BJ Druker

CL Sawyers

Inas A Asfour

M Baccarani

National Comprehensive Cancer Network (NCCN)

OG Ottmann

S Faderl

SG O'Brien

Shereen A Elshazly

English

PubMed

Springer - Publisher Connector

Changing therapy from Glivec® to a "copy" imatinib results in a worsening of chronic myeloid leukemia disease status: two case reports

BioMed CentralCases Journal
ssOpen AcceCase Report
Changing therapy from Glivec® to a "copy" imatinib results in a 
worsening of chronic myeloid leukemia disease status: two case 
reports
Inas A Asfour and Shereen A Elshazly*
Address: Department of Internal Medicine, Clinical Hematology Unit, Faculty of Medicine, Ain Shams University, Cairo, Egypt
Email: Inas A Asfour - inasasfour_@hotmail.com; Shereen A Elshazly* - drshereenahmed@gmail.com
* Corresponding author    
Abstract
Introduction: Imatinib mesylate (Glivec®/Gleevec®) is the standard first-line therapy for the
treatment of chronic myeloid leukemia due to its high hematologic, cytogenetic, and molecular
response rates and favorable long-term safety profile. A copy version of imatinib is currently
available in several countries. We report on two cases of CML who were originally treated with
Glivec in Egypt and subsequently switched to the copy drug
Case presentation: Case one was a 35-year old female with chronic myeloid leukemia in blast
crisis who began treatment with combination chemotherapy and Glivec. The patient achieved and
maintained a complete hematologic response and continued on Glivec 400 mg/day. In March 2007,
she was switched to the copy drug In September 2007, the patient presented in hematologic
relapse. At this time, treatment with chemotherapy in combination with Glivec 400 mg/day was
resumed. The patient quickly achieved, and maintained, complete hematologic response on Glivec
400 mg/day. The second patient was a 64-year old male with chronic myeloid leukemia in blast crisis
who began treatment with truncated chemotherapy in combination with Glivec 400 mg/day. After
6 months, the patient achieved a partial hematologic response and continued on alternating cycles
of chemotherapy with continuous administration of Glivec 400 mg/day. The patient received Glivec
from January 2006 to February 2007, after which time he was switched to the copy drug. In
November 2007, he presented with upper gastrointestinal bleeding and multiple gastric erosions
and died the same day.
Conclusion: The safety and efficacy of the copy drug has not been established in randomized
clinical trials. It is unknown whether patients, who respond to Glivec and then switch to copy
versions of imatinib, will tolerate the copy drug and maintain their response.
Introduction
Chronic myeloid leukemia (CML) is a clonal myeloprolif-
erative disease characterized by the presence of the Phila-
delphia chromosome. The Philadelphia chromosome is
formed from the rearrangement of the long arms of chro-
mosomes 9 and 22, resulting in the constitutively active
protein tyrosine kinase, BCR-ABL [1,2]. Without treat-
ment, CML progresses within several years from a chronic
phase (CML-CP) to an accelerated phase, and ultimately
to a blast crisis (CML-BC) which may be myeloid or lym-
phoid in origin and rapidly leads to death without inten-
sive treatment [2].
Published: 17 December 2009
Cases Journal 2009, 2:9342 doi:10.1186/1757-1626-2-9342
Received: 6 November 2009
Accepted: 17 December 2009
This article is available from: http://www.casesjournal.com/content/2/1/9342
© 2009 Asfour and Elshazly; 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.Page 1 of 4
(page number not for citation purposes)
Cases Journal 2009, 2:9342 http://www.casesjournal.com/content/2/1/9342The introduction of imatinib mesylate (Glivec/Gleevec;
Novartis Pharmaceuticals), a tyrosine kinase inhibitor of
BCR-ABL, has revolutionized the treatment of CML. Imat-
inib is widely accepted as the standard of care for the first-
line treatment of CML due to its well-documented clinical
activity resulting in durable responses and prolonged sur-
vival [3-6]. Seven year follow-up of the phase III licensing
trial, the International Randomized Study of Interferon
and STI571 (IRIS) showed sustained responses, high sur-
vival rates, and favorable long-term safety for patients ran-
domized to first-line imatinib, with a cumulative
complete cytogenetic response (CCyR) rate of 82%, rate of
freedom from progression to AP/BC of 93%, 81% event-
free survival (EFS) and 86% overall (OS) survival rate for
this group [7].
Unfortunately, cost and access to medication can be a bar-
rier to patient compliance. Recently, a copy-version of
imatinib, has become available in several countries.
Unlike a generic version of a pharmaceutical that must
demonstrate bioequivalence to the branded drug by a reg-
ulatory agency, this copy-drug claims to be "comparable"
to imatinib but has not been rigorously tested to deter-
mine its purity and efficacy. As a result of lower pricing
and easy access, often not requiring a prescription, some
patients and healthcare agencies have substituted this
copy-version for imatinib in some countries.
Here, we report 2 cases of patients diagnosed with CML-
CP, both treated in Egypt, at Ain Shams University Hospi-
tal's clinical hemato-oncology unit, who were originally
treated with branded Glivec and subsequently switched to
a copy version of imatinib.
Case presentation
Case report 1
The first patient was a 35-year old Egyptian female (Ara-
bic), diagnosed with CML-CP in 2004. She was initially
treated with hydroxyurea, resulting in control of her dis-
ease for approximately 2 years. She presented to our clinic
in September 2006 with complaints of increasing fatigue
and bruising. On clinical exam she exhibited several skin
bruises and subcutaneous bleeds, huge splenomegaly 4
cm below the costal margin hepatomegaly, and no palpa-
ble lymphadenopathy. Her initial laboratory assessment
revealed a total leukocyte count of 12.7 × 109/L, with 32%
blast cells in the peripheral blood smear, hemoglobin
(Hgb) concentration of 7.3 g/dL, and platelet count of 66
× 109/L. Bone marrow aspiration revealed a hypercellular
marrow due to infiltration, with 84% heterogeneous blast
cells exhibiting diffuse negativity for myeloperoxidase
stain and suppression of all other marrow elements.
On immunophenotypic examination the isolated blast
cells were more than 90% positive for CD34, HLA-DR,
and CD10. Eighty-four percent of isolated blast cells were
CD19 positive, with 44% positive for CD13 and 54% pos-
itive for CD33. Cytogenetic examination using the G-
band method displayed a Ph+ clone, with subclonal evo-
lution acquiring rearranged chromosomes 4 and 13. Flu-
orescent in situ hybridization (FISH) showed a
Philadelphia chromosome in all metaphase cells and 80%
in interphase cells. Other laboratory results were within
normal limits, including a negative viral screen.
A diagnosis of CML-BC was made and the patient began
treatment with combination chemotherapy (consisting of
prednisone, asparaginase, vincristine, doxorubicin, cyclo-
phosphamide, cytarabine, mercaptopurine, and meth-
otrexate) and Glivec [8]. The patient initially experienced
a hematologic response (HR) with subsequent examina-
tion after induction therapy showing a complete hemato-
logic response (CHR), defined as < 2% blasts on bone
marrow exam. The patient was maintained on Glivec 400
mg daily and remained in CHR. Cytogenetic and molecu-
lar analyses were not performed on this patient. In March
2007 the patients was switched to a copy-version of imat-
inib, at the same dose of 400 mg daily due to unavailabil-
ity of Glivec at the patient's hospital. Three months after
the change in medication, an increase in liver transami-
nases was noted on a routine follow-up visit, necessitating
a dose reduction.
In September 2007, the patient presented in hematologic
and central nervous system (CNS) relapse, with a total
leukocyte count of 7.8 × 109/L, with a differential of 77%
neutrophils, 2% myelocytes, 2% metamyelocytes, 15%
lymphocytes, and 2% immature cells. Bone marrow aspi-
ration revealed 20% blast cells which were myeloperoxi-
dase negative. Immunophenotypic examination
demonstrated similar markers to those observed at initial
diagnosis. At this time, treatment utilizing the initial strat-
egy of systemic chemotherapy in combination with
branded Glivec 400 mg daily was resumed. The patient
also received intrathecal chemotherapy for treatment of
the CNS relapse.
On day 28 after reinduction with chemotherapy and
Glivec, a CHR was documented. The patient declined
stem cell transplantation during her first remission and
again at this time. As of April 2008, seven months after
reinduction with chemotherapy and Glivec, the patient
remained in CHR on 400 mg daily Glivec. Figure 1, Figure
2 and Figure 3 illustrate the changes in her hematologic
indices over the course of treatment.
Case report 2
The second patient was a 64-year-old Egyptian male (Ara-
bic), diagnosed with CML in 1998. The patient initially
received treatment with hydroxyurea and subcutaneous
interferon. He presented to our clinic in December, 2005
with complaints of increasing fatigue, abdominal girth,Page 2 of 4
(page number not for citation purposes)
Cases Journal 2009, 2:9342 http://www.casesjournal.com/content/2/1/9342and bruising. Physical examination revealed splenomeg-
aly reaching the umbilicus and a moderate hepatomegaly
of 4 cm/below the costal margin. Initial laboratory results
revealed a total leukocyte count of 200 × 109/L3 with 66%
blast cells in the peripheral blood smear, Hgb concentra-
tion of 8 g/dL, and platelet count of 622 × 109/mL3. Bone
marrow aspiration revealed a hypercellular marrow due to
infiltration with 73% blast cells, with an increase in eosi-
nophils and basophils, constituting 14% of marrow cells.
On immunophenotypic examination, the isolated blast
cells showed an acute myeloid pattern with a major
monocytic component. Cytogenetic examination using
the G-band method revealed all cells were Philadelphia
chromosome positive. Other laboratory results showed
positivity for hepatitis C antibodies, but the patient exhib-
ited normal liver and renal function.
A diagnosis of CML-BC was made and the patient began
treatment with subcutaneous cytarabine and oral etopo-
side in combination with branded Glivec 400 mg daily.
The patient was unable to receive conventional therapy
due to poor performance status. After six months, the
patient achieved a partial hematologic response with
bone marrow examination showing a hypercellular mar-
row with 10% blast cells. The patient continued on alter-
nating cycles of oral etoposide and subcutaneous
cytarabine with continuous administration of Glivec 400
mg daily. The patient received branded Glivec from Janu-
ary 2006 to February 2007, after which he was switched to
a copy-version of imatinib 400 mg daily due to unavaila-
bility of Glivec at the patient's hospital. In November
2007, the patient presented with upper gastrointestinal
bleeding, and endoscopy revealed multiple small gastric
erosions. His hematological profile showed a total leuko-
cyte count of 188 × 109/L with 36% blast cells and marked
absolute neutrophilia and monocytosis in the peripheral
blood smear, Hgb concentration of 5.8 g/dL, and platelet
count of 539 × 109/L. The patient was given blood trans-
fusions and admitted to the hospital for further evalua-
tion. The next day his total leukocyte count doubled to
400 × 109/L, and his coagulation profile showed markers
consistent with disseminated intravascular coagulation
with hyperkalemia. Unfortunately, the patient expired the
same day.
Case 1: Changes in hemoglobinFigure 1
Case 1: Changes in hemoglobin.
Case 1: Changes in plateletsFigure 2
Case 1: Changes in platelets.
Case 1: Changes in total leukocyte countFigure 3
Case 1: Changes in total leukocyte count.Page 3 of 4
(page number not for citation purposes)
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Discussion
The advent of Glivec has greatly improved the treatment
of CML. Both patients presented here achieved adequate
responses while undergoing treatment with Glivec. Subse-
quently, both patients switched to a copy version of imat-
inib. Although other explanations might be offered (eg,
lack of compliance, advanced disease), the loss of hema-
tologic response in both patients and CNS relapse and
gastric erosions in case 1 and 2, respectively, were tempo-
rally related to the change from branded Glivec to the
copy.
Patient safety with copy drugs needs to be considered
before making a switch from Glivec. Typical clinical
results are well known with branded Glivec, the only drug
that has been tested in clinical trials and has shown cumu-
lative CCyR and EFS rates of 82% and 81%, respectively,
after 7 years of follow-up [7]. No data exists to show that
copies are safe and effective. Physicians need to be aware
of the risks associated with copy drugs, and make these
risks known to their patients. These data underscore the
importance of maintaining proper medication with care-
ful monitoring in CML patients to achieve, maintain, and
sustain hematologic responses. For this reason, Novartis
established the Glivec International Patient Assistance
Program (GIPAP). This program is one of the most gener-
ous patient assistance programs in existence and is cur-
rently available in more than 80 countries worldwide.
Conclusions
Imatinib mesylate is the current standard first-line therapy
for CML. A copy version of the drug is available in some
countries, for which patient data are limited, and this drug
has not been shown to be safe and effective in rand-
omized clinical trials. Major guidelines recommend indef-
inite continuation of imatinib treatment unless loss of
response or intolerance is experienced [5,6].
Consent
Written informed consent was obtained from the patients
or their guardians for publication of this case series and
any accompanying images. A copy of the written consent
is available for review by the Editor-in-Chief of this jour-
nal.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
IA postulated the concept and designed the study; SA
interpreted the data, reviewed the literature, and prepared
the manuscript. All authors have read and approved the
final manuscript.
Acknowledgements
Financial support for medical editorial assistance was provided by Novartis 
Pharmaceuticals. The authors thank Erinn Goldman, PhD (Articulate Sci-
ence) and Helen Leather, PhD (Articulate Science) for medical editorial 
assistance with this manuscript.
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Changing therapy from Glivec to a "copy" imatinib results in a worsening of chronic myeloid leukemia disease status: two case reports

Crossref

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Chronic myeloid leukemia.

European LeukemiaNet: Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood

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Changing therapy from Glivec® to a "copy" imatinib results in a worsening of chronic myeloid leukemia disease status: two case reports

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