Early Dose-Escalation in Chronic Myeloid Leukaemia Patients with Low Plasma Imatinib Levels Leads to Equivalent BCR-ABL Values and Drug Levels at 6 Months to Those with Optimal Drug Levels: First Analysis From the TIDEL II Trial of De-Novo Patients Treated with 600mg Imatinib.
Authors: Osborn Michael P , White Deborah L , Saunders Verity A , Cambareri Bronwyn , Branford Susan , Menelaou Andrew , Khodr Bereha , Slader Cassandra , Hertzberg Mark , Schwarer Anthony , Ma David , Arthur Christopher , Forsyth Cecily J. , Issa Samar , Kwan Yiu Lam , Taper John , Grigg Andrew , Hughes Timothy P. 
Published: October 2019

Abstract
Abstract 1131
Poster Board I-153

Aim
Low trough plasma imatinib levels have been associated with a poorer response to treatment in chronic myeloid leukaemia (CML) in chronic phase. We hypothesised that dose-escalation in patients with low day 22 trough levels could improve outcomes. In this interim analysis, we compared the BCR-ABL levels for patients who were dose escalated due to initial suboptimal imatinib levels to those with optimal imatinib levels. We also determined whether dose escalation leads to an increase in plasma imatinib levels.

Method
Imatinib trough and peak levels were measured in 74 chronic phase CML patients enrolled to the Australasian Leukaemia and Lymphoma Group TIDEL II study at day 8, day 22, and 3 and 6 months after commencing imatinib 600 mg. Patients with a day 22 imatinib trough level of <1000 ng/ml were dose escalated to 800 mg daily where tolerated. BCR-ABL levels were measured at 1, 2, 3 and 6 months using RQ-PCR and values were reported on the international reporting scale (IS).

Results
The median follow-up was 36 weeks, with 64 of 74 patients having 3 month data and 50 having 6 month data. At day 22, 11 (15%) patients had an imatinib trough level <1000 ng/ml, with 7 of these able to dose-escalate to 800 mg. The other 4 subjects with a low imatinib trough level were either unable to tolerate dose-escalation or were already on a dose <600 mg. At 3 and 6 months, the mean (±SD) imatinib trough level in those who had been dose escalated to 800 mg due to a day 22 trough level of <1000 ng/ml was no longer significantly different from those with a day 22 trough level of ≥1000 ng/ml (1710 ±392 vs 1760 ±949 ng/ml at 3 months, p=0.74; 1642 ±566 vs 1535 ±755 ng/ml at 6 months, p=0.75). At 2 months, the patients who were dose escalated had a significantly higher median BCR-ABL% IS level compared with those with optimal imatinib levels at day 22 (17.5% vs 6.4%, p=0.02). By 3 and 6 months this difference in BCR-ABL level had diminished and was no longer significantly different (7.3% vs 1.9% at 3 months, p=0.06; 2.1% vs 2.7% at 6 months, p=0.66).

Conclusion
This data suggests that selective dose-escalation based on Day 22 imatinib trough levels of <1000 ng/ml may result in subsequent plasma concentrations equivalent to patients with day 22 levels of >1000 ng/ml and equivalent BCR-ABL reductions. Whether this strategy can ameliorate the adverse prognostic impact of low plasma imatinib concentrations on standard dose will be the subject of ongoing study.

Disclosures
White: Novartis and Britol-Myers Squibb: Research Funding. Branford:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Slader:Novartis Pharmaceuticals Australia: Employment, Equity Ownership. Hughes:Bristol Meyers Squibb: Advisor, Honoraria, Research Funding; Novartis: Advisor, Honoraria, Research Funding.