Pharmacokinetics of dasatinib for Philadelphia-positive acute lymphocytic leukemia with acquired T315I mutation.

Abstract

BACKGROUND:

The BCR-ABL T315I kinase domain mutation is insensitive to dasatinib therapy for Philadelphia-positive acute lymphoid leukemia (Ph + ALL) patients. Resistant T315I clone may be present prior to initiating dasatinib, which could expand under selective pressures during treatment. However, it is also possible that Ph + ALL patients newly acquire the T315I mutation during dasatinib therapy. Despite the potent inhibition of BCR-ABL kinase by dasatinib, little is known about the relationship between dasatinib pharmacokinetics and the emergence of kinase domain mutations in vivo.

METHODS:

To determine whether plasma dasatinib pharmacokinetics influences the emergence of BCR-ABL mutations, we measured plasma dasatinib levels in 11 Ph + ALL patients undergoing dasatinib monotherapy.

RESULTS:

Bone marrow relapse occurred in 5 of the 11 Ph + ALL patients (45%). Importantly, a T315I mutation was detected in 4 of the 5 relapsed patients, despite the absence of BCR-ABL mutations in any patient at baseline. The median plasma concentration at 2 hours (C(2h)), the median plasma maximum concentration (C(max)), and the median area under the observed plasma concentration-time curve from 0 to 4 hours (AUC(0-4)) were all significantly lower in patients with T315I than those without the mutation (C(2h), 22.3 ng/mL vs. 111.6 ng/mL, P = 0.0242; C(max), 43.8 ng/mL vs. 112.4 ng/mL, P = 0.0242; AUC(0-4), 108.3 ng·h/mL vs. 268.3 ng·h/mL, P = 0.0061, respectively).

CONCLUSIONS:

These data indicate that the emergence of the T315I mutation among Ph + ALL patients treated with dasatinib is, in part, dependent on plasma dasatinib pharmacokinetics. Notably, these data also suggest that newly acquired BCR-ABL mutations may be inhibited by an increased exposure of dasatinib.

• Authors: Naoto Takahashi, Masatomo Miura, Stuart A Scott, Takenori Niioka, Kenichi Sawada
• Journal: Journal of hematology & oncology (J Hematol Oncol) Vol. 5 Pg. 23 (May 15 2012) ISSN: 1756-8722 [Electronic] England
• PMID: 22587422 (Publication Type: Journal Article)

Chemical References

• Protein Kinase Inhibitors
• Pyrimidines
• Thiazoles
• Fusion Proteins, bcr-abl
• Dasatinib

Topics

• Adult
• Aged
• Aged, 80 and over
• Dasatinib
• Drug Resistance, Neoplasm (genetics)
• Female
• Fusion Proteins, bcr-abl (genetics)
• Humans
• Male
• Middle Aged
• Mutation (genetics)
• Philadelphia Chromosome
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (blood, drug therapy, genetics)
• Protein Kinase Inhibitors (pharmacokinetics)
• Pyrimidines (blood, pharmacokinetics)
• Thiazoles (blood, pharmacokinetics)
• Tissue Distribution
• Young Adult