Biomedical Engineering Reference
In-Depth Information
E255V
Insensitive
Intermediate
Intermediate
T315I
mutation
Highly resistant
Highly resistant
Highly resistant
Multidrug-
resistant
protein-
1(MDR-1)
Substrate
for MDR-1
protein(efflux
protein)
Not a substrate for
MDR-1 protein
Substrate for
MDR-1 protein
Timing
Take with meal
Take with or
without meals
Take 1 hour before
or 2 hours after a
meal
Source
: Refs. 27, 40, 46, 49, 54, 55, and 56; Soverini S, Hochhaus A, Nicolini FE, Gruber
F. (2011) BCR-ABL kinase domain mutation analysis in chronic myeloid leukemia
patients treated with tyrosine kinase inhibitors: recommendations from an expert
panel on behalf of European LeukemiaNet.
Blood
, 118, pp. 1208-1215.
8.5.3.1
Bosutinib
Bosutinib (SKI-606) is a dual SRC/ABL TKI with 200-fold greater
potency than imatinib against BCR-ABL in biochemical assays [63].
Bosutinib (SKI-606; Wyeth) has potent antiproliferative activity
against imatinib-sensitive and -resistant BCR-ABL-positive cell lines,
including the Y253F, E255K and D276G mutants, but not the T315I
mutant. Like dasatinib, bosutinib is able to bind to both inactive
and intermediate conformations of BCR-ABL [64]. Compared with
dasatinib, bosutinib has a more favorable toxicity profile because;
bosutinib does not significantly inhibit Kit or PDGFR [64].
Early results from Phase II studies have demonstrated its
efficacy and safety [65]. Data were reported for 88 patients who
were previously treated with imatinib and dasatinib. Among the
88 patients 36 were dasatinib resistant, and 52 were dasatinib-
intolerant patients, of which 32 of 36 dasatinib-resistant and 29 of
52 dasatinib-intolerant patients were imatinib resistant. Response
rates with bosutinib were comparable to those seen in trials of
dasatinib and nilotinib in the second-line setting, including CCyR
in 50% and MMR in 52% of evaluated patients, of which 32% were
complete. At 24 months, rates of progression-free and OS were
80% and 95%, respectively. Twenty different mutations were found
at baseline in 45 (45%) of 99 patients. The CHR rate was 78% in
patients with mutations and 89% in patients without mutations,
