Personalized Daily Doses of Imatinib By Therapeutic Drug Monitoring Increase the Rates of Molecular Responses in Patients with Chronic Myeloid Leukemia. Final Results of the Randomized OPTIM Imatinib Study
Authors: Rousselot Philippe , Johnson-Ansah Hyacinthe , Huguet Françoise , Legros Laurence , Escoffre-Barbe Martine , Gardembas Martine , Cony-Makhoul Pascale , Coiteux Valérie , Sutton Laurent , Abarah Wajed , Pouaty Camille , Pignon Jean Michel , Choufi Bachra , Visanica Sorin , Deau Bénédicte , Bouchet Stephane , Guilhot Francois , Mahon Francois-Xavier , Morisset Laure , Cayuela Jean-Michel , Maneglier Benjamin 
Published: October 2019

Abstract

Background
Imatinib mesylate (IM) at 400 mg/d remains a standard for first line therapy in patients (pts) with newly diagnosed chronic phase CML (CP-CML). A sub analysis of the IRIS study (Larson et al. Blood, 2008) demonstrated that pts with high IM trough levels achieved higher rates of major molecular response (MMR). The level of 1000 ng/ml was established as the [C]min value threshold to predict molecular response (Picard et al. Blood, 2007).
We conducted a randomized trial to evaluate the value of IM dose optimization based on the monitoring of [C]min levels in newly diagnosed CP-CML pts (OPTIM-imatinib trial, EudraCT number 2008-006854-17).
Patients and Methods
Pts diagnosed with CP- CML for less than 3 months, not previously treated or treated with IM for less than 3 months were eligible and treated with IM 400 mg/d. IM [C]min was determined by chromatography-tandem mass-mass spectrometry 15 days after enrollment. Pts with a [C]min < 1000 ng/ml were randomized between a dose-increase strategy aiming to reach the threshold of 1000 ng/ml (arm A1) versus standard IM management (arm A2). Pts with [C]min levels ≥1000 ng/ml were observed (arm A3). All pts were managed according to the ELN 2009 recommendations (amended with ELN 2013 recommendations). IM [C]min levels were assessed monthly in A1 and A2 and every 3 months in A3. BCR-ABLIS was assessed every 3 months. The primary end-point was MMR rates at 12 months.
Results
One hundred thirty nine pts were enrolled. Median follow-up was 31 months. Median age was 64y (25 to 88y), sex ratio (M/F) was 1.4 and Sokal score distribution was 21%, 41% and 38% for high, intermediate and low categories respectively, equally distributed in the 3 arms. In 6 pts the initial [C]min was not assessed (3 were intolerant and 3 declined the dosage). Thus 133 pts were studied. In 86 pts (65%), initial [C]min value was < 1000 ng/ml. These pts were randomized between A1 (43 pts) and A2 (43 pts). [C]min was ≥1000 ng/ml in the 47 remaining pts followed in A3. Table 1 shows the significant improvement of the median IM [C]min after dose adjustment in A1 (p<0.0001) as compared to standard management in A2. Correspondingly, IM daily dose increased in A1 (p<0.0001) to reach a mean value of 600 mg/d. In the experimental A1 arm, the distribution of IM doses at 12 months was 13% for 500 mg/d, 30% for 600 mg/d, 34% for 800 mg/d whereas 16% of the pts remained at 400 mg/d and 7% were dose decreased at 300 mg/d.
During follow-up, a similar proportion of pts with AE was observed in A1 (58%) and A2 (51%). Eight SAE related to IM were equally distributed in A1, A2 and A3. Cumulative incidences of treatment discontinuation were comparable in the 3 arms (overall, 18.8% by 12 months and 34.1% by 24 months). Reasons for discontinuation were not similar in A1 and A2 with a trend for more treatment failures in A2 as compared to A1 (60% versus 18%, p=0.08). At 12 months, MMR was achieved in 27 out of 43 pts (63%; 95%CI 49-77) in A1 as compared to 16 out 43 pts (37%; 95%CI 23-51) in A2 (p=0,031). The rates of MMR were not statistically different between A1 and A3 (p=0.12).
Conclusions
Only 1/3 of pts on IM400 were correctly dosed and may not require systematic high dose IM. Two-thirds of the pts were not exposed enough to IM at standard dose and may benefit from individualized strategies. A tailored dose adjustment based on pharmacology resulted in higher MMR rate at 12 months (63% vs 37%), a magnitude in line with the results previously reported with second generation tyrosine kinase inhibitors or high dose IM front line. Our results may provide a strong rational to early personalize the use of IM and IM generic formulations in order to optimize the outcome for each patient.
This study was supported by a grant from the French Department of Health (Programme Hospitalier de Recherche Clinique).
Table 1. Median [C]min (ng/ml; (95% CI)) Initial Assessment M3 M6 M9 M12 A1 591; (508-654) 838; (746-922) 1001; (748-1261) 1062; (918-1221) 1013; (830-1277) A2 651; (558-797) 605; (487-786) 591; (517-722) 605; (460-720) 646; (576-894) A3 1314; (1199-1514) 1032; (899-1143) 1002; (784-1205) 935; (737-1073) 1000; (846-1098) Mean IM daily dose (mg/d; (95% CI)) Inclusion M3 M6 M9 M12 A1 400 538; (508-568) 611; (563-658) 607; (545-668) 600; (535-665) A2 400 395; (387-402) 392; (383-401) 391; (381-401) 391; (381-401) A3 400 400; (400-400) 398; (385-410) 389; (376-402) 382; (370-395)

Disclosures
Rousselot: BMS: Consultancy, Speakers Bureau; Novartis: Speakers Bureau; Pfizer: Consultancy. Johnson-Ansah:BMS: Speakers Bureau; Hybrigenics SA: Consultancy, Research Funding; Novartis: Consultancy, Speakers Bureau. Huguet:PFIZER: Consultancy, Speakers Bureau; ARIAD: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Novartis: Consultancy, Research Funding. Legros:Novartis: Research Funding, Speakers Bureau; ARIAD: Speakers Bureau; BMS: Speakers Bureau. Gardembas:Novartis: Speakers Bureau. Coiteux:ARIAD: Speakers Bureau; BMS: Speakers Bureau; Novartis: Speakers Bureau. Deau:BMS: Honoraria. Mahon:ARIAD: Consultancy; Pfizer: Consultancy; Bristol-Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria.