Patan hospital experience in treating philadelphia chromosome/BCR-ABL1 positive chronic myeloid leukemia patients with gleevec (imatinib mesylate); the first generation specific tyrosine kinase inhibitor.

Abstract

Chronic Myeloid Leukemia (CML) is caused by the abnormal fusion protein BCR-ABL1, a constitutively active tyrosine kinase and product of the Philadelphia chromosome. Gleevec (Imatinib mesylate) is a selective inhibitor of this kinase. Treatment with this agent is known to result in hematologic, cytogenetic, and molecular responses. Patan hospital (Patan, Nepal) is one of the Gleevec International Patient Assistance Program (GIPAP) centers for patients with CML.
A total of 106 Philadelphia positive CML patients were enrolled in our center between Feb 2003 and Jun 2008, and 103 of them were eligible for cytogenetic and/or hematologic response analyses.
Out of 103 patients, 27% patients underwent cytogenetic analysis. Imatinib induced major cytogenetic responses in 89% and complete hematologic responses in almost 100% of the patients with confirmed CML. After a mean follow up of 27 months, an estimated 90% of the patients on imatinib remained in hematologic remission and more than 90% of the patients are still alive. About 30% of patients developed some form of manageable myelosuppression. A few patients developed non-hematologic toxic side effects such as edema and hepatotoxicity.
Our study demonstrates that imatinib is safe to use in a developing country. Furthermore, we demonstrate that imatinib is very effective and induced long lasting responses in a high proportion of patients with Ph chromosome/BCR-ABL1 positive CML. Imatinib is well tolerated by our patients. The lack of cytogenetic analysis in the majority of our patients hindered our ability to detect inadequate responses to imatinib and adjust therapy appropriately.

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RESEARCH ARTICLEOpen Access
Patan hospital experience in treating philadelphia
chromosome/BCR-ABL1 positive chronic myeloid
leukemia patients with gleevec (imatinib
mesylate); the first generation specific tyrosine
kinase inhibitor
Gyan K Kayastha1*, Padma Gurung1, Paras K Acharya1, Buddhi P Paudyal1, Bruce Hayes2, Mark Zimmerman3,
Arjun Karki1, Aaron S Mansfield4
Abstract
Background: Chronic Myeloid Leukemia (CML) is caused by the abnormal fusion protein BCR-ABL1, a constitutively
active tyrosine kinase and product of the Philadelphia chromosome. Gleevec (Imatinib mesylate) is a selective
inhibitor of this kinase. Treatment with this agent is known to result in hematologic, cytogenetic, and molecular
responses. Patan hospital (Patan, Nepal) is one of the Gleevec International Patient Assistance Program (GIPAP)
centers for patients with CML.
Methods: A total of 106 Philadelphia positive CML patients were enrolled in our center between Feb 2003 and
Jun 2008, and 103 of them were eligible for cytogenetic and/or hematologic response analyses.
Results: Out of 103 patients, 27% patients underwent cytogenetic analysis. Imatinib induced major cytogenetic
responses in 89% and complete hematologic responses in almost 100% of the patients with confirmed CML. After
a mean follow up of 27 months, an estimated 90% of the patients on imatinib remained in hematologic remission
and more than 90% of the patients are still alive. About 30% of patients developed some form of manageable
myelosuppression. A few patients developed non-hematologic toxic side effects such as edema and hepatotoxicity.
Conclusions: Our study demonstrates that imatinib is safe to use in a developing country. Furthermore, we
demonstrate that imatinib is very effective and induced long lasting responses in a high proportion of patients
with Ph chromosome/BCR-ABL1 positive CML. Imatinib is well tolerated by our patients. The lack of cytogenetic
analysis in the majority of our patients hindered our ability to detect inadequate responses to imatinib and adjust
therapy appropriately.
Background
Chronic myeloid leukemia (CML), is a myeloprolifera-
tive disorder caused by a translocation between chromo-
somes 9 and 22 that results in the Philadelphia (Ph)
chromosome [t(9;22) (q34;q11)] [1]. The Ph chromo-
some was found to encode a reconstituted fusion gene
known as BCR-ABL1, which is the principal cause of
CML [2]. The BCR-ABL1 fusion gene encodes the BCR-
ABL1 oncoprotein. This oncoprotein, which is constitu-
tively active due to its uncontrolled tyrosine kinase
activity, activates signal transduction pathways that lead
to DNA replication and cell proliferation [3-5].
The incidence of CML is similar in countries around
the world and may affect ethnic groups equally. The
annual incidence of CML in the US is 1.6 cases per
100,000 adults (approximately 5000 new cases per year),
with a male-to-female ratio of 1.4 to 1 [6,7]. The median
age at diagnosis is approximately 55 years, with fewer
than 10% of patients under the age of 20 years [8].
* Correspondence: kayasthagk@hotmail.com
1Department of Internal Medicine, Patan Hospital, Lalitpur Nepal
Full list of author information is available at the end of the article
Kayastha et al. BMC Blood Disorders 2010, 10:8
http://www.biomedcentral.com/1471-2326/10/8
© 2010 Kayastha et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.

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During the chronic phase of the disease there is clonal
expansion of myeloid cells which continue to differenti-
ate. Over time, however, the leukemic clone loses their
ability to differentiate, and the disease ultimately pro-
gresses to blast crisis [3,9,10].
Until the 1980s, CML was regarded as incurable and
thus inevitably fatal. Only some selected patients could
afford treatment with, and in many cases were cured by
allogeneic stem cell transplantation. However, because of
the scarcity of matching donors and the high incidence
of potentially fatal graft-versus-host disease in older
patients, allogeneic stem cell transplantation is often not
a feasible treatment strategy. Imatinib [11-16], is a potent
first generation selective inhibitor of tyrosine kinase
activity of BCR-ABL1. It was first approved by the Food
and Drug Administration for CML in May 2001 and has
been proven to be one of the most effective medications
in achieving hematologic and cytogenetic remissions.
Imatinib is a major break-through in the management of
CML and has become the standard first line treatment
strategy in the management of CML [17].
Patan hospital is the first Gleevec International Patient
Assistance Program (GIPAP) center in Nepal. GIPAP
was introduced by Dr. Zimmerman, the medical director
of this hospital at that time, for patients with Ph chro-
mosome/BCR-ABL1 positive CML since February 2003.
Under this program patients with Philadelphia chromo-
some/BCR-ABL1 positive CML who cannot afford Ima-
tinib receive it free of cost.
Methods
Study Design
Patients with Ph Chromosome/BCR-ABL1 positive CML
at any stage of the disease were eligible for enrolment in
GIPAP irrespective of prior therapy. Patients diagnosed
with CML by blood and by bone marrow evaluation in
our hospital, or referred from other hospitals, were sent
for Ph chromosome/BCR-ABL1 analysis. All positive
cases were enrolled in GIPAP. Patients who were diag-
nosed with CML and found to be Ph chromosome/
BCR-ABL1 positive in other hospitals and referred to
our hospital were also enrolled in GIPAP. Hydroxycar-
bamide and other medications for the treatment of
CML were tapered off over a few days. Before com-
mencement of the treatment with imatinib patients were
screened for adequate renal and hepatic function, along
with assessment of their performance status. Written
informed consent was obtained from all patients before
they were enrolled in GIPAP. Ethical approval was not
considered necessary as GIPAP made available treat-
ment that was already considered standard of care.
Patients were assigned to receive imatinib 400 mg/day
for chronic phase and 600 mg/day for accelerated phase
and blast crisis. Patients received continuous therapy
unless unacceptable adverse effects or disease progres-
sion occurred. No other anticancer therapy was given.
All patients received allopurinol until the total WBC
count was 20,000/mL or less.
Complete blood counts and liver function tests were
obtained once a week for the first month, every two
weeks for next 2 months, and every 6 weeks afterwards.
Patients were monitored for any adverse effects, clinical,
and hematologic responses. Cytogenetic analyses were
done for those patients who could afford this test, and
patients who developed resistance to imatinib under-
went mutation analysis. Only three patients underwent
mutation analysis. Standard protocol for managing
adverse effects during imatinib therapy was followed.
Assessment of Toxicity and Response
Safety assessments included the evaluation of adverse
events and vital signs, hematological tests, biochemical
tests, and physical examination. Toxicity was graded in
accordance with the Common Toxicity Criteria of the
National Cancer Institute.
Results
Patient Enrolment and Characteristics
Enrolment in GIPAP was started in Feb 2003. During
the period from February 2003 to June 2008, a total of
106 patients ranging from age 10 to 71 years (median
39) were enrolled in GIPAP in our hospital. Starting
with the first patient in February 2003, the enrolment
steadily increased over the years. The most patients
were enrolled in 2006 and 2007, with 26 and 23 patients
in each of those years respectively. Most of the patients
were from the Kathmandu and Lalitpur districts. There
were patients from 37 of the 75 districts of Nepal.
There were 70 males and 36 female patients (Table 1).
The majority of the patients were in the 31-50 years age
group (51%) (Table 2). Of the total 106 patients, 29
patients were diagnosed at Patan Hospital and the rest (77
patients) were referred from other hospitals for GIPAP
assistance. Of the 77 referred patients 36 patients were
diagnosed by blood and/or bone marrow in different hos-
pitals in Nepal and required additional investigations
including Ph chromosome/BCR-ABL1 translocation sta-
tus. The remaining 41 patients were referred from other
hospitals for GIPAP enrolment after confirmation with Ph
chromosome/BCR-ABL1 translocation analysis.
Of the total 106 patients, three patients were excluded
from the study and the remaining 103 patients were eli-
gible for analysis. The three patients excluded were: one
who died before starting imatinib, one who registered
but did not show up afterwards, and one who registered
but then moved to another country. Among the 28
patients who were diagnosed at Patan hospital, only 10
patients presented with abdominal complaints such as
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abdominal fullness, swelling, mass, early satiety, abdom-
inal discomfort or pain. The remaining patients pre-
sented with other diverse complaints.
Of the 103 patients, 96 patients were in chronic phase,
5 patients were in accelerated phase, and two patients
were in blast crisis at the time of presentation. During
enrolment, there were 61 patients on hydroxycarbamide,
one on busulfan, and one on imatinib. Two other
patients were taking combination therapy; one with
hydroxycarbamide and imatinib and the other one was
on hydroxycarbamide with busulfan (Table 3). The
mean follow up was 27 months (median 24, range 1-66).
Twenty-nine patients had repeated quantitative Ph chro-
mosome/BCR-ABL1 status; most of them by Fluorescent
In-Situ Hybridization (FISH) method.
Safety profile
Imatinib was generally well tolerated. The most notable
adverse effects were some form of myelosuppression:
neutropenia and/or thrombocytopenia. Grade 1 or 2
elevation of liver enzymes, edema and weight gain,
rashes, nausea, vomiting and diarrhea were other com-
mon adverse effects. Patients treated with higher doses
of imatinib were more likely to develop grade 1 or 2
nausea, edema, or diarrhea than patients given lower
doses of the drug. Neutropenia and/or thrombocytope-
nia were the most frequent adverse effects and occurred
in about 30% of the patients (Table 4).
There was a total of 2 deaths and 8 patients lost to
follow up. Of the 2 deaths both of them died due to dis-
ease progression and subsequent complications. Of the 8
patients lost to follow up, two patients who did not
return for follow-up were found to have died due to dis-
ease progression and blast crisis. The causes of death of
the other 6 patients are not known.
Hematologic and cytogenetic responses
Out of 103 patients, 15% of the patients were already in
complete hematologic remission before enrolment in
GIPAP. Seventy-eight percent of the patients went into
complete hematologic remission within 3 months of
starting imatinib and only seven percent of the patients
took more than 3 months for complete hematologic
remission. Of the 29 patients who had cytogenetic ana-
lysis done, 26 (89.66%) patients had major cytogenetic
response [20 (68.97%) Complete Response and 6
(20.69%) Partial Response], 2 (6.89%) patients had minor
cytogenetic responses, and 1 (3.45%) patient had mini-
mal cytogenetic response (Table 5). The cytogenetic
testing was performed between 9 and 61 months (med-
ian 26 months) from enrolment in patients who were
able to afford testing.
Table 1 Patient characteristics
Patient categories Number of
Patients
Eligible Patients
HRCR Total
Registered in GIPAP
Diagnosed in Patan
Diagnosed at Other
Hospitals
Excluded
Chronic Phase
Accelerated Phase
Blast Crisis
Male/Female
Follow up (Mean/
Median) (m)
Age (mean/median)
Lost to f/u
Mortality
106
29
77
74
16
58
29
12
17
103
28
75
3
98
5
3
70/36
27/24
0
69
5
0
51/23
23/19
0
27
0
2
17/12
39/42
0
96
5
2
68/35
27/24
39/39
8
2
39/40
8
2
38/38
0
0
39/39
8
2
HR = hematologic response
CR = cytogenetic response
Table 2 GIPAP enrolment by age groups
GIPAP Enrollment by Age Groups
Age groupsNo of patients
< 20
21-30
31-40
41-50
51-60
61-70
71-80
Total
13
16
31
23
13
8
2
106
Table 3 Medication use at enrolment
Medication Use at Presentation
MedicationsNo
Hydroxycarbamide
Busulfan
Imatinib
Hydroxycarbamide+Imatinib
Hydroxycarbamide+Busulfan
No anticancer drugs
61
1
1
1
1
41
Total106
Table 4 Adverse effects
Side EffectsNo of PatientsSide Effects No of Patients
Wt Gain
Rashes
Swelling
Nausea
Vomiting
Diarrhea
6
6
9
5
5
5
Pigmentation
Hepatotoxicity
Myelosuppresion
Gum bleeding
Mild arthralgia
Others
4
9
31
3
2
9
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Of the 29 patients who underwent cytogenetic analysis,
four patients who had had major cytogenetic responses
initially showed minimal to minor responses with subse-
quent FISH analysis. Two of these patients were actually
taking reduced doses of imatinib. Another patient tem-
porarily stopped taking imatinib. All three of them
responded to dose escalation. The fourth patient
responded temporarily to an increased dose but even-
tually relapsed. This patient who relapsed had been to
other hospitals in India and had been treated with inter-
feron and other chemotherapeutic medications before
starting imatinib. He had a complete hematologic
response only for few months after the beginning of ther-
apy at our hospital. He underwent dose escalation to 600
mg/day initially and then to 800 mg/day, but complete
hematologic response was not achieved. Quantitative
BCR/ABL by FISH repeated after 6 months showed par-
tial cytogenetic response, but repeat analysis showed lack
of response. Subsequent mutation analysis revealed a
F359V mutation in the ABL domain of the BCR/ABL
oncogene. This patient may have developed secondary
resistance due to the mutation. Even with the change of
medication to the second generation tyrosine kinase inhi-
bitor nilotinib, his response was not satisfactory. While
preparing for this presentation this patient started taking
dasatinib and he is responding well to this drug. One
more patient who developed secondary hematologic fail-
ure showed loss of complete cytogenetic response upon
repeat cytogenetic analysis by FISH. Subsequent muta-
tion analysis in this patient revealed L387 M mutation in
the ABL domain of BCR/ABL oncogene. This patient is
responding to an increased dose of imatinib.
The cumulative survival (including 2 deaths and 8 lost to
follow up) is more than 80% (figure 1) with a mean follow
up period of 27 months. The overall Survival function
(with 4 confirmed CML deaths excluding lost to follow
up) is 92% (figure 2) without any difference in mortality
between sexes (figure 3). The cumulative survival
approaches 100% in patients who underwent cytogenetic
analysis (figure 4). Of the 103 CML patients on imatinib,
about 90% of the patients did not progress to the acceler-
ated phase or blast crisis with a median follow up of 24
months, and more than 90% of them are still alive.
We also looked at differences between characteristics
of patients who were analyzed for both cytogenetic and
hematologic responses compared to those who were
analyzed for only hematologic response. All the patients
who died or lost to follow up were from the group who
only had hematologic analysis performed, and had not
repeated cytogenetic analysis. Patients with cytogenetic
analysis had a longer follow up. The cumulative survival
approaches 100% in the group who had repeated cytoge-
netic analysis (figure 4).
Discussion
The prevalence of CML is more common in the 31-50y
age group in our study than in most demographic
Table 5 Hematologic and cytogenetic analyses
Hematologic AnalysisCytogenetic Analysis
Total patients
Excluded
Total Patients Eligible
CHR at Presentation
CHR in <3 months
CHR in >3 months
106
3
103
15
81
7
Complete
Partial
Major
Minor
Minimal
Total
20
6
26
2
1
29
68.97%
20.69%
89.66%
6.89%
3.45%
100%
15%
78%
7%
CHR: complete hematologic response
Figure 1 Kaplan-Meier of cumulative survival of all patients.
This figure shows the cumulative survival of all patients enrolled in
GIPAP.
Figure 2 Kaplan-Meier of cumulative survival of patients
excluding those lost to follow-up. The cumulative survival of
patients, excluding those lost to follow-up, enrolled in GIPAP is
shown.
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studies. The demographic characteristics between
patients with or without cytogenetic analysis were not
significantly different. Most of the patients were from
Kathmandu and Lalitpur districts. Patients who had
cytogenetic analysis repeated had a longer follow up
period compared to the patients who had not. The
increased number of deaths seen in patients who had
not repeated cytogenetic analysis might be related to
not being able to assess optimum responses to therapy.
Imatinib is currently the standard frontline therapy for
treatment of CML. Druker and colleagues’ five year fol-
low-up of chronic phase CML patients treated initially
with imatinib showed that the cumulative best rates for
complete cytogeneticresponses andcomplete
hematologic response were 87% and 98% respectively
[11]. An estimated 7% of the patients progressed to
accelerated or blast phase. The overall survival rate was
89%, with more patients dying from causes unrelated to
CML than their disease. Review of the International
Randomized Study of Interferon vs STI571 (IRIS) data
suggests that 63% of patients were successfully treated
by imatinib at five years, while 37% of patients were no
longer receiving the drug. In our study at Patan, 89.7%
of our patients had major cytogenetic response (BCR-
ABL1/Ph chromosome 0-34%), 6.9% of our patients had
minor cytogenetic responses (BCR-ABL1/Ph chromo-
some 35-64%), and 3.4% of our patients had minimal
cytogenetic response (BCR-ABL1/Ph chromosome 65-
94%). After a mean follow up of 27 months (median fol-
low up 24 months), CML had not progressed to the
accelerated phase or blast crisis in 90% of the patients
and more than 90% of the patients are still alive. Our
patients’ responses to imatinib were similar to those
reported in IRIS by Druker and colleagues.
Importantly, our study establishes that imatinib is safe
to use in a developing county. Myelosuppression was
the most common side effect, and this was easily moni-
tored in our setting with complete blood counts. Our
monitoring allowed for appropriate dose adjustments.
Quite often patients on imatinib develop resistance,
and the identification of resistance should trigger muta-
tional analysis of BCR-ABL1 kinase domain. Reviews on
managing imatinib resistance have been published
[18-22]. A few of our patients treated with imatinib
relapsed, reflecting the emergence of resistance to imati-
nib. Although there are multiple mechanisms involved
in the emergence of resistance, usually resistance devel-
ops because of a mutation in the adenosine tripho-
sphate-binding pocket of the BCR-ABL1 oncoprotein,
which makes imatinib binding impossible. Molecular
studies of resistant CML cells have been performed and
have identified mutations that mediate this effect
[23-27]. Several potent inhibitors of imatinib-resistant
BCR-ABL1 have been identified and approved for clini-
cal use [28-32]. Two of our patients developed second-
ary hematologic failure. Subsequent mutation analyses
revealed mutations in ABL domain of BCR/ABL onco-
gene. The patient who had the L387 M mutation
responded to dose escalation of Imatinib to 600 mg/day
from 400 mg/day [33-36]. Another patient who had
F359V mutation did not show response even with dose
escalation to 800 mg/day. He was switched to second
generation tyrosine kinase inhibitor (TKI) nilotinib but
the response was not satisfactory. Failure to achieve
major cytogenetic response by 12 months usually
defines inadequate response [37]. He was then switched
to dasatinib (another second generation TKI) and the
response was remarkable. He went into hematological
Figure 3 Kaplan-Meier of survival based on gender. The survival
of patients, based on gender is shown.
Figure 4 Kaplan-Meier of survival based on cytogenetic or
hematologic follow-up. This figure demonstrates that the survival
of patients who were able to obtain cytogenetic follow-up was
superior to that of patients who only obtained hematologic
follow-up.
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