Elevated Imatinib Dose, Second-generation TKIs Have Superior Responses in CML

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Complete cytogenetic response was found to be higher in patients treated with elevated doses of imatinib and second-generation TKIs.
Complete cytogenetic response was found to be higher in patients treated with elevated doses of imatinib and second-generation TKIs.

Patients treated for chronic myeloid leukemia in chronic phase (CML-CP) with imatinib 800 mg or the second-generation tyrosine kinase inhibitors (TKIs) dasatinib or nilotinib had better responses than patients who were treated with standard-dose imatinib, a retrospective cohort analysis has found.1 The study also showed that treatment with imatinib 800 mg or second-generation TKIs similarly affect long-term survival.

Imatinib, the first TKI to be used to treat CML-CP, has previously been used at elevated doses in efforts to improve outcomes compared to the standard 400-mg dose. Second-generation TKIs have also previously been demonstrated to result in better responses than imatinib. 

“The motivation to do this analysis was the absence of randomized trials to compare some of these approaches,” Jorge Cortes, MD, of The University of Texas MD Anderson Cancer Center in Houston, TX, said in an interview with Cancer Therapy Advisor.  “This is the first study that looks at these 4 different TKI-based treatment strategies.”

Most patients with CML are diagnosed when they are already in chronic phase. Treatment with standard-dose imatinib results in complete response, the absence of Philadelphia chromosomal translocations in bone marrow, in many patients with CML-CP. Patients who do not achieve complete response with imatinib 400 mg are moved to second-generation TKLs.

“These 3 drugs are currently approved for CML frontline therapy, although the higher dose of imatinib is not standard,” said Dr Cortes. “Both nilotinib and dasatinib have been compared to standard-dose imatinib, and standard-dose imatinib and high-dose imatinib have been compared in randomized trials to each other. But dasatinib and nilotinib have never been compared head-to-head, neither has high-dose imatinib to dasatinib or nilotinib.”

The study analyzed 492 patients who were treated with imatinib 400 mg daily (68 patients), imatinib 800 mg daily (200 patients), dasatinib 50 mg twice daily or 100 mg daily (106 patients), or nilotinib 400 mg twice daily (108 patients).

Eighty-seven percent of patients who received standard-dose imatinib achieved complete cytogenetic response, compared to 90% of patients who received the elevated dose. Ninety-three percent of patients who received nilotinib and 96% of those who received dasatinib achieved complete response.

Major molecular response was 76% for imatinib 400 mg, 86% for imatinib 800 mg, 93% for dasatinib, and 97% for nilotinib.

Imatinib 400 mg had the lowest rate of significant reduction in BCR-ABL transcripts, the fusion gene Philadelphia translocations result in. Seventy-four percent of patients who received imatinib 800 mg and 71% of patients who received nilotinib and dasatinib had significant reduction of BCR-ABL transcripts.

RELATED: Multiple Low-level BCR-ABL1 Mutations Not Associated With Poor Response to Ponatinib in CML

Therapy with 800 mg imatinib and both second-generation TKIs also predicted for better event-free survival than standard-dose imatinib, but failure-free, transformation-free, and overall survival were comparable for all 4 therapies.

“The analysis suggests that dasatinib and nilotinib, as has been shown in randomized trials, are superior to standard-dose imatinib in many ways but not in overall survival,” said Dr Cortes. “The analysis also suggests that higher-dose imatinib is also superior to standard-dose imatinib and might be equivalent to dasatinib and nilotinib.”

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