Cognitive dysfunction after withdrawal of tyrosine kinase inhibitor therapy in chronic myeloid leukaemia
Authors: Simone Claudiani, Jane F. Apperley, Simona Deplano, Jamshid Khorashad, Letizia Foroni, Renuka Palanicawandar, Richard Perry, Dragana Milojkovic
Journal: American Journal of Hematology (2016)

To the Editor: Recent studies suggest that a proportion of patients who achieve deep and sustained molecular responses following tyrosine kinase therapy (TKI) for chronic myeloid leukaemia (CML) can discontinue the drugs without experiencing relapse of disease. However, up to 30% of patients experience a spectrum of symptoms 1–6 weeks after cessation, which include musculoskeletal pain and skin rash 1. To date, no late adverse events have been noted. We report three female patients that experienced significant cognitive impairment 4–12 months after stopping TKI therapy in the absence of any other identifiable cause. The median duration of CML and TKI therapy were 15.8 years (range 13.6–16 years) and 12.3 years (range 12.2–13.1 years), respectively. Patient 1 (Table 1) presented with CML in chronic phase (CP) age 50 in 1999 and following primary resistance to imatinib, dasatinib, and nilotinib proceeded to allogeneic stem cell transplantation after 8 years of TKI therapy in 2007. She experienced molecular relapse, but as she did not respond to donor lymphocyte infusions, nilotinib 400 mg daily was restarted in 2013. After achievement of complete molecular response (MR5) 12 months later, nilotinib was discontinued after 2 years of therapy. Six months after stopping nilotinib she developed progressive onset of cognitive impairment, memory loss and episodes of disorientation. The clinical course was complicated by zoster affecting the T1 dermatome that subsequently aggravated her confusional state, however, frontal lobe impairment has persisted with continued cognitive decline which remains unexplained. Imatinib Dasatinib Nilotinib Allo-SCT/DLI Nilotinib Imatinib Dasatinib Nilotinib ABMT IFN Imatinib Nilotinib Bosutinib Imatinib Patient 2 was diagnosed with CML in CP in 2002, age 55 years and following failure of imatinib and dasatinib was treated with nilotinib in 2007 which induced a sustained CMR (MR4.5). Nilotinib was discontinued 7 years later following the development of peripheral artery occlusive disease. Four months later she developed significant and progressive undetermined cognitive impairment without detection of cerebrovascular disease. Patient 3 was diagnosed with CML in CP in 1999, age 55 years, and eventually received imatinib from 2001 which induced a durable CMR5. In 2012, imatinib was discontinued because of persistent side-effects and therapy was changed to nilotinib. This in turn was discontinued after 8 months following intolerance, as was bosutinib after 2 months of therapy. As the patient perceived imatinib to be the best tolerated TKI, this was resumed in 2013. After 12 months, because of on-going CMR5 and return of side effects, imatinib was discontinued. After twelve months off TKI therapy she was diagnosed with early dementia in the absence of other identifiable factors. TKI withdrawal syndrome has been attributed to sudden reversal of imatinib induced c-kit inhibition and release of c-kit suppression of mast cell function and activation, but neurological consequences after TKI withdrawal have not previously been described 2. Nilotinib and bosutinib are able to cross the blood-brain barrier and due to their ability to strongly inhibit Abl they have been reported to effectively decrease the systemic and central nervous system immune response involved in neuronal damage 7 and have recently been linked with the inhibition of disease-generating lesions in both Alzheimer's disease (AD) and Parkinson's. AD is a neurodegenerative disorder characterized by accumulation of β-amyloid (plaques) and hyper-phosphorylated Tau protein 3. Animal model studies suggest a potential role of TKIs in interfering with the pathogenetic step of neurodegenerative disorders emphasising the link between c-Abl receptor tyrosine kinase and neurodegeneration. Activation of c-Abl regulates the neural death response to amyloid-beta fibrils in AD animal models 4 and furthermore, Abl inhibition by TKIs is responsible for increased amyloid-beta clearance and reduced behavioral deficit 5. In addition, Imatinib can ameliorate the neurodegenerative changes in animal studies through the transcriptional induction of gene involved in the clearance of amyloid-beta fibrils 6, the regulation of the apoptotic response 7 and the decrease of pathological Tau protein hyperphosphorylation 8. These findings in the case of Nilotinib and Bosutinib have led to the suggestion that these agents could be investigated as potential treatments for AD 9. In view of these observations in animal models, one can postulate that TKI discontinuation after a prolonged duration of therapy may be responsible for a "rebound" increase in neuronal Abl activity and precipitate a neurodegenerative process, which is in parallel with the rationale for the more immediate symptoms that occur after TKI withdrawal. More than 2000 patients have stopped TKI therapy and the goal of modern day CML therapy categorically involves the aim of treatment free remission. These findings in patients that have stopped TKI therapy emphasise the need to stop therapy in the context of clinical studies and importantly physicians should remain vigilant for unexplained neurological findings. We would like to acknowledge the BRC. Simone Claudiani,1 Jane F. Apperley,1 Simona Deplano,1 Jamshid Khorashad,1 Letizia Foroni,1 Renuka Palanicawandar,1 Richard Perry,2 and Dragana Milojkovic1* 1Department of Haematology, The Hammersmith Hospital, Imperial College, London, United Kingdom; 2Department of Neurology, The Hammersmith Hospital, Imperial College, London, United Kingdom