Longer treatment duration and history of osteoarticular symptoms predispose to tyrosine kinase inhibitor withdrawal syndrome

The effectiveness of tyrosine kinase inhibitors (TKIs) has made it possible to consider treatment discontinuation in chronic myeloid leukaemia (CML) patients that achieve an excellent response. However, a few of the patients included in the Europe Stop Tyrosine Kinase Inhibitors (EURO‐SKI) trial reported musculoskeletal pain shortly after stopping TKIs, considered as a withdrawal syndrome (WS). To identify factors that may predispose to TKI WS, we analysed the pharmacovigilance declarations for the 6 months after stopping TKIs in a large cohort of CML (n = 427) that combined the French patients included in the STop IMatinib 2 (STIM2; n = 224) and EURO‐SKI (n = 203) trials. Among these patients, 23% (99/427) developed TKI WS after stopping imatinib (77/373; 20·4%), nilotinib (12/29; 41·4%) or dasatinib (10/25; 40%). WS concerned mainly the upper body joints, and required multiple symptomatic treatments in 30% of patients. Univariate and multivariate analyses identified two risk factors: duration of TKI treatment [risk ratio (RR) = 1·68 (1·02–2·74)] with a 93‐month cut‐off time, and history of osteoarticular symptoms [RR = 1·84 (1·04–3·28)]. These findings confirm that WS is a TKI class effect. CML patients should be carefully screened before treatment initiation to identify pre‐existent osteoarticular symptoms. Moreover, before TKI discontinuation, patients should be informed of the possibility of WS, particularly after a long treatment period.

[1]  J. Cayuela,et al.  Discontinuation of tyrosine kinase inhibitors in chronic myeloid leukemia: Recommendations for clinical practice from the French Chronic Myeloid Leukemia Study Group , 2018, Cancer.

[2]  Martin C. Müller,et al.  Discontinuation of tyrosine kinase inhibitor therapy in chronic myeloid leukaemia (EURO-SKI): a prespecified interim analysis of a prospective, multicentre, non-randomised, trial. , 2018, The Lancet. Oncology.

[3]  J. Radich,et al.  Durable treatment-free remission in patients with chronic myeloid leukemia in chronic phase following frontline nilotinib: 96-week update of the ENESTfreedom study , 2018, Journal of Cancer Research and Clinical Oncology.

[4]  J. Lipton,et al.  Treatment-Free Remission After Second-Line Nilotinib Treatment in Patients With Chronic Myeloid Leukemia in Chronic Phase , 2018, Annals of Internal Medicine.

[5]  W. Wiktor-Jedrzejczak,et al.  Treatment-free remission following frontline nilotinib in patients with chronic myeloid leukemia in chronic phase: results from the ENESTfreedom study , 2017, Leukemia.

[6]  I. Blijdorp,et al.  A proof-of-concept study with the tyrosine kinase inhibitor nilotinib in spondyloarthritis , 2016, Journal of Translational Medicine.

[7]  Paul W Dickman,et al.  Life Expectancy of Patients With Chronic Myeloid Leukemia Approaches the Life Expectancy of the General Population. , 2016, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[8]  Sukjoong Oh,et al.  Imatinib withdrawal syndrome and longer duration of imatinib have a close association with a lower molecular relapse after treatment discontinuation: the KID study , 2016, Haematologica.

[9]  Sukjoong Oh,et al.  Change of health-related profiles after Imatinib cessation in chronic phase chronic myeloid leukemia patients , 2016, Leukemia & lymphoma.

[10]  M. Konopleva,et al.  Prospective Analysis: Relative Survival in Patients with Chronic Myeloid Leukemia in Chronic Phase in the Era of Tyrosine Kinase Inhibitors , 2015, The Lancet. Haematology.

[11]  J. Cayuela,et al.  Reply to J. Richter et al. , 2014, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[12]  U. Olsson‐Strömberg,et al.  Musculoskeletal pain in patients with chronic myeloid leukemia after discontinuation of imatinib: a tyrosine kinase inhibitor withdrawal syndrome? , 2014, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[13]  G. Lewin,et al.  Inhibition of c-Kit signaling is associated with reduced heat and cold pain sensitivity in humans , 2014, PAIN®.

[14]  J. Cayuela,et al.  Loss of major molecular response as a trigger for restarting tyrosine kinase inhibitor therapy in patients with chronic-phase chronic myelogenous leukemia who have stopped imatinib after durable undetectable disease. , 2014, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[15]  G. Massonnet,et al.  Erosion of the chronic myeloid leukaemia stem cell pool by PPARγ agonists , 2013, Nature.

[16]  G. Azizi,et al.  Imatinib Mesylate: An Innovation in Treatment of Autoimmune Diseases , 2013 .

[17]  Francisco Cervantes,et al.  European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. , 2013, Blood.

[18]  J. Melo,et al.  Safety and efficacy of imatinib cessation for CML patients with stable undetectable minimal residual disease: results from the TWISTER study. , 2013, Blood.

[19]  R. Maki,et al.  Effect of long term imatinib on bone in adults with chronic myelogenous leukemia and gastrointestinal stromal tumors. , 2013, Leukemia research.

[20]  A. Branca,et al.  Effects of second‐generation tyrosine kinase inhibitors towards osteogenic differentiation of human mesenchymal cells of healthy donors , 2012, Hematological oncology.

[21]  H. Shimada,et al.  Distinct impact of imatinib on growth at prepubertal and pubertal ages of children with chronic myeloid leukemia. , 2011, The Journal of pediatrics.

[22]  O. Dittrich‐Breiholz,et al.  Identification of novel target genes of nerve growth factor (NGF) in human mastocytoma cell line (HMC-1 (V560G c-Kit)) by transcriptome analysis , 2011, BMC Genomics.

[23]  A. Nagler,et al.  Multicenter independent assessment of outcomes in chronic myeloid leukemia patients treated with imatinib. , 2011, Journal of the National Cancer Institute.

[24]  M. Baccarani,et al.  Second-Generation Tyrosine Kinase Inhibitors: The Future of Frontline CML Therapy , 2011, Clinical Cancer Research.

[25]  M. Deininger,et al.  Management of adverse events associated with tyrosine kinase inhibitors in the treatment of chronic myeloid leukemia , 2011, Leukemia.

[26]  Philippe Rousselot,et al.  Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial. , 2010, The Lancet. Oncology.

[27]  M. Feldmann,et al.  Treatmentof murine osteoarthritis withTrkAd5 reveals a pivotal rolefor nerve growth factor in non-inflammatory joint pain , 2010, PAIN®.

[28]  A. B. Lyons,et al.  Nilotinib inhibits the Src-family kinase LCK and T-cell function in vitro , 2009, Journal of cellular and molecular medicine.

[29]  C. Mol,et al.  Dasatinib is a potent inhibitor of tumour-associated macrophages, osteoclasts and the FMS receptor , 2008, Leukemia.

[30]  T. Tamura,et al.  Inhibition of Abl tyrosine kinase enhances nerve growth factor-mediated signaling in Bcr–Abl transformed cells via the alteration of signaling complex and the receptor turnover , 2008, Oncogene.

[31]  S. Fitter,et al.  Long-term imatinib therapy promotes bone formation in CML patients. , 2008, Blood.

[32]  H. Einsele,et al.  Modulation of T-effector function by imatinib at the level of cytokine secretion. , 2007, Experimental hematology.

[33]  J. Cayuela,et al.  Imatinib Mesylate Discontinuation in Patients with Chronic Myelogenous Leukemia in Complete Molecular Remission: An Update Follow Up. , 2006 .

[34]  Martin C. Müller,et al.  STOPPING TYROSINE KINASE INHIBITORS IN A VERY LARGE COHORT OF EUROPEAN CHRONIC MYELOID LEUKEMIA PATIENTS: RESULTS OF THE EURO-SKI TRIAL , 2016 .

[35]  P. Cony-Makhoul,et al.  Nilotinib and peginterferon alfa-2a for newly diagnosed chronic-phase chronic myeloid leukaemia (NiloPeg): a multicentre, non-randomised, open-label phase 2 study. , 2015, The Lancet. Haematology.

[36]  K. Vandyke,et al.  Prospective histomorphometric and DXA evaluation of bone remodeling in imatinib-treated CML patients: evidence for site-specific skeletal effects. , 2013, The Journal of clinical endocrinology and metabolism.

[37]  J. Cayuela,et al.  Imatinib mesylate discontinuation in patients with chronic myelogenous leukemia in complete molecular remission for more than 2 years. , 2007, Blood.