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Petrola MJ, Castro AM, Pitombeira MH, Barbosa MC, Quixadá AT, Duarte FB, Gonçalves RP
Rev Bras Hematol Hemoter. 2012;34(5):352-5
study patients. In recent years, there has been a decrease in mean
age at diagnosis of CML. Studies in India, Pakistan and Brazil
showed mean ages of 38, 35 and 41 years, respectively. This
fact may be attributed to the occurrence of widespread routine
screening, as well as genetic factors, environmental factors and
public health
(23,24)
.
The prognosis of CML may vary significantly even in
patients who are at the same stage of the disease. Strategies for
risk stratification are important as a guide for the prognosis and
treatment of patients. The Sokal score is the most widely used
and has prognostic significance for factors such as age over
60 years, spleen size, platelet count above 700 x10
9
/L and the
number of basophils and blasts in peripheral blood and bone
marrow
(25,26)
. In the present study, most patients treated with
second-generation TKIs had high Sokal risk at diagnosis and
were in advanced stages of the disease at the time of the study.
This finding suggests that the Sokal score, although it was
created for patients on drugs that are no longer used to treat this
disease, retains its predictive value after the advent of TKIs to
treat CML as has been reported in recent studies
(27)
.
Markers of cell damage are being studied in order to
elucidate the role of oxidative stress in CML
(28)
. These include
the free radical, nitrite (NO
2
-
), which is associated to direct
damage of cellular components and MDA, which reflects the
extent of lipid peroxidation and modulates the expression
of genes related to promoting tumor progression. Previous
studies have shown severe oxidative stress in CML and other
hematological cancers
(29-35)
.
Imatinib has been u
s
ed as first-line therapy for CML
providing lasting responses in most patients, especially those
in the chronic phase. Even so some in the chronic phase and
a higher proportion of patients in the more advanced stages
of CML are resistant or intolerant to imatinib
(36)
. Mechanisms
of resistance to imatinib can be classified as BCR-ABL
independent or dependent. The first group includes the binding
of imatinib-α 1-acid glycoprotein, increased expression of
drug efflux pumps and reduced expression of drug influx
transporters. The BCR-ABL dependent mechanisms are
increased expression of the oncoprotein and point mutations
in the tyrosine kinase domain. These are the most common
occurrences in imatinib resistance
(8,37,38)
.
Second-generation TKIs (dasatinib and nilotinib) are
inhibitors of multiple targets, able to inhibit the active and inactive
forms of the bcr-abl tyrosine kinase protein as well as Src family
kinases. In addition, second-generation TKIs have been shown
to be active against all the mutations of the Bcr-Abl oncoprotein
resistant to imatinib except T315I
(8,37-39)
.
In the present study, patients treated with second-generation
TKIs had significantly higher levels of nitrite and MDA when
compared to patients treated with imatinib. Such results suggest
that oxidative stress parameters can be used to predict lack of
response to 1st generation TKIs. Patients who are refractory to
imatinib had higher levels of oxidative damage markers, possibly
due to a high rate of additional mutations, the leading causes of
resistance to first-line therapy. Studies show that the occurrence of
mutations is closely associated with oxidative stress and disease
progression
(39)
. Therefore, it is likely that reactive oxygen species
(ROS) participate in combination with the BCR-ABL gene by
introducing new mutations in the fusion protein, including those
that cause resistance to imatinib
(40,41)
.
The results of this study suggest that high levels of oxidative
stress may be associated with mutations that cause resistance
to first-line treatment. Moreover, high levels of oxidative stress
markers are associated with the group of patients with high
Sokal scores suggesting that this score may also be useful as
a prognostic tool to identify patient’s response to imatinib.
However, detailed studies are needed to identify the origin of
oxidative stress and the ROS produced by cells in BCR-ABL
to better understand the role and prognostic impact of elevated
levels of ROS in CML.
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