Imatinib Optimized Therapy Improves Major Molecular Response Rates in Patients with Chronic Myeloid Leukemia

Groupe Français pour la LMC (Fi-LMC)

doi:10.3390/pharmaceutics14081676

Imatinib Optimized Therapy Improves Major Molecular Response Rates in Patients with Chronic Myeloid Leukemia

Groupe Français pour la LMC (Fi-LMC)

Population Health Sciences

Research output: Contribution to journal › Article › peer-review

6 Citations (Scopus)

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::ABL1 ^IS ≤ 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.

Original language	English
Article number	1676
Journal	Pharmaceutics
Volume	14
Issue number	8
DOIs	https://doi.org/10.3390/pharmaceutics14081676
Publication status	Published - 12 Aug 2022

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@article{d6b10c7828b743779d09dc4412a16235,

title = "Imatinib Optimized Therapy Improves Major Molecular Response Rates in Patients with Chronic Myeloid Leukemia",

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{\textquoteright}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::ABL1 IS ≤ 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. ",

author = "{Groupe Fran{\c c}ais pour la LMC (Fi-LMC)} and Hyacinthe Johnson-Ansah and Benjamin Maneglier and Fran{\c c}oise Huguet and Laurence Legros and Martine Escoffre-Barbe and Martine Gardembas and Pascale Cony-Makhoul and Val{\'e}rie Coiteux and Laurent Sutton and Wajed Abarah and Camille Pouaty and Jean-Michel Pignon and Bachra Choufi and Sorin Visanica and B{\'e}n{\'e}dicte Deau and Laure Morisset and Emilie Cayssials and Mathieu Molimard and St{\'e}phane Bouchet and Fran{\c c}ois-Xavier Mahon and Franck Nicolini and Philippe Aegerter and Jean-Michel Cayuela and Marc Delord and Heriberto Bruzzoni-Giovanelli and Philippe Rousselot",

note = "Funding Information: The study was funded with the public funding from the French Health Department by the Programme Hospitalier de Recherche Clinique (PHRC-I 2008) and was sponsored by the “D{\'e}l{\'e}gation {\`a} la Recherche Clinique et {\`a} l{\textquoteright}Innovation, DRCI”, Centre Hospitalier de Versailles, Versailles, France. Publisher Copyright: {\textcopyright} 2022 by the authors.",

year = "2022",

month = aug,

day = "12",

doi = "10.3390/pharmaceutics14081676",

language = "English",

volume = "14",

journal = "Pharmaceutics",

issn = "1999-4923",

publisher = "Multidisciplinary Digital Publishing Institute",

number = "8",

}

TY - JOUR

T1 - Imatinib Optimized Therapy Improves Major Molecular Response Rates in Patients with Chronic Myeloid Leukemia

AU - Groupe Français pour la LMC (Fi-LMC)

AU - Johnson-Ansah, Hyacinthe

AU - Maneglier, Benjamin

AU - Huguet, Françoise

AU - Legros, Laurence

AU - Escoffre-Barbe, Martine

AU - Gardembas, Martine

AU - Cony-Makhoul, Pascale

AU - Coiteux, Valérie

AU - Sutton, Laurent

AU - Abarah, Wajed

AU - Pouaty, Camille

AU - Pignon, Jean-Michel

AU - Choufi, Bachra

AU - Visanica, Sorin

AU - Deau, Bénédicte

AU - Morisset, Laure

AU - Cayssials, Emilie

AU - Molimard, Mathieu

AU - Bouchet, Stéphane

AU - Mahon, François-Xavier

AU - Nicolini, Franck

AU - Aegerter, Philippe

AU - Cayuela, Jean-Michel

AU - Delord, Marc

AU - Bruzzoni-Giovanelli, Heriberto

AU - Rousselot, Philippe

N1 - Funding Information: The study was funded with the public funding from the French Health Department by the Programme Hospitalier de Recherche Clinique (PHRC-I 2008) and was sponsored by the “Délégation à la Recherche Clinique et à l’Innovation, DRCI”, Centre Hospitalier de Versailles, Versailles, France. Publisher Copyright: © 2022 by the authors.

PY - 2022/8/12

Y1 - 2022/8/12

N2 - 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::ABL1 IS ≤ 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.

AB - 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::ABL1 IS ≤ 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.

UR - http://www.scopus.com/inward/record.url?scp=85137458820&partnerID=8YFLogxK

U2 - 10.3390/pharmaceutics14081676

DO - 10.3390/pharmaceutics14081676

M3 - Article

C2 - 36015302

SN - 1999-4923

VL - 14

JO - Pharmaceutics

JF - Pharmaceutics

IS - 8

M1 - 1676

ER -

Imatinib Optimized Therapy Improves Major Molecular Response Rates in Patients with Chronic Myeloid Leukemia

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