ORLANDO, FloridaTwo phase I/II studies indicate that combination
treatment with imatinib mesylate (Gleevec, also known as STI571) produces a
high rate of hematologic response in patients in the chronic phase of
chronic myelogenous leukemia (CML). Dose-limiting toxicities were mainly
hematologic, and researchers advocate further studies were recommended to
establish efficacy and recommended dosing.
Michael E. O’Dwyer, MD, of the Leukemia Center at Oregon Health and
Science University in Portland, cited previous studies with imatinib that
demonstrated remarkable response rates in chronic phase CML patients who
have failed interferon therapy. Approximately 50% of these patients,
however, do not achieve a major cytogenetic response. Even among those who
achieve complete cytogenetic remissions, most have detectable Bcr-Abl. These
studies, along with concern about patients developing resistance to imatinib
as a single agent, plus in vitro studies showing an additive or synergistic
effect when interferon (IFN)-alfa is used in combination with imatinib, led
to a phase I/II trial evaluating imatinib in combination with IFN-alfa.
"Clearly this does provide a strong rationale for combination therapy,
which may maximize the chances of achieving molecular remission and prevent
emergence of resistance," Dr. O’Dwyer said.
Maximum Tolerated Dose
"The primary objective of this study was to establish the maximum
tolerated dose," Dr. O’Dwyer explained. For the purposes of the
study, maximum tolerated dose was defined as the dose that produces grade
3/4 nonhematologic toxicity in less than 33% of patients. Patients were
excluded if they had a history of greater than grade 3 nonhematologic
toxicity due to interferon. Hematologic and cytogenetic response rates were
secondary end points.
Data were reported on nine patientsfour males and five females, all
positive for the Philadelphia chromosome. The median age of patients was 53
years (range: 37-71), and the median duration of disease was 2.5 months
(range: 1-37 months). All patients but one have had prior treatment with
at least hydroxyurea, three have been treated with interferon, and one with
For the first 2 weeks of the trial, patients were treated with imatinib
at 400 or 600 mg/d. Then IFN-alfa was added at either 3 million IU per day
or three times per week.