Phospho-CRKL monitoring for the assessment of BCR-ABL activity in imatinib-resistant chronic myeloid leukemia or Ph+ acute lymphoblastic leukemia patients treated with nilotinib.

Abstract

Actual BCR-ABL kinase inhibition in vivo as determined by phospho-CRKL (pCRKL) monitoring has been recognized as a prognostic parameter in patients with chronic myelogenous leukemia treated with imatinib. We report a biomarker sub-study of the international phase I clinical trial of nilotinib (AMN107) using the established pCRKL assay in imatinib-resistant chronic myeloid leukemia or Ph+ acute lymphoblastic leukemia. A minimum dose (200 mg) required for effective BCR-ABL inhibition in imatinib resistant/intolerant leukemia was determined. The pre-clinical activity profile of nilotinib against mutant BCR-ABL was largely confirmed. Substantial differences between peripheral blood baseline pCRKL/CRKL ratios were observed when comparing chronic myeloid leukemia with Ph+ acute lymphoblastic leukemia. Finally, rapid BCR-ABL-reactivation shortly after starting nilotinib treatment was seen in acute lymphoblastic leukemia patients with progressive disease carrying the P-loop mutations Y253H, E255K, or mutation T315I. Monitoring the actual BCR-ABL inhibition in nilotinib treated patients using pCRKL as a surrogate is a means to establish effective dosing and to characterize resistance mechanisms against nilotinib.

• Authors: Paul La Rosée, Susanne Holm-Eriksen, Heiko Konig, Nicolai Härtel, Thomas Ernst, Julia Debatin, Martin C Mueller, Philipp Erben, Anja Binckebanck, Lydia Wunderle, Yaping Shou, Margaret Dugan, Ruediger Hehlmann, Oliver G Ottmann, Andreas Hochhaus
• Journal: Haematologica (Haematologica) Vol. 93 Issue 5 Pg. 765-9 (May 2008) ISSN: 1592-8721 [Electronic] Italy
• PMID: 18367481 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• Antineoplastic Agents
• Benzamides
• CRKL protein
• Nuclear Proteins
• Piperazines
• Pyrimidines
• Imatinib Mesylate
• Fusion Proteins, bcr-abl
• nilotinib

Topics

• Adaptor Proteins, Signal Transducing (chemistry)
• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents (pharmacology)
• Benzamides
• Female
• Fusion Proteins, bcr-abl (metabolism)
• Gene Expression Regulation, Leukemic
• Humans
• Imatinib Mesylate
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (drug therapy, metabolism)
• Male
• Middle Aged
• Nuclear Proteins (chemistry)
• Piperazines (pharmacology)
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, metabolism)
• Pyrimidines (pharmacology)