Pleural Effusions Associated with Use of Dasatinib in Chronic Myeloid Leukemia May Have an Auto-Immune Pathogenesis.
Authors: Punnialingam Sinthiya , de Lavallade Hugues , Milojkovic Dragana , Marco Bua , Khorashad Jamshid S. , Goldman John M. , Apperley Jane F. , Marin David 
Published: October 2019

Abstract
Pleural effusions (PE) are a relatively common side effect of dasatinib (an oral multi-targeted kinase inhibitor) and have been reported in 20–30% of CML patients. The underlying mechanism is unclear but may be related to inhibition of the PDGFR gene. We report a series of 43 patients, who received dasatinib while in first chronic phase, after imatinib resistance (n=31) or intolerance (n=12). Twenty two patients had previously received interferon. Patients were treated with dasatinib 70 mg twice daily. The median follow-up was 149 days (range 21–730). Of the 43 patients, 14 developed PE at a median of 150 days (range 21–698) after starting dasatinib. The dasatinib was interrupted in all cases and not resumed until the PE had resolved completely, which occurred in all cases. Diuretics were administered in some cases. The median duration of discontinuation was 14 days (range 7–65). In 8 of the 14 patients the drug was re-started at reduced dose following the first episode of PE. PE recurred in 4 patients (3 patients had two and 1 patient 5 episodes). The dose was further reduced in these cases and eventually abandoned in 2 patients. We performed univariate and multivariate analysis to identify prognostic factors for the development of PE. Significant variables were: prior skin rash on imatinib therapy, [21% non PE vs 57% PE (p=0.035)], skin rash on dasatinib [(before the development of PE vs any time during the follow up) 4% non PE vs 47% PE (p=0.002)], and previous history of autoimmune disease, [non PE 7% vs 50% PE (p=0.006)]. The documented autoimmune diseases were: hyperthyroidism (n=1), hypothyroidism (n=3), systemic lupus erythematosus (n=1), Sweets syndrome (n=1) and auto-immune hepatitis (n=1). We did not find correlation between the previous history of autoimmune disorders and having been treated with interferon. The dose of dasatinib prior to the onset of PE was compared with the dose in patients who did not develop PE at 6 months; patients still receiving 70 mg twice a day were more likely to develop PE than those for whom the dose had been reduced, with a relative risk (RR) for the development of PE of 4.7 (95CI 1.2–18.4, p=0.02). The only variables that were predictive in the multivariate analysis were a history of autoimmune disease and the dose of dasatinib [RR 13 (95CI 1.6–103) and RR 7.4 (95CI 1.2–44.3) respectively]. Interestingly the presence of generalised fluid retention was not found to be significant (p=0.54) nor the previous therapy with interferon (p=1.0). Our results are in agreement with recent reports which suggest that dasatinib-induced PE does not correlate with generalised fluid retention and may be mediated by an immune mechanism. Moreover dasatinib-induced PE are usually exudates and are believed to respond to steroids. In summary in this series PE occurred more frequently in patients with a previous history of autoimmunity and imatinib-related dermatological side effects; both observations support the notion that PE secondary to dasatinib therapy may have an auto-immune pathogenesis.