High-dose imatinib mesylate therapy in newly diagnosed Philadelphia chromosome–positive chronic phase chronic myeloid leukemia

Abstract

Imatinib mesylate (STI571) is effective in chronic phase chronic myelogenous leukemia (CML). However, most patients treated with 400 mg imatinib daily have variable levels of residual molecular disease. We treated 114 patients with newly diagnosed chronic phase CML with 400 mg imatinib twice daily. Overall, 109 patients (96%) had a major cytogenetic response (Philadelphia chromosome [Ph] < 35%), and 103 (90%) had a complete response (Ph 0%). With a median follow-up of 15 months, no patient has progressed to accelerated or blastic phase. The estimated 2-year survival rate was 94%. By quantitative polymerase chain reaction (QPCR) studies, 71 (63%) of 112 patients showed BCR-ABL/ABL percentage ratios decrease to less than 0.05%, and 31 (28%) to undetectable levels. Compared with standard-dose imatinib, high-dose imatinib was associated with significantly better complete cytogenetic response (P ‫؍‬ .0005), major molecular response (QPRC < 0.05%; P ‫؍‬ .00001), and complete molecular response (undetectable BCR-ABL; P ‫؍‬ .001). High-dose imatinib was well tolerated but resulted in more frequent myelosuppression; 82% of patients continue to receive 600 mg or more of imatinib daily. In conclusion, high-dose imatinib induced higher rates of complete cytogenetic response and of molecular response in patients with newly diagnosed chronic phase CML. (Blood. 2004;

Imatinib plasma trough concentration and its correlation with characteristics and response in Chinese CML patients

“…It was reported that dose intensity was critical to optimize response in CML [23][24][25][26][27] . Based on higher drug exposure in Chinese patients and dose-proportional imatinib exposure [18,19] , a rational conjecture is that Chinese patients would have a better disease response.…”

Optimizing therapy for patients with chronic myelogenous leukemia in chronic phase

“…42 High-dose imatinib may prevent the development of mutations that confer imatinib resistance. 43 The prognostic impact of BCR-ABL mutations is difficult to determine, and routine mutational analysis is not recommended currently in the absence of treatment failure or suboptimal response. 40,44,45 Suboptimal imatinib response, for instance, may be caused by BCR-ABLindependent factors, such as lack of compliance with long-term therapy.…”

“…In a cohort of 114 newly diagnosed patients who received 800 mg daily imatinib, highdose imatinib was associated with improved rates of CCyR (P ¼ .0005), MMR (P ¼ .00001), and complete molecular response (P ¼ .001) compared with a historic control group that received standard-dose imatinib. 43 A phase 2 dose-escalation study in imatinib-naive patients who were started on 600 mg daily and increased to 800 mg daily if response criteria were not met further demonstrated CCyR and MMR rates that exceeded those of the IRIS trial. 50 These promising results prompted the initiation of several prospective randomized trials evaluating high-dose imatinib in newly diagnosed patients.…”

Tyrosine Kinase Inhibitor Therapy for Chronic Myeloid Leukemia: Approach to Patients with Treatment-Naive or Refractory Chronic-Phase Disease

“…7 However, single-arm, nonrandomized trials have suggested that rates of CCyR and MMR might be improved with a higher initial dose of imatinib. [8][9][10][11] To formally address this question, the Tyrosine Kinase Inhibitor Optimization and Selectivity (TOPS) study randomly assigned 476 patients 2:1 to imatinib 800 or 400 mg daily. At 12 months, there was no statistically significant difference in MMR (46% vs 40%, P ϭ .2035) or CCyR (70% vs 66%, P ϭ .3470), but MMR rates at 3 and 6 months were higher in patients randomly assigned to imatinib 800 mg, as was the CCyR rate at 6 months (57% vs 45%, P ϭ .0146).…”