Chylothorax: complication attributed to dasatinib use

Abstract

A 63-year-old woman with a medical history of chronic myelogenous leukaemia treated with dasatinib, chronic obstructive pulmonary disease and heart failure with preserved ejection fraction presented with difficulty in breathing. Chest X-ray showed large right-sided pleural effusion, which was confirmed on a CT angiogram of the chest. Echocardiogram showed an ejection fraction of 61% with moderate to severely dilated right ventricle and right ventricular systolic pressure of 60 mm Hg. Diagnostic and therapeutic thoracentesis was performed, and 2.2 L of pleural fluid was removed. Pleural fluid analysis was consistent with chylothorax. Significant symptomatic improvement was noted after thoracentesis. In the absence of an alternate explanation, chylothorax was attributed to dasatinib, which was switched to nilotinib. This resulted in resolution of her pleural effusions.

Background

Chylothorax usually results from disruption of the normal chyle flow in the thoracic duct, resulting in leakage of lymphatic fluid into the pleural space.¹ Malignancy-induced thoracic duct obstruction, typically from lymphoma, is the leading cause of nontraumatic chylothorax.¹ Tyrosine kinase inhibitors, particularly dasatinib, have been associated with exudative pleural effusions. Growing evidence from case reports has associated dasatinib with development of chylous effusions as well.^1–3

Case presentation

A 63-year-old woman with a medical history of chronic myelogenous leukaemia (CML), chronic obstructive pulmonary disease and heart failure with preserved ejection fraction presented to the hospital with a 2-day history of increasing shortness of breath. The patient was diagnosed with CML 4 years perviously and was treated with dasatinib. The patient had two admissions over the past year for shortness of breath with bilateral pleural effusions, greater on the right. Diagnostic and therapeutic thoracentesis both times were consistent with exudative chylous effusions. On this admission, she reported dyspnoea unresponsive to inhaled albuterol, without symptoms of chest pain, orthopnea or pedal oedema. She had no significant surgical or family history. She was an everyday smoker of five cigarettes daily for 40 pack years. In the emergency department, she required 3 L of oxygen to maintain her oxygen saturation above 89% but did appear to be in significant respiratory distress. Physical examination was remarkable for diminished breath sounds on both lungs but more so on the right side.

Investigations

On admission, laboratory workup revealed elevated brain natriuretic peptide at 1131 pg/mL, haemoglobin of 9.5 10³/μL; white blood cell count and electrolytes were within normal limits. Chest X-ray (figure 1) showed large right-sided pleural effusion, which was confirmed on CT angiogram of the chest (figure 2). There was no evidence of pulmonary embolism, mediastinal lymphadenopatμhy or pulmonary lesions. Echocardiogram showed an ejection fraction of 61% with moderate to severely dilated right ventricle and right ventricular systolic pressure of 60 mm Hg. Thoracentesis was performed and 2.2 L of pleural fluid was removed. Pleural fluid analysis showed triglycerides 700 mg/dL, cholesterol 145 mg/dL, lactate dehydrogenase level (LDH) 125 U/L and total protein 4.2 g/dL. Serum LDH and total protein were 210 U/L and 8 g/dL, respectively. Pleural fluid white cell count was 1100 with 82% lymphocyte predominance, and fluid cytology was negative for any malignant cells.

Figure 1.

Chest X-ray showing right-side pleural effusion.

Figure 2.

CT angiogram of the chest showing right-side pleural effusion.

Differential diagnosis

The differential diagnosis for recurrent pleural effusions is broad. Chylothorax due to lymphoma was ruled out as pleural fluid cytology was negative for malignant cells; chylothorax secondary to trauma was ruled out as the patient denied a history of trauma, specifically chest trauma, and thoracic surgical interventions, while chylothorax due to pulmonary sarcoidosis was low on the differential as CT of the chest did not show hilar adenopathy, bronchial wall thickening or ground glass opacities.

Treatment

On admission, the patient was treated with supplemental oxygen, ipratropium bromide–albuterol sulfate nebulised treatments, prednisone, doxycycline, ceftriaxone and furosemide. Due to persistent hypoxia, diagnostic and therapeutic thoracentesis was performed. Chylothorax was attributed to dasatinib in light of her recurrent effusions and the absence of an alternate explanation. On her prior admissions, the dose of dasatinib had been reduced from 100 to 80 mg to try to prevent reaccumulation of pleural fluid. Despite dose reduction, she had two hospital admissions in 3 months for symptomatic right-sided pleural effusion requiring thoracentesis. Dasatinib was changed to nilotinib.

Outcome and follow-up

The patient was followed up as an outpatient with her primary care physician for 1 year. Electronic medical records review and phone interview confirmed no evidence of recurrent chylothorax.

Discussion

Chylothorax by definition is the presence of chyle in the pleural space.⁴ Chylothorax results from any disruption to the thoracic duct.⁵ It can be classified as traumatic or non-traumatic. The leading causes are thoracic surgery and malignancy, respectively.¹ Medications typically do not cause chylous effusions. On literature review, dasatinib is one of the few medications associated with the development of chylous effusion.

Dasatinib is a second-generation tyrosine kinase inhibitor that has a dual BCR–ABL1 and Src inhibiting activity.⁶ It is approved for the treatment of CML.⁷ Fluid retention, including transudative pleural effusions, has been associated with dasatinib.⁸

Chylothorax has been associated with dasatinib use, without clear explanation.^1–3 One suggested mechanism is inhibition of platelet-derived growth factor receptor beta (PDGFR-β) expressed in pericytes.³ PDGFR-β regulates angiogenesis as well as lymphangiogenesis, and inhibition of PDGFR-β results in disruption of tumour vasculature, which can result in significant fluid retention.^{3 9} Another mechanism is Src kinase inhibition by dasatinib. Src is a proto-oncogene encoding a non-receptor tyrosine kinase which is widely expressed in haematopoietic cells in lung tissue.^{1 10 11} It is responsible for capillary integrity by inducing the expression of vascular endothelial growth factor.^{1 12 13} Inhibition of Src results in changes in vascular permeability as well as pleural epithelium. Either mechanism could eventually affect lymphatic drainage, resulting in chylous effusions.

It is difficult to understand why some people would be more prone to developing chylothorax rather than simple pleural effusions.¹⁴ Pleural fluid analysis usually shows lymphocyte predominance, which suggests an immune-mediated mechanism.¹⁵

A PubMed search revealed seven cases of dasatinib-related chylothorax (table 1). Treatment in these cases included diuretics, steroids, dose reduction and completely stopping the medication. The role of other therapies, such as octreotide, remains unclear. Octreotide is a somatostatin analogue that decreases the absorption of fat in the intestine, hence decreasing chyle production.¹⁶ Studies have shown that octreotide decreases the need for surgical repair following traumatic surgical chylothorax.¹⁷ It has not been tried in any of the reported cases and could be a potential therapeutic modality if switching to another kinase inhibitor (ie, bosutinib, imatinib, ponatinib or nilotinib) is not feasible.

Table 1.

Reported cases of dasatinib-associated chylothorax

Case	Age–sex	Laterality	Dose (mg daily)	Duration of treatment with dasatinib until development of chylothorax (months)	Coexisting infiltrates	Treatment
Baloch et al 1	69–male	Right	100	10	None	Dose reduction, then stopped
Ferreiro et al 2	71–female	Bilateral	140	2	None	Dose reduction
Huang et al 3	40–female	Bilateral	100	40	None	Steroids and diuretics, then stopped dasatinib
Trivedi et al 18	62–male	Bilateral	Unknown	Around 24	Yes	Prednisone
Chua et al 19	44–female	Right	100	Around 36	Yes	Dasatinib stopped
Korotun et al 20	44–male	Left	Unknown	Unknown	None	Dasatinib held, unknown follow-up
Sasaki H et al 21	73–female	Right	70	12	None	Dasatinib changed to bosutinib, then imatinib, then furosemide plus Japanese herbal medicine ‘goreisan’

Patient’s perspective.

I was scared that I had to stop the medication suddenly, but I was relieved to find out that there are alternative therapies to treat my cancer. I will fight till the end.

Learning points.

• Pleural effusion is seen in 14%–32% of patients receiving dasatinib.

• Although tyrosine kinase–BCR-ABL inhibitors can cause pleural effusions, only dasatinib has been reported with chylothorax in the literature.

• Decreasing the dose of dasatinib may prevent recurrence of chylothorax.

• For recurrent chylothorax, alternative tyrosine kinase–BCR–ABL inhibitors should be used.