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| |  High-Dose Imatinib Offers No Benefit as First- Line Therapy for High-Risk Chronic-Phase CML: Presented at EHA By Emma Hitt, PhD COPENHAGEN, Denmark -- June 15, 2008 -- In patients with Sokal high-risk, chronic-phase chronic myeloid leukaemia (CML), cytogenetic response (CyR) was no different in patients receiving the standard imatinib dose or a higher dose; although a trend was observed for the relationship between the dose of imatinib taken and CyR. Michele Baccarani, MD, Department of Haematology-Oncology, Institute of Hematology Seràgnoli, University of Bologna, Bologna, Italy, reported the findings here on June 14 at the 13th Congress of the European Hematology Association (EHA). This phase 3, multicentre, open-label study was designed to investigate the efficacy and feasibility of imatinib mesylate at a conventional dose (400 mg QD) versus a high dose (800 mg QD) in previously untreated patients with Philadelphia chromosome (Ph)-positive CML at high Sokal risk. The primary endpoint was complete cytogenetic response (CCyR) at 1 year. "We decided to evaluate high-risk patients because these patients do not fare as well on the standard dose of imatinib," noted Dr. Baccarani during his presentation. By contrast, the Tyrosine Kinase Inhibitor Optimization and Selectivity (TOPS) study, also evaluating standard-dose versus high-dose imatinib, is being conducted in patients of all risk levels. A total of 219 patients from Italy, Norway, Turkey, and Israel were included in the analysis. The trial was 4 years in length, conducted from 2004 to 2007. Treatment discontinuations during the first year of treatment were required in 28% of the patients on the standard dose of imatinib and 30% of patients in the high-dose arm. In an intention-to-treat analysis, no significant differences in CCyR were observed between the standard-dose and high-dose arms at any time point. At 1 year, 61% of patients in the standard-dose arm achieved a CCyR versus 64% of those in the high-dose arm. At 6 months, 52% of patients in both arms had achieved a CCyR, and at 3 months, 20% in the standard-dose arm and 25% in the high-dose arm had achieved a CCyR. The mean daily dose taken by the patients who completed 1 year of therapy or who failed treatment during the first year of therapy was also evaluated. Among the patients in the standard-dose arm, 87% had received a mean daily dose of 350 to 400 mg. By contrast, only 62% of patients in the high-dose arm had received a mean daily dose at least 600 mg (26% received 800 mg and 36% received <800 mg). However, in patients achieving a CCyR, the majority of patients received the full dose of imatinib, and 23 out of 24 patients who achieved a CCyR in the high-dose arm had received the full 800-mg daily dose of imatinib. Thus, it appeared that patients achieving CCyR were more likely to receive a higher dose; although Dr. Baccarani pointed out that the numbers were too small for statistical analysis. For major molecular response (MMR), no significant differences were observed between the standard-dose and high-dose arms at any time point in an intention-to-treat analysis. At 1 year, MMR was achieved in 34% of those in the standard-dose arm and in 40% of patients in the high-dose arm. At 6 months, the MMR was 25% in the standard-dose arm and 31% in the high-dose arm, and at 3 months, 6% versus 12% had achieved MMR. A >=4.5-log reduction in Bcr-Abl at 12 months was observed in 15% of patients in the high-dose group versus 7% of those in the standard-dose arm. In patients with CCyR, the rates were higher: 12% of those in the standard-dose arm and 23% of those in the high-dose arm. Again, no significant difference between the groups was observed. During follow-up, a similar number of patients progressed to accelerated blast phase in the standard-dose (n = 7) and high-dose arms (n = 9). A total of 8 (standard-dose) and 6 (high-dose) patients died during follow-up. "Cytogenetic response was no different between groups, although there was a trend for a relationship between the dose taken and CCyR," Dr. Baccarani concluded. [Presentation title: A Prospective Randomized Study of Imatinib 400 mg vs 800 mg as a Frontline Therapy in Sokal High Risk (HR) Ph-Pos Chronic Myeloid Leukemia (CML) Patients. Abstract 405.]
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