Originally published as JCO Early Release 10.1200/JCO.2009.21.8230 on August 3 2009

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Impact of Baseline BCR-ABL Mutations on Response to Nilotinib in Patients With Chronic Myeloid Leukemia in Chronic Phase

From the Hanson Institute, Adelaide, Australia; University of Turin, San Luigi Gonzaga Hospital, Torino; and Institute of Hematology and Medical Oncology, Bologna, Italy; The Catholic University of Korea, Seoul, Korea; Universitätsmedizin Mannheim der Universität Heidelberg, Mannheim, Germany; M. D. Anderson Cancer Center, Houston, TX; Fred Hutchinson Cancer Research Center, Seattle, WA; and Novartis, East Hanover, NJ.

Corresponding author: Timothy Hughes, MD, MBBS, Institute of Medical and Veterinary Science, Hanson Center for Cancer Research, Department of Hematology, Frome Rd, Adelaide, 5000, Australia; e-mail: Timothy.hughes{at}imvs.sa.gov.au.

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.

Supported by research funding from Novartis Pharmaceuticals; by Grant No. DJCLS H 02/01 from the German José-Carreras Foundation (A.H.); and by Australian National Health and Medical Research Council practitioner fellowship (T.P.H).

Presented in part at the 49th Annual Meeting of the American Society of Hematology, December 8-11, 2007, Atlanta, GA; the 44th Annual Meeting of the American Society of Clinical Oncology, May 30-June 3, 2008, Chicago, IL; and the 13th Annual Congress of the European Haematology Association, June 12-15, 2008, Copenhagen, Denmark.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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