Incidence of Pleural Effusion with Dasatinib and the Effect of Switching Therapy to Bosutinib in Patients with Chronic Phase CML
Authors: Jain Akriti G , Gesiotto Quinto J , Ball Somedeb , Nodzon Lisa , Rodriguez Amanda , Komrokji Rami S. , Sallman David A. , Padron Eric , Kuykendall Andrew T. , Chan Onyee , Lancet Jeffrey E. , Pinilla Ibarz Javier , Sweet Kendra 
Published: November 2021

Abstract
Introduction:
Dasatinib is a second generation tyrosine kinase inhibitor (TKI) which is approved for treatment of chronic myeloid leukemia (CML). Pleural effusion (PE) is a unique toxicity associated with dasatinib use. The risk of development of PE with dasatinib was reported to be 6-9% per year in DASISION and 5-15% per year in CA180-034. At a 5 and 7 year follow up 28% and 33% of patients developed PE in DASISION and CA180-034, respectively (Cortes et. al. J Clin Onc 2016 and Shah et. al. Am J Hematol 2016). PE led to discontinuation of dasatinib in only 6% and 7% patients in DASISION and CA180-034, respectively. Alternative TKIs are required in these cases with the goal to avoid recurrence of PE. Recently, switching to bosutinib after development of a PE while on dasatinib has been shown to be associated with a 30% risk of developing a recurrent PE, higher than the reported rate in front line trials (Tribelli et. al. Ann Hematol 2019).
Objective:
The aim of this study was to identify the incidence of pleural effusions in a cohort of patients treated with dasatinib for chronic phase (CP)-CML, and the safety of switching therapy to bosutinib.
Methods:
A retrospective chart review of all patients who had received dasatinib for treatment of CP-CML between 1992 and 2020 at Moffitt Cancer Center was performed. Patient data including baseline characteristics, date of diagnosis, line of treatment, date of initiation and termination of treatment, reason for discontinuation and dose were collected. PE was graded according to the CTCAE v5.0 (common terminology criteria for adverse events). A descriptive analysis of the data collected is reported.
Results:
A total of 390 patients, 184 males and 206 females, were treated with dasatinib during their course of treatment for CP-CML. The median age of diagnosis of CML was 50 years. 79% of patients were Caucasian. Dasatinib was used as front line therapy in 150 (38.4%) patients, second line in 177 (45.3%) patients and third line or above in 63 (16.1%) patients. A total of 69 patients (17.6%) developed any grade of PE, with 33 (48%) patients considered to have CTCAE grade 2 PE, 34 (49%) patients grade 3, and only 1 patient developed grade 4 PE. The dose of dasatinib for the patients that developed PE was 140 mg (6%), 100 mg (71%), 70 mg BID (4.3%), 70 mg (3%), 20 mg (3%) and unknown (13%). Therapy was changed to another TKI without a dose modification in 43% patients, the dose was reduced in 46% patients and we do not have information about dose available for the other 11% patients. Recurrence of PE was observed in 34 (49%) patients. PE directed treatment included a combination of furosemide (49%), steroids (20%) and thoracentesis (49%). The median time from initiation of dasatinib to development of PE was 31 months. Only 12 patients (17.3%) continued dasatinib after development of PE, while the other 57 patients discontinued the drug. Median duration of therapy on dasatinib was 39 months in patients that developed PE. Therapy was switched to bosutinib in 13 patients out of whom 6 (46%) re-developed PE. The median time to re-accumulation of PE after switching to bosutinib was 9 months. While only 14.2% patients developed re-accumulation of pleural fluid in patients switched to imatinib, none of the patients switched to nilotinib re-developed PE.
Conclusion:
A change in TKI to bosutinib was associated with a 46% risk of recurrence of pleural effusion in patients who develop pleural effusion on dasatinib for the treatment of CP-CML. The incidence of recurrent PE was markedly lower in patient switched to imatinib or nilotinib. Further prospective studies are needed to determine the safety of bosutinib in this setting.

Disclosures
Nodzon: Takeda: Consultancy. Komrokji: BMSCelgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PharmaEssentia: Membership on an entity's Board of Directors or advisory committees; Geron: Consultancy; Jazz: Consultancy, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; Acceleron: Consultancy; Taiho Oncology: Membership on an entity's Board of Directors or advisory committees. Sallman: Kite: Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Aprea: Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Magenta: Consultancy; Incyte: Speakers Bureau; Takeda: Consultancy; Intellia: Membership on an entity's Board of Directors or advisory committees. Padron: Stemline: Honoraria; Blueprint: Honoraria; Incyte: Research Funding; Kura: Research Funding; BMS: Research Funding; Taiho: Honoraria. Kuykendall: Prelude: Research Funding; PharmaEssentia: Honoraria; Novartis: Honoraria, Speakers Bureau; Incyte: Consultancy; CTI Biopharma: Honoraria; Celgene/BMS: Honoraria, Speakers Bureau; BluePrint Medicines: Honoraria, Speakers Bureau; Abbvie: Honoraria; Protagonist: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Lancet: Jazz: Consultancy; Astellas: Consultancy; BerGenBio: Consultancy; Agios: Consultancy; ElevateBio Management: Consultancy; Daiichi Sankyo: Consultancy; Celgene/BMS: Consultancy; Millenium Pharma/Takeda: Consultancy; AbbVie: Consultancy. Pinilla Ibarz: Sellas: Other: ), patents/royalties/other intellectual property; MEI, Sunesis: Research Funding; AbbVie, Janssen, AstraZeneca, Takeda: Speakers Bureau; AbbVie, Janssen, AstraZeneca, Novartis, TG Therapeutics, Takeda: Consultancy, Other: Advisory. Sweet: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees.