Pleural effusion in dasatinib-treated CML patients: incidence and management in a real-life italian multicenter series

Introduction: Dasatinib (DAS) is a dual BCR-ABL1 and SRC inhibitor approved for the first- and second-line treatment of chronic myeloid leukemia (CML) with a distinct toxicity profile that includes pleural effusion (PE), the latter representing the leading cause of DAS discontinuation. PE may occur through potent inhibition of the PDGFR-, leading to a reduction in interstitial fluid pressure, or inhibition of SRC-family kinases, resulting in vascular permeability changes. However the exact pathogenic mechanism of this adverse event (AE) still remains unknown. Aim: To evaluate incidence and management of PE in a real-life DAS-treated CML population. Methods: Data were collected in 21 Italian hematological centers. Globally we identified 184 cases of PE in a series of 790 DAS-treated CML-chronic phase patients (incidence: 23.3%), with a median follow-up of 7.9 years (range 0.1-26.0). Male:female ratio was approximately 2:1 with a median age at diagnosis of 60.7 years. Results: DAS starting dose was 100 mg QD in 71.2% of the patients, less than 100 mg QD in 14.7% and more than 100 mg QD in the remaining cases. Median time from DAS start to PE was 16.4 months (range 0.3-109), with 63.1% of cases within the first two years. In 62.5% of the cases PE severity was graded as 2 according to CT-CAE. At the time of PE, 28.2% of patients showed a MMR, and 37% a deep molecular response (DMR); a response less than MMR was reported in the remaining cases. DAS was temporary interrupted in 73.7%, with a dose reduction in 59.8% of the cases. Recurrence was observed in 60.1% of the cases, with a median time from the first episode to the subsequent one of 8.9 months (range 0.5-69.9). Treatment was definitively discontinued in 56.5% of the cases. Interestingly, among patients whose DAS dosage was reduced, 59.1% experienced PE recurrence. Conclusions: Comparing our data to that reported in the literature, we identified a MMR and a DMR response rate at the median time of PE superior to that of both first- and second-line DAS-treated CML population (globally 51% at 12 months in the DASISION and 37% at 24 months in the CA180-034 study), also distinguishing between imatinib-intolerant and resistant cases. Furthermore, it has to be highlighted a high PE recurrence rate also after DAS dose reduction. Therefore, considering the latter aspect together with the confirmed DAS efficacy, it could be useful to consider a DAS dosage modulation as soon as a confirmed DMR is achieved in order to prevent this AE.