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.
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.
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DOI：
10.1186/2050-7771-2-6
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发表时间：
2014-03-20
影响因子：
11.1
通讯作者：
Sawada K
中科院分区：
文献类型：
--
作者：
Takahashi N;Miura M;Kuroki J;Mitani K;Kitabayashi A;Sasaki O;Kimura H;Imai K;Tsukamoto N;Noji H;Kondo T;Motegi M;Kato Y;Mita M;Saito H;Yoshida C;Torimoto Y;Kimura T;Wano Y;Nomura J;Yamamoto S;Mayama K;Honma R;Sugawara T;Sato S;Shinagawa A;Abumiya M;Niioka T;Harigae H;Sawada K
尼罗替尼是第二代酪氨酸激酶抑制剂，作为慢性粒细胞白血病 (CML) 患者的一线或二线治疗显示出显着疗效。我们进行了一项多中心 II 期临床试验，以评估尼洛替尼在伊马替尼耐药或不耐受的 CML 慢性期 (CP) 或加速期 (AP) 的日本患者中的安全性和有效性。我们分析了 49 名患者（33 名伊马替尼耐药和 16 名伊马替尼不耐受），每天两次接受尼洛替尼 400 毫克治疗。在 35 名在研究开始时未表现出 MMR 的患者中，12 个月时的主要分子缓解 (MMR) 率为 47.8%。在 12 个月或停用尼洛替尼后，在 3 名患者中检测到体细胞 BCR-ABL1 突变（Y253H、I418V 和外显子 8/9 35-bp 插入 [35INS]）。尽管 75.5% 的患者在 12 个月时仍在接受治疗，但由于 1 名患者病情进展、2 名患者效果不足以及 9 名患者出现不良事件，尼洛替尼治疗被终止。MMR 与尼洛替尼谷浓度之间没有统计学上显着的相关性。同样，除了瘙痒和低钾血症外，谷浓度与不良事件之间没有观察到相关性。高胆红素血症很常见（所有级别，51.0%；2-4 级，29%；3-4 级，4.1%）。高于 2 级的高胆红素血症与尿苷二磷酸葡萄糖醛酸基转移酶 (UGT)1A9 I399C/C 基因型显着相关（P = 0.0086；比值比，21.2；95% 置信区间 2.2–208.0）。尼罗替尼对伊马替尼耐药或不耐受的 CML-CP/AP 患者有效且耐受性良好。高胆红素血症可以在尼洛替尼治疗前预测，并且可以通过减少 UGT1A9 多态性患者的尼洛替尼每日剂量来控制。临床试验.gov：UMIN000002201
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). 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). 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. clinicaltrials.gov: UMIN000002201