2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

TARGETED TREATMENT OF NEWLY DIAGNOSED DISEASE
and less than 10% in blastic-phase CML. Similarly, achievement
of undetectable BCR-ABL levels (more than 4–4.5 log
reduction of CML burden) was observed in 20% to 50% of
patients with newly diagnosed CML treated with TKI therapy
but was uncommon in advanced CML.
Optimal Dose of Targeted Therapy
Historically, most anticancer agents have been tested at
their maximum-tolerated dose, typically defined as a dose
below the one that produced severe toxicities in less than
one third of the patients. The assumption that the
maximum-tolerated dose is optimal is based on observations
that the highest possible tolerable dose would result in the
greatest antitumor results. This assumption may not apply
to targeted therapies, as was observed with both TKIs in
CML and the response rates of targeted therapies in phase
I trials. 16 The phase I study of imatinib noted rare complete
cytogenetic responses at doses below 300 mg orally daily and
frequent complete cytogenetic responses at doses ranging
from 400 to 800 mg per day (on average, there were higher
responses with 800 mg than 400 mg). 17 Interestingly, no
further improvement in complete cytogenetic responses
were seen at doses of 1000 mg daily and above, although
these doses were reasonably tolerated by patients. The
phase II study proceeded with imatinib doses of 400 mg
orally daily based on the imatinib plasma levels that were
anticipated to produce maximum anti-CML activity. Higher
doses of imatinib (800 mg daily) were later observed to
induce higher rates of complete cytogenetic and major molecular
responses, but the additional benefit (as measured by
survival) was controversial. The experience with nilotinib
indicated that despite the long half-life of the drug, gastrointestinal
absorption plateaued at a dose of 400 mg, resulting
in schedules of 400 mg orally twice daily, implemented
into phase II studies in late chronic-phase CML.
The randomized studies of nilotinib compared with imatinib
in newly diagnosed CML (Evaluating Nilotinib Efficacy
and Safety in clinical Trials-Newly Diagnosed patients
[ENEST-nd] trial) also compared a lower dose schedule of
nilotinib, 300 mg twice daily, with the approved standard
dose of 400 mg twice daily, demonstrating the equal efficacy
of the lower dose schedule and the benefit of a lower cost
and toxicity. 14 Nilotinib 300 mg orally twice daily is now the
standard dose schedule for newly diagnosed CML. The early
studies with dasatinib suggested twice-daily schedules
(based on the short half-life of the drug) and doses of 140 mg
daily to be optimal. Subsequent randomized trials of four
different schedules established the single-daily 100 mg dose
of dasatinib to be the optimal schedule (equal efficacy, lower
toxicity), which is now used as the standard of care in
CML. 15 These studies suggest that treatment with optimal
biologic dosages, as opposed to maximum-tolerated doses, of
TKIs in CML is best.
This finding has subsequently been validated by the
experience with epigenetic therapy (decitabine, azacitidine)
in myelodysplastic syndrome. Following early studies of
these drugs in the 1980s at the maximum-tolerated clinical
dosages, the drugs were almost abandoned until the 1990s,
when the concept of epigenetic therapy was developed. 18
Using optimal biologic dosages of the drugs, decitabine 50 to
100 mg per m 2 per course (instead of 1000 to 2500 mg per m 2
per course) and azacitidine 250 to 525 mg per m 2 per course
(instead of higher dosages), resulted in high efficacy results
and acceptable toxicities and established these agents at the
optimal biologic dosages as new standards of care in myelodysplastic
syndrome. 19
Progression to Blastic Phase of CML Is Rare with
TKI Treatment and Occurs Early Rather than Late
The expectation during the International Randomized
Study of Interferon and STI571 (IRIS) trial was that leukemic
cells would develop resistance and transform into
blastic-phase CML either at a uniform annual rate or later
in the course of therapy. This expectation was based on
the assumption that resistance develops under a timeassociated
selective pressure from TKIs. Surprisingly, the
opposite was in fact observed. 3 The annual transformation
rate during imatinib therapy was low, but if transformation
occurred, it happened early (2% to 4% annually in the first 3
years, and less than 1% annually thereafter). These data are
now interpreted to suggest that some patients with newly
diagnosed chronic-phase CML may harbor a small subset(s)
of CML clones with a priori TKI resistance, silently displaying
the molecular resistance mechanisms of transformation
that would not be influenced by imatinib therapy. In these
patients transformation will develop within the first 2–3
years of therapy. In contrast, most patients with newly
diagnosed chronic-phase CML have clones that do not harbor
intrinsic transformation mechanisms at diagnosis. In
these patients, imatinib therapy will ultimately reduce the
transformation rate to less than 1% per year.
Mutations as a Mechanism of Resistance in CML
During imatinib therapy, clinical resistance will develop
at a rate of 2% to 4% annually. Mutations at the BCR-ABL
kinase domain were noted in 30% to 40% of patients with
resistance in chronic phase and in more than 50% of patients
with resistance in transformation. 20 Of note, a portion of
these mutations would alone be insufficient to result in
resistance to imatinib therapy (suggesting that other mechanisms
of resistance were operational). Other mutations had
intermediate to high resistance to imatinib but were sensitive
to second-generation TKIs. A pan-TKI resistant mutation,
T315I (also referred to as “gatekeeper” mutation), was
detected in 20% of mutations (5% to 10% of resistant cases),
was resistant to second-generation TKIs (eg, dasatinib,
nilotinib, bosutinib), but was sensitive to several thirdgeneration
TKIs including ponatinib. 21 This experience suggests
that in CML, and possibly in solid tumors, resistance
to targeted therapy may develop through the selective pressure
of the targeted agent, resulting in mutations at the
target site that prevent the targeted agent from exerting
its effect. This phenomenon has now been observed with
FLT3 inhibitors (development of FLT3 point mutations
associated with resistance to FLT3 inhibitors) and in patients
with solid tumors treated with targeted agents (eg,
development of mutations in the epidermal growth factor
receptor [EGFR] associated with resistance to EGFR TKI
therapy). 22,23
Rationally Designed More Potent TKIs Overcome CML
Resistance to Imatinib
The development of mutations at the Bcr-Abl kinase
domain sites in TKI-treated CML had been predicted in
vitro from selection pressure models that identified several
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