Myeloid Leukemia

94 Branford and Hughes
blast crisis, which is distinguished by large numbers of immature blast cells
that populate the bone marrow and peripheral blood. The only chance of cure
for selected patients is an allogeneic transplant, which is most successful if
performed early after diagnosis while the patient is still in the chronic phase.
However, the procedure is associated with considerable morbidity and mortality.
Treatment options for patients with CML have been substantially improved
in recent years by the use of the specific tyrosine kinase inhibitor imatinib
mesylate (Glivec, Novartis Pharmaceuticals, Basel, Switzerland) (4–9). The
inhibitor binds to the Bcr-Abl protein in the inactive conformation by binding
to amino acids in the ATP binding pocket of the ABL kinase domain and blocking
ATP binding (10,11). The downstream signal transduction pathways are
thereby blocked, because the transfer of phosphate from ATP is prevented.
Phosphorylation of proteins in the signal transduction pathways has a critical
role in a range of biological processes, including cell growth, differentiation,
and apoptosis. Imatinib therapy leads to growth arrest or apoptosis of BCR-
ABL-expressing cells (4,12,13).
Despite the efficacy and safety of imatinib therapy, relapse and resistance
occurs in a number of patients, particularly those in the accelerated phase or
blast crisis. Relapse occurs in almost all patients treated in the blast crisis,
while approx 15 to 20% of chronic-phase patients also relapse within the first
2–3 yr of therapy. The majority of patients who acquire resistance after an
initial response have evidence of activated Bcr-Abl tyrosine kinase (14). The
major mechanism of activation is now recognized as point mutation within the
BCR-ABL kinase domain (14–16), and 36 different point mutations within
this region have been identified to date (refs. 15–22 and Branford, unpublished
data) (Fig. 1). It is believed that the mutations emerge under the selective pressure
of imatinib therapy, and it is likely that further mutations will be detected.
In a recent comprehensive survey of amino acid substitutions that confer resistance
using an in-vitro screen of randomly mutated BCR-ABL, numerous substitutions
were identified in addition to those reported in patients (23).
Mutations within the kinase domain can prevent imatinib from binding either
by interrupting critical contact points between imatinib and the protein or by
inducing a conformation to which imatinib is unable to bind. Biochemical and
cellular assays have demonstrated that the different BCR-ABL mutations result
in varying levels of resistance (15,17,18,24,25), and clinical studies have shown
that the location of the mutation may impact on the disease outcome. Mutations
located in a region of the kinase domain known as the P-loop confer a
worse prognosis (16,20,26). The different mutations may therefore require differing
strategies to overcome resistance, such as dose escalation for those that
confer moderate resistance, and combination therapy or transplant for highly
resistant mutations. In some cases, cessation of imatinib may be advantageous.