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Tyrosine kinase inhibitors (TKIs) used in the management of chronic myeloid leukemia are associated with hematologic toxicities - which TKI is the safest?

Before imatinib, patients with chronic myeloid leukaemia (CML) received hydroxycarbamide, or interferon‐alpha alone or in combination with low‐dose cytarabine. Younger and fit patients with a suitable donor could be allografted, which was the only potentially therapeutic approach that would result in long‐term disease‐free survival; however, substantial morbidities or even mortality was observed. The discovery of tyrosine kinase inhibitors (TKIs) against the BCR‐ ABL1 oncogenic fusion protein has revolutionized the management of CML. Imatinib, the first BCR‐ABL1 TKI, was introduced in early 2000s, and in the upcoming years, more potent second‐generation TKIs (2GTKIs)—dasatinib, nilotinib, and bosutinib—have been approved, first for the imatinib resistant/intolerant cases and subsequently for the upfront treatment. Although not globally approved, another 2GTKI—radotinib—is currently approved for both the frontline and salvage settings in Korea. Other than these TKIs, ponatinib is a third‐generationTKI, an option in patients with CML who fail two lines of TKI treatment and in those harbouring a T315I mutation. Imatinib therapy can be associated with some adverse events (AEs), both haematologic and non‐haematologic, which are generally easy to manage, but sometimes, they may have a negative impact on the health‐related quality of life (HRQoL). The newer TKIs generally induce more rapid and profound responses than imatinib; however, these drugs can also be associated with additional specific non‐ haematologic toxicities resulting in morbidities that might interfere with patient HRQoL. Overall, haematologic toxicities (myelosuppression) during TKI treatment is quite common, and it occurs both due to the suppression of the leukemic clone and the inhibition of non‐leukemic haematopoiesis. When leukemic haematopoiesis is reduced by the TKI treatment, normal stem and progenitor cells need time to recover from pre‐existing suppression by the malignant clone and to re‐populate the bone marrow. Myelosuppression is usually limited to the first weeks or months of TKI therapy, and the incidence of grade III‐IV myelosuppression is usually predominant only at the initial phase of the TKI treatment, decreasing substantially with longer duration of any TKI therapy. Haematologic AEs of TKIs are mostly dose and concentration dependent, reversible on treatment cessation or dose reduction, and affect all three lineages to a variable degree. Thus, myelosuppression is an expression of exposure of the consumed TKI. It is important, because it is the major cause of temporary and/or permanent cessation of the TKI. In this issue of the British Journal of Clinical Pharmacology, Fachi and coworkers performed a systematic review and a meta‐analysis on the serious (grade III‐IV) haematologic AEs (anaemia, leukopenia, neutropenia, and thrombocytopenia) of all TKIs (imatinib, dasatinib, nilotinib, bosutinib, radotinib, or ponatinib, at any dose or regimen) utilized in the management of CML in chronic phase (CML‐CP) focusing on the randomized controlled trials (RCTs) mainly included newly diagnosed and treatment naïve patients. After the initial evaluation, the authors included 17 trials for the final analysis. As expected, none of the trials were placebo controlled, majority of them were sponsored by pharmaceutical companies, and all of the studies were open‐label and with direct head‐to‐head comparison, including all TKIs (bosutinib [n = 2], dasatinib [n = 5], imatinib [n = 16], nilotinib [n = 4], ponatinib [n = 1], and radotinib [n = 1]). Imatinib was the main comparator in all trials but one, in which different doses of dasatinib were tested in the second‐line setting among cases with CML‐CP following imatinib failure/intolerance. Although dose equivalence between these agents is unclear, the authors demonstrated that doses above 100‐mg dasatinib caused anaemia in significantly more patients than that caused by imatinib up to 600 mg/day, or 600‐mg nilotinib. However, there was no significant difference between dasatinib 100 mg and imatinib 400 mg (the recommended daily doses in newly diagnosed CML‐CP cases) regarding the number of cases with grade III‐IV anaemia. Supporting this finding, in the DASISION trial, where dasatinib 100 mg was tested against imatinib 400 mg in the first‐line setting among patients with CML‐CP, the percentages of grade III‐IV anaemia were found to be 10% and 7% for dasatinib and imatinib, respectively. Similarly, when the authors compared all TKIs that are approved in the upfront setting in CML‐CP with the recommened daily doses (imatinib 400 mg/day, nilotinib 600 mg/day, dasatinib 100 mg/day, bosutinib 400 mg/day, and radotinib 600 mg/day) with each other, there were no significant differences between these TKIs at those doses for the generation of grade III‐IV anaemia. Both dasatinib 100 and 140 mg and imatinib 400 and 800 mg caused more leukopenia than nilotinib daily doses of 600 or 800 mg. Received: 23 April 2019 Revised: 6 August 2019 Accepted: 6 August 2019