
their follow-up. However, several instances of late relapse and fluctuations of BCRABL1
levels after imatinib discontinuation also occurred, thus questioning the ability of
imatinib to lead to a lasting cure of the disease in these patients. One treatment option
that has been suggested to succeed in curing CML is allogeneic stem cell
transplantation. Complete molecular response (CMR) is commonly achieved after
allogeneic transplantation and is associated with long-term disease-free survival;
furthermore, CMR induced by allografts was found to be more stable than CMR induced
by imatinib therapy.41 However, late molecular relapses were reported even after this
treatment option.9 In the allograft setting it is possible that ongoing immune surveillance
is essential to suppress a pool of residual CML cells. Similarly, for the small number of
patients who achieve CMR after administration of interferon-? therapy, ongoing immune
surveillance may be important. This agent may represent an attractive therapeutic
option since several recent clinical studies15,42-44 as well as in vitro data45 suggested that
interferon-? selectively impairs proliferation of primitive CML progenitors. While the
ability of allografts and interferon-? to cure CML remains incompletely understood, we
believe that, based on our analyses, continuous TKI therapy has the potential to
diminish the leukemic stem cell population at least in a subset of patients. The rate of
depletion might vary between patients and may also depend on other factors such as
the immune system and previous treatment with interferon-?, AraC or other agents. In
addition, it remains a possibility that those patients who tolerate TKI therapy for up to
ten years without adverse effects or progression of disease represent a distinct subset
of patients whose leukemia is exquisitely sensitive to treatment. Future clinical studies
will demonstrate the general applicability of these findings and will allow for the
identification of predictors of the long-term response to TKI therapy.

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