Chronic phase chronic myeloid leukemia patients with low OCT-1 activity randomized to high-dose imatinib achieve better responses and have lower failure rates than those randomized to standard-dose imatinib.

Abstract

BACKGROUND:

The functional activity of the organic cation transporter 1 (OCT-1) protein (OCT-1 activity) is an excellent predictor of molecular response and progression-free survival in patients with newly diagnosed chronic phase chronic myeloid leukemia treated with imatinib as front-line therapy.

DESIGN AND METHODS:

In this study the predictive value of OCT-1 activity in patients treated with imatinib 400 mg/day or 800 mg/day was evaluated in relation to trough imatinib plasma levels assessed in 100 patients enrolled in the Tyrosine Kinase Inhibitor Optimization and Selectivity (TOPS) trial.

RESULTS:

The rate of major molecular responses by 24 months in patients on imatinib 400 mg/day was significantly higher in those with high OCT-1 activity than in those with low OCT-1 activity (low OCT-1 activity, 57% of patients; high OCT-1 activity, 100%; P < 0.001); the corresponding difference in patients treated with imatinib 800 mg/day did not reach statistical significance (low OCT-1 activity, 68%; high OCT-1 activity, 95%; P = 0.073). In addition, the combination of low trough imatinib levels (< 1200 ng/mL) and low OCT-1 activity defined a group of patients who had the lowest rates of major molecular response (47%) by 24 months compared to all other patients (81%, P = 0.009). These patients were also at the highest risk of failed imatinib therapy when compared to all other patients (P<0.001).

CONCLUSIONS:

High-dose imatinib leads to superior molecular responses in patients with low OCT-1 activity. In this group trough imatinib levels may define a group with inferior outcomes. Among patients with high OCT-1 activity, neither higher imatinib dose nor monitoring imatinib trough levels was found to be of significant clinical value. Hence OCT-1 activity determined prior to the start of therapy in newly diagnosed CML patients provides a valuable prognostic tool to determine the optimal up-front dose of imatinib in patients with newly diagnosed chronic phase chronic myeloid leukemia.

• Authors: Deborah L White, Jerald Radich, Simona Soverini, Verity A Saunders, Amity K Frede, Phuong Dang, Daniela Cilloni, Peter Lin, Lidia Mongay, Richard Woodman, Paul Manley, Cassandra Slader, Dong Wook Kim, Fabrizio Pane, Giovanni Martinelli, Giuseppe Saglio, Timothy P Hughes
• Journal: Haematologica (Haematologica) Vol. 97 Issue 6 Pg. 907-14 (Jun 2012) ISSN: 1592-8721 [Electronic] Italy
• PMID: 22207690 (Publication Type: Clinical Trial, Phase III, Journal Article, Multicenter Study, Randomized Controlled Trial)

Chemical References

• Antineoplastic Agents
• Benzamides
• Biomarkers, Tumor
• Organic Cation Transporter 1
• Piperazines
• Pyrimidines
• Imatinib Mesylate

Topics

• Antineoplastic Agents (administration & dosage, therapeutic use)
• Benzamides
• Biological Transport
• Biomarkers, Tumor (genetics, metabolism)
• Disease-Free Survival
• Drug Administration Schedule
• Drug Dosage Calculations
• Female
• Gene Expression
• Humans
• Imatinib Mesylate
• Leukemia, Myeloid, Chronic-Phase (drug therapy, metabolism, mortality)
• Male
• Organic Cation Transporter 1 (genetics, metabolism)
• Piperazines (administration & dosage, therapeutic use)
• Pyrimidines (administration & dosage, therapeutic use)
• Treatment Outcome