Impact of baseline BCR-ABL mutations on response to nilotinib in patients with chronic myeloid leukemia in chronic phase

Timothy Hughes, Giuseppe Saglio, Susan Branford, Simona Soverini, Dong Wook Kim, Martin C. Müller, Giovanni Martinelli, Jorge Cortes, Lan Beppu, Enrico Gottardi, Dongho Kim, Philipp Erben, Yaping Shou, Ariful Haque, Neil Gallagher, Jerald Radich, Andreas Hochhaus

Research output: Contribution to journalArticle

Abstract

Purpose: Nilotinib is a second-generation tyrosine kinase inhibitor indicated for the treatment of patients with chronic myeloid leukemia (CML) in chronic phase (CP; CML-CP) and accelerated phase (AP; CML-AP) who are resistant to or intolerant of prior imatinib therapy. In this subanalysis of a phase II study of nilotinib in patients with imatinib-resistant or imatinib-intolerant CML-CP, the occurrence and impact of baseline and newly detectable BCR-ABL mutations were assessed. Patients and Methods: Baseline mutation data were assessed in 281 (88%) of 321 patients with CML-CP in the phase II nilotinib registration trial. Results: Among imatinib-resistant patients, the frequency of mutations at baseline was 55%. After 12 months of therapy, major cytogenetic response (MCyR) was achieved in 60%, complete cytogenetic response (CCyR) in 40%, and major molecular response (MMR) in 29% of patients without baseline mutations versus 49% (P = .145), 32% (P = .285), and 22% (P = .366), respectively, of patients with mutations. Responses in patients who harbored mutations with high in vitro sensitivity to nilotinib (50% inhibitory concentration [IC50] ≤ 150 nM) or mutations with unknown nilotinib sensitivity were equivalent to those responses for patients without mutations (not significant). Patients with mutations that were less sensitive to nilotinib in vitro (IC50 > 150 nM; Y253H, E255V/K, F359V/C) had less favorable responses, as 13%, 43%, and 9% of patients with each of these mutations, respectively, achieved MCyR; none achieved CCyR. Conclusion: For most patients with imatinib resistance and with mutations, nilotinib offers a substantial probability of response. However, mutational status at baseline may influence response. Less sensitive mutations that occurred at three residues defined in this study, as well as the T315I mutation, may be associated with less favorable responses to nilotinib.

Original languageEnglish (US)
Pages (from-to)4204-4210
Number of pages7
JournalJournal of Clinical Oncology
Volume27
Issue number25
DOIs
StatePublished - Sep 1 2009
Externally publishedYes

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Leukemia, Myeloid, Chronic Phase
Mutation
Cytogenetics
Inhibitory Concentration 50
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Leukemia, Myeloid, Accelerated Phase
4-methyl-N-(3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-pyridin-3-ylpyrimidin-2-yl)amino)benzamide
Mutation Rate
Protein-Tyrosine Kinases

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Hughes, T., Saglio, G., Branford, S., Soverini, S., Kim, D. W., Müller, M. C., ... Hochhaus, A. (2009). Impact of baseline BCR-ABL mutations on response to nilotinib in patients with chronic myeloid leukemia in chronic phase. Journal of Clinical Oncology, 27(25), 4204-4210. https://doi.org/10.1200/JCO.2009.21.8230

Impact of baseline BCR-ABL mutations on response to nilotinib in patients with chronic myeloid leukemia in chronic phase. / Hughes, Timothy; Saglio, Giuseppe; Branford, Susan; Soverini, Simona; Kim, Dong Wook; Müller, Martin C.; Martinelli, Giovanni; Cortes, Jorge; Beppu, Lan; Gottardi, Enrico; Kim, Dongho; Erben, Philipp; Shou, Yaping; Haque, Ariful; Gallagher, Neil; Radich, Jerald; Hochhaus, Andreas.

In: Journal of Clinical Oncology, Vol. 27, No. 25, 01.09.2009, p. 4204-4210.

Research output: Contribution to journalArticle

Hughes, T, Saglio, G, Branford, S, Soverini, S, Kim, DW, Müller, MC, Martinelli, G, Cortes, J, Beppu, L, Gottardi, E, Kim, D, Erben, P, Shou, Y, Haque, A, Gallagher, N, Radich, J & Hochhaus, A 2009, 'Impact of baseline BCR-ABL mutations on response to nilotinib in patients with chronic myeloid leukemia in chronic phase', Journal of Clinical Oncology, vol. 27, no. 25, pp. 4204-4210. https://doi.org/10.1200/JCO.2009.21.8230
Hughes, Timothy ; Saglio, Giuseppe ; Branford, Susan ; Soverini, Simona ; Kim, Dong Wook ; Müller, Martin C. ; Martinelli, Giovanni ; Cortes, Jorge ; Beppu, Lan ; Gottardi, Enrico ; Kim, Dongho ; Erben, Philipp ; Shou, Yaping ; Haque, Ariful ; Gallagher, Neil ; Radich, Jerald ; Hochhaus, Andreas. / Impact of baseline BCR-ABL mutations on response to nilotinib in patients with chronic myeloid leukemia in chronic phase. In: Journal of Clinical Oncology. 2009 ; Vol. 27, No. 25. pp. 4204-4210.
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abstract = "Purpose: Nilotinib is a second-generation tyrosine kinase inhibitor indicated for the treatment of patients with chronic myeloid leukemia (CML) in chronic phase (CP; CML-CP) and accelerated phase (AP; CML-AP) who are resistant to or intolerant of prior imatinib therapy. In this subanalysis of a phase II study of nilotinib in patients with imatinib-resistant or imatinib-intolerant CML-CP, the occurrence and impact of baseline and newly detectable BCR-ABL mutations were assessed. Patients and Methods: Baseline mutation data were assessed in 281 (88{\%}) of 321 patients with CML-CP in the phase II nilotinib registration trial. Results: Among imatinib-resistant patients, the frequency of mutations at baseline was 55{\%}. After 12 months of therapy, major cytogenetic response (MCyR) was achieved in 60{\%}, complete cytogenetic response (CCyR) in 40{\%}, and major molecular response (MMR) in 29{\%} of patients without baseline mutations versus 49{\%} (P = .145), 32{\%} (P = .285), and 22{\%} (P = .366), respectively, of patients with mutations. Responses in patients who harbored mutations with high in vitro sensitivity to nilotinib (50{\%} inhibitory concentration [IC50] ≤ 150 nM) or mutations with unknown nilotinib sensitivity were equivalent to those responses for patients without mutations (not significant). Patients with mutations that were less sensitive to nilotinib in vitro (IC50 > 150 nM; Y253H, E255V/K, F359V/C) had less favorable responses, as 13{\%}, 43{\%}, and 9{\%} of patients with each of these mutations, respectively, achieved MCyR; none achieved CCyR. Conclusion: For most patients with imatinib resistance and with mutations, nilotinib offers a substantial probability of response. However, mutational status at baseline may influence response. Less sensitive mutations that occurred at three residues defined in this study, as well as the T315I mutation, may be associated with less favorable responses to nilotinib.",
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T1 - Impact of baseline BCR-ABL mutations on response to nilotinib in patients with chronic myeloid leukemia in chronic phase

AU - Hughes, Timothy

AU - Saglio, Giuseppe

AU - Branford, Susan

AU - Soverini, Simona

AU - Kim, Dong Wook

AU - Müller, Martin C.

AU - Martinelli, Giovanni

AU - Cortes, Jorge

AU - Beppu, Lan

AU - Gottardi, Enrico

AU - Kim, Dongho

AU - Erben, Philipp

AU - Shou, Yaping

AU - Haque, Ariful

AU - Gallagher, Neil

AU - Radich, Jerald

AU - Hochhaus, Andreas

PY - 2009/9/1

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N2 - Purpose: Nilotinib is a second-generation tyrosine kinase inhibitor indicated for the treatment of patients with chronic myeloid leukemia (CML) in chronic phase (CP; CML-CP) and accelerated phase (AP; CML-AP) who are resistant to or intolerant of prior imatinib therapy. In this subanalysis of a phase II study of nilotinib in patients with imatinib-resistant or imatinib-intolerant CML-CP, the occurrence and impact of baseline and newly detectable BCR-ABL mutations were assessed. Patients and Methods: Baseline mutation data were assessed in 281 (88%) of 321 patients with CML-CP in the phase II nilotinib registration trial. Results: Among imatinib-resistant patients, the frequency of mutations at baseline was 55%. After 12 months of therapy, major cytogenetic response (MCyR) was achieved in 60%, complete cytogenetic response (CCyR) in 40%, and major molecular response (MMR) in 29% of patients without baseline mutations versus 49% (P = .145), 32% (P = .285), and 22% (P = .366), respectively, of patients with mutations. Responses in patients who harbored mutations with high in vitro sensitivity to nilotinib (50% inhibitory concentration [IC50] ≤ 150 nM) or mutations with unknown nilotinib sensitivity were equivalent to those responses for patients without mutations (not significant). Patients with mutations that were less sensitive to nilotinib in vitro (IC50 > 150 nM; Y253H, E255V/K, F359V/C) had less favorable responses, as 13%, 43%, and 9% of patients with each of these mutations, respectively, achieved MCyR; none achieved CCyR. Conclusion: For most patients with imatinib resistance and with mutations, nilotinib offers a substantial probability of response. However, mutational status at baseline may influence response. Less sensitive mutations that occurred at three residues defined in this study, as well as the T315I mutation, may be associated with less favorable responses to nilotinib.

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