Multicenter phase II clinical trial of nilotinib for patients with imatinib-resistant or -intolerant chronic myeloid leukemia from the East Japan CML study group evaluation of molecular response and the efficacy and safety of nilotinib.

Abstract

BACKGROUND:

Nilotinib is a second-generation tyrosine kinase inhibitor that exhibits significant efficacy as first- or second-line treatment in patients with chronic myeloid leukemia (CML). We conducted a multicenter Phase II Clinical Trial to evaluate the safety and efficacy of nilotinib among Japanese patients with imatinib-resistant or -intolerant CML-chronic phase (CP) or accelerated phase (AP).

RESULTS:

We analyzed 49 patients (33 imatinib-resistant and 16 imatinib-intolerant) treated with nilotinib 400 mg twice daily. The major molecular response (MMR) rate was 47.8% at 12 months among 35 patients who did not demonstrate an MMR at study entry. Somatic BCR-ABL1 mutations (Y253H, I418V, and exon 8/9 35-bp insertion [35INS]) were detected in 3 patients at 12 months or upon discontinuation of nilotinib. Although 75.5% of patients were still being treated at 12 months, nilotinib treatment was discontinued because of progressing disease in 1 patient, insufficient effect in 2, and adverse events in 9. There was no statistically significant correlation between MMR and trough concentrations of nilotinib. Similarly, no correlation was observed between trough concentrations and adverse events, except for pruritus and hypokalemia. Hyperbilirubinemia was frequently observed (all grades, 51.0%; grades 2-4, 29%; grades 3-4, 4.1%). Hyperbilirubinemia higher than grade 2 was significantly associated with the uridine diphosphate glucuronosyltransferase (UGT)1A9 I399C/C genotype (P = 0.0086; Odds Ratio, 21.2; 95% Confidence Interval 2.2-208.0).

CONCLUSIONS:

Nilotinib was efficacious and well tolerated by patients with imatinib-resistant or -intolerant CML-CP/AP. Hyperbilirubinemia may be predicted before nilotinib treatment, and may be controlled by reducing the daily dose of nilotinib in patients with UGT1A9 polymorphisms.

TRIAL REGISTRATION:

clinicaltrials.gov: UMIN000002201.

• Authors: Naoto Takahashi, Masatomo Miura, Jun Kuroki, Kinuko Mitani, Atsushi Kitabayashi, Osamu Sasaki, Hideo Kimura, Kiyotoshi Imai, Norifumi Tsukamoto, Hideyoshi Noji, Takeshi Kondo, Mutsuhito Motegi, Yuichi Kato, Masayuki Mita, Hajime Saito, Chikashi Yoshida, Yoshihiro Torimoto, Tomofumi Kimura, Yuji Wano, Jun Nomura, Satoshi Yamamoto, Ko Mayama, Riko Honma, Tomohiro Sugawara, Shinji Sato, Atsushi Shinagawa, Maiko Abumiya, Takenori Niioka, Hideo Harigae, Kenichi Sawada
• Journal: Biomarker research (Biomark Res) Vol. 2 Issue 1 Pg. 6 (Mar 20 2014) ISSN: 2050-7771 [Print] England
• PMID: 24650752 (Publication Type: Journal Article)