Abstract
The chronic myeloid leukemia (CML) therapeutic landscape has dramatically changed with tyrosine kinase inhibitor (TKI) development, which allows a near-normal life expectancy. However, long-term TKI exposure has been associated with persistent adverse events (AEs) which negatively impact on quality of life (QoL) and have the potential to cause significant morbidity and mortality. In clinical practice, TKI dose reduction is usually considered to reduce AEs and improve QoL, but dose optimization could have also another aim, i.e., the achievement and maintenance of cytogenetic and molecular responses. While therapy cessation appeared as a safe option for about half of the patients achieving an optimal response, no systematic assessment of long-term TKI dose de-escalation has been made. The present review is focused on the most recent evidences for TKIs dose modifications in CML clinical studies and in the real-life setting. It will consider TKI dose modifications in newly diagnosed patients, dose reduction for AEs, or in deep molecular response, either as a prelude to treatment-free remission (TFR) or as continuous maintenance therapy in those patients not wishing to attempt TFR. In addition, it will focus on patients not achieving a molecular response deep enough to go to TFR, and for whom dose reduction could be an option to avoid AEs.
Highlights
The therapeutic landscape of this disease has dramatically changed with the development of small molecule tyrosine kinase inhibitors (TKIs) targeting BCR-ABL1
Chronic myeloid leukemia (CML)-Study IV [20] tried to deal with two of these problems, i.e., the best TKI dose and adverse events (AEs) reduction [51]: in particular, they report that 90% of the subjects initially randomized to receive high-dose imatinib, i.e., 800 mg/day, and achieving a stable major molecular response (MMR), could reduce the dosage to 400 mg/day without losing their molecular response, with the benefits of preventing AEs and reducing costs, and likely increasing compliance
The original first-line study of bosutinib in newly diagnosed CML-chronic phase (CP) patients failed its primary endpoint of demonstrating a cytogenetic response superior to imatinib, partly due to the AEs profile at the recommended dose of 500 mg once daily [9]
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. It has to be underlined that though the MTD usually represents the maximally effective dose (MED), in the case of CML the MED is defined as the dose associated with both maximal inhibition of BCR-ABL1 and safety, especially when given over a long period of time. It has been shown that a continuous BCR-ABL1 monitoring can provide a patient-specific prediction of an optimal reduced dose without decreasing the anti-leukemic effect on residual LSCs, suggesting that dose-halving should be considered as a long-term treatment option for CML patients with good response under continuing maintenance TKI therapy with the clinical potential of reducing both treatment-related.
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