ORLANDO, Florida—Two phase I/II studies indicate that combination treatment with imatinib(Drug information on 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.
Study Rationale
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 patients—four 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 imatinib.
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.
