It is now recognized that discontinuation of dasatinib therapy is a critical factor in the achievement and maintenance of an optimal response to dasatinib therapy [
11]. In the DASISION study, dasatinib treatment was interrupted in 63% of patients, the dose of dasatinib was reduced in 31% of patients [
5]. At the end of the 3-year observation period, 29% patients discontinued dasatinib therapy for various reasons (AE: 10%, disease progression or treatment failure: 10%, unrelated AE: 2%, death: 2%, or other reason: 5%) [
5]. However, the detailed course leading to discontinuation in each case has not been reported. To the best of our knowledge, there have been no previous reports regarding the timing of dasatinib reduction, interruption, and/or discontinuation in midterm observation. In the present study, 28% of patients experienced a dose reduction and 25% of patients experienced temporarily interruption of treatment after initiating dasatinib therapy. The 1-year overall dasatinib treatment alteration-free rate was 66%. 9% of patients discontinued the treatment due to withdrawal of consent or an AE at 1-year from dasatinib therapy. No patients experienced disease progression while being treated with dasatinib.
As it often necessitates treatment discontinuation, PE can limit the therapeutic efficacy of dasatinib [
12‐
14]. On the other hand, several studies reported that the pleural effusion was common in elderly patients and did not affect any negative treatment results if that were clinically manageable [
15,
16]. In the present study, the incidence of PE by 12 months in high age (≥ 60) group was higher than that in low age (< 60) group, but did not reach statistical significance (
p = 0.1864). Several studies have reported that a higher Cmax of dasatinib was associated with greater clinical response rates, and lower trough concentrations were associated with a lower risk of PE [
12,
17‐
19]. In the prospective OPTIM dasatinib trial, patients with a dasatinib trough concentration of − 3 nM (1.5 ng/mL) at day 15 were randomized to the non-dose adjustment group or the dose adjustment group to obtain a C0 of < 3 nM [
20]. The overall rates of pleural effusion at 36 months were 49% and 11%, respectively, in the non-adjustment and adjustment groups, and the discontinuation rates of dasatinib therapy were 27% and 13%, respectively (
p = 0.008) [
20]. They concluded that monitoring dasatinib PK parameters could help predict the risk of side effects and prevent discontinuation of dasatinib therapy [
20]. In the present study, patients who had high
Cmin/
D/
W showed higher incidence of PE than that in low
Cmin/
D/
W group (38% vs. 13%, respectively), despite it did not reach statistical significance (
p = 0.220). Indeed, among 8 patients who had PE, 5 patients experienced treatment alteration. However, pleural effusions were well managed effectively through administration of diuretics or steroid therapy and/or dasatinib dose modifications. After then, they could continue dasatinib therapy. Better management of PE might contribute to prevent discontinuation of dasatinib therapy. In the present study, age was significantly correlated with
Cmin (
p = 0.012) (Fig.
2), and the correlation remained significant after adjusting for
Cmin/
D/
W (
p = 0.026). The treatment alteration-free rate was significantly greater in the low
Cmin group (< 1.4 ng/mL) compared with the high
Cmin group (81% and 50%, respectively,
p = 0.0473) (Fig.
4). And also, the treatment alteration-free rate in low
Cmin/
D/
W group was significantly greater than that in the high
Cmin/
D/
W group (88% and 44%, respectively,
p = 0.0047) (Fig.
4). The higher
Cmin/
D/
W, instead of higher
Cmin, was significantly correlated with the incidence dasatinib treatment alteration rate in the multivariate analysis. The
Cmin/
D/
W possibly could reflect patient’s ability to metabolize and/or excretion dasatinib. A larger patient sample is needed to determine which would be better to predict the dasatinib treatment alteration and to prevent discontinuation of dasatinib therapy.
To our knowledge, this is the first prospective study evaluating prognostic factors that influence the treatment alteration of dasatinib therapy in patients with CML. However, the limitations of our study need to be considered. Our study was limited by the presence of residual confounding factors, both known and unknown.
The present study focused on clinical outcomes of 32 patients at the midterm point (1 year) of the observation period of the DARIA 01 study; however, dasatinib therapy can be continued for much longer periods of time. A long-term observation study including more large number of patients is needed to clarify the risks for the treatment alteration of dasatinib therapy.