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

27 Citations (Scopus)

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 2008
Externally publishedYes

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Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Clinical Trials, Phase I
Mutation
4-methyl-N-(3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-pyridin-3-ylpyrimidin-2-yl)amino)benzamide
Imatinib Mesylate
Leukemia
Phosphotransferases
Biomarkers

Keywords

  • BCR-ABL
  • CRKL
  • Nilotinib
  • Resistance

ASJC Scopus subject areas

  • Hematology

Cite this

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. / 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.

In: Haematologica, Vol. 93, No. 5, 05.2008, p. 765-769.

Research output: Contribution to journalArticle

La Rosée, P, Holm-Eriksen, S, Konig, H, Härtel, N, Ernst, T, Debatin, J, Mueller, MC, Erben, P, Binckebanck, A, Wunderle, L, Shou, Y, Dugan, M, Hehlmann, R, Ottmann, OG & 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, vol. 93, no. 5, pp. 765-769. https://doi.org/10.3324/haematol.12186
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. / 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. In: Haematologica. 2008 ; Vol. 93, No. 5. pp. 765-769.
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