An unexpected new adverse event after imatinib discontinuation in patients with chronic myelogenous leukemia: A withdrawal syndrome?

Introduction: Imatinib (IM) has revolutionized drug therapy of chronic myelogenous leukemia (CML). IM is well-known to induce frequent musculoskeletal adverse effects. However, clinicians at the hematology-oncology ward of Clermont- Ferrand (CF) teaching hospital have observed cases of patients experiencing musculoskeletal pain even after stopping IM. The aim of this study is to describe the features of musculoskeletal events in a cohort of patients who discontinued IM therapy. Material and methods: Several trials of tyrosine kinase inhibitor (TKI) discontinuation are ongoing. In EURO-SKI trial, patients with CML who interrupted their IM treatment after having achieved and maintained for at last 1 year a complete molecular remission CMR4 (either detectable disease ≤0.01% BCR-ABL IS or undetectable disease in cDNA with ≥10 000 ABL or ≥24 000 GUS transcripts) are being recruited at the CF center since July 2012 and were followed until October 2014. Results: The study cohort consisted of 26 patients who stopped IM therapy. They were followed for at least 3 months (range, 3 to 24 months). Twelve patients (46%) reported musculoskeletal pain that arose with a median time of onset of 88 days IQR[17-112] after IM discontinuation. The 12 patients consisted of seven men (58%) and five women with a median age of 46 years [40-51]. The median duration of CML disease and IM therapy were 8.2 years [7.6-11.5] and 7.5 years [5-9] respectively. The pain was permanent and associated with sleep disturbances. It was bilateral and mainly localized in the shoulder and the superior member. In seven patients the symptoms were severe (grade 3), interfering with daily life activities. Biological markers for inflammation remained normal. There was no radiological abnormality. Pain responded poorly to common analgesics (paracetamol, nonsteroidal anti-inflammatory drugs, corticosteroids infiltration). Among these 12 patients, three lost major molecular reponse and restarted IM. Subsequently the symptoms completely resolved within 15 days to 3 months. Discussion / Conclusion: If confirmed, clinicians should be aware of the potential appearance of musculoskeletal adverse events after the cessation of long-term IM therapy. Recently, Richter noted similar symptoms in 15/50 patients and qualified these manifestations as a TKI withdrawal syndrome [1]. Underlying mechanisms need to be investigated and may provide insight into modalities of IM discontinuation.