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’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.

Keywords: chronic myelogenous leukemia; imatinib; therapeutic drug monitoring.

Figure 1

CONSORT diagram of the OPTIM-imatinib study. [C]min: trough imatinib plasma level, ELN: European Leukemia Net, AE: adverse event.

Figure 2

Major molecular response rates at 12 months (A) and by 36 months (B,C). (A) Twenty-nine patients (67% (95% CI, 51–81)) achieved MMR at month 12 in the TDM arm, as opposed to 39% (95% CI, 24–55) in the control arm (p = 0.017) (dark plots). The rate of MMR was 49% (95% CI, 34–64) for patients included in the observational arm (dark plots). TDM: therapeutic drug monitoring arm, MMR: major molecular response (dark plots), no MMR: grey plots, [C)min: trough imatinib plasma level at inclusion. (B) Cumulative incidence of MMR in both the TDM arm (continuous line) and the control arm (dashed line) during the 36-month study period. Patients were censored in case of imatinib cessation (as is usual for studies comparing imatinib and second-generation tyrosine kinase inhibitors [6,7,8]). (C) The cumulative incidence of MMR in both the TDM arm (continuous line) and the control arm (dashed line) during the 36-month study period. Patients were not censored in case of imatinib cessation.

Figure 3

Imatinib daily dose over the 12-month adaptation period for the patients included in the TDM arm (A), the control arm (B) and the observational arm (C). The violin plots represent the distributions of individual daily doses.