Dasatinib‐induced chylothorax: An unusual presentation of a common adverse event—A case report with literature review

Abstract Tyrosine kinase inhibitors (TKIs) are the key agents for treating CML and BCR–ABL+ B‐ALL. Dasatinib is a potent second‐generation TKI. Here, we have discussed the case of a 51‐year‐old gentleman diagnosed with B‐myeloid mixed‐phenotype acute leukemia with t(9;22)(q34.1;q11.2); BCR–ABL1p210, in complete hematological, cytogenetic, and molecular remission, who developed chylothorax. Though pleural effusion is a commonly observed adverse effect of dasatinib therapy, chylothorax is rare. The ability of Dasatinib to inhibit multiple families of tyrosine kinases could be considered the etiology. Discontinuation of the drug resolved the symptom, but pleural effusion recurred once Dasatinib was resumed. Chylothorax induced by Dasatinib is a differential to be kept in mind, owing to the limited number of cases being reported.


INTRODUCTION
Tyrosine kinase inhibitors (TKIs) are the cornerstone agents for treating CML and BCR-ABL + B-ALL. Approved in 2006 by the FDA, Dasatinib is a potent second-generation TKI, used as a first-line treatment of CML and BCR-ABL + B-ALL [1]. Pleural effusion is a common adverse effect occurring around 28%-33% of patients on longterm therapy with Dasatinib [2]. Chylothorax is an extremely unusual

CASE
A 51-year-old gentleman with only known past medical history of essential hypertension presented in June 2019, with severe anemia symptoms of fatigue, exertional shortness of breath, and dizziness.  After resolution of the pleural effusion, the patient was finally discharged home after switching to Imatinib.

DISCUSSION
The patient in this report presented with bilateral chylothorax. After reviewing detailed history and investigations, no other etiology for the chylothorax was identified other than Dasatinib.
Chylothorax is the accumulation of chyle in the pleural cavity caused by its extravasation into the pleural space. It can be due to obstruction or injury to the thoracic duct or its tributaries or transdiaphragmatic flow from the peritoneal cavity. Pleural fluid is often milky in appearance with triglycerides >1.24 mmol/L (>110 mg/dl) or the presence of chylomicrons [3,4]. Chylothorax is a lesser common pleural effusion with a broad differential centering around impaired lymphatic drainage, most commonly due to trauma, malignancy, or lymphatic disorders. Despite these numerous etiologies of chylothorax, Dasatinib is the only drug described in the literature associated with such a finding [5].
Dasatinib is a potent TKI with the ability to inhibit multiple tyrosine kinases, including the SRC family of kinases in addition to BCR-ABL1.
It is an orally administered small molecule with additional inhibitory F I G U R E 3 CT thorax showing significant bilateral pleural effusion with associated collapse/ consolidation of the bases of both lungs and areas of ground-glass appearances and incomplete consolidations activity for c-KIT, EPHA2, and platelet-derived growth factor receptorbeta (PDGFR-B) [6][7][8].
In vitro, Dasatinib was found to be 325-fold more potent in inhibiting the wild type of BCR-ABL1 compared to Imatinib, making it an effective agent in Imatinib-resistant BCR-ABL1 mutants [9]. Src family of kinases are well expressed on the hematopoietic cells in the lung tissue and mediate the pleural epithelium's vascular permeability and stability [13,14]. Both these actions are compromised by the ability of Dasatinib to inhibit multiple tyrosine kinases. The pleural fluid's lymphocytic predominance in all the cases also points toward the possibility of an immune-mediated mechanism for this adverse event [15].
Dasatinib-induced pleural effusions are managed with various strategies, including temporary interruptions, diuretics, and/or lowdose steroids and thoracocentesis [16]. Discontinuation of the drug resolved the symptom, and around 70% of the patients had a recurrence of pleural effusion once Dasatinib was resumed. The development of pleural effusion was also found to be dose related [17]. A dose of 100 mg daily was found to have lower pleural effusion incidences than higher doses [18]. The other management strategies included daily dose reduction or, as an alternative option, an on/off treatment with a weekend drug holiday was also found to be effective [19]. With persistence or recurrence of pleural effusion, the patient was challenged with a different TKI instead of Dasatinib such as Imatinib, which was associated with a much lesser pleural effusion incidence [20].

CONCLUSION
Though pleural effusion is a commonly observed adverse effect of dasatinib therapy, chylothorax is particularly rare. Imatinib was thought to be ideal, with a short duration of steroids, diuretics, and bilateral thoracocentesis to relieve the symptoms. He was also started on statin for hyperlipidemia developed. The diverse spectrum of metabolic adverse events of Dasatinib is not fully explored.
More studies are needed to ascertain the need for regular monitoring for the development of adverse impact of Dasatinib on glucose-lipid metabolism so as to address the cardiovascular risks early.

ACKNOWLEDGMENT
Qatar National Library provided open access funding.