Biomedical Engineering Reference
In-Depth Information
3. Inhibition of apoptosis
. Multiple signals initiated by BCR-
ABL have proliferative and anti-apoptotic potential. The BCR-
ABL shifts the balance toward the inhibition of apoptosis while
simultaneously providing a proliferative stimulus [21,22].
4. Degradation of inhibitory proteins
. The BCR-ABL induces
the proteosome mediated degradation of Abi-1 and Abi-2
proteins which have inhibitory function, another mechanism
by which BCR-ABL induces cellular transformation [23].
8.5
Targeted Therapies of Chronic Myeloid
Leukemia
8.5.1
First-Generation Tyrosine Kinase Inhibitors
8.5.1.1 Imatinib mesylate
Imatinib is a 2-phenylaminopyrimidine compound [24]. The drug
was first evaluated in the second line treatment for CML following
interferon failure. In a phase II trial, 454 of the 532 patients had CP
CML. At 18 months 60% of patients had a major cytogenetic response
(MCyR) and 41% had a complete cytogenetic response (CCyR), with
no Ph-positive cells in metaphase seen in the bone marrow. At 60
months, 67% had achieved MCyR and 57% had achieved CCyR
[25]. Followed by the success of the phase II study, a phase III trial,
International Randomized study of Interferon and imatinib (IRIS
trial) was designed to compare prospectively the administration
of imatinib 400 mg with the interferon-alpha and cytarabine in
previously untreated CML-CP. The study recruited 1106 patients and
the preliminary data were published in 2003.
In the IRIS trial [26], the CCyR at 18 months was 76% for patients
in the imatinib group and 14% for those in the interferon-cytarabine
group. The rate of freedom from progression to AP or BP was 97%
and 92%, respectively. The 5-year follow-up study of the IRIS trial
showed the estimated cumulative CCyR was 87%, progression-free
survival (PFS) was 83%, and overall survival (OS) was 89% in the
imatinib group.
Seven-year follow-up data have been recently reported [27].
The OS is 86% and the event free survival (EFS) is 81% at 7 years.
Seven percent of the patients progressed to the accelerated or the
