Haematological adverse events associated with tyrosine kinase inhibitors in chronic myeloid leukaemia: A network meta‐analysis

Abstract

Despite their overall favourable safety profile, tyrosine kinase inhibitors (TKIs) are related to severe adverse events including haematological toxicities such as anaemia, leucopenia, neutropenia and thrombocytopenia. We designed a systematic review and network meta-analysis of randomised controlled trials to compare safety among TKIs (bosutinib, dasatinib, imatinib, nilotinib, ponatinib and radotinib) used by patients diagnosed with chronic myeloid leukaemia. Methods: We obtained data from the PubMed, Scopus, Web of Science, and SciELO databases. The Bayesian approach was used for direct and indirect comparisons, and the treatments were ranked by the surface under the cumulative ranking curve (SUCRA). Results: Seventeen studies were included in the network meta-analysis. Our data show that dasatinib was generally considered worse than the other TKIs, with SUCRA values for 140 mg dasatinib of 90.3% for anaemia, 87.4% for leucopenia, 90.6% for neutropenia and 97.2% for thrombocytopenia. In addition, nilotinib was shown to be safer, with SUCRA values for 600 and 800 mg doses of 21.9 and 35.8% for anaemia, 23.8 and 14.6% for leucopenia, 33.0 and 17.7% for neutropenia, and 28.7 and 32.6% for thrombocytopenia, respectively. Conclusion: Dasatinib appeared as the least safe drug for chronic myeloid leukaemia, probably because it binds to multiple key kinase targets, being more prone to cause serious haematological adverse events. Nilotinib demonstrated a safer profile, mostly due to its selective binding capacity. KEYWORDS chronic myeloid leukaemia, drug-related side effects and adverse reactions, network meta-analysis, tyrosine kinase inhibitors 1 | INTRODUCTION Tyrosine kinase inhibitors (TKIs) represent a milestone in chronic myeloid leukaemia (CML) treatment. Although these drugs are effective and have an overall favourable safety profile with mild to moderate adverse events (AEs), they can also cause severe events including haematological AEs, such as anaemia, leucopenia, neutropenia and thrombocytopenia, which occur due to myelosuppression. Moreover, The authors confirm that the PI for this paper is Roberto Pontarolo and that he had responsibility for this review.

Tyrosine kinase inhibitors (TKIs) used in the management of chronic myeloid leukaemia are associated with haematologic toxicities—Which TKI is the safest?

“…If all TKIs approved for the upfront setting with the recommended daily doses were compared with each other, no significant differences between each other regarding the development of leukopenia or neutropenia were detected. 6 Regarding thrombocytopenia, 140-mg dasatinib was the less safe option, imatinib (400-600 mg) and 600-mg radotinib presented the lowest probabilities of causing this event. 6 When all TKIs approved for the upfront setting were compared with each other for the recommended daily doses, dasatinib 100 mg had significantly more cases with thrombocytopenia than imatinib 400 mg/day, but no such significant difference was observed between other TKIs.…”

“…6 Regarding thrombocytopenia, 140-mg dasatinib was the less safe option, imatinib (400-600 mg) and 600-mg radotinib presented the lowest probabilities of causing this event. 6 When all TKIs approved for the upfront setting were compared with each other for the recommended daily doses, dasatinib 100 mg had significantly more cases with thrombocytopenia than imatinib 400 mg/day, but no such significant difference was observed between other TKIs. This is consistent with the finding in the DASISION trial, with grade III-IV thrombocytopenia in the dasatinib and imatinib arms were 19% and 10%, respectively.…”

“…5 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. 6 Both dasatinib 100 and 140 mg and imatinib 400 and 800 mg caused more leukopenia than nilotinib daily doses of 600 or 800 mg.…”

“…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. 6 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. 7 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.…”

“…In the upfront setting, 600-mg nilotinib presented a 27% probability of being the least safe drug of choice. 6 The most common 2GTKIs used in the daily clinical practice are dasatinib and nilotinib, and literature shows conflicting results regarding the toxicity profiles of these two 2GTKIs. For example, in the multicenter observational study by Kizaki and colleagues, 11 the grade ≥III haematologic AEs (anaemia, neutropenia, and thrombocytopenia) were all significantly more common with dasatinib than those with imatinib and nilotinib, when these TKIs were used as a first-line treatment in patients with CML-CP.…”