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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.

Authors
  • La Rosée, Paul
  • Holm-Eriksen, Susanne
  • Konig, Heiko
  • Härtel, Nicolai
  • Ernst, Thomas
  • Debatin, Julia
  • Mueller, Martin C
  • Erben, Philipp
  • Binckebanck, Anja
  • Wunderle, Lydia
  • Shou, Yaping
  • Dugan, Margaret
  • Hehlmann, Ruediger
  • Ottmann, Oliver G
  • Hochhaus, Andreas
Type
Published Article
Journal
Haematologica
Publisher
Ferrata Storti Foundation
Publication Date
May 01, 2008
Volume
93
Issue
5
Pages
765–769
Identifiers
DOI: 10.3324/haematol.12186
PMID: 18367481
Source
Medline
License
Unknown

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.

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