Efficacy and safety of nilotinib produced in China in the treatment of patients with newly diagnosed chronic myeloid leukemia in chronic phase
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摘要: 目的 探讨国产尼洛替尼对新诊断的慢性髓系白血病(chronic myeloid leukemia，CML)慢性期(chronic phase，CP)患者的临床疗效及安全性。方法 收集2023年9月1日—2024年10月1日于华中科技大学附属协和医院、长江大学附属荆州医院、宜昌市中心医院就诊的CML-CP患者，未经过除羟基脲以外其他任何抗CML治疗的CML-CP患者，给予国产尼洛替尼300 mg/次，口服，2次/d，评估治疗3、6、12个月时患者的血液学、细胞遗传学和分子学反应及安全性。结果 治疗≥3个月的患者23例，治疗≥6个月的患者17例，治疗≥12个月的患者9例。治疗3个月时，23例患者中21例获得完全血液学反应(complete hematologic response，CHR)；19例患者获得完全遗传学反应(complete cytogenetic response，CCyR)；23例均进行了分子检测(实时定量PCR法检测，BCR-ABL转录水平以IS表示)，BCR-ABLIS≤10%的患者21例，其中BCR-ABLIS≤0.1%7例，BCR-ABLIS≤0.01%2例。治疗6个月时，17例患者中16例获得CHR；17例患者获得CCyR；17例均进行了分子检测，BCR-ABLIS≤1%的患者14例，其中14例BCR-ABLIS≤0.1%，4例BCR-ABLIS≤0.01%。治疗12个月时，9例患者中全部获得CHR和CCyR；6例BCR-ABLIS≤0.1%，其中5例BCR-ABLIS≤0.01%。Ⅲ~Ⅳ级白细胞减少、中性粒细胞减少、贫血、血小板减少的发生率分别为17.4%、26.1%、17.4%、26.1%，有2例患者发生Ⅳ级血小板减少持续不能恢复而停药。主要的非血液学不良反应依次为皮肤瘙痒(21.7%)、皮疹(17.4%)、肌肉酸痛(13.0%)、恶心(13.0%)、高胆红素血症(13.0%)、腹胀(8.7%)，均为Ⅰ~Ⅱ级，无患者发生Ⅲ~Ⅳ级非血液学不良反应。无药物毒性相关性死亡。结论 国产尼洛替尼治疗新诊断的CML-CP能够使患者早期、快速获得深层分子学反应和细胞遗传学反应，且安全性良好。Abstract: Objective To explore the clinical efficacy and safety of Nilotinib produced in China in patients with newly diagnosed chronic myeloid leukemia in chronic phase(CML-CP).Methods We collected data from CML-CP patients who visited Huazhong University of Science and Technology Union Hospital, Yangtze University Affiliated Jingzhou Hospital, and Yichang Central Hospital from September 1, 2023, to October 1, 2024. Patients included in the study had not received any anti-CML treatment other than hydroxyurea. They were treated with Nilotinib produced in China at a dose of 300 mg per dose, orally, twice daily. The hematologic, cytogenetic and molecular responses were assessed at 3, 6, and 12 months of treatment, and adverse effects of the drug were evaluated.Results 23 patients were treated with Nilotinib produced in China for≥3 months, of which 17 patients were treated for ≥6 months and 9 patients were treated for≥12 months. At 3rd month of treatment, 21 out of 23 patients achieved complete hematologic response(CHR); 19 achieved complete cytogenetic response(CCyR); Among 23 patients who underwent molecular testing, 21 patients had BCR-ABLIS≤10%, including 7 patients with BCR-ABLIS≤0.1%, and 2 patients with BCR-ABLIS≤0.01%. At 6th month of treatment, 16 out of 17 patients achieved CHR; all 17 achieved CCyR; Among 17 patients who underwent molecular testing, 14 patients had BCR-ABLIS≤1%, including 14 patients with BCR-ABLIS≤0.1% and 4 patients with BCR-ABLIS≤0.01%. At 12nd month of treatment, all 9 patients achieved CHR and CCyR; 6 patients had BCR-ABLIS≤0.1%, with 5 patients having BCR-ABLIS≤0.01%. The incidence rates of grade Ⅲ-Ⅳ leukopenia, neutropenia, anemia, and thrombocytopenia were 17.4%, 26.1%, 17.4%, and 26.1%, respectively, with 2 patients experiencing grade Ⅳ thrombocytopenia that persisted and led to discontinuation of treatment. The main non-hematological adverse reactions were skin itching(21.7%), rash(17.4%), muscle pain(13.0%), nausea(13.0%), hyperbilirubinemia(13.0%), and abdominal distension(8.7%), all of which were grade Ⅰ-Ⅱ, with no patients experiencing grade Ⅲ-Ⅳ non-hematological adverse reactions. No drug toxicity-related deaths occurred.Conclusion Nilotinib produced in China, as the firstline treatment for newly diagnosed CML-CP, can enable the patients to achieve early and deep molecular and cytogenetic responses, and shows good safety.
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表 1 23例CML-CP患者基线特征
例(%)，中位数(范围) 基线特征 数值 诊断年龄/岁 46(18~68) 性别 男 12(52.2) 女 11(47.8) Sokal评分 低 13(56.5) 中 4(17.4) 高 6(26.1) ETLS评分 低 17(73.9) 中 1(4.3) 高 5(21.7) ECOG评分 0分 22(95.7) 1分 1(4.3) 外周血原始细胞/% 0(0~8) 骨髓原始细胞/% 0.5(0~9.5) WBC/(×109/L) 124.5(17.7~393.0) Hb/(g/L) 109(64~159) PLT/(×109/L) 392(162~1 092) Ph+细胞/% 100(0~100) 初诊BCR/ABLIS水平/% 66.8(22.7~287.5) 注：Hb：血红蛋白。 
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表 2 CML-CP患者疗效评估
例(%) 治疗反应 3个月
(n=23)6个月
(n=17)12个月
(n=9)CHR 21(91.3) 16(94.1) 9(100.0) CCyR 19(82.6) 17(100.0) 9(100.0) BCR-ABLIS >10% 2(8.7) 0 0 ≤10% 21(91.3) 17(100.0) 9(100.0) ≤1% 15(65.2) 14(82.4) 8(88.9) ≤0.1% 7(30.4) 14(82.4) 6(66.7) ≤0.01% 2(8.7) 4(23.5) 5(55.6)
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表 3 国产尼洛替尼治疗23例新诊断的CML-CP患者安全性评估
例(%) 不良事件 Ⅰ~Ⅱ级 Ⅲ~Ⅳ级 合计 血液学不良事件 白细胞减少 9(39.1) 4(17.4) 13(56.5) 中性粒细胞减少 8(34.8) 6(26.1) 14(60.9) 贫血 8(34.8) 4(17.4) 12(52.2) 血小板减少 10(43.5) 6(26.1) 16(69.6) 非血液学不良事件 皮疹 4(17.4) 0 4(17.4) 皮肤瘙痒 5(21.7) 0 5(21.7) 头痛 1(4.3) 0 1(4.3) 肌肉酸痛 3(13.0) 0 3(13.0) 脱发 1(4.3) 0 1(4.3) 恶心 3(13.0) 0 3(13.0) 腹胀 2(8.7) 0 2(8.7) 高胆红素血症 3(13.0) 0 3(13.0) 转氨酶升高 1(4.3) 0 1(4.3)
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表 4 7例CML-CP患者口服国产尼洛替尼剂量调整情况
类型 病例1 病例2 病例3 病例4 病例5 病例6 病例7 性别 女 男 男 女 女 男 男 年龄/岁 61 68 21 46 38 67 50 合并症 高血压 无 无 无 无 无 慢性乙肝 Sokal评分 中危 高危 低危 低危 高危 中危 低危 ETLS评分 低危 低危 低危 低危 中危 低危 低危 WBC/(×109/L) 171.1 333.1 147.7 248.4 91.1 124.5 28.9 Hb/(g/L) 105 69 105 71 114 90 150 PLT/(×109/L) 633 1 092 392 204 424 586 426 脾脏大小(肋缘下)/cm 0 5.7 3.5 4.8 0 4.3 0 初诊BCR/ABLIS水平/% 85.32 56.78 73.14 22.70 72.65 61.53 61.21 尼洛替尼初始剂量/(mg/d) 600 600 600 600 600 600 600 尼洛替尼服药后至减量时间 6周 5周 34周 9周 1周 4周 8周 尼洛替尼减量原因 腹胀、恶心 Ⅲ级白细胞、血小板减少 2级皮疹 Ⅱ级白细胞、Ⅲ级血小板减少 Ⅲ级血小板减少 2级胆红素升高 Ⅲ级血小板减少 减量后尼洛替尼剂量/(mg/d) 300 300 450 450 300 300 300 减量后尼洛替尼浓度/(ng/mL) 未做 未做 1 120 1 400 872 未做 未做 是否再次进行剂量调整 否 否 30周后加量为600 mg/d 否 否 否 4周后减量为150 mg/d 3个月BCR/ABLIS水平/% 0.85 13.74 0.33 7.39 0.28 0.04 0.01 6个月BCR/ABLIS水平/% 0.03 未达到 0.04 0.27 0.01 0.02 0.02 12个月BCR/ABLIS水平/% 未达到 未达到 0.02 未达到 未达到 0 未达到
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