Discussion and Conclusions
Approximately 3%–5% of the cases of childhood ALL show a t(9;22) (q34;q11)/Ph+ status[7]. In comparison with Ph- ALL, Ph+ ALL cases show a higher degree of malignancy and a poor response to conventional chemotherapy with lower rates of survival. TKIs can inhibit tyrosine kinase activation by competitively binding to the active site of tyrosine kinase, thereby impeding leukemia cell proliferation. The long-term survival of pediatric patients with Ph+ ALL has improved significantly since the advent of TKIs[4]. In one study of 30 pediatric patients with Ph+ ALL who received TKI treatment in combination with induction chemotherapy at the early stage of treatment, the postinduction complete remission rate was 96.7%, complete remission rate was 100%, and the 3-year OS was nearly 80%[3]. However, relapse and drug resistance were relatively frequent events in Ph+ ALL patients treated with the first-generation TKI imatinib. The second-generation TKI dasatinib is more clinically potent in inhibiting multiple tyrosine kinases, including Src family tyrosine kinase, BCR-ABL kinase, and C-Kit. Additionally, dasatinib also shows higher selectivity and affinity to the BCR/ABL kinase domain than imatinib, and dasatinib can cross the blood–brain barrier to prevent and eradicate central nervous system leukemia. It is used to treat patients with imatinib resistance or relapse while receiving imatinib[8]. According to the Chinese Children’s Cancer Group study ALL-2015 (CCCG-ALL-2015), patients treated with dasatinib had significantly higher rates of 4-year EFS (71.0% vs 48.9%) and OS (88.4% vs 69.2%) and lower relapse rates (19.8% vs 34.4%) than the 97 patients treated with imatinib[4]. Therefore, dasatinib in combination with conventional chemotherapy is currently more recommended for pediatric Ph+ ALL patients.
PAH is a severe disease characterized by elevated pulmonary arterial pressure and pulmonary vascular resistance, resulting in right ventricular failure and even death. Changes in pulmonary vascular structure or function have been attributed to multiple etiologies and various distinctive pathogeneses. PAH is a rare adverse reaction of dasatinib, and the mechanisms underlying the occurrence of PAH in patients receiving dasatinib are unclear. In addition to inhibiting BCR/ABL kinase activity, dasatinib can also inhibit the activity of normal Src family tyrosine kinase and platelet-derived growth factor. This may be one of the factors associated with the occurrence of PAH, since normal Src family tyrosine kinase is widely expressed in endothelial cells of blood vessels and promotes proliferation of vascular smooth muscle cells and vasoconstriction. In addition, the occurrence of PAH may involve changes in vascular permeability related to the expression of vascular endothelial growth factor (VEGF), since inhibition of VEGF expression by dasatinib may induce PAH and secondary multiplasmic effusion[9].
After nine cases of dasatinib-induced PAH were reported by the French PAH Registry in 2008, 29 cases of dasatinib-induced PAH (including the two pediatric patients of this study) have been reported in subsequent studies (Table 3). Of the 29 patients aged 5 to 73 years (24 cases involved CML, while the remaining five involved ALL), 19 were male and 10 were female. The present study is the first to describe the findings for pediatric patients. Most of these patients had already developed associated clinical symptoms before receiving a definitive diagnosis. Although elevated pulmonary arterial pressure was observed in only one patient (case 2 of this study) during the routine echocardiography reexaminations, she did not develop meaningful clinical manifestations of PAH. Twenty-two of the 29 patients showed different degrees of comorbid pleural effusion, and 13 had comorbid pericardial effusion. All of the 29 patients immediately discontinued oral dasatinib and received symptomatic treatment after the diagnosis of PAH. Subsequently, the clinical symptoms were alleviated, and the PASP was progressively restored to normal levels in all patients.
For the two pediatric patients in this study, oral dasatinib was discontinued immediately after a diagnosis of PAH, and oral captopril was simultaneously administered to treat PAH. The subsequent reexaminations using echocardiography demonstrated that the PASP progressively improved to normal levels. After discontinuation of oral dasatinib in these 29 patients, five received oral imatinib, two received oral bosutinib, one received ponatinib, 14 received nilotinib, and seven did not receive other TKIs. Only one patient who changed to bosutinib subsequently showed aggregated PAH, while the condition of the remaining patients improved. Consequently, close monitoring is still necessary to avoid the reoccurrence of PAH when altering to other TKIs for therapy.
In summary, Ph+ pediatric ALL patients receiving dasatinib for maintenance therapy should be closely monitored for the potential adverse effects of dasatinib administration. In patients who show these adverse effects, dasatinib should be discontinued immediately and active treatment for complications such as PAH and multiple-cavity effusion should be administered. Determination of the long-term quality of life of these patients requires multicenter studies with large sample sizes.