Efficacy and Safety of Bosutinib in Chronic Phase CML Patients Developing Pleural Effusion Under Dasatinib Therapy
Authors: Tiribelli Mario , Abruzzese Elisabetta , Capodanno Isabella , Sorà Federica , Trabacchi Elena , Iurlo Alessandra , Luciano Luigia , Binotto Gianni , Bonifacio Massimiliano , Annunziata Mario , Crugnola Monica , Fanin Renato 
Published: October 2019

Abstract
Introduction
Dasatinib (DAS) is a second-generation (2G) tyrosine-kinase inhibitor (TKI) approved for the first- and second-line treatment of chronic myeloid leukemia (CML) patients. Though highly effective, DAS displays a distinct safety profile, with pleural effusion (PE) occurring in a significant proportion of patients. Among factors associated with DAS-related PE, concomitant pulmonary and cardiovascular diseases have emerged as the most common. Bosutinib (BOS) is another 2G-TKI that has proved to be effective in CML patients failing previous TKIs, with limited cardiac and pleural toxicity.
Aims
To analyse safety and efficacy of BOS therapy in chronic phase (CP) CML patients developing PE under DAS.
Methods
We retrospectively collected 20 CP-CML patients referring to several Italian hematology centers who have been receiving BOS in second- or subsequent line, after development of one or more PE with DAS. Cytogenetic and molecular responses were evaluated according to the ELN recommendations, with major molecular response (MMR) defined as BCR-ABLIS ratio <0.1% and deep molecular response (MR4) as BCR-ABLIS ratio ≤0.01% or undetectable disease with ≥10,000 ABL copies. Toxicities under TKIs treatment were graded according to the Common Terminology Criteria for Adverse Events (CTC-AE) v4.03.
Results
Twenty patients (12 males and 8 females) with median age at CML diagnosis of 60 years (range: 44-78) were included in the present study. Four patients received DAS as first TKI, while 16 started imatinib and then switched to DAS, three of them after second-line nilotinib, for resistance (n=9) or intolerance (n=7); DAS starting daily dose was 100 mg in 15 patients, 80 mg in two and 50 mg in three. Median time to first PE was 20 months (range: 1-58). First PE grade was 1 in three, 2 in fifteen and 3 in two patients, respectively; 11/20 patients (55%) developed at least a second PE, with a median number of PE episodes of 2 (range: 1-6). Median duration of DAS therapy was 32 months (range: 6-75).
Median age at BOS start was 68 years (range: 49-82), and 17/20 patients (85%) had at least one comorbidity requiring therapy, the most common being cardiovascular diseases (n=9), hypertension (n=8), diabetes (n=6), pulmonary diseases (n=4), secondary neoplasms (n=3) thyroid diseases (n=3). Median number of comorbidities and concomitant medications were 4 (range: 0-7) and 7 (range: 0-11), respectively. At BOS start 9 patients (45%) were at least in MMR (2 in DMR), 6 (30%) were in CCyR without MMR and 5 (25%) had less than a CCyR; two cases displayed ABL mutations (F317V in one, compound mutations in one). Only a minority of patients (n=4) commenced BOS at the canonical daily dose of 500 mg, while 10 and 6 cases started with 200 and 300 mg, respectively.
After a median time from BOS start of 18 months (range: 3-39), 15 patients are still on treatment (median duration 13 months, range 3-38). 5 patients discontinued BOS for resistance (n=2) or toxicities (n=3); median actual BOS daily dose is 300 mg (range: 200-500). No patient progressed to accelerated/blast phase, 1 patient died of cerebral hemorrhage 6 months after BOS stop. Among the 15 patients still in BOS, 7 improved their response and 8 maintained response level: at last follow-up 9/15 (60%) were in DMR, 3/15 (20%) in MMR and 3/15 (20%) in CCyR.
By all of 20 patients, 6 (30%) developed PE during BOS treatment, that was grade 1 in two cases and grade 2-3 in four; 3/4 of these latter patients permanently stopped BOS for this reason. Median time from BOS to 1st PE was 3 months (range:1-28). No patient experienced hematologic toxicities with BOS, while non-PE extra-hematologic side effects were recorded in 8 cases (diarrhea = 2, skin rash = 2, nausea = 1, increased creatinine = 1, increased lipase = 1, headache = 1); all these were grade 1-2 and none led to BOS discontinuation.
Discussion
With the limits of the retrospective nature and the small number of patients, our data suggest that BOS is a suitable therapeutic option in CML patients developing PE during DAS treatment. Of interest is the acceptable incidence of PE recurrence and lack of other serious toxicities even in a population of relatively elderly and with comorbidities.

Disclosures
Abruzzese: Novartis: Consultancy; Ariad: Consultancy; BMS: Consultancy; Pfizer: Consultancy.