Imatinib Optimized Therapy Improves Major Molecular Response Rates in Patients with Chronic Myeloid Leukemia
Hyacinthe Johnson‐Ansah, Benjamin Manéglier, Françoise Huguet, Laurence Legros, Martine Escoffre‐Barbe, Martine Gardembas, Pascale Cony‐Makhoul, Valérie Coiteux, Laurent Sutton, Wajed Abarah, Camille Pouaty, Jean‐Michel Pignon, Bachra Choufi, Sorin Visanica, Bénédicte Deau, Laure Morisset, Émilie Cayssials, Mathiéu Molimard, Stéphane Bouchet, F.-X. Mahon, Franck E. Nicolini, Philippe Aegerter, Jean‐Michel Cayuela, Marc Delord, Heriberto Bruzzoni‐Giovanelli, Philippe Rousselot
Abstract
The registered dose for imatinib is 400 mg/d, despite high inter-patient variability in imatinib plasmatic exposure. Therapeutic drug monitoring (TDM) is routinely used to maximize a drug’s efficacy or tolerance. We decided to conduct a prospective randomized trial (OPTIM-imatinib trial) to assess the value of TDM in patients with chronic phase chronic myelogenous treated with imatinib as first-line therapy (NCT02896842). Eligible patients started imatinib at 400 mg daily, followed by imatinib [C]min assessment. Patients considered underdosed ([C]min < 1000 ng/mL) were randomized in a dose-increase strategy aiming to reach the threshold of 1000 ng/mL (TDM arm) versus standard imatinib management (control arm). Patients with [C]min levels ≥ 1000 ng/mL were treated following current European Leukemia Net recommendations (observational arm). The primary endpoint was the rate of major molecular response (MMR, BCR::ABL1IS ≤ 0.1%) at 12 months. Out of 133 evaluable patients on imatinib 400 mg daily, 86 patients had a [C]min < 1000 ng/mL and were randomized. The TDM strategy resulted in a significant increase in [C]min values with a mean imatinib daily dose of 603 mg daily. Patients included in the TDM arm had a 12-month MMR rate of 67% (95% CI, 51−81) compared to 39% (95% CI, 24−55) for the control arm (p = 0.017). This early advantage persisted over the 3-year study period, in which we considered imatinib cessation as a censoring event. Imatinib TDM was feasible and significantly improved the 12-month MMR rate. This early advantage may be beneficial for patients without easy access to second-line TKIs.