Efficacy of nilotinib in chronic myeloid leukemia patients resistant to or intolerant of imatinib: Results after 2 years

JOURNAL OF MEDICAL RESEARCH

EFFICACY OF NILOTINIB IN CHRONIC MYELOID LEUKEMIA
PATIENTS RESISTANT TO OR INTOLERANT OF IMATINIB:
RESULTS AFTER 2 YEARS
Phu Chi Dung¹, Nguyen Tan Binh², Pham Quang Vinh³
¹Blood Transfusion Hematology Hospital, Hochiminh City
²Department of Health, Hochiminh city
³Department of Hematology, Hanoi Medical University
Imatinib has been the first-line option for chronic myeloid leukemia (CML) and provides excellent
outcomes for many. However, a number of patients were resistant to or intolerant of imatinib. This study
aims to evaluate the 2-year results of treatment with nilotinib in these resistant or intolerant patients. A
case series study was conducted in 72 resistant or intolerant CML patients at Ho Chi Minh City (HCMC)
Blood Transfusion Hematology hospital who received nilotinib between January 2015 and December 2017.
Overall, there were 60/72 patients who were resistant to imatinib. Mutations were observed in 30.6% of
patients. Approximately two-thirds of cases had the duration of greater than 1 year from imatinib resistance/
intolerance to nilotinib therapy. After 24 months of nilotinib, complete cytogenetic response (CCyR) and
major molecular response (MMR) were achieved in 51.3% and 44.8% of patients, respectively. Complete
hematologic response (CHR) was rapidly obtained (97.2% after 6 months). Two-year overall survival (OS) and
progression-free survival (PFS) were 98.5% and 91.4%, respectively. In conclusion, nilotinib is an effective
therapeutic option for CML patients who were resistant to or intolerant of imatinib in Vietnam condition.
Keywords: chronic myeloid leukemia, resistant, intolerant, imatinib, nilotinib.

I. INTRODUCTION
Chronic myeloid leukemia (CML) is a
common malignant hematologic disease. Its
pathogenic mechanism involves a reciprocal
translocation between chromosomes 9 and 22
which is known as Philadelphia chromosome
(Ph). This cytogenetic abnormality causes the
BCR-ABL fusion gene which then encodes the

BCR-ABL oncoprotein. The augmented tyrosine
kinase activity of BCR-ABL protein induces
the activation of multiple signaling pathways.
Corresponding author: Phu Chi Dung, Blood Transfusion Hematology Hospital, Hochiminh City
Email:
Received: 27/11/2018
Accepted: 12/03/2019

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Therefore, it leads to the proliferation of mature
granulocytes, reduced stromal adherence and
inhibited apoptosis.
Imatinib is the first-generation tyrosine
kinase inhibitor (TKI) which made extraordinary
progress in treating CML. A recent result
of IRIS study showed that 10-year overall
survival (OS) rate was 83.3% and the rate of
progression decreased dramatically (6.9%) [1].
However, approximately 36% of patients had to
discontinue their treatment due to unexpected
responses or adverse events. These findings
were also seen in Vietnam’s studies. [2; 3].
Management of CML patients who were
resistant to or intolerant of imatinib has been
a challenge, especially in countries with limited
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resources like Vietnam. In general, three
methods have been mentioned, including highdose imatinib, switching to second or thirdgeneration TKIs or allogeneic hematopoietic
stem cell transplantation (HSCT). Actually,
switching to another TKI (such as nilotinib,
dasatinib, bosutinib or ponatinib) is a preferred
option because they have greater effectiveness
and lower toxicities than allogeneic HSCT.
Since 2015, in Vietnam, several hospitals
have utilized nilotinib as salvage therapy for
resistant or intolerant CML. A few studies
were conducted to prove the efficacy of
nilotinib but sample size and follow-up duration
were inadequate. Thus, the main aim of this
study to determine the efficacy of nilotinib in
imatinib-resistant or intolerant CML patients
between January 2015 and December 2017 at
Hochiminh city Blood Transfusion Hematology
Hospital.

This was a retrospective, case series
study which was conducted at HCMC Blood
Transfusion Hematology Hospital from From
January 2015 to December 2017. Seventytwo patients who were resistant to or intolerant
of imatinib were recruited. Inclusive criteria
required individuals to be in chronic or
accelerated phase with ECOG performance
status score under 2. Patients did not carry
mutations which were insensitive to nilotinib
and had normal liver / renal function. The
patients who used other TKIs (not imatinib

or nilotinib) previously or had increased
risks of severe toxicities of nilotinib (such as
pregnancy, breastfeeding, history of acute
pancreatitis) were excluded. The patients with
high cardiovascular risks after nilotinib or had
the unmanageable comorbidities were not
allowed to participate in the study.
2. Study process
Figure 1 is the diagram which showed the
process of study:

II. METHODS
1. Study design

Figure 1. Flow chart of study
3. Assessment of response to nilotinib
Responses were evaluated according to the criteria of European LeukemiaNet (ELN) [4],
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including 3 types:
- Complete hematologic response (CHR)
was characterized by platelet count from 150
to 450 x 109/L, white blood cell count from 4
to 10 x109/L without blasts in peripheral blood
smear and splenohepatomegaly.
- Cytogenetic response (CyR): there were

different levels
+ Partial cytogenetic response (PCyR) was
defined as # 35% Ph+ cells.
+ Complete cytogenetic response (CCyR)
was defined as absence of Ph+ cell.
+ Major cytogenetic response (MCyR)
included both PCyR and CCyR.
- Molecular responses were divided into
2 levels: Major molecular response (MMR) if
BCR/ABL # 0.1% and complete molecular
response (CMR) if BCR/ABL fusion gene was
undetected.
4. Statistical analysis
Data were analyzed using SPSS software.
Survival probability was estimated by KaplanMeier and compared with the log-rank test.
Overall survival (OS) was defined from the start
of nilotinib to the date of death or last follow-up.
Progression-free survival (PFS) was calculated
from the date of starting nilotinib to the date of
death or last follow-up or documented disease
progression to accelerated/blastic phase.

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III. RESULTS
1. Patient characteristics
From January 2015 to December 2017, 72
patients who matched inclusive criteria were
recruited for this study. Median age at nilotinib
start was 48 years. At diagnosis, the majority of

patients were categorized into a high-risk group
according to Sokal and Eutos index (63,9%
and 76,4%, respectively). Almost all patients
with treatment failure were resistant to imatinib.
The proportion of primary resistance was more
than 60%. Mutation screening detected 30.6%
of patients carrying resistant mutations and
among them, 26.4% of cases had at least 2
mutations. Distribution of mutations in our
study was diverse, such as Q252H, G250,
M244V (P loop); L298V, M388L (SH3 domain);
E355A, E355G, M351T (SH2 domain); L387M
(activation loop); E450V, E453K, S438C
(catalytic loop). There were 47.2% of patients
receiving high-dose imatinib but only 11/34
(32.4%) achieved PCyR or better (Table 1).
Most of the patients were in chronic
phase at baseline. Before starting nilotinib,
approximately 60% of cases attained CHR
and one-third had less than 35% Ph+ cells.
In our study, about two-thirds of participants
had duration from diagnosis of resistance/
intolerance to nilotinib over 1 year (Table 1).

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Table 1. Patient characteristics
Characteristic

Median age at nilotinib start (range)
Gender, n (%)

Best response to standard-dose imatinib (400mg/day)

Imatinib resistance or intolerance

n = 72
48 (16-77)

Male

45 (62.5%)

Female

27 (37.5%)

Complete hematologic response (CHR)

40 (55.6%)

Complete cytogenetic response (CCyR)

6 (8.3%)

Partial cytogenetic response (PCyR)

13 (18.1%)

Major molecular response (MMR)

7 (9.7%)

No response

6 (8.3%)

Imatinib resistance

60 (83.3%)

Imatinib intolerance

12 (16.7%)

Mutations associated with imatinib
resistance

22 (30.6%)

Receiving high-dose imatinib before
starting nilotinib

34 (47.2%)

Phases of CML at baseline

Chronic phase
Accelerated phase

Duration from diagnosis of resistance/ ≤ 1 year
intolerance to nilotinib
> 1 year

67 (93.1%)
5 (6.9%)
28 (38.9%)
44 (61.1%)

2. Response assessment after nilotinib
In our study, at 6 months, there were 97.2% of patients achieving CHR. The 24-month rate of
CCyR and MCyR were 51,3% and 80.3%, respectively. We found that 44.8% of patients attaining
MMR, of whom 12 cases had CMR (12.7%) (Figure 2).

Figure 2. Cumulative incidence of responses after nilotinib
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There was a significant correlation between
the rate of CCyR and age at nilotinib start,
deep responses to high-dose imatinib, Ph+ #
35% before nilotinib or duration from diagnosis
of resistance/intolerance to nilotinib (Table 2).

of mutations, Ph+ # 35% before nilotinib
or duration from diagnosis of resistance/

intolerance to nilotinib (Table 2). A multivariate
analysis demonstrated that the patients who
had Ph+ # 35% before nilotinib or duration
from diagnosis of resistance/intolerance to
nilotinib # 1 year achieved better CCyR and
MMR (p < 0.05).

On the other hand, achievement
of MMR was significantly related to deep
responses to high-dose imatinib, the presence

Table 2. Univariate Cox regression analyses of patients’ characteristics and 24-month
CCyR, MMR.
n

24-month
CCyR

≤ 40

30

64.4%

> 40

42

31.7%

Reponse to highdose imatinib

Not achieve MCyR

24

17.9%

Achieve MCyR

11

89.4%

Mutation of BCR/
ABL

No
Yes

22

58.9%

Ph+ ≤ 35% before
nilotinib

No

46

30.8%

Yes

26

84.3%

28

70.0%

44

38.3%

Variable

Age

Durarion from
≤ 1 year
diagnosis of resistance/intolerance to > 1 year
nilotinib

50

47.9%

p

0.029
0.003

0.165

0.000

24-month
MMR
57.9%
38.3%
15.4%
69.3%
38.9%
57.8%
21.2%
79.7%

p

0.099
0.002

0.019

0.000

60.2%

0.005

34.9%

0.030

3. Survival rates
After 2 years of nilotinib, overall survival
(OS) was 98.5% and progression-free survival
(PFS) was 91.4% (Figure 3). Subgroup
analysis showed that chronic-phase patients
had better survival (2-year OS 100% and PFS
93.8%) than those in accelerated phase (2year OS 75.5% and PFS 40.0%) (p = 0.000).

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In addition, the groups achieving CCyR and
MCyR after nilotinib had greater PFS (2-year
PFS was 100% and 97.8%, respectively) than
those without these responses (2-year PFS
was 82.8% and 75.6%, respectively) (p = 0.010
and 0.001). However, two factors did not affect
OS (p= 0.264 and 0.751).

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Figure 3. Overall survival (OS) and progression-free survival (PFS) after nilotinib

IV. DISCUSSION
In our study, more than 80% of patients were resistant to imatinib. Several mechanisms were
involved in imatinib resistance, such as BCR/ABL overexpression, abnormalities of drug pumps or
alternative pathways…[5]. However, point mutations of BCR/ABL still played an important role so
that structural changes affected drug binding. The incidence of resistant mutations in this study was
30.6% higher than the rates in the reports of Takahashi [6] and Kuo [7]. In our insufficient conditions,
late switching from imatinib to other second-generation TKIs after imatinib resistance/intolerance
was confirmed may result in reproliferation of cancer cells and the rapid emergence of mutations
in BCR-ABL. This can explain our relatively higher rate of mutations than others in some countries.

We found that 6-month CHR was 97.2%. Our 24-month CCyR, MCyR and MMR were
51.3%, 80.3%. and 44.8%, respectively. These results were similar to those of other reports which
demonstrated the good efficacy of using nilotinib in Vietnam (Table 3).
Table 3. Compare the rates of response to other studies
Reference

CHR

CCyR

Kantarjian
H.M.
(n = 321) [8]

NR

44%
(24 months)

Kuo C.Y.
(n = 85) [7]

80.0%
75.3%
(6 months) (24 months)

Takahashi
N.
(n = 49) [6]

73.9%
(12 months)

Our study
(n = 72)

97.2%
51.3%
(6 months) (24 months)

MCyR

MMR

OS

PFS

59%

28%
87%
64%
(24 months) (24 months) (24 months) (24 months)
85.6%
56.8%
(24 months) (24 months)

NR

87%
47.8%
95%
(12 months) (12 months) (36 months)

NR
NR

80.3%
44.8%
98.5%
91.4%
(24 months) (24 months) (24 months) (24 months)

According to our analysis, there was a significant correlation between age and achievement of
24-month CCyR. This finding was also recognized in studies of Lipton [9] and Giles [10]. Therefore,
elder patients should receive a different treatment strategy in order to optimize responses but
reduce toxicities as much as possible.
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Interestingly, our patients with imatinibresistant mutations more likely attained
MMR than those without mutations. All of
the mutations occurring in this study had low
IC50. Although Jabbour and his colleagues
just paid attention to CCyR, they realized
that the patients who carried low-IC50
mutations achieved better responses than
those without mutations [11]. Thus, screening
mutations before starting second- or thirdgeneration TKIs is an important component
which helps physicians not only choose the
suitable medications but also predict long-term
responses of CML patients [12].
Previous deep responses to imatinib were
associated with the likelihood of achieving
responses to nilotinib. This finding was clearly
demonstrated in the study of Koren-Michowitz
[13]. The good responses to imatinib were
identified as the percentage of Ph+ cells
before starting nilotinib. The study of Jabbour
indicated that patients who had the lower
percentage of Ph+ cells attained better CyR
rate [14]. Our study also determined this
significant relationship.
We provided strong evidence that late
switching to nilotinib after confirming imatinib
resistance/intolerance dramatically affected

the achievement of CCyR and MMR. The
data of TIDEL-II study demonstrated that early
switching to nilotinib had more benefits [15].
There are several possible explanations for this
prolonged waiting time for using nilotinib, but
commonly it might be related to inaccessibility
to second- or third-generation TKIs in Vietnam.
This may lead to the uncontrollable proliferation
of malignant cells which is accompanied by
genetic instability. Consequently, it is possible
to emerge new mutations which impact the
outcome of other TKIs.
At 24 months of nilotinib, the probability
34

of OS and PFS were comparable to those in
other studies (Table 3). Again, these results
indicate that nilotinib was effective in resistant
or intolerant patients of Vietnam.
Subgroup analysis revealed that phases
of the disease had an important correlation
with both OS and PFS. This finding was also
consistent with several previous studies of
Kuo, Rossi and Jabbour [7; 14; 16]. Patients
with accelerated phase had intrinsic resistant
mechanisms, such as stronger BCR-ABL
overexpression, greater genetic instability and
high risk of acquiring new mutations. Although
nilotinib was still beneficial for patients with
accelerated phase, an intensive therapy should

be required to well manage the disease, such
as hematopoietic stem cell transplantation.
Achievement of CCyR after TKIs is usually
a good indicator of the superior outcome.
Our study provided additional evidence that
attaining MCyR or CCyR reduced the risk
of disease progression. This relationship
was enhanced in the study of Jabbour [14].
Generally, careful monitoring of cytogenetic
tests should be maintained regularly in order
to early identify and manage the patients
with treatment failure and prevent disease
progression. The major limitation of this study
lies in the fact that the sample size was small
and lack of random assigment. However it
showed some benefits of nilotinib in treating
resistant or intolerant CML patients in Vietnam.

V. CONCLUSION
Taken together, our study contributed some
evidence about the efficacy of nilotinib for CML
patients who were resistant to or intolerant
of imatinib in Vietnam. To improve further
responses to nilotinib, switching to second- or
third-generation TKIs should be implemented
as soon as possible when patients are
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diagnosed as resistant/intolerant CML,
especially for those who maintain cytogenetic
responses.

MAIN RESEARCH
Evaluating the efficacy of nilotinib in chronicphase chronic myeloid leukemia patients who
were resistant to or intolerant of imatinib.

ACKNOWLEDGMENTS
We would like to thank all patients who
participated in our study; HCMC Blood
Transfusion Hematology Hospital; and our
colleagues for their assistance in the study.

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