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.