Management of adverse events associated with tyrosine kinase inhibitors in chronic myeloid leukemia

Abstract

Tyrosine kinase inhibitors (TKIs) targeting the breakpoint cluster region-Abelson 1 (BCR-ABL1) oncoprotein represent an outstanding progress in chronic myeloid leukemia (CML), and long-term survival has become a reality. However, the majority of patients need to be treated during their entire life span; thus, outcome does not solely depend on treatment efficacy but also on how well therapy is tolerated. TKIs have an overall favorable safety profile in clinical practice. Although many patients may encounter adverse events, these usually occur early after treatment initiation, are mild to moderate in intensity and resolve spontaneously, or are easily controlled with adequate supportive care. Whenever treatment interruption is necessary, re-exposition to the same TKI or switch to an alternative TKI is successful in the majority of the cases. However, long-term safety issues have not been fully elucidated at present, especially for new-generation TKIs. Recent evidence has emerged that these new agents may sometimes impinge on vital organs such as the heart and lung in an irreversible fashion especially when comorbidities are present; thus, decision regarding of which TKI should be used must take into account disease-related, TKI-related, and patient-related variables. The purpose of this article is to provide an up-to-date review of common adverse events associated with TKIs and how these events may be optimally managed.

Bosutinib induced pleural effusions: Case report and review of tyrosine kinase inhibitors induced pulmonary toxicity

“…Even though they are relatively well tolerated they have significant side effect profiles, including hematologic, gastrointestinal, dermatologic, musculoskeletal, cardiovascular, metabolic and pulmonary toxicities [8], [9], [10], [11], [12].…”

Best Practices in Chronic Myeloid Leukemia Monitoring and Management

“…First-line use of dasatinib and nilotinib has been shown to induce faster and deeper responses, with a lower percentage of cases developing drug resistance and progressing to advanced phase [16][17][18][19]. However, the shorter follow-up of patients on nilotinib and dasatinib, together with the occurrence of some severe adverse events (especially cardiovascular and pulmonary) that were never reported in patients treated with imatinib, currently poses a question about the long-term safety of second-generation TKIs [20].…”

Pharmacokinetic drug-drug interactions of tyrosine kinase inhibitors: A focus on cytochrome P450, transporters, and acid suppression therapy

“…Nevertheless, TKI's have specific side effect profiles that differ from those observed with cytotoxic agents. Furthermore, their side effects are rather numerous and occur with a high frequency for some of them …”

“…Most TKIs are weak bases that have a pH-dependent solubility. 15 This decreases their solubility in the gastrointestinal tract at the site of absorption in the jejunum (pH around [5][6] or in the ileum (pH around [7][8]. Moreover, their poor solubility results also from a rather high lipophilicity, with the exception of ruxolitinib.…”