Pioglitazone together with imatinib in chronic myeloid leukemia: A proof of concept study
Mené en France sur 24 patients atteints d'une leucémie myéloïde chronique et âgés de 24 à 79 ans, cet essai de phase II évalue l'efficacité, du point de vue de la progression de la réponse moléculaire sur 12 mois, et la toxicité de l'ajout du pioglitazone à un traitement par imatinib
BACKGROUND: 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. METHODS: 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/ABL1IS RNA 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 MR4.5 over 12 months. RESULTS: 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 MR4.5 was 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 MR4.5 by 48 months. The cumulative incidence of MMR to MR4.5 spontaneous conversions over 12 months was estimated to be 23% with imatinib alone in a parallel cohort of patients. CONCLUSION: 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 2016. © 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.
Cancer 2016