2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

RESISTANCE TO TARGETED THERAPIES IN AML AND CML
Fig. 1. Schematic depicting primary and secondary
tyrosine kinase inhibitor resistance, and on-target/offtarget
resistance mechanisms.
AML: Emerging Targets and Emerging Resistance
The success of imatinib in CML has driven the desire to
translate the paradigm of targeted therapy to other cancers,
including other hematologic malignancies such as AML.
Unlike CML however, the genetic drivers underlying AML
pathogenesis are heterogeneous, and though multiple recurrent
molecular abnormalities have emerged in recent years,
to date, no therapies targeting these lesions have been
approved. It is likely that, in contrast to the experience with
BCR-ABL, many of these molecular lesions represent cooperating
rather than initiating genetic events in disease
pathogenesis, which common wisdom would deem to be
unlikely therapeutic targets.
Among the most common genetic lesions in AML are
constitutively activating mutations of FLT3. ITD mutations
in FLT3 are found in approximately 20% of patients with
AML and are associated with poor prognosis. 29,30 Another
5% to 10% of patients with AML express constitutively
activating point mutations in the tyrosine kinase domain. 31
Despite early enthusiasm, initial attempts to target FLT3
with small molecule inhibitors were largely unsuccessful,
resulting in only transient reductions in peripheral blasts
with few bone marrow responses. 32,33 Emerging data have
further suggested that FLT3 mutations are likely secondary
rather than initiating genetic lesions in AML, hinting
that FLT3 mutations may not be critical for disease
pathogenesis. 34-36
The recent success of the investigational FLT3 inhibitor
AC220 in achieving a composite complete remission rate of
45% in an interim analysis of a multinational phase II study
in patients with relapsed/refractory FLT3-ITD–positive
AML has rekindled interest in FLT3 as a therapeutic target.
The evolution of tyrosine kinase domain mutations in eight
of eight patients whose leukemias relapsed after a bone
marrow response on AC220 confirmed that clinical response
in these patients was achieved by inhibition of FLT3, and
that relapses were mediated by the reactivation of FLT3
kinase activity. 37 Similar to BCR-ABL/T315I, F691, the
“gatekeeper” residue in FLT3, was mutated in a subset of
patients in whom AC220-resistant disease developed (to
leucine; 3 patients), but mutations at the activation loop
residue D835 developed in the remaining six patients (including
one patient in whom both a F691L and D835V
mutation developed), suggesting that substitutions at the
D835 residue may be a common cause of AC220 resistance.
These findings validate FLT3-ITD as a therapeutic target
and further suggest that the activity of “cooperating” genetic
events that are believed to occur relatively late during
evolution of the malignant clone, such as FLT3-ITD, can
nonetheless be critically important to the survival of cells in
which they arise. Though this limited study suggests that
on-target resistance mechanisms are largely responsible for
secondary resistance to AC220, the lower overall response
rates to AC220 imply that off-target mechanisms are likely
to be important in both primary and secondary resistant
cases, as has been similarly postulated in cases of AP-CML.
It is hypothesized that cooperative genetic events in AP-
CML and FLT3-ITD–positive AML can be placed into two
general categories, those that preserve reliance on the activated
oncogene and those that bypass it. The latter category
may explain the lower initial response rates in blast phase
CML and FLT3-ITD–positive AML when compared with
chronic phase CML.
It has been suggested that another potential clinically
relevant FLT3-dependent mechanism of primary resistance
may involve increases in FLT3 ligand levels following chemotherapy,
which is predicted to increase the concentration
of inhibitor required to effect cytotoxicity. 38 This mechanism
may be more relevant in patients treated concurrently with
FLT3 inhibitors and chemotherapy, and further studies are
necessary to more accurately define its clinical importance.
Other targeted therapies currently undergoing clinical
development in AML include inhibitors of mammalian target
of rapamycin, 39 PI3K, and MEK, 40 but the lack of clear
clinical efficacy to date precludes the establishment of clinically
relevant resistance mechanisms. As was the case with
inhibitors of BCR-ABL and FLT3, elucidation of clinically
relevant resistance mechanisms necessitates inhibitors that
effect deep clinical responses when administered as monotherapy
and detailed analysis of samples isolated from
patients at the time of secondary evolution.
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