Incidence, outcomes, and risk factors of pleural effusion in patients receiving dasatinib therapy for Philadelphia chromosome-positive leukemia

Abstract

Dasatinib, a second-generation BCR-ABL1 tyrosine kinase inhibitor, is approved for the treatment of chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia, both as first-line therapy and after imatinib intolerance or resistance. While generally well tolerated, dasatinib has been associated with a higher risk for pleural effusions. Frequency, risk factors, and outcomes associated with pleural effusion were assessed in two phase 3 trials (DASISION and 034/Dose-optimization) and a pooled population of 11 trials that evaluated patients with chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia treated with dasatinib (including DASISION and 034/Dose-optimization). In this largest assessment of patients across the dasatinib clinical trial program (N=2712), pleural effusion developed in 6% to 9% of patients at risk annually in DASISION, and in 5% to 15% of patients at risk annually in 034/Dose-optimization. With a minimum follow-up of 5 and 7 years, drug-related pleural effusion occurred in 28% of patients in DASISION and in 33% of patients in 034/Dose-optimization, respectively. A significant risk factor identified for developing pleural effusion by a multivariate analysis was age. We found that overall responses to dasatinib, progression-free survival, and overall survival were similar in patients who developed pleural effusion and in patients who did not.

Dasatinib vs. imatinib in patients with chronic myeloid leukemia in chronic phase (CML-CP) who have not achieved an optimal response to 3 months of imatinib therapy: the DASCERN randomized study

“…A similar rate (14%) was observed in the phase 3 dasatinib dose optimization study (CA180-034), in which most cases were managed with temporary dose interruption or reduction; only three (1.4%) patients required dasatinib discontinuation due to pleural effusion [25]. The lower incidence of pleural effusion in DASCERN may be due to the relatively young age of the patients, as younger patients have been reported to be at a reduced risk of developing pleural effusion after initiating dasatinib therapy [26]. However, a longer follow-up is required as pleural effusions may occur later in the course of therapy with dasatinib.…”

European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia

“…Pleural effusion is primarily associated with dasatinib, with a 5-year cumulative incidence of 37%. Risk factors include older age, twice daily dosing, previous or concomitant cardiac disease or autoimmune disorders, hypertension, hypercholesterolemia, and advanced phase CML [85]. Diarrhea or constipation may occur with any TKI.…”

Chronic Myeloid Leukemia, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology

“…77 Pleural effusion was also more common with dasatinib (28% in the DASISION study compared with ,1% with imatinib and 33% in a dose optimization study) and age has been identified as a significant risk factor for the development of pleural effusion. 78 The occurrence of pleural effusion is significantly reduced with dasatinib 100 mg once daily compared with 70 mg twice daily. Patients with prior cardiac history, with hypertension, and receiving dasatinib 70 mg twice daily are at increased risk of developing pleural effusions.…”