TY - JOUR
T1 - 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
AU - Takahashi, Naoto
AU - Miura, Masatomo
AU - Kuroki, Jun
AU - Mitani, Kinuko
AU - Kitabayashi, Atsushi
AU - Sasaki, Osamu
AU - Kimura, Hideo
AU - Imai, Kiyotoshi
AU - Tsukamoto, Norifumi
AU - Noji, Hideyoshi
AU - Kondo, Takeshi
AU - Motegi, Mutsuhito
AU - Kato, Yuichi
AU - Mita, Masayuki
AU - Saito, Hajime
AU - Yoshida, Chikashi
AU - Torimoto, Yoshihiro
AU - Kimura, Tomofumi
AU - Wano, Yuji
AU - Nomura, Jun
AU - Yamamoto, Satoshi
AU - Mayama, Ko
AU - Honma, Riko
AU - Sugawara, Tomohiro
AU - Sato, Shinji
AU - Shinagawa, Atsushi
AU - Abumiya, Maiko
AU - Niioka, Takenori
AU - Harigae, Hideo
AU - Sawada, Kenichi
N1 - Funding Information:
The authors thank the East Japan CML study group (EJCML), Ibaraki Hematology, Oncology and Palliation Expert Meeting (IB-HOPE), and the Akita CML study group for their participation in this study. This work was supported by a grant (No. 23590168) from the Japan Society for the Promotion of Science, Tokyo, Japan.
Publisher Copyright:
© 2014 Takahashi et al.
PY - 2014/3/20
Y1 - 2014/3/20
N2 - 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.
AB - 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.
KW - BCR-ABL1 mutation
KW - Chronic myeloid leukemia
KW - Hyperbilirubinemia
KW - Major molecular response
KW - Nilotinib
KW - Uridine diphosphate glucuronosyltransferase
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U2 - 10.1186/2050-7771-2-6
DO - 10.1186/2050-7771-2-6
M3 - Article
AN - SCOPUS:85032570358
SN - 2050-7771
VL - 2
JO - Biomarker Research
JF - Biomarker Research
IS - 1
M1 - 6
ER -