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Chronic Myeloid Leukemia
Incidence, outcomes, and risk factors of pleural effusion in patients receiving dasatinib therapy for Philadelphia chromosome-positive leukemia
Ferrata Storti Foundation
Timothy P. Hughes,1 Pierre Laneuville,2 Philippe Rousselot,3 David S. Snyder,4 Delphine Rea,5 Neil P. Shah,6 David Paar,7 Elisabetta Abruzzese,8
Andreas Hochhaus,9 Jeffrey H. Lipton10 and Jorge E. Cortes11
1Cancer Theme, SAHMRI, Division of Haematology, SA Pathology, University of Adelaide, South Australia, Australia; 2McGill University Health Centre, Montreal, QC, Canada; 3Hôpital Mignot, Université Versailles Saint-Quentin-en-Yvelines, Le Chesnay, France; 4City of Hope, Duarte, CA, USA; 5Service d'Hématologie Adulte, Hôpital Saint-Louis, Paris, France; 6UCSF School of Medicine, San Francisco, CA, USA; 7Bristol-Myers Squibb, Princeton, NJ, USA; 8Hematology, S. Eugenio Hospital, Tor Vergata University, Rome, Italy; 9Hematology/Oncology, Universitätsklinikum Jena, Germany; 10Princess Margaret Cancer Centre, Toronto, ON, Canada and 11University of Texas MD Anderson Cancer Center, Houston, TX, USA
Haematologica 2019 Volume 104(1):93-101
ABSTRACT
Dasatinib, a second-generation BCR-ABL1 tyrosine kinase inhibitor, is approved for the treatment of chronic myeloid leukemia and Philadelphia chromosome-positive acute lym- phoblastic leukemia, both as first-line therapy and after imatinib intoler- ance or resistance. While generally well tolerated, dasatinib has been associated with a higher risk for pleural effusions. Frequency, risk fac- tors, 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 6-9% of patients at risk annually in DASISION, and in 5-15% 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, respec- tively. 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. clinicaltrials.gov identifier 00481247; 00123474.
Introduction
Dasatinib is a potent second-generation BCR-ABL1 tyrosine kinase inhibitor (TKI) approved at 100 mg once daily (QD) as first-line therapy in patients with chronic myeloid leukemia in chronic phase (CML-CP), and in patients with CML- CP who are resistant to or intolerant of prior therapy.1 Dasatinib is also approved at 140 mg QD in patients with accelerated or blast phase CML (CML-AP/BP) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) with resistance to or intolerance of prior therapy.2-4
Although fluid retention has been associated with TKIs used to treat CML, pleu- ral effusions, specifically with exudate characteristics, have been reported more commonly with dasatinib.1,5,6 The exact mechanisms behind treatment-related pleu- ral effusion remain to be elucidated; however, it has been suggested that immune mechanisms may play a role, based on reports of association with lymphocytosis and the presence of lymphocyte-dominant exudates and chyle accumulate.7-9 Alternatively, pleural effusion (with or without exudates) may also occur through inhibition of platelet-derived growth factor receptor-β or SRC-family kinases.10,11 In
Correspondence:
jcortes@mdanderson.org
Received: January 18, 2018. Accepted: August 3, 2018. Pre-published: August 9, 2018.
doi:10.3324/haematol.2018.188987
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/1/93
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