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      A case of worsening pulmonary arterial hypertension and pleural effusions by bosutinib after prior treatment with dasatinib

      case-report

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          Abstract

          A 52-year-old man with a past medical history of chronic myeloid leukemia (CML) in remission developed progressive shortness of breath over a two-month period. He was initially treated with dasatinib for four years, until developing pulmonary arterial hypertension (PAH) with pleural effusions. His symptoms improved after stopping dasatinib. He was then switched to bosutinib for approximately one year, which was then stopped before admission due to worsening shortness of breath. His initial workup showed bilateral pleural effusions with severe PAH and cor pulmonale. He had symptomatic improvement with PAH-specific therapy following discontinuation of the bosutinib.

          The life expectancy of CML patients has increased in the era of the tyrosine kinase inhibitors (TKIs), and managing adverse events (AEs) of the TKIs and improving quality of life are becoming more important.

          Pulmonary hypertension (PH) and pleural effusions are rarely reported AEs of bosutinib. More reports with PH and pleural effusions arising after bosutinib use in patients previously treated with dasatinib is furthermore concerning. In this era with novel chemotherapeutic agents, physicians ought to be weary of the significant morbidity implicated by these agents in the lives of patients.

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          Most cited references10

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          Pulmonary arterial hypertension in patients treated by dasatinib.

          The French pulmonary hypertension (PH) registry allows the survey of epidemiological trends. Isolated cases of precapillary PH have been reported in patients who have chronic myelogenous leukemia treated with the tyrosine kinase inhibitor dasatinib. This study was designed to describe incident cases of dasatinib-associated PH reported in the French PH registry. From the approval of dasatinib (November 2006) to September 30, 2010, 9 incident cases treated by dasatinib at the time of PH diagnosis were identified. At diagnosis, patients had moderate to severe precapillary PH with functional and hemodynamic impairment. No other incident PH cases were exposed to other tyrosine kinase inhibitors at the time of PH diagnosis. Clinical, functional, or hemodynamic improvements were observed within 4 months of dasatinib discontinuation in all but 1 patient. Three patients required PH treatment with endothelin receptor antagonist (n=2) or calcium channel blocker (n=1). After a median follow-up of 9 months (min-max 3-36), the majority of patients did not demonstrate complete clinical and hemodynamic recovery, and no patients reached a normal value of mean pulmonary artery pressure (≤20 mm Hg). Two patients (22%) died at follow-up (1 of unexplained sudden death and 1 of cardiac failure in the context of septicemia, respectively, 8 and 12 months after dasatinib withdrawal). The lowest estimate of incident PH occurring in patients exposed to dasatinib in France was 0.45%. Dasatinib may induce severe precapillary PH fulfilling the criteria of pulmonary arterial hypertension, thus suggesting a direct and specific effect of dasatinib on pulmonary vessels. Improvement is usually observed after withdrawal of dasatinib.
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            Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: results from the BELA trial.

            Bosutinib is an oral Src/Abl tyrosine kinase inhibitor. The phase III Bosutinib Efficacy and Safety in Newly Diagnosed Chronic Myeloid Leukemia (BELA) trial compared bosutinib with imatinib in newly diagnosed, chronic-phase chronic myeloid leukemia (CML). A total of 502 patients were randomly assigned 1:1 to bosutinib 500 mg per day or imatinib 400 mg per day. The complete cytogenetic response (CCyR) rate at 12 months was not different for bosutinib (70%; 95% CI, 64% to 76%) versus imatinib (68%; 95% CI, 62% to 74%; two-sided P = .601); therefore, the study did not achieve its primary end point. The major molecular response (MMR) rate at 12 months was higher with bosutinib (41%; 95% CI, 35% to 47%) compared with imatinib (27%; 95% CI, 22% to 33%; two-sided P < .001). Time to CCyR and MMR was faster with bosutinib compared with imatinib (two-sided P < .001 for both). On-treatment transformation to accelerated/blast phase occurred in four patients (2%) on bosutinib compared with 10 patients (4%) on imatinib. A total of three CML-related deaths occurred on the bosutinib arm compared with eight on the imatinib arm. The safety profiles of bosutinib and imatinib were distinct; GI and liver-related events were more frequent with bosutinib, whereas neutropenia, musculoskeletal disorders, and edema were more frequent with imatinib. This ongoing trial did not meet its primary end point of CCyR at 12 months, despite the observed higher MMR rate at 12 months, faster times to CCyR and MMR, fewer on-treatment transformations to accelerated/blast phase, and fewer CML-related deaths with bosutinib compared with imatinib. Each drug had a distinct safety profile.
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              Dasatinib induces lung vascular toxicity and predisposes to pulmonary hypertension.

              Pulmonary arterial hypertension (PAH) is a life-threatening disease that can be induced by dasatinib, a dual Src and BCR-ABL tyrosine kinase inhibitor that is used to treat chronic myelogenous leukemia (CML). Today, key questions remain regarding the mechanisms involved in the long-term development of dasatinib-induced PAH. Here, we demonstrated that chronic dasatinib therapy causes pulmonary endothelial damage in humans and rodents. We found that dasatinib treatment attenuated hypoxic pulmonary vasoconstriction responses and increased susceptibility to experimental pulmonary hypertension (PH) in rats, but these effects were absent in rats treated with imatinib, another BCR-ABL tyrosine kinase inhibitor. Furthermore, dasatinib treatment induced pulmonary endothelial cell apoptosis in a dose-dependent manner, while imatinib did not. Dasatinib treatment mediated endothelial cell dysfunction via increased production of ROS that was independent of Src family kinases. Consistent with these findings, we observed elevations in markers of endothelial dysfunction and vascular damage in the serum of CML patients who were treated with dasatinib, compared with CML patients treated with imatinib. Taken together, our findings indicate that dasatinib causes pulmonary vascular damage, induction of ER stress, and mitochondrial ROS production, which leads to increased susceptibility to PH development.
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                Author and article information

                Journal
                Pulm Circ
                Pulm Circ
                PUL
                sppul
                Pulmonary Circulation
                SAGE Publications (Sage UK: London, England )
                2045-8932
                2045-8940
                24 October 2017
                December 2017
                : 7
                : 4
                : 808-812
                Affiliations
                [1 ]Department of Internal Medicine, University of Florida College of Medicine, Jacksonville, FL, USA
                [2 ]Department of Pulmonary Disease and Critical Care Medicine, University of Florida College of Medicine, Jacksonville, FL, USA
                Author notes
                [*]Karan Seegobin, 4500 Baymeadows Road, Apt 200, Jacksonville, FL 32217, USA. Email: karanseegobin@ 123456hotmail.com
                Author information
                http://orcid.org/0000-0002-8129-9723
                Article
                10.1177_2045893217733444
                10.1177/2045893217733444
                5703128
                28914582
                82720de7-6edd-4134-baa6-2747bf66ceab
                © The Author(s) 2017

                This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License ( http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages ( https://us.sagepub.com/en-us/nam/open-access-at-sage).

                History
                : 15 August 2017
                : 4 September 2017
                Categories
                Case Reports
                Custom metadata
                October-December 2017

                Respiratory medicine
                pulmonary arterial hypertension,pleural effusions,bosutinib,dasatinib
                Respiratory medicine
                pulmonary arterial hypertension, pleural effusions, bosutinib, dasatinib

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