High dose imatinib (Gleevac) in CML
Presenter: Hagop Kantarjian, MD
Affiliation: M.D. Anderson Cancer Center
The Philadelphia chromosome and the resultant bcr-abl oncogene cause a majority of cases of CML. Imatinib, a selective bcr-abl tyrosine kinase inhibitor, has recently been shown to be efficacious in all phases of CML. Using 400 mg orally per day, cytogenetic responses have been seen in 85% of patients. Sixty to 75% of patients have demonstrated a complete cytogenetic response. The disappearance of the bcr-abl oncogene was noted in 5-15% of patients, with an estimated median survival time of over 15 years. When compared to previous standard therapy, interferon + ara-C, the 18 month progression free survival was higher with imatinib (92% vs. 73%), with 90% of patients in the control arm crossing over to receive imatinib.
Recently, there has been evidence that higher dose imatinib may be even more efficacious. Rationale for using higher dose imatinib include the fact that there has been no maximal tolerated dose noted, that there has been a dose response noted, and that there is response to higher dose imatinib in those resistant to 400 mg.
In the study presented, frontline use of 400 mg BID (for a total of 800 mg per day) was studied in 114 patients, comparing the results with historical controls who had received 400 mg per day. In the high dose arm, greater than 90% of patients had a complete cytogenetic response, compared with 76% in the historical arm. Perhaps more impressive, 62% had a major molecular response (defined as greater than a three log reduction in bcr-abl seen after PCR) and approximately 33% had a complete molecular response. None of the patients had a transformation, compared with 4/50 treated at the lower dose. At this time, there were not enough events to document a difference in survival.
This data indicates that using higher doses of imatinib could result in better outcomes, as the cytogenetic responses and molecular responses were both higher in the higher dose arm. There are not enough numbers to make conclusions about the transformation rate, though it is obviously encouraging that none transformed in the high dose arm. Whether this will translate into better clinical outcome with patients remains to be seen. In prior studies comparing imatinib to interferon and ara-C, higher cytogenetic and molecular responses eventually did translate into better outcomes, so these data are encouraging. What was not mentioned was toxicity of higher dose therapy. Overall, imatinib is well-tolerated, though there are definite side effects of therapy. The efficacy of using 800 mg per day as frontline therapy, rather than reserving it as salvage therapy (which has been done successfully in the past), must be balanced by the toxicity of the higher dose. This, as of yet, is not known.