Laurence Legros1,2, Franck E Nicolini3,4, Gabriel Etienne5, Philippe Rousselot6, Delphine Rea7, Stéphane Giraudier8, Agnès Guerci-Bresler9, Françoise Huguet10, Martine Gardembas11, Martine Escoffre12, Jean-Christophe Ianotto13, Marie-Pierre Noël14, Bruno R Varet15, Thomas Pagliardini1, Irit Touitou1, Stéphane Morisset3, Francois-Xavier Mahon16. 1. Hematology Department, Nice University Hospital, Nice, France. 2. Valrose Institute of Biology, National Center for Scientific Research (CNRS) Unit 7277, National Institute of Health and Medical Research (INSERM) Unit 1091, Nice, France. 3. Hematology Department, Lyon University Hospital, Pierre Benite, France. 4. INSERM Unit 1052, Leon Berard Center, Lyon, France. 5. Haematology Department, Bergonie Institute, Bordeaux, France. 6. Haematology and Oncology Department, Hopital A Mignot, INSERM Unit 1173, Versailles, University of Versailles St.-Quentin-Yvelines, France. 7. Adult Hematology Department, INSERM Unit 1160, St. Louis Hospital, Paris, France. 8. Hematology Laboratory, Henri-Mondor Hospital, Creteil, France. 9. Hematology Department, Brabois University Hospital, Vandoeuvre-les-Nancy, France. 10. Hematology Department, Toulouse-Oncopole University Cancer Institute, Toulouse, France. 11. Blood Disorder Department, Angers University Hospital, Angers, France. 12. Adult Hematology Department, Rennes University Hospital, Rennes, France. 13. Hematology Department, Brest University Hospital, Brest, France. 14. Blood Disorders Department, Lille University Hospital, Lille, France. 15. Blood Disorders Department, Necker Hospital, Paris-Descartes University, Paris, France. 16. Laboratory of Mammary and Leukemic Oncogenesis, Genetic Diversity, and Resistance to Treatment, INSERM Unit 1218, Bordeaux, France.
Abstract
BACKGROUND: Several studies have demonstrated that approximately one-half of patients with chronic myeloid leukemia (CML) who receive treatment with tyrosine kinase inhibitors (TKIs) and achieve and maintain a deep molecular response (DMR) are able to successfully discontinue therapy. In patients who have a molecular relapse, a DMR is rapidly regained upon treatment re-initiation. METHODS: The authors report the results from RE-STIM, a French observational, multicenter study that evaluated treatment-free remission (TFR) in 70 patients who re-attempted TKI discontinuation after a first unsuccessful attempt. After the second TKI discontinuation attempt, the trigger for treatment re-introduction was the loss of a major molecular response in all patients. RESULTS: The median follow-up was 38.3 months (range, 4.7-117 months), and 45 patients (64.3%) lost a major molecular response after a median time off therapy of 5.3 months (range, 2-42 months). TFR rates at 12, 24, and 36 months were 48% (95% confidence interval [CI], 37.6%-61.5%), 42% (95% CI, 31.5%-55.4%), and 35% (95% CI, 24.4%-49.4%), respectively. No progression toward advanced-phase CML occurred, and no efficacy issue was observed upon TKI re-introduction. In univariate analysis, the speed of molecular relapse after the first TKI discontinuation attempt was the only factor significantly associated with outcome. The TFR rate at 24 months was 72% (95% CI, 48.8%-100%) in patients who remained in DMR within the first 3 months after the first TKI discontinuation and 36% (95% CI, 25.8%-51.3%) for others. CONCLUSIONS: This study is the first to demonstrate that a second TKI discontinuation attempt is safe and that a first failed attempt at discontinuing TKI does not preclude a second successful attempt. Cancer 2017;123:4403-10.
BACKGROUND: Several studies have demonstrated that approximately one-half of patients with chronic myeloid leukemia (CML) who receive treatment with tyrosine kinase inhibitors (TKIs) and achieve and maintain a deep molecular response (DMR) are able to successfully discontinue therapy. In patients who have a molecular relapse, a DMR is rapidly regained upon treatment re-initiation. METHODS: The authors report the results from RE-STIM, a French observational, multicenter study that evaluated treatment-free remission (TFR) in 70 patients who re-attempted TKI discontinuation after a first unsuccessful attempt. After the second TKI discontinuation attempt, the trigger for treatment re-introduction was the loss of a major molecular response in all patients. RESULTS: The median follow-up was 38.3 months (range, 4.7-117 months), and 45 patients (64.3%) lost a major molecular response after a median time off therapy of 5.3 months (range, 2-42 months). TFR rates at 12, 24, and 36 months were 48% (95% confidence interval [CI], 37.6%-61.5%), 42% (95% CI, 31.5%-55.4%), and 35% (95% CI, 24.4%-49.4%), respectively. No progression toward advanced-phase CML occurred, and no efficacy issue was observed upon TKI re-introduction. In univariate analysis, the speed of molecular relapse after the first TKI discontinuation attempt was the only factor significantly associated with outcome. The TFR rate at 24 months was 72% (95% CI, 48.8%-100%) in patients who remained in DMR within the first 3 months after the first TKI discontinuation and 36% (95% CI, 25.8%-51.3%) for others. CONCLUSIONS: This study is the first to demonstrate that a second TKI discontinuation attempt is safe and that a first failed attempt at discontinuing TKI does not preclude a second successful attempt. Cancer 2017;123:4403-10.