Cognitive dysfunction after withdrawal of tyrosine kinase inhibitor therapy in chronic myeloid leukaemia To the Editor: Recent studies suggest that a proportion of patients who achieve deep and sustained molecular responses following tyrosine kinase therapy (TKI) for chron- ic 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 experi- enced 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 I) presented with CML in chronic phase (CP) age 50 in 1999 and following primary resistance to imatinib, dasatinib, and nilotinib proceeded to allogene- ic 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 (MR 5 ) 12 months later, nilotinib was discontinued after 2 years of therapy. Six months after stopping nilotinib she developed progressive onset of cognitive impairment, mem- ory loss and episodes of disorientation. The clinical course was complicated by zoster affecting the T1 dermatome that subsequently aggravated her confusional state, howev- er, frontal lobe impairment has persisted with continued cognitive decline which remains unexplained. Patient 2 was diagnosed with CML in CP in 2002, age 55 years and following fail- ure of imatinib and dasatinib was treated with nilotinib in 2007 which induced a sus- tained CMR (MR 4.5 ). 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 CMR 5 . In 2012, imatinib was dis- continued 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 CMR 5 and return of side effects, imatinib was discontinued. After twelve months off TKI therapy she was diag- nosed 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 b-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 Bosuti- nib have led to the suggestion that these agents could be investigated as potential treat- ments for AD [9]. In view of these observations in animal models, one can postulate that TKI discontin- uation 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 neu- rological findings.  Acknowledgments 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 MILOJKOVIC 1 * 1 Department of Haematology, The Hammersmith Hospital, Imperial College, London, United Kingdom; 2 Department of Neurology, The Hammersmith Hospital, Imperial College, London, United Kingdom *Correspondence to: Dragana Milojkovic, Department of Haematology, The Hammersmith Hospital, Imperial College, Du Cane Road, London W12 0HS, UK. E-mail: d.milojkovic@imperial.ac.uk Received for publication: 22 July 2016; Accepted: 26 July 2016 Published online: 28 July 2016 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/ajh.24495  References 1. Richter J, S€ oderlund S, L€ ubking A, et al. Musculoskeletal pain in patients with chronic myeloid leukemia after discontinuation of imatinib: A tyrosine kinase inhibitor withdrawal syndrome? J Clin Oncol 2014;32:2821–2823. 2. Rousselot P, Charbonnier A, Cony-Makhoul P, et al. Reply to Richter et al. J Clin Oncol 2014;32:2823–5. 3. Lonskaya I, Hebron ML, Desforges NM, et al. Nilotinib-induced autophagic changes increase endogenous parkin level and ubiquitination, leading to amyloid clearance. J Mol Med (Berl) 2014;92:373–86. TABLE I. Patient Summary Patient characteristics CML Sequential previous therapy TKI on stopping Onset of cognitive dysfunction after stopping TKI (mo) Age at cognitive dysfunction, yr Molecular response at last follow-up Case Age, yr, Gender 1 50, F CP Imatinib Dasatinib Nilotinib Allo-SCT/DLI Nilotinib Nilotinib 6 66 CMR 5 2 55, F CP Imatinib Dasatinib Nilotinib Nilotinib 4 67 CMR 4.5 3 55, F CP ABMT IFN Imatinib Nilotinib Bosutinib Imatinib Imatinib 12 68 CMR 4.5 CP, chronic phase; allo-SCT, allogeneic stem-cell transplant; ABMT, autologous stem cell transplant; IFN, interferon; CMR, complete molecular response (definitions of molecular response are as previously described in Ref. 10). CORRESPONDENCE E480 American Journal of Hematology, Vol. 91, No. 11, November 2016 doi:10.1002/ajh.24496