Haematologica
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Published online 26 March 2008
Haematologica, Vol 93, Issue 5, 765-769 doi:10.3324/haematol.12186
Copyright © 2008 by Ferrata Storti Foundation
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Chronic Myeloid Leukemia

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

Paul La Rosée1, Susanne Holm-Eriksen1, Heiko Konig1, Nicolai Härtel1, Thomas Ernst1, Julia Debatin1, Martin C. Mueller1, Philipp Erben1, Anja Binckebanck2, Lydia Wunderle2, Yaping Shou3, Margaret Dugan3, Ruediger Hehlmann1, Oliver G. Ottmann2, Andreas Hochhaus1

1 III Medizinische Universitätsklinik, Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany;
2 Medizinische Klinik II, Johann Wolfgang Goethe Universität, Frankfurt, Germany and
3 Novartis Pharmaceuticals, East Hanover, NJ, USA

Correspondence: Paul La Rosée, III. Medizinische Klinik, Medizinische Fakultät Mannheim, Universität Heidelberg, Theodor-Kutzer-Ufer 1-3 68167 Mannheim, Germany. E-mail: paul.larosee{at}med3.ma.uni-heidelberg.de

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.

Key words: CRKL, BCR-ABL, nilotinib, resistance.






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Copyright © 2008 by the Ferrata Storti Foundation.