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首页> 外文期刊>Biomarker Research >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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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

机译：尼洛替尼治疗伊马替尼耐药或不耐受的慢性粒细胞白血病的多中心II期临床试验，来自日本东部CML研究组，评估了其分子响应以及尼洛替尼的疗效和安全性

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BackgroundNilotinib 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). ResultsWe 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). ConclusionsNilotinib 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 registrationclinicaltrials.gov: UMIN000002201
机译：背景尼洛替尼是第二代酪氨酸激酶抑制剂，在慢性粒细胞白血病（CML）患者中作为一线或二线治疗具有显着疗效。我们进行了一项多中心II期临床试验，以评估尼洛替尼在日本伊马替尼耐药或不耐受CML慢性期（CP）或加速期（AP）患者中的安全性和有效性。结果我们分析了每天两次用尼洛替尼400？mg治疗的49例患者（33例伊马替尼耐药和16例伊马替尼不耐受）。在35例在研究开始时未表现出MMR的患者中，在12个月时的主要分子反应（MMR）率为47.8％。在12个月或停用尼洛替尼的3例患者中检测到了体细胞BCR-ABL1突变（Y253H，I418V和外显子8/9 35 bp插入[35INS]）。尽管有75.5％的患者在12个月时仍在接受治疗，但由于1名患者的疾病进展，2名患者的疗效不足以及9名患者的不良事件而终止了尼洛替尼的治疗。MMR与尼洛替尼谷浓度之间无统计学意义的相关性。同样，除瘙痒和低钾血症外，谷浓度与不良事件之间也没有相关性。经常观察到高胆红素血症（所有等级为51.0％; 2-4级为29％; 3-4级为4.1％）。高于2级的高胆红素血症与尿苷二磷酸葡萄糖醛酸糖基转移酶（UGT）1A9 I399C / C基因型显着相关（P =？0.0086;几率21.2; 95％可信区间2.2-208.0）。结论尼洛替尼对伊马替尼耐药或不耐受的CML-CP / AP患者有效且耐受。高胆红素血症可以在尼洛替尼治疗之前进行预测，并且可以通过降低UGT1A9多态性患者的尼洛替尼每日剂量来控制。试用注册clinicaltrials.gov：UMIN000002201

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