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Purpose Imatinib (IM) can safely be discontinued in patients with chronic myeloid leukemia (CML) who have had undetectable minimal residual disease (UMRD) for at least 2 years. We report the final results of the Stop Imatinib (STIM1) study with a long follow-up. Patients and Methods IM was prospectively discontinued in 100 patients with CML with UMRD sustained for at least 2 years. Molecular recurrence (MR) was defined as positivity of BCR-ABL transcript in a quantitative reverse transcriptase polymerase chain reaction assay confirmed by a second analysis point that indicated an increase of one log in relation to the first analysis point at two successive assessments or loss of major molecular response at one point. Results The median molecular follow-up after treatment discontinuation was 77 months (range, 9 to 95 months). Sixty-one patients lost UMRD after a median of 2.5 months (range, 1 to 22 months), and one patient died with UMRD at 10 months. Molecular recurrence-free survival was 43% (95% CI, 33% to 52%) at 6 months and 38% (95% CI, 29% to 47%) at 60 months. Treatment was restarted in 57 of 61 patients with MR, and 55 patients achieved a second UMRD with a median time of 4 months (range, 1 to 16 months). None of the patients experienced a CML progression. Analyses of the characteristics of the study population identified that the Sokal risk score and duration of IM treatment were significantly associated with the probability of MR. Conclusion With a median follow-up of more than 6 years after treatment discontinuation, the STIM1 study demonstrates that IM can safely be discontinued in patients with a sustained deep molecular response with no late MR.

Purpose More than half of patients with chronic-phase chronic myelogenous leukemia (CP-CML) in complete molecular response (CMR) experience molecular relapse after imatinib discontinuation. We investigated loss of major molecular response (MMR) as a criterion for resuming therapy. Patients and Methods A multicenter observational study (A-STIM [According to Stop Imatinib]) evaluating MMR persistence was conducted in 80 patients with CP-CML who had stopped imatinib after prolonged CMR. Results Median time from imatinib initiation to discontinuation was 79 months (range, 30 to 145 months);median duration of CMR before imatinib discontinuation was 41 months (range, 24 to 96 months); median follow-up after discontinuation was 31 months (range, 8 to 92 months). Twenty-nine patients (36%) lost MMR after a median of 4 months off therapy (range, 2 to 17 months). Cumulative incidence of MMR loss was estimated as 35% (95% CI, 25% to 46%) at 12 months and 36% (95% CI, 26% to 47%) at 24 months, whereas probability of losing CMR was higher. Fluctuation of BCR-ABL transcript levels below the MMR threshold (≥ two consecutive positive values) was observed in 31% of patients after imatinib discontinuation. Treatment-free remission was estimated as 64% (95% CI, 54% to 75%) at 12 and 24 months and 61% (95% CI, 51% to 73%) at 36 months. Median to time to second CMR was estimated as 7.3 months in re-treated patients. Conclusion Loss of MMR is a practical and safe criterion for restarting therapy in patients with CML with prolonged CMR.

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.

7045 Background: Nilotinib is a tyrosine kinase inhibitor targeting the BCR-ABL1 oncoprotein. It has been approved for the treatment of chronic myeloid leukemia-CP. Recently, a higher rate of cardi...