Elsevier

Leukemia Research

Volume 38, Issue 7, July 2014, Pages 781-787
Leukemia Research

Chronic myeloid leukemia patients who develop grade I/II pleural effusion under second-line dasatinib have better responses and outcomes than patients without pleural effusion

https://doi.org/10.1016/j.leukres.2014.04.004Get rights and content

Abstract

Dasatinib is a potent second generation TKI, and it is widely used in patients with CML, both in the up-front setting and failure after imatinib. Lymphocytosis in cases receiving dasatinib therapy has been shown to be associated with pleural effusion (PE) and better outcome. Although patients who gather lymphocytosis during dasatinib have superior responses, there is only little data about the correlation between PE, response rates, and survival. In order to answer this question, the aim of our study was to determine the frequency of PE and lymphocytosis among our CML patients receiving second-line dasatinib, and to compare the responses and outcomes between patients with or without PE. There were 18 patients (44%) who developed PE, in a total of 41 patients, with a median time of 15 months. Lymphocytosis was observed in nine patients (9/41, 22%) with a median duration of 6.5 months of dasatinib treatment. There were fourteen patients with at least one comorbidity that may play a role in the generation of PE. The cumulative MMR and CCyR rates were greater in PE+ patients (p < 0.05). The PFS was significantly higher in PE+ group than PE− patients (p = 0.013), also the OS was higher among PE+ patients than PE− group (p = 0.042). In patients with a grade I/II PE, and durable responses under dasatinib, performing the management strategies for the recovery of effusion, together with continuing dasatinib can be a reasonable choice mainly in countries where third generation TKIs are not available. But alternative treatment strategies such as nilotinib or third generation TKIs can be chosen in patients with grade III/IV PE especially if the quality of life is severely affected.

Introduction

Dasatinib (Sprycel; Bristol-Myers Squibb, New York, USA) is a novel, orally available second generation tyrosine kinase inhibitor (TKI) which is approved for the treatment of BCR-ABL1 positive chronic myeloid leukemia (CML) in chronic (CP), and accelerated (AP) phases, and blast crisis (BC) in the up-front setting as well as after imatinib failure, and also for the treatment of Philadelphia (Ph) chromosome positive acute lymphoblastic leukemia (ALL) after imatinib failure [1]. Dasatinib is an inhibitor of multiple tyrosine kinases, including the oncogene fusion protein BCR-ABL1, and also inhibits Src family of kinases (SFKs) and platelet-derived growth factor receptor, beta polypeptide (PDGFR-b) [2]. Imatinib (Gleevec; Novartis, East Hanover, New Jersey, USA) induces complete cytogenetic responses (CCyR) in approximately 80% of patients with CP-CML [3], [4]. Although the responded patients usually maintain their responses, some patients may eventually develop resistance [5].

Dasatinib is 325 times more potent in vitro against unmutated BCR-ABL1 than imatinib [2], and dasatinib is able to bind to both the active and inactive conformations of the ABL kinase domain, which is why it is effective against many imatinib-resistant cases. Although dasatinib is a potent and efficacious drug, patients are also subject to various adverse events (AEs). The most common AEs are gastrointestinal, peripheral edema, and myelosuppression [6]. Lymphocytosis can be seen during dasatinib treatment [7], [8], and this phenomenon is thought to be associated with superior response rates [9], [10]. Fluid retention has been associated with imatinib, dasatinib, and nilotinib, but pleural effusions (PEs) may be more common with dasatinib [11]. The real-life data with CML patients receiving dasatinib after imatinib failure is associated with higher incidence of pleural and pericardial effusions [12], [13], than reported in clinical trails. The therapeutic activity of dasatinib against the Src kinases is thought to be responsible for several of its “off-target effects”. Also it has been shown that lymphocytosis can accompany PE [8], [10], and these two manifestations are shown to be in a strong association. Although patients who gather lymphocytosis during dasatinib treatment have superior responses, there is only little data about the correlation between PE, response rates, and survival [11]. In order to answer this question, the aim of our study was to determine the frequency of PE and lymphocytosis among our CML patients receiving second-line dasatinib, and to divide these patients into two groups (i.e. patients with or without PE), and compare these groups by means of responses and outcomes. Also we wanted to determine the effusion management strategies in our patient cohort.

Section snippets

Study population

Forty-one CML patients who were in CP at diagnosis, and received dasatinib due to resistance or intolerance to imatinib were enrolled in the study. Patients’ demographics, disease risk scores, comorbidities [including preexisting cardiac disease, renal insufficiency, hypertension and chronic obstructive pulmonary disease (COPD)], dasatinib dose, dosing intervals and treatment durations, durations of imatinib therapy prior to dasatinib, and if any, treatments prior to imatinib (including

Results

Twenty-one patients were female (51%), and the median age of the patient cohort was 52 years (range, 18–84 years). There were eighteen patients (44%) who developed PE (PE+), and PE− group consisted of 23 patients with no PE under dasatinib. The median ages of PE+ and PE− groups were 55.5 and 51 years, respectively (p > 0.05) (Table 1). In PE− group, advanced disease (AP + BC) was more frequent than in PE+ patients (8 vs. 2, p = 0.01). The mean follow-up for PE+ and PE− groups were 92.3 and 99.2

Discussion

Dasatinib is a potent second generation TKI, and it is widely used in patients with CML, both in the up-front setting and failure after imatinib. As being an efficacious drug, it inhibits TEC kinases and SFKs, which are responsible for its AEs, so-called “off-target effects” [18].

Clonal expansion of large granular lymphocytes in cases receiving dasatinib therapy has been shown to be associated with pleural effusion and better outcome [9], [10], [19]. The mechanism underlying this phenomenon of

Conflict of interest

None of the authors of this paper has a financial or personal relationship with other people or organisations that could inappropriately influence or bias the content of the paper.

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