Imatinib in the treatment of chronic myeloid leukemia: current perspectives on optimal dose
the Cancer Therapy Advisor take:
Imatinib mesylate (Gleevec) is a first-generation tyrosine kinase inhibitor (TKI) used for the treatment of patients with Philadelphia chromosome–positive (Ph+) chronic myeloid leukemia (CML) in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha therapy.
The TKI, which inhibits activity of BCR-ABL1 kinase, was the first of its kind to be successfully used in the treatment of CML.
Several clinical studies established that 400 mg daily of imatinib is safe and effective; however, doses ≥600 mg daily have also been explored to improve treatment outcomes.
One meta-analysis in particular that compared frontline imatinib 400 mg daily with high-dose imatinib in patients with CML in chronic phase demonstrated significantly higher rates of complete cytogenetic response and major molecular response at 12 months in patients who received the high dose; however, high-dose imatinib does not improve overall survival or progression-free survival and is therefore not recommended for patients as frontline therapy for chronic-phase CML.
Furthermore, high-dose imatinib is not recommended in standard-dose imatinib-resistant patients, as second- and third-generation TKIs have been shown to be more effective in these patients.
On the other hand, high-dose imatinib is recommended as a potential treatment option for CML in acute phase or blast phase.
Imatinib was the first tyrosine kinase inhibitor, successfully used in a clinical setting.
Abstract: Imatinib was the first tyrosine kinase inhibitor (TKI), successfully used in a clinical setting. It inhibits activity of BCR-ABL1 oncogenic tyrosine kinase which is crucial in the pathogenesis of chronic myeloid leukemia (CML).
The safety and efficacy of imatinib dose 400 mg daily was established in several clinical studies. Nevertheless, imatinib dose escalation (≥600 mg daily) has been widely explored as an option to improve clinical outcomes.
Results of the meta-analysis comparing frontline therapy with imatinib 400 mg daily vs high dose (HD, ≥600 mg daily) in patients with chronic phase CML (CML-CP) showed that the rate of complete cytogenetic response as well as major molecular response (MMR) at 12 months was significantly higher in HD imatinib group. However, HD imatinib does not improve overall survival and progression-free survival.
Thus, the routine use of HD imatinib as frontline treatment for CML-CP is not recommended. In patients with CML-CP resistant to standard dose, HD imatinib does not significantly improve patient outcomes without a prior cytogenetic response.
Therefore, in second-line therapy, the current CML-CP treatment guidelines do not recommend imatinib dose escalation but the use of second-or third-generation TKIs.
In the therapy of TKI-naïve patients with accelerated or blastic phase of CML, HD imatinib (400 mg twice daily) is one of the recommended standards. In case of disease progression while on imatinib, second- or third-generation TKIs should be administered.
Keywords: imatinib, standard dose, dose escalation, chronic myeloid leukemia, BCR-ABL1, high dose