The standard imatinib dose for patients treated in chronic phase is 400 mg daily. The selection of this dose after the dose-finding phase I study was somewhat arbitrary, as no dose limiting toxicity was identified at doses of up to 1000 mg daily.25 It also provided some suggestion of improved responses with higher doses, as few responses were observed at the lowest doses, and 53% of those treated with 140-250 mg daily had a hematologic response (11% had a cytogenetic response). Nearly all patients treated at doses of 300 mg or higher had a hematologic response and 54% achieved a cytogenetic response.25 Thus, current recommendations are to avoid treating patients with less than 300 mg of imatinib daily. Furthermore, there is a growing evidence that higher doses of imatinib (600-800 mg daily) may result in significantly higher response rates (and faster responses) compared to the standard dose. One study used 800 mg daily for patients who had failed prior IFN-a-based therapy but had never received imatinib.32 A complete cytogenetic response was achieved in 90% of the patients, compared to the historical 48% with standard dose in a similar population. More importantly, 50% of the patients had undetectable levels of BCR-ABL with nested PCR.32 A subsequent study used the same approach for untreated patients with CML in early chronic phase. Among 114 such patients treated with 800 mg of imatinib daily (in two divided doses of 400 mg), a complete cytogenetic response was achieved in 90%, most within 6 months of the start of therapy. After 18 months of therapy, 28% of the patients had undetectable BCR-ABL by nested PCR, compared to 4-10% with standard dose imatinib.32 A third study, from a different group, used 600 mg of imatinib and previously untreated patients with early chronic-phase CML, increasing the dose to 800 mg if responses were not progressing according to predetermined desired endpoints. After 6 months of therapy, 79% of patients had achieved a complete cytogenetic response. Patients who received the target dose with no dose reductions had a significantly better molecular response than those receiving lower average doses, even if higher than the standard, suggesting improved molecular responses with increasing doses.33 Thus, although today the standard dose of imatinib for chronic-phase CML is still 400 mg daily, the data summarized above suggest that this may be changing in the near future.

0 0

Post a comment