CLINICAL TRIALS AND OBSERVATIONS
Brief report
Poor adherence is the main reason for loss of CCyR and imatinib failure for
chronic myeloid leukemia patients on long-term therapy
Amr R. Ibrahim,1 Lina Eliasson,1 Jane F. Apperley,1 Dragana Milojkovic,1 Marco Bua,1 Richard Szydlo,1
Francois-Xavier Mahon,2 Kasia Kozlowski,1 Christos Paliompeis,1 Letizia Foroni,1 Jamshid S. Khorashad,1 Alex Bazeos,1
Mathieu Molimard,3 Alistair Reid,1 Katayoun Rezvani,1 Gareth Gerrard,1 John Goldman,1 and David Marin1
1Department
of Haematology, Imperial College London, Hammersmith Hospital, London, United Kingdom; 2Laboratoire Hématopoïèse Leucémique et Cible
Thérapeutique, Université Victor Ségalen Bordeaux 2, Bordeaux, France; and 3Department of Clinical Pharmacology and Toxicology, Hospitalier Universitaire de
Bordeaux, Bordeaux, France
We studied the relation between adherence to imatinib measured with microelectronic monitoring systems and the probabilities of losing a complete cytogenetic
response (CCyR) and of imatinib failure in
87 CCyR chronic myeloid leukemia patients receiving long-term therapy. We
included in our analysis the most relevant
prognostic factors described to date. On
multivariate analysis, the adherence rate
and having failed to achieve a major molecular response were the only independent predictors for loss of CCyR and
discontinuation of imatinib therapy. The
23 patients with an adherence rate less
than or equal to 85% had a higher probability of losing their CCyR at 2 years
(26.8% vs 1.5%, P ⴝ .0002) and a lower
probability of remaining on imatinib
(64.5% vs 90.6%, P ⴝ .006) than the
64 patients with an adherence rate more
than 85%. In summary, we have shown
that poor adherence is the principal factor contributing to the loss of cytogenetic
responses and treatment failure in patients on long-term therapy. (Blood. 2011;
117(14):3733-3736)
Introduction
Lack of adherence to oral therapy for chronic diseases is a
well-recognized problem.1-4 Several recent studies have shown that
lack of adherence to imatinib is frequent and has a significant
impact on the degree of response to therapy obtained by the
patient.5,6 For example, a Belgian study found that one-third of
169 patients were nonadherent to imatinib and only 14% took all of
their prescribed dose.5 In this study, nonadherence was associated
with reduced clinical response. We recently reported that 26% of
the patients on long-term imatinib therapy had an adherence rate
lower than 90% and 14% had a rate lower than 80%.6 In our study,
multivariate analysis identified adherence and the level of expression of the molecular transporter hOCT1 as the only independent
predictors for achieving major molecular response (MMR).
We now present the follow-up data, where we investigated the
relation between adherence to imatinib and the probabilities of
losing a complete cytogenetic response (CCyR) and of imatinib
failure in patients receiving long-term therapy.
Methods
scribed.6 Briefly, a medication event monitoring system is an electronic
device fitted into the cap of a normal looking medication bottle that
automatically records each time the bottle is opened. Medication event
monitoring systems are considered the “gold standard” for measuring
adherence.1,2,9,10 After the 3-month monitoring period, the patients were
followed subsequently for a median of 19 months (range, 14-24 months).
Data from the patients were censored in March 2010, when our previous
work was published, to ensure that the results of this study were not
influenced by possible changes in a patient’s behavior. The study was
approved by the Imperial College London Institutional Review Board and
the Medicines and Healthcare Products Regulatory Agency.
Laboratory assessments
BCR-ABL1 transcripts were measured in the blood at 6- to 12-week
intervals as previously described.6 Trough imatinib plasma levels, levels of
hOCT1, and the polymorphism 1236C 3 T in ABCB1 were assessed as
previously reported.6,11,12 Cytogenetic relapse (loss of CCyR) was defined
by the detection of one or more Ph-positive marrow metaphases, confirmed
by a second test. Bone marrow examination was triggered by a rise in
BCR-ABL1 transcript numbers to a level consistent with cytogenetic
relapse.13,14
Patient variables and treatment
Statistical methods
Between April 2008 and February 2009, we measured the adherence to
imatinib in 87 (Table 1) consecutive chronic-phase chronic myeloid
leukemia patients who had received imatinib 400 mg/day as first-line
therapy for a median of 59.7 months before enrollment (www.clinicaltrials.
gov, #NCT00632255).6 Adherence levels were monitored during a 3-month
period using a medication event monitoring system as previously de-
The probability of event-free survival (EFS) (the reverse of imatinib failure)
was calculated using the Kaplan-Meier method. To define imatinib failure
the event was death from any cause, progression from chronic phase, loss of
complete hematologic response, loss of CCyR, or imatinib discontinuation
on account of unacceptable toxicity or inadequate response.14 The probability of cytogenetic relapse was calculated using the cumulative incidence
Submitted October 12, 2010; accepted January 31, 2011. Prepublished online
as Blood First Edition paper, February 23, 2011; DOI 10.1182/blood-2010-10309807.
payment. Therefore, and solely to indicate this fact, this article is hereby
marked ‘‘advertisement’’ in accordance with 18 USC section 1734.
The publication costs of this article were defrayed in part by page charge
© 2011 by The American Society of Hematology
BLOOD, 7 APRIL 2011 䡠 VOLUME 117, NUMBER 14
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IBRAHIM et al
Table 1. Patient characteristics and 24-month probabilities of
cytogenetic relapse and EFS
Variables
n
24-month
probability of
losing the
CCyR, %
24-month
probability of
EFS, %
procedure. Univariate and multivariate analyses were performed as described elsewhere.6
Results and discussion
Variables at diagnosis
P ⫽ .41
Sex
Male
49
Female
38
ⱕ 45 y
42
⬎ 45 y
45
5.8
90.9
Low
33
Intermediate
High
P ⫽ .20
9.6
76.6
6.9
89.7
P ⫽ .13
Sokal risk group
P ⫽ .79
6.6
85.8
32
3.4
85.3
22
17.9
79.7
P ⫽ .82
Hemoglobin
ⱕ 115 g/L
40
⬎ 115 g/L
47
ⱕ 140 ⫻ 109/L
44
⬎ 140 ⫻ 109/L
43
81.9
7.3
83.7
40
P ⫽ .99
7.2
85.1
7.1
82.3
P ⫽ .72
BCR-ABL1 transcript type
P ⫽ .77
8.1
P ⫽ .95
Leukocytes
e14a2
79.0
P ⫽ .55
Age
P ⫽ .12
10.3
10.9
P ⫽ .43
89.0
e13a2
33
9.4
74.6
e13a2 and e14a2
14
4.6
75.0
P ⫽ .30
hOCT1 transcript level*
ⱕ 0.16
30
⬎ 0.16
30
C/C
T/C
Early molecular response†
Yes
81.1
3.4
86.7
P ⫽ .82
MDR-1 polymorphism
75
12
55
32
No
P ⫽ .79
10.1
82.3
7.9
80.2
P ⫽ .08
P ⫽ .13
4.1
92.9
15.0
78.0
P ⫽ .0006
Baseline response
P ⫽ .51
11.2
P ⫽ .0007
CCyR and no MMR
34
21.1
67.5
MMR
53
0
94.4
On study variables
n
P ⫽ .18
Age
ⱕ 50 y
42
⬎ 50 y
45
74.7
4.6
91.7
P ⫽ .57
Weight
ⱕ 74 kg
47
⬎ 74 kg
40
ⱕ 1 ␮g/mL
43
⬎ 1 ␮g/mL
41
90.9
10.4
75.5
⬎ 85%
69
ⱕ 85%
18
86.7
7.0
83.9
P ⫽ .0002
1.4
91.4
36.3
54.2
P ⫽ .73
Dose of imatinib
P ⫽ .80
6.8
P ⬍ .0001
Adherence rate§
P ⫽ .14
6.5
P ⫽ .98
Imatinib plasma level‡
P ⫽ .03
12.5
P ⫽ .79
400 mg/day
55
7.7
81.6
⬎ 400 mg/day
32
9.2
87.1
*Samples were not available in 27 patients.
†Early molecular response is defined as having achieved a 1-log reduction
(BCR-ABL1/ABL1 ratio ⱕ 10%) by 3 months.6-8
‡In 3 patients, the trough plasma level was not available.
§We explored different cutoff levels for the adherence rate. In all cases, the
patients in the group with the lower adherence rate were more likely to lose their
CCyR during the follow-up, namely, ⱕ 80 vs ⬎ 80 (54.5 vs 2, P ⬍ .0001),
ⱕ 85 vs ⬎ 85 (36.3 vs 1.4, P ⬍ .0001), ⱕ 90 vs ⬎ 90 (26.9 vs 1.6, P ⫽ .0002), and
ⱕ 95 vs ⬎ 95 (24.5 vs 0, P ⫽ .0001). We use a multivariate Cox model to choose the
better cutoff, which was 85. The adherence rate also predicted for loss of CCyR when
considered as a continuous variable (RR ⫽ 1.05; P ⫽ .0001).
As previously reported,6 the median adherence rate was 97.6%
(range, 24%-103.8%). In 23 (26.4%) patients, adherence was less
than or equal to 90% (median, 76%) and in 18 (20.7%) less than or
equal to 85% (median, 73.8%). During follow-up, 7 (8%) patients
lost their CCyR (6 of whom became ⬎ 35% Ph-positive before
alternative therapy could be commenced) and 12 (13.8%) discontinued the imatinib therapy (7 resulting from loss of CCyR and
5 resulting from side effects).
We performed univariate analysis to identify factors associated
with loss of CCyR and with EFS (Table 1). The 18 patients with an
adherence rate less than or equal to 85% had a higher probability of
losing their CCyR than the 69 patients with an adherence rate more
than 85%, namely, 36.3% versus 1.4% (P ⬍ .0001). None of the
57 patients with an adherence rate more than 95% lost their CCyR
(P ⫽ .0001). Patients who were in MMR at the beginning of the
study had a significantly lower probability of losing their CCyR by
the end of follow-up (Table 1; Figure 1). Multivariate analysis
identified an adherence rate less than or equal to 85% (relative risk
[RR] ⫽ 27.8, P ⫽ .002) and never having achieved a MMR
(RR ⫽ 14.9, P ⫽ .01) as the only 2 independent predictors for loss
of CCyR.
The median adherence rate in the 12 patients who eventually
failed imatinib therapy was significantly lower than that of the
patients who continued on therapy (78.1% vs 97.8%, P ⫽ .02).
Patients with an adherence rate less than or equal to 85% had a
significantly lower EFS than the adherent patients (54.4% vs
91.4%, P ⫽ .0002). Again, we performed univariate (Table 1) and
multivariate analysis to identify prognostic factors for imatinib
failure. An adherence rate less than or equal to 85% (RR ⫽ 0.22,
P ⫽ .01) and having failed to achieve an MMR (RR ⫽ 0.14,
P ⫽ .15) were the only independent predictors for EFS.
The multivariate analysis identified adherence rate and the
degree of molecular response as the only independent predictors
for loss of CCyR and imatinib failure. Figure 1 shows the 2-year
probabilities of loss of CCyR (Figure 1B) and EFS (Figure 1D)
according to the combination of both variables. The 53 patients
who started the study in MMR fared well, with a 2-year probability
of losing the CCyR of 0% and an EFS of 94.4%. We have
previously shown that patients who achieve MMR are less likely to
lose their CCyR15 and that the achievement of MMR depends on
the adherence to imatinib therapy and, to a lesser extent, on
ill-defined intrinsic biologic factors, such as higher expression of
hOCT1.6 It is impossible to establish the relative contributions of
these 2 factors to the sustained responses, both of which may
militate in favor of MMR.
The outcome for the 34 patients who were not in MMR at the
beginning of the study was less satisfactory (probability of losing
their CCyR, 67.5%, P ⫽ .0007). Within this second cohort, the
impact of adherence on their outcome was dramatic. The 23 patients
who had an adherence rate more than 85% had a prognosis similar
to that of the MMR patients (probability of losing their CCyR,
4.3%), whereas the 11 patients with a low adherence rate had
54.5% cumulative incidence of loss of CCyR (P ⬍ .0001; Figure 1).
Thus, good adherence to therapy seemed to be able to overcome
any possible biologic difference as patients who had failed to
achieve MMR but had a good adherence to therapy had a prognosis
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LOSS OF CCyR AND IMATINIB FAILURE
3735
Figure 1. Two-year probability of losing the CCyR and imatinib failure (EFS) according to the adherence rate and to the combination of adherence and the prior
achievement of MMR. The 18 patients with an adherence rate ⱕ85% had higher 2-year probability of both losing their CCyR (A; 36.3% vs 1.4%, P ⬍ .0001) and of failing
imatinib therapy (C; 54.4% vs 91.4%, P ⫽ .0002) than the 69 patients with an adherence rate ⬎85%. The 53 patients who had achieved MMR at the moment of enrollment had
a similar 2-year probability of losing their CCyR during follow-up (B) and a 2-year EFS (D) to that of the 23 patients who were not in MMR at enrollment but had an adherence
rate ⬎85% (0% vs 4.3%, P ⫽ .31; and 94.4% vs 86.1%, P ⫽ .14). However, the 11 patients who were not in MMR at the moment of enrollment and had an adherence rate
ⱕ85% had a significantly higher probability of losing their CCyR (54.5%) and lower EFS (28.3%) (B,D).
similar to that of MMR patients. This must mean that, for patients
who have achieved CCyR, good adherence to therapy and not the
further achievement of MMR should be the main clinical focus.
In conclusion, we have studied the reasons for cytogenetic
relapse and imatinib failure in a cohort of patients on long-term
imatinib therapy. We have included in our analysis the more
important prognostic factors identified to date. Our data show that
poor adherence to imatinib therapy is the most important factor
contributing to cytogenetic relapse and imatinib failure. It is
therefore of paramount importance that physicians recognize this
problem and work toward improving adherence in chronic myeloid
leukemia patients treated with tyrosine kinase inhibitors.
Acknowledgments
The authors thank the patients who participated in this study.
This work was supported by the NIHR Biomedical Research
Center Funding Scheme.
Authorship
Contribution: A.R.I. and L.E. collected patient data, performed
statistical analysis, and wrote the manuscript; G.G., J.S.K., and
A.B. performed the molecular studies, assembled the molecular
data, and commented on the manuscript; K.K. and C.P. collected
patient data and commented on the manuscript; M.B., D. Milojkovic,
and J.F.A. provided patient care and commented on the manuscript;
R.S. reviewed the statistical analysis and commented on the
manuscript; M.M. and F.-X.M. performed the imatinib plasma
levels and commented on the manuscript; L.F. supervised the
day-to-day running of the Minimal Residual Disease service and
commented on the manuscript; A.R. performed the cytogenetics
and commented on the manuscript; K.R. reviewed the manuscript;
J.G. wrote some of the manuscript; and D. Marin designed the
study, performed the statistical analysis, supervised patient care,
and wrote the manuscript.
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IBRAHIM et al
Conflict-of-interest disclosure: D. Marin received research support
from Novartis and is a consultant for Novartis and Bristol Myers-Squid.
The other authors declare no competing financial interests.
Correspondence: David Marin, Department of Haematology,
Imperial College London, Du Cane Road, London W12 0NN,
United Kingdom; e-mail: [email protected].
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