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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.

Author(s): La Rosee P, Holm-Eriksen S, Konig H, Hartel N, Ernst T, Debatin J, Mueller MC, Erben P, Binckebanck A, Wunderle L, Shou Y, Dugan M, Hehlmann R, Ottmann OG, Hochhaus A

Affiliation(s): III. Medizinische Klinik, Medizinische Fakultat Mannheim, Universitat Heidelberg, Theodor-Kutzer-Ufer 1-3 68167 Mannheim, Germany. paul.larosee@med3.ma.uni-heidelberg.de

Publication date & source: 2008-05, Haematologica., 93(5):765-9. Epub 2008 Mar 26.

Publication type: Research Support, Non-U.S. Gov't

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.

Page last updated: 2008-08-10

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