title: Pioglitazone together with imatinib in chronic myeloid leukemia: A proof of concept study.
abstract: We recently reported that peroxisome proliferator-activated receptor γ agonists target chronic myeloid leukemia (CML) quiescent stem cells in vitro by decreasing transcription of STAT5. Here in the ACTIM phase 2 clinical trial, we asked whether pioglitazone add-on therapy to imatinib would impact CML residual disease, as assessed by BCR-ABL1 transcript quantification.
  
  
  
  CML patients were eligible if treated with imatinib for at least 2 years at a stable daily dose, having yielded major molecular response (MMR) but not having achieved molecular response 4.5 (MR4.5) defined by BCR-ABL1/ABL1ISRNA levels ≤ 0.0032%. After inclusion, patients started pioglitazone at a dosage of 30 to 45 mg/day in addition to imatinib. The primary objective was to evaluate the cumulative incidence of patients having progressed from MMR to MR4.5over 12 months.
  
  
  
  Twenty-four patients were included (age range, 24-79 years). No pharmacological interaction was observed between the drugs. The main adverse events were weight gain in 12 patients and a mean decrease of 0.4 g/dL in hemoglobin concentration. The cumulative incidence of MR4.5was 56% (95% confidence interval, 37%-76%) by 12 months, despite a wide range of therapy duration (1.9-15.5 months), and 88% of 17 evaluable patients who were still on imatinib reached MR4.5by 48 months. The cumulative incidence of MMR to MR4.5spontaneous conversions over 12 months was estimated to be 23% with imatinib alone in a parallel cohort of patients.
  
  
  
  Pioglitazone in combination with imatinib was well tolerated and yielded a favorable 56% rate. These results provide a proof of concept needing confirmation within a randomized clinical trial (EudraCT 2009-011675-79). Cancer 2017;123:1791-1799. © 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
authors.affiliation: Department of Hematology and Oncology, Centre Hospitalier de Versailles, INSERM UMR 1173, Université Versailles Saint-Quentin-en-Yvelines, Université Paris Saclay, Le Chesnay, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Rousselot
authors.affiliation: CEA, Institute of Emerging Diseases and Innovative Therapies, University Paris-Sud UMR 007, Fontenay-aux-Roses, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Prost
authors.affiliation: INSERM CIC 1402, CHU de Poitiers, Poitiers, France.
authors.forename: Joelle
authors.initials: J
authors.lastname: Guilhot
authors.affiliation: Department of Hematology, Hôpital Henri Mondor, AP-HP, Créteil, France.
authors.forename: Lydia
authors.initials: L
authors.lastname: Roy
authors.affiliation: Department of Hematology, Institut Bergonié, Bordeaux, France.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Etienne
authors.affiliation: Department of Hematology, CHU de Nice, Nice, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Legros
authors.affiliation: Department of Hematology, Institut Paoli Calmettes, Marseille, France.
authors.forename: Aude
authors.initials: A
authors.lastname: Charbonnier
authors.affiliation: Valérie Coiteux, Department of Hematology, Hôpital Claude Huriez CHU de Lille, Lille, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Coiteux
authors.affiliation: Department of Hematology, Centre Hospitalier Annecy Genevois, Pringy, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Cony-Makhoul
authors.affiliation: Department of Hematology, Institut Universitaire du Cancer, Toulouse, France.
authors.forename: Francoise
authors.initials: F
authors.lastname: Huguet
authors.affiliation: INSERM CIC 1402, CHU de Poitiers, Poitiers, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Cayssials
authors.affiliation: Laboratoire de Biologie Moléculaire, Hôpital Saint Louis AP-HP, Paris, France.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Cayuela
authors.affiliation: CEA, Institute of Emerging Diseases and Innovative Therapies, University Paris-Sud UMR 007, Fontenay-aux-Roses, France.
authors.forename: Francis
authors.initials: F
authors.lastname: Relouzat
authors.affiliation: Institut Universitaire d'Hématologie, Université Paris VII, Paris, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Delord
authors.affiliation: Heriberto Bruzzoni-Giovanelli, INSERM CIC 9504, Hôpital Saint-Louis, AP-HP, Paris, France.|University Paris Diderot, Sorbonne Paris Cité, UMRS 1160, Paris, France.
authors.forename: Heriberto
authors.initials: H
authors.lastname: Bruzzoni-Giovanelli
authors.affiliation: Délégation pour la Recherche Clinique et l'Innovation, Centre Hospitalier de Versailles, Le Chesnay, France.
authors.forename: Laure
authors.initials: L
authors.lastname: Morisset
authors.affiliation: Laboratoire d'Hématologie, Hôpital Haut Lévèque CHU de Bordeaux, Institut Bergonie, Bordeaux, France.
authors.forename: François-Xavier
authors.initials: FX
authors.lastname: Mahon
authors.affiliation: INSERM CIC 1402, CHU de Poitiers, Poitiers, France.
authors.forename: François
authors.initials: F
authors.lastname: Guilhot
authors.affiliation: CEA, Institute of Emerging Diseases and Innovative Therapies, University Paris-Sud UMR 007, Fontenay-aux-Roses, France.|Philippe Leboulch, Genetics Division, Brigham & Women's Hospital and Harvard Medical School, Boston, Massachusetts.|Hematology Division, Ramathibodi Hospital and Mahidol University, Bangkok, Thailand.
authors.forename: Philippe
authors.initials: P
authors.lastname: Leboulch
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000235:genetics; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D000068877:Imatinib Mesylate / Q000627:therapeutic use*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D000077205:Pioglitazone; D012333:RNA, Messenger / Q000378:metabolism; D045162:Thiazolidinediones / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D007004:Hypoglycemic Agents; D012333:RNA, Messenger; D045162:Thiazolidinediones; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; D000077205:Pioglitazone
keywords: Imatinib; Molecular response; PPAR gamma agonists; chronic myeloid leukemia