Impact of baseline BCR-ABL Mutations w/Nilotinib

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JCO Early Release, published online ahead of print Aug 3 2009

Journal of Clinical Oncology, 10.1200/JCO.2009.21.8230

Impact of Baseline BCR-ABL Mutations

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" 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. "

http://jco.ascopubs.org/cgi/content/abstract/JCO.2009.21.8230v1

FYI,

Lottie Duthu