Biomedical Engineering Reference
In-Depth Information
potent activity against most of the known imatinib-resistant kinase
domain mutations, with the exception of T315I [30,47]. Dasatinib
is also more potent than imatinib, with 325-fold greater
in vitro
activity against unmutated BCR-ABL [46]. The sensitivity of BCR-
ABL mutants to dasatinib can be classified as sensitive (IC50 ≤ 5 nM),
intermediately sensitive (IC50 = 5 to 11 nM; i.e., E255K/V and F317L)
and insensitive (IC50 > 11 nM; i.e., T315I). T315I, a contact point
mutation, is insensitive to all currently approved BCR-ABL inhibitors
[27,28,30-32,45-49]. P-loop mutated BCR-ABL is generally sensitive
or intermediately sensitive to dasatinib, with IC50 values falling in
the range of 1 to 11 nM [10,35].
The initial approval of dasatinib was based on the data from
the START program (SRC/ABL Tyrosine kinase inhibition Activity:
Research trials of dasatinib). In the START-C trial dasatinib was
evaluated in patients with CML-CP who were previously treated with
imatinib or intolerant to imatinib [23,50]. Dasatinib 70 mg twice
daily was associated with a high rate of durable cytogenetic response
in imatinib-resistant CML-CP or patients who were intolerable to
imatinib. After 24 months of treatment 62% of the patients achieved
MCyR, 53% achieved CCyR and the 47% achieved MMR. At 24 months
the PFS was 75% with the imatinib-resistant group and 94% in the
imatinib-intolerant group. The OS was 92% and 100% in imatinib-
resistant and imatinib-intolerant group, respectively.
The first approved dose of dasatinib was 70 mg twice daily for all
stages of CML. The label has been updated after the open label dose
optimization study, in which patients were randomized (1:1:1:1) to
receive 100 mg once daily, 50 mg twice daily, 140 mg once daily or
70 mg twice daily [51,52]. The patients on the 100 mg arm showed
equivalent efficacy compared with the 70 mg twice daily dosage arm
and demonstrated fewer grade 3 and 4 adverse effects (AEs; 30%
vs. 48%) with the 100 mg dosage. Most significantly the 100 mg
dose was associated with less pleural effusions (7% vs. 16%). The
patient's adherence to the medication was superior with the 100 mg
dosage. The recommended starting dose for imatinib-resistant CML-
CP or imatinib-intolerant patients is 100 mg once daily.
[33,53] assessed the response of dasatinib in
imatinib-resistant patients based on the baseline mutational status.
The patient s with p-loop mutations had a CCyR of 43% and 42% on
all other mutations except those with T315I and F317L mutations.
In this study no patients with T315I mutation achieved CCyR and
Mueller
et al.
