Tyrosine Kinase Inhibitor–Associated Platelet Dysfunction: Does This Need to Have a Significant Clinical Impact?

The management of chronic myeloid leukemia (CML) entirely changed after the emergence of tyrosine kinase inhibitors (TKIs). In the era of TKIs, the 10-year overall survival now exceeds 80%, and the prevalence of patients receiving longterm TKI therapy has substantially increased. In addition to the efficacy, CML caring physicians now mainly focus on the management of the TKI-associated long-term nonhematologic toxicities, generally so-called the “off-target” effects of these drugs. Second-generation TKIs—dasatinib, nilotinib, and bosutinib—are more potent than imatinib and these drugs also have different off-target multikinase inhibitory effects than imatinib. These adverse events (AEs) may or may not have an impact on the health-related quality of life (HRQoL), especially depending on the grades of these toxicities. The nonhematologic AEs may occur anytime during the follow-up, and sometimes they can have a negative clinical impact. TKIs are known to be associated with defective platelet function. Dasatinib, a potent inhibitor of BCR-ABL1 and SRC family kinases (SFK), is known to cause aberrant platelet function and can induce bleeding, independent of thrombocytopenia. But many patients with a clinically significant bleeding have low platelet counts and advanced disease phases (eg, blast crisis) that usually require higher daily dasatinib doses. Platelet function abnormalities have been described to a lesser extent with imatinib and bosutinib, but these laboratory tests generally appear not to be affected by nilotinib because of the different spectrum and intensity of inhibition of off-target signaling pathways by the individual TKIs. Also, the thirdgeneration TKI, ponatinib, is known to cause atherothrombotic events; on the other hand, it may also impair platelet functions. In this issue of the Journal, Sener and colleagues investigated the possible effects of TKI therapy on platelet functions and other hemostatic parameters in 68 patients with CML in chronic phase (CML-CP) receiving different TKIs. The authors divided their patient cohort into 3 according to the TKI consumed (eg, imatinib [n 1⁄4 47], dasatinib [n 1⁄4 15], and nilotinib [n 1⁄4 6]), and there were no cases with bosutinib nor ponatinib. For all patients, the platelet counts were >100 10/L, and only 1.5% of the patients had minimal prolongation in prothrombin time, and 3% of them had minimally prolonged activated partial thromboplastin time. Similar to what was observed in the previous studies performed among patients with CML receiving various TKIs, in this study, impaired platelet functions detected by light transmission aggregometry were observed in 29.8%, 40%, and 50% of the patients in imatinib, dasatinib, and nilotinib groups, respectively. The mechanism of this effect is not fully understood, and Quintás-Cardama and coworkers analyzed the impact of TKI therapy on platelet functions via the stimulation of platelet aggregation with adenosine diphosphate, arachidonic acid, epinephrine, collagen, and ristocetin, together with using the platelet function analyzer (PFA-100) in 75 patients with CML-CP. The authors observed that most of the patients receiving dasatinib (23/27, 85%) had platelet dysfunction. Also, they found that 4 (15%) of the 26 patients receiving bosutinib and 10 (66%) of the 15 patients receiving imatinib had impaired platelet function test. On the other hand, they also revealed that all patients treated with nilotinib (n 1⁄4 7) had normal platelet functions in vitro. There are other studies reporting TKI—mainly dasatinibinduced platelet dysfunction and the possible underlying mechanisms of this sometimes clinically relevant situation. Dasatinib may alter platelet aggregation by inhibiting key