Imatinib Mesylate

The first clinical use of imatinib mesylate (imatinib) in CML was among patients who had failed prior therapy with IFN-a-based therapy or who could not tolerate this therapy. In a dose-finding study, using daily doses of 25-1000 mg daily, few responses were observed at doses of up to 250 mg daily.25 However, 98% of patients receiving a dose of at least 300 mg daily achieved a complete hematologic response (CHR), and 54% achieved a cytogenetic response. In addition, imatinib proved to be well tolerated at doses up to 1000 mg, with no dose limiting toxicity identified, and a maximum tolerated dose was not reached.25 A dose of 400 mg daily was selected for a subsequent study including 454 patients in late chronic phase who had failed or were intolerant to IFN-a therapy.26 At the most recent update, a CHR was achieved in 95% and a major cytogenetic response in 60 % (complete in 48%). After a median follow-up of 18 months, the progression-free survival rate was 89%, and 95% of the patients were alive.26 Similar results have been reported in more recent, smaller series.910 The use of imatinib in this setting is now over 5-years old, and longer-term follow-up has been reported in a cohort of 261 patients treated at a single institution.27 A major cytogenetic response has been achieved in 73% of patients, including a complete response in 61%. Responses have been durable, with over 90% of patients who achieved a complete cytoge-netic response maintaining a major response. With a median follow-up of nearly 4 years, 80% of patients were alive and free of progression and 86% are alive. More importantly, the molecular responses to imatinib have continued to improve, with 31% of patients with a BCR-ABL/ABL ratio of <0.05% and 15% with undetectable BCR-ABL transcripts by nested PCR. These results show that the favorable response to imatinib is durable after 4 years for the majority of patients; these results may continue to improve with continuation of therapy.27

These favorable results have been confirmed with imatinib in early chronic-phase CML when used as first-line therapy. A multicenter randomized trial compared imatinib with IFN-a and low-dose ara-C in patients with previously untreated, early chronic-phase CML (IRIS trial).28 After a median follow-up of 18 months, the estimated rate of a major cytogenetic response was 87% in the imatinib group and 35% in the IFN-a plus ara-C group (p <0.001). The estimated rates of complete cytogenetic response were 76% and 15%, respectively (p <0.001). At 18 months, the estimated rate of freedom from progression to accelerated or blastic phase was 97% in the imatinib group and 92% in the IFN-a group (p <0.001). The toxicity profile and quality of life were significantly better for patients treated with imatinib.29 However, a survival advantage could not be demonstrated in this study for patients treated with imatinib, mostly due to early crossover from IFN-a to imatinib (by protocol design or by patient's choice) in over 85% of the patients randomized to IFN-a. An analysis of ima-tinib-treated patients compared to a historical control treated with IFN-a-based therapy shows the significant survival advantage that would be expected with the higher rate of cytogenetic and molecular responses seen with imatinib.30 A recent update of the IRIS trial reported a rate of complete cytogenetic response of 86%. These responses have been durable, with 93% of patients who achieved a complete cyto-genetic response still having this response after 60 months. The estimated survival free of transformation at 5 years is 93% and the overall survival is 89% (95% if only CML-related deaths are considered). Another independent series of 50 similar patients treated with the standard dose (400 mg) of imatinib reported similar results: a major cytogenetic response in 90% and a complete cytogenetic response in 72%.31 Thus, imatinib has become the standard initial therapy for patients with CML. A discussion regarding the decision between transplant and ima-tinib and treatment algorithms will be presented at the end of this chapter.

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