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.