A Rare Case of Recurrent Dasatinib-Induced Chylothorax Years After Initial Treatment

Background: Chronic myeloid leukemia (CML) is characterized by the Philadelphia chromosome containing the BCR-ABL protein with deregulated tyrosine kinase activity. Tyrosine kinase inhibitors (TKIs) were developed to target this oncogene. Dasatinib, a TKI, has rarely been associated with spontaneous chylothorax. The majority occur within 1 year of dasatinib initiation and resolve after drug cessation. In contrast, we present a patient with CML on dasatinib therapy for 8 years who developed recurrent unilateral chylothorax even after cessation of dasatinib.

Case: A 57-year-old male with a history of CML on dasatinib therapy presented to the hospital for nausea and vomiting. A computed tomographic scan revealed a large right-sided pleural effusion with thoracentesis yielding 1.5 liters of chylous fluid. The patient’s hospital course was complicated by intracranial hemorrhage and subsequent admission to the intensive care unit. Dasatinib was stopped during this time. The patient experienced multiple recurrences of this effusion with significant output via thoracentesis and chest tube despite dietary changes. Lymphangiography was performed but revealed no evidence of thoracic duct leakage.

Conclusions: Chylothorax from dasatinib is rare, usually occurs within 1 to 2 years of treatment onset, and resolves with discontinuation. However as supported by this case and others, it may occur as late as 8 years from treatment onset and chylothorax may continually re-accumulate or persist up to 1 year from dasatinib cessation. It is imperative to rule out underlying thoracic duct disruption prior to attributing etiology to dasatinib as a misdiagnosis may result in treatment delays.

Introduction

Chronic myeloid leukemia is a hematopoietic disorder with a cytogenetic hallmark of a reciprocal t (9;22) (q34; q11) chromosomal translocation, known as the Philadelphia chromosome, which contains the BCR-ABL protein with deregulated tyrosine kinase activity. With the development of tyrosine kinase inhibitors targeting the BCR-ABL oncogene, the ability to treat and cure chronic myeloid leukemia has been revolutionized.

The first FDA-approved tyrosine kinase inhibitor for the treatment of Philadelphia chromosome-positive chronic myeloid leukemia was Imatinib. Despite significant responses to therapy, some patients develop resistance to Imatinib, commonly due to mutations within the BCR-ABL kinase domain, even after attaining a therapeutic response [1]. Resistance to Imatinib led to the development of second-generation tyrosine kinase inhibitors, such as dasatinib and nilotinib, which are highly potent and approved for use as first-line and subsequent therapy for those who are resistant or do not tolerate treatment [2].

Although a highly favored option, treatment with dasatinib has been linked to pulmonary adverse events such as pleural effusion and less commonly pulmonary arterial hypertension [3]. The incidence of dasatinib-associated pleural effusion was found to be 20%, in those who receive once-daily dosing [4]. However, pleural effusion in the form of chylothorax has seldom been reported and the pathophysiologic mechanism is poorly understood. Chylothorax is an uncommon condition most frequently reported due to damage to the thoracic duct resulting in chyle leakage into the> right pleural space. The discontinuation, decrease in dosage, or halting of dasatinib therapy has been reported to decrease the size and incidence of pleural effusion. Here we present the case of a 56-year-old patient with CML on dasatinib therapy for 8 years, who suddenly developed persistent right-sided chylothorax.

Case Presentation

This is a 56-year-old male with a past medical history of chronic myeloid leukemia (CML), chronic pleural effusion, diabetes mellitus type 2, hypertension, and hyperlipidemia who presented to the emergency department with a 1-day history of nausea and vomiting that suddenly began that morning. Of note, he was first diagnosed with CML 9 years prior and was started on nilotinib at the time of his initial diagnosis, and then switched to dasatinib 1 year later. The patient had medication adherence issues due to side effects, with a pleural effusion first documented 6 years after starting dasatinib which prompted a dosage decrease from 100mg to 70mg resulting in improvement. Despite this, he remained nonadherent for the following year.

In addition to his acute nausea and vomiting, he experienced worsening abdominal pain, lower extremity weakness, and lethargy. He denied hemoptysis, fever, chills, headache, chest pain, recent diarrhea, melena/hematochezia, or urinary symptoms.

In the emergency department, he was tachycardic, tachypnic, and hypertensive with systolic blood pressures ranging in the 180s–200s. He was afebrile and his remaining vitals were unremarkable. He was found to have a white blood cell (WBC) count of 16.4 × 10³, (4.4 to 10.5 × 10³) with lactic acid was 4.7 mmol/L (<2 mmol/L). He was given fluids, blood cultures were drawn, and started on ampicillin-sulbactam and vancomycin. Chest x-ray and computerized tomography (CT) scan of the chest revealed a right-sided large pleural effusion (Fig. 1) and thoracentesis was undertaken which drained 1.5 liters of yellow fluid. (Table I) The fluid analysis yielded cloudy, exudative effusion with a fluid triglyceride count greater than 110 mg/dL, confirming the diagnosis of chylothorax. Cultures from this and future thoracentesis remained negative and cytology was unremarkable.

Fig. 1. Chest X-ray obtained on admission prior to first thoracentesis (A) Followed by chest X-ray obtained immediately post-thoracentesis (B) Obscuring and blunting of the costophrenic angle were noted on the admission chest X-ray (red arrows). Full resolution of the effusion is noted.

Table I. Pleural Fluid Findings from Serial Thoracentesis

Lab analysis	Sample # and Value				Reference
	#1	#2	#3	#4
pH	7.7	7.7	8.66	7.74	7.35–7.45
Fluid LDH/erum LDH ratio	0.32	0.56	—	1.22*	See caption
Fluid protein/Serum protein ratio	0.65*	0.61*	0.80*	0.80*	See caption
Triglyceride	363	285	145	41	<110 mg/dL
Cholesterol	30	50	—	—	<45 mg/dL
Red blood cell count	6,000	9,000	26,000	21,000	<100 RBC/uL
Fluid character, appearance	Cloudy, yellow	Cloudy, milky	Cloudy, blood tinged	Slightly cloudy, blood tinged	Clear

The patient’s hospital course was subsequently complicated by acute onset stroke-like symptoms. CT imaging was obtained and he was found to have had a large right cerebellar cortical infarct without hemorrhagic transformation and with associated effacement of the fourth ventricle resulting in obstructive hydrocephalus. The patient subsequently underwent a decompressive suboccipital craniotomy with a right frontal external ventricular drain (EVD) placement and was admitted to the intensive care unit. During this time the patient was intubated for airway protection. Oncology was consulted for the resumption of dasatinib but after a risk-benefit discussion ultimately decided that dasatinib should remain held due to his severe illness and decreased functional capacity. The patient was unable to wean from the ventilator due to poor mental status and a tracheostomy was placed.

During this time, merely 12 days from the first thoracentesis, the patient’s pleural effusion reaccumulated such that he began experiencing increased oxygen requirements and the need for frequent suctioning. These symptoms prompted repeat therapeutic thoracentesis and 1.2 liters of milky fluid was drained. The pleural fluid again demonstrated chylothorax with cloudy, alkaline fluid and elevated triglycerides. All values were minimally changed from previously observed values.

Due to persistent and rapid reaccumulation of the pleural effusion, a chest tube was placed with 1.4 liters of fluid removed on the first day of placement. Tube feeds were changed to a low-fat and low-chylomicron formula. The patient experienced 5 days of 300–500 cc output which decreased gradually. Pleural fluid labs were drawn on the 3rd day as seen in Table I. The triglyceride level drawn from the sample remained elevated and the patient was started on octreotide for 7 days. On the 6th day, output fell below 200cc prompting chest tube removal. The patient was downgraded from the ICU and was monitored by pulmonology. The effusion reaccumulated once more over the next 8 days, prompting paracentesis and placement of another chest tube.

The patient experienced roughly 400cc output over the next week despite switching diet to elemental tube feeds, and in the context of frequent reaccumulation of chylothorax, suspicion of a thoracic duct leak was raised. Interventional radiology (IR) lymphangiography was undertaken but revealed no evidence of active thoracic duct leakage and the patient did not undergo embolization. The chest tube was removed once more as output dropped below 25 cc/day. Effusion was not noted again until 3/30. The patient underwent a final thoracentesis prior to discharge to a long-term care facility with the removal of about 1.2 L of fluid, whose characteristics are seen in Table I.

Tabulated above are pleural fluid values from 4 separate instances during the hospital course. Sample #1 was collected from the 1st thoracentesis, Sample #2 was collected from the thoracentesis 12 days later. Sample #3 was collected from fluid from the first chest tube, and Sample #4 was collected from the final thoracentesis. Starred values indicate exudative effusion. Pleural/serum protein ratio is >0.5 in an exudatve effusion and <0.5 in a transudative effusion, similarly pleural/serum LDH ratio is >0.6 in an exudative effusion and <0.6 in a transudative effusion. Cholesterol level in chylothorax is <200 mg/dL. Levels above 200 mg/dL would indicate the fluid is a pseudochylous effusion. Hemothorax is considered when pleural/serum hematocrit is ≥0.5, none of the above met this criterion.

Discussion

Dasatinib is a highly potent, orally administered small molecule inhibitor of multiple tyrosine kinases and indicated for the treatment of adults with Philadelphia chromosome-positive (Ph+) CML in chronic phase and for Ph+ acute lymphoblastic leukemia (ALL) as first-line therapy or after failure or intolerance of other treatment options, including Imatinib [5]. It should be noted that dasatinib is the only tyrosine kinase inhibitor (TKI) available that has been rarely linked to chylothorax as a potential side effect [6]. The majority of these cases of chylothorax are seen bilaterally, however, when they are unilateral, they tend to present on the right side as seen in our patient. Consideration has been made that chylothorax in these cases may be related to CML, as this link exists for another lymphoma such as Hodgkin lymphoma [7]. However, there is no current evidence of the association between the natural course of CML and chylothorax [6]. There is one case report linked CML and chylothorax and this was in the setting of Adams-Oliver syndrome [8].

The mechanism underlying chylothorax secondary to dasatinib is not completely elucidated. However, it is theorized to be driven by disturbed angiogenesis from the downregulation of platelet-derived growth factor receptor beta (PDGFR-β), Src kinase inhibition impairing capillary integrity, and changes of vascular endothelial growth factor (VEGF) mediated permeability and stability of pleural epithelium [9]–[11].

Per a recent literature review, the estimated time for chylothorax development following dasatinib initiation ranged from 2 to 50 months [12]. Virtually all cases were resolved with its discontinuation, which has further tightened the link between the two [6]. This rare association has drawn enough attention in recent years that it has occasionally led to treatment delay and misattribution of thoracic duct leakage to dasatinib in patients that develop persistently recurrent chylothorax >5 years from initiation of dasatinib despite discontinuation [6], [13]. However, contrary to previous thought, dasatinib-associated chylothorax may still be infrequently present without these features.

In a retrospective study conducted in 2007, 138 patients were treated with dasatinib after treatment failure with imatinib [6], [14]. Of these patients, 48 had pleural effusions and one had recurrent chylous effusion requiring 12 thoracentesis treatments [6], [14]. Additionally, there have been both unilateral and bilateral cases of chylothorax occurring up from 1 year to as late as 10 years after initiation of dasatinib, and recurrence up to 1 year after discontinuation of dasatinib [6], [15]–[17]. Our patient was on dasatinib for nearly 8 years total, with persistent adherence issues and symptomatic pleural effusions at year 6 of treatment. The role of chronic effusions in the recurrence of dasatinib-associated chylothorax can only be speculated, but they may increase the likelihood of recurrence as seen in our patient and other similar cases of recurrent chylothorax [6], [11], [15]–[17].

Pleural triglyceride concentration greater than 110 mg/dL and pleural cholesterol <200 confirm the diagnosis of chylothorax [6], [11]. Pleural cholesterol greater than 200 with concomitant triglyceride elevation would be typical in pseudochylothorax. Infrequently, chylothorax can present with triglyceride concentrations less than 110 mg depending on the time of the last meal and the fat content of the diet [6]. In our patient, the triglyceride concentration content of the pleural fluid was consistently above 110 mg/dl except in the final reading, likely due to being given low-fat tube feeds for nearly 1 month to that point.

There is no current consensus on the treatment of dasatinib-associated chylothorax. In virtually all cases that chylothorax is identified, the dasatanib dose is either reduced and tapered or discontinued and replaced with an alternative agent. Dosages of dasatanib 70 mg and above are often associated with pleural effusion [11]. Diuresis and low-fat and low-chylomicron diets are often employed. Management of our case differed from the literature by administering a 1-week course of octreotide and not opting for steroids.

Conclusion

Chylothorax from dasatinib therapy is a rare side effect that usually occurs within 1 to 2 years of treatment onset, but can occur as late as 8 years from treatment onset. Chylothorax in these cases often resolves shortly after the discontinuation of dasatinib, however, there remain cases where chylothorax continually re-accumulates or persists up to 1 year from dasatinib cessation. Long-standing chylothorax may increase the risk of developing future chylothorax, even in the absence of the offending drug. It is imperative to rule out underlying thoracic duct disruption prior to attributing the etiology to dasatinib, as clinicians anchoring on dasatinib chylothorax may result in treatment delays.