DISCUSSION
The prognosis of CML has changed from a fatal hematological malignancy to a curable disease thanks to the use of BCR-ABL TKIs. Since most patients will require treatment indefinitely, it is essential to understand the potential risks of such medications. TKI selectivity is often a critical issue as most TKIs have inhibitory actions against a wide variety of kinases. 8 Since multiple signaling pathways contribute to tumor pathogenesis, inhibiting several kinases simultaneously sometimes represents an advantage. The overall toxicity of TKIs correlates with the nonselective inhibition of several kinases.9 Risk factors for the adverse effects include a higher dose, a longer duration of treatment, older age, and a history of cardiac disease. 10
Among the different BCR-ABL TKIs, dasatinib is the drug most related to pulmonary toxicities. 11 Dasatinib-induced pleural effusion has an incidence of 15% to 35%. 2,12,13 Other pulmonary complications, such as pulmonary arterial hypertension (PAH) and interstitial pneumonitis, have also been reported.2,10,12,14
Bosutinib is uncommonly associated with pulmonary side effects. In a long-term safety study on bosutinib, the incidence of pleural effusion ranged between 4% and 8%, with a median time to onset of 33 months after initiation of treatment. 10,13–15 Moguillansky et al. reported a case of bosutinib-associated pleural effusions that resolved after discontinuation of the medication7. Jutant et al. reported a case of bosutinib-related pneumonitis.12 As is in the case we are presenting, bosutinib may also be associated with interstitial lung disease and pleural effusion—the spectrum of lung complications previously described with other TKIs16.
Although the mechanism of bosutinib-induced lung injury is unclear, it could be causing oxidative and reticular endothelium stress, similar to dasatinib17. Guignabert et al.’s studies showed that dasatinib mediated endothelial cell dysfunction and vascular damage in a dose-dependent manner. The risk factors for bosutinib-induced lung complications are a higher dosage, longer therapy duration, older age, and a history of cardiac disease, hypertension, or hypercholesterolemia.2,9,10 Patients on TKIs need careful monitoring of respiratory symptoms, such as rapid weight gain, progressive dyspnea, or nonproductive cough. A physical exam result suggestive of pleural effusion includes dull percussion or focally diminished breath sounds. This requires prompt confirmation with imaging studies. Depending on the size of the effusion and the index of suspicion for possible pleural space infection, a thoracentesis confirms the diagnosis. Typically, pleural fluid in drug-induced pleural effusion is exudative with lymphocyte predominance 18, as in our patient’s case. Much of the information on managing pulmonary toxicity during TKI therapy comes from case reports of events observed in dasatinib- or imatinib-treatment patients. The management of TKI-associated pleural effusion depends on the radiographic findings and clinical compromise2. If symptoms are minimal, no treatment is necessary. For large symptomatic pleural effusions, diuresis and a short steroid course can be used besides TKI dose reduction or discontinuation (temporarily or permanently). 2,19
Although interstitial lung disease (ILD) was a non-reported side effect of BCR-ABL TKI during the pre-approval clinical trials, case reports in the post-marketing period suggest ILD could be a side effect of BCR-ABL TKIs. 1 Peerzada et al. showed patients with BCR-ABL TKIs-induced ILD often presented with dyspnea, cough, hypoxia, and bilateral ground-glass opacities. 20 ILD due to TKIs is a diagnosis of exclusion. A detailed history and physical examination are necessary, and CT chest and sometimes lung biopsy can guide diagnosis. The mechanism of TKIs-induced pulmonary injury seems to be dose-dependent and typically reversible with discontinuation of TKI therapy. In some cases, the addition of corticosteroids confers some clinical benefit to avoid TKI therapy cessation. 3,11In patients who develop moderate to severe TKI-associated interstitial lung disease, re-challenging with alternative TKI therapy requires close monitoring since the risk of recurrence is high. 11.