Open Access Research article

Rapid initial decline in BCR-ABL1 is associated with superior responses to second-line nilotinib in patients with chronic-phase chronic myeloid leukemia

Andrew M Stein1*, Giovanni Martinelli2, Timothy P Hughes3, Martin C Müller4, Lan Beppu5, Enrico Gottardi6, Susan Branford3, Simona Soverini2, Richard C Woodman7, Andreas Hochhaus8, Dong-Wook Kim9, Giuseppe Saglio6 and Jerald P Radich5

Author Affiliations

1 Novartis Institutes for BioMedical Research, Inc., 45 Sidney St, Cambridge, MA 02139, USA

2 University of Bologna, Department of Hematology and Oncological Sciences “L. e A. Seràgnoli, Bologna, Italy

3 Centre for Cancer Biology/SA Pathology, Royal Adelaide Hospital, Adelaide, Australia

4 Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany

5 Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

6 University of Turin, Orbassano, Italy

7 Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA

8 Universitätsklinikum Jena, Jena, Germany

9 Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul, Korea

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BMC Cancer 2013, 13:173  doi:10.1186/1471-2407-13-173

Published: 2 April 2013



We evaluated BCR-ABL1 kinetics in patients treated with nilotinib and analyzed whether a dynamic model of changes in BCR-ABL1 levels over time could be used to predict long-term responses.


Patients from the nilotinib registration trial (CAMN107A2101; registered at webcite as NCT00109707) who had imatinib-resistant or -intolerant Philadelphia chromosome–positive (Ph+) chronic myeloid leukemia (CML) in chronic phase (CP) or accelerated phase with BCR-ABL1 > 10% (on the international scale [IS]) at baseline and, in the first 6 months, had at least three BCR-ABL1 transcript measurements and an average daily dose of at least 720 mg were included in this analysis (N = 123).


More than half of patients (65/123; 53%) had a slow monophasic response and the remainder (58/123; 47%) had a biphasic response, in which patients had a rapid initial decrease in BCR-ABL1 transcripts followed by a more gradual response. The biphasic response type strongly correlated with improved event-free survival (EFS). Data in the first 6 months of follow-up were sufficient to predict EFS at 24 months.


Unlike newly diagnosed patients with Ph+ CML-CP—in whom the majority had a biphasic response—approximately half of patients with imatinib-resistant or -intolerant CML had a slower, monophasic response. Second-line patients who did have a biphasic response had an EFS outlook similar to that of newly diagnosed patients treated with imatinib. Our model was comparable to using BCR-ABL1 (IS) ≤ 10% at 6 months as a threshold for predicting EFS.

Chronic myeloid leukemia; Nilotinib; Mathematical modeling; BCR-ABL; Molecular response