Discussion
The main aim of the TKI therapy is the antileukemic effect that frequently causes manageable adverse events [1]. These events depend on the TKI prescribed, posology, schedule chosen, disease phase, possible interactions with other medications in use and body size [1]. Ocular toxicity has been described as a possible TKI adverse event, usually minor and self-limited. The most common manifestations are papillitis and macular edema. In spite of TKIs having similar mechanisms of action, Imatinib is the most commonly connected to ocular toxicity (periorbital edema can occur in up 70% of the patients); Nilotinib is less reported than Imatinib and Ponatinib, and is rarely described as having this type of adverse events [1, 8, 9, 10, 11]. There is scarce information about Dasatinib and Bosutinib on this subject (there is a case report of optic neuropathy caused by Dasatinib) [12-15]. Bosutinib is being compared with Imatinib in efficacy and adverse events (ocular toxicity included) for CP-CML (chronic phase) in first line; previous trials did not focus particularly on this toxicity [14-15]. It is advised that a loss of visual acuity should prompt an examination of the optic disc and retina, in order to consider additional systemic steroid therapy and even TKI discontinuation [1].
In order to established a cause-effect relationship between a drug and a secondary effect, we should identify a temporal association, a relationship with the dosage, an improvement after discontinuation (except in cases of continuous aggression for long time, that can cause irreparable damage), a worsening of the symptoms after re-introduction, a possible pathophysiological mechanism, similar effects after introduction of a drug from the same family and the absence of alternative mechanisms that may explain the secondary effect.
In this particular case report besides having visual defects diagnosed previously to the CML, the old lesions worsened (possibly triggered and accelerated by the TKI) and new deficits were found in the right eye, which begun and persisted along the TKI therapy and worsened in each drug exposure (except the papillitis which was treated). A new and unusual lesion (not described in the literature) is the retinal detachment caused by a macular edema, which persisted in time. There was clinical evidence of toxicity in the ophthalmologic exam and in the OCT exams demanded regularly (irreversible lesions, besides three different treatments with oral corticosteroids). A deeper investigation should be made before assuming toxicity of the drug, as exclusion of an infectious process in peripheral blood and central nervous system (search for active syphilis, HSV, CMV, EBV, ADV, Brucella, Bartonella, HIV, HBV, HCV, HAV; flow cytometry for search of leukemic infiltration), an autoimmune disease (rarely found in older age; antibodies anti-ANA, antiDNA, AntiRO, Anti-La, cANCA, rheumatoid factor) or a vitamin deficit (A, B1, B6, B12, folic acid). A cerebral image as a MRI is relevant for exclusion of infection and malignant infiltration. Evaluation of the main disease (in this clinical case the CML), the past medical history, travels and expositions in daily life are also demanding.
This case confirms the short time between drug exposure and the ocular toxicity and raises the possibility that the visual toxicity identified in this patient might have been a shared event between TKIs (possibly through a common mechanism of action). This can be a limiting factor for the use of these drugs (mainly in older patients with previous ophthalmologic disease). The authors think that an ophthalmologic evaluation before and along TKIs could be a very important surveillance in CML, mainly in patients with previous ophthalmologic disease.
In this specific clinical case, the change of TKI generation was not guided by the ocular toxicity alone (besides the relevant impact in the quality of life of this patient), but also by the absence of optimal response to the last treatment prescribed. However, a better response was never achieved. The treatment was not changed before for the clinical frailty of this patient (age and comorbidities). Only the last TKI achieved a more suitable response compared to the others, but no sufficiently good to ensure an optimal response. In face of an intolerable toxicity in an aged palliative patient (refractory to three generation of TKIs), hydroxyurea was prescribed. This decision improved this patient’s quality of life and was enough to control his disease until today.