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 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

Research output: Contribution to journalArticle

30 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)765-769
Number of pages5
JournalHaematologica
Volume93
Issue number5
DOIs
StatePublished - May 1 2008
Externally publishedYes

Keywords

  • BCR-ABL
  • CRKL
  • Nilotinib
  • Resistance

ASJC Scopus subject areas

  • Hematology

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    La Rosée, P., Holm-Eriksen, S., Konig, H., Härtel, N., Ernst, T., Debatin, J., Mueller, M. C., Erben, P., Binckebanck, A., Wunderle, L., Shou, Y., Dugan, M., Hehlmann, R., Ottmann, O. G., & Hochhaus, A. (2008). 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. Haematologica, 93(5), 765-769. https://doi.org/10.3324/haematol.12186