Reply to J. Richter et al

We appreciate the correspondence from Richter et al reporting for the first time a so-called tyrosine kinase inhibitor withdrawal syndrome consisting of musculoskeletal pain after imatinib discontinuation in patients with chronic myelogenous leukemia (CML). All patients (15 of 50; 30%) were graded as 1 to 2 on the Common Terminology Criteria for Adverse Events scale (version 4.0), and 11 patients (22%) did not experience any musculoskeletal pain before discontinuation. Richter et al ask whether such events were observed in the According to Stop Imatinib (A-STIM) study. The A-STIM study was not designed to collect data on low-grade events, either before discontinuation or after discontinuation. We thus tried to retrospectively collect this information and asked the A-STIM investigators to check their patients’ files. As a result, we estimated that four of 80 patients presented similar symptoms after discontinuation. Because of the retrospective collection of the data, we believe that this proportion may be underestimated. French investigators have pioneered the field of tyrosine kinase discontinuation from the first pilot study in 2007 to the multicentric Stop Imatinib 1 (STIM1) study. In none of these studies was the collection of data on low-grade adverse events planned. We are currently conducting the Stop Imatinib 2 (STIM2) study for patients treated only with imatinib and are prospectively recording events of all grades at the time of discontinuation and after discontinuation. We calculated that 400 patients were enrolled in discontinuation studies in France from 2007 to 2013. Few grade 3 or grade 4 events were reported as being possibly related to the discontinuation of tyrosine kinase inhibitors. Such events were mainly related to exacerbation of preexisting inflammatory diseases such as Crohn’s disease or rheumatoid arthritis, as reported. In a recently published study, thermal pain thresholds were significantly increased in 39 patients with CML who were treated with imatinib or nilotinib as compared with ageand sex-matched healthy controls. The authors suggested that c-Kit inhibition may modulate nociceptive sensitivity in humans, as reported in mice. Sudden discontinuation of imatinib may reverse this phenomenon. Prolonged inhibition of c-Kit signaling by imatinib may also suppress mast cell function and activation over the long term, as suggested by the observation that imatinib may improve asthma in asthmatic patients with CML. Taken together, these observations favor the hypothesis that c-Kit signaling may contribute to the symptoms that were observed by Richter et al after imatinib discontinuation.