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.