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 Philippe Rousselot, Aude Charbonnier, Pascale Cony-Makhoul, Philippe Agape, Franck E. Nicolini, Bruno Varet, Martine Gardembas, Gabriel Etienne, Delphine Re ´a, Lydia Roy, Martine Escoffre-Barbe, Agne `s Guerci-Bresler, Michel Tulliez, Ste ´phane Prost, Marc Spentchian, Jean Michel Cayuela, Josy Reiffers, Jean Claude Chomel, Ali Turhan, Joe ¨lle Guilhot, Franc ¸ois Guilhot, and Franc ¸ois-Xavier Mahon See accompanying articles on pages 379 and 415 Author affiliations appear at the end of this article. Published online ahead of print at www.jco.org on December 30, 2013. Written on behalf of the Intergroupe Franc ¸ ais des Leuce ´ mies Mye ´ loı ¨des Chroniques (Fi-LMC). Terms in blue are defined in the glos- sary, found at the end of this article and online at www.jco.org. Authors’ disclosures of potential con- flicts of interest and author contribu- tions are found at the end of this article. Corresponding author: Philippe Rousselot, MD, PhD, Service d’He ´ matologie et d’Oncologie, Ho ˆ pital Mignot, 177 rue de Versailles, 78157 Le Chesnay, France; e-mail: phrousselot@ch-versailles.fr. © 2013 by American Society of Clinical Oncology 0732-183X/14/3205w-424w/$20.00 DOI: 10.1200/JCO.2012.48.5797 A B S T R A C T 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. J Clin Oncol 32:424-430. © 2013 by American Society of Clinical Oncology INTRODUCTION Discontinuation of imatinib (Glivec/Gleevec, STI571; Novartis, Summit, NJ) is currently an investiga- tional approach for patients with chronic-phase chronic myelogenous leukemia (CML) in pro- longed complete molecular response (CMR). In 2007, we reported a pilot study to evaluate the feasi- bility and safety of imatinib discontinuation in pa- tients in CMR  2 years and observed that half of the patients experienced molecular relapse during the 6 months after treatment discontinuation. 1 No late molecular relapses were observed in the remaining patients, with an extended follow-up  4 years. These results were confirmed in the multicenter STIM (Stop Imatinib) study. 2 The initial analysis reported the results of 69 patients with 12-month follow-up. Forty-two patients (61%) lost CMR, including 40 within the first 6 months. At 12 months, the probability of persistent CMR was 41%. These results were confirmed in more pa- tients, with longer follow-up, 3 as well as in three independent studies. 4-6 Molecular relapse in the STIM study was de- fined as positivity of BCR-ABL transcripts with quantitative reverse transcriptase polymerase chain JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T VOLUME 32  NUMBER 5  FEBRUARY 10 2014 424 © 2013 by American Society of Clinical Oncology Downloaded from jco.ascopubs.org by FRANCISCO PEDROSA on April 15, 2014 from 177.19.142.26 Copyright © 2014 American Society of Clinical Oncology. All rights reserved.