Efficacy of Frontline Nilotinib Therapy in Patients (Pts) with Newly Diagnosed Philadelphia Chromosome (Ph)-Positive Chronic Myeloid Leukemia in Early Chronic Phase (CML-CP)
Efficacy of Frontline Nilotinib Therapy in Patients (Pts) with Newly Diagnosed Philadelphia Chromosome (Ph)-Positive Chronic Myeloid Leukemia in Early Chronic Phase (CML-CP)
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DOI：
10.1182/blood.v118.21.454.454
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发表时间：
2011-11
期刊：
影响因子：
20.3
通讯作者：
A. Quintás-Cardama;H. Kantarjian;R. Luthra;S. O'brien;E. Jabbour;G. Borthakur;F. Ravandi;G. Garcia-Manero;S. Faderl;M. Konopleva;W. Wierda;E. Burton;J. Cortes
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作者：
A. Quintás-Cardama;H. Kantarjian;R. Luthra;S. O'brien;E. Jabbour;G. Borthakur;F. Ravandi;G. Garcia-Manero;S. Faderl;M. Konopleva;W. Wierda;E. Burton;J. Cortes
摘要 454 一线尼罗替尼治疗对新诊断的费城染色体 (Ph) 阳性慢性粒细胞白血病早期慢性期 (CML-CP) 患者 (Pts) 的疗效 Alfonso Quintas-Cardama, Hagop Kantarjian, Raja Luthra, Susan O9Brien, Elias Jabbour, Gautam Borthakur, Farhad Ravandi, Guillermo Garcia-Manero、Stefan Faderl、Marina Konopleva、William Wierda、Elizabeth Burton、Jorge Cortes 1 MD 安德森癌症中心，德克萨斯大学，休斯顿，德克萨斯州 背景：2005 年，我们启动了一项尼罗替尼作为新诊断 CML-CP 患者一线治疗的 II 期研究，以调查尼罗替尼作为 CML-CP 患者一线治疗的有效性和安全性。方法：主要目标是估计 12 个月 (mo) 时达到主要分子缓解 (MMR) 的患者比例。诊断后 6 个月内未经治疗的 CML-CP 患者符合资格，接受尼罗替尼 400 毫克，每天两次。结果：100 名患者（41% 女性）接受治疗的时间中位数为 24 个月（范围 1 至 72 个月）。中位年龄为 49 岁（范围 17-86 岁）。 WBC、PB 原始细胞、PB 嗜碱性粒细胞、血红蛋白和血小板计数中位数分别为 42.6、0%、2.5%、12.3、307。 5 名患者 (5%) 存在费城染色体变异，1 名患者 (1%) 存在衍生 9 号染色体缺失。72 名患者 (72%)、20 名患者 (20%) 和 8 名患者 (8%) 具有低、中和高 Sokal 风险评分。在开始时未进行 CHR 的 102 名 CP 患者中，有 100 名 (98%) 达到了 CHR（一名患者在 2 周后没有不良事件情况下停药）。在 73 名 CP 患者中随访至少 12 个月，其中 69 名 (95%) 实现了完全细胞遗传学反应 (CCyR)。 51 名患者 (89%) 已在 18 个月时实现了 MMR，其中 30 名患者 (52%) 具有完整的分子反应 (CMR)（表 1）。达到 CCyR、MMR 的中位时间均为 6 个月。 9%、12% 和 6% 的患者出现 3-4 级血小板减少症、中性粒细胞减少症和贫血。最常见的非血液毒性是皮疹（62%）、疼痛（57%）、转氨酶（45%）和胆红素（42%）升高。然而，3-4级非血液学不良事件（仅可能、很可能或怀疑相关）很少见，包括：疼痛和胆红素升高（各4%）、脂肪酶升高、疲劳和转氨酶升高（各2%）和高血糖（1%）。一名 (1%) 患者出现 QTc 延长（2 级；QTc 从 444 毫秒延长至 483 毫秒），与心律失常无关，并在短暂的治疗中断后得到缓解。 45 名 (45%) 患者出现短暂的治疗中断（中位停用尼罗替尼天数 7 天 [范围 1-68]），27 名 (27%) 患者减少剂量。在剂量减少的患者中，他们当前或最后已知的剂量为每天 200 毫克 (n = 7)、每天两次 200 毫克 (n = 14) 或每天 400 毫克 (n = 6)。 19 名 (19%) 患者因毒性 (n=7)、个人原因或失访 (n=7)、MCyR 丧失 (n=2)、进展为 BP (n=2) 或死亡 (n=1) 终止尼罗替尼治疗。在停止治疗的患者中，有 3 人接受了 BCR-ABL1 突变检测； 2 个被发现有突变（F359C 和 Y253H）。 48 个月 EFS（事件 = CHR 丧失、MCyR、AP/BP 丧失或死亡）的概率为 88%。随访前 48 个月的年事件发生率分别为 4%、0%、2%、5% 和 0%，转化率分别为 2%、0%、0% 和 0%。转化为 BP 的 2 名患者对尼洛替尼取得的最佳反应分别是 CCyR 和 PCyR。 48 个月时的总生存率为 96%。一名患者死于中风，与尼洛替尼无关。迄今为止尚未观察到其他血管事件。结论：尼洛替尼 400 mg 每日两次，早在治疗开始后 3 个月内就可诱导 78% 的患者出现 CCyR，并在治疗开始后 12 个月时诱导 86% 的患者出现 MMR，进展为 AP/BP 的比率非常低，毒性特征也较轻微。披露：没有需要声明的相关利益冲突。
Abstract 454 Efficacy of Frontline Nilotinib Therapy in Patients (Pts) with Newly Diagnosed Philadelphia Chromosome (Ph)-Positive Chronic Myeloid Leukemia in Early Chronic Phase (CML-CP) Alfonso Quintas-Cardama, Hagop Kantarjian, Raja Luthra, Susan O9Brien, Elias Jabbour, Gautam Borthakur, Farhad Ravandi, Guillermo Garcia-Manero, Stefan Faderl, Marina Konopleva, William Wierda, Elizabeth Burton, Jorge Cortes 1 MD Anderson Cancer Center, University of Texas, Houston, TX Background: In 2005, we initiated a phase II study of nilotinib as 1 st line therapy in pts with newly diagnosed CML-CP to investigate the efficacy and safety of nilotinib as frontline therapy for pts with CML-CP. Methods: The primary objective was to estimate the proportion of pts attaining major molecular response (MMR) at 12 months (mo). Pts with untreated CML-CP within 6 mo from diagnosis were eligible and received nilotinib 400 mg twice daily. Results: 100 pts (41% female) have received for a median of 24 mo (range 1 to 72mos). Median age was 49 years (range 17–86). Median WBC, PB blasts, PB basophils, hemoglobin, and platelet count was 42.6, 0%, 2.5%, 12.3, 307, respectively. Five pts (5%) had a variant Philadelphia chromosome and 1 (1%) had deletion of derivative chromosome 9. Seventy-two (72%), 20 (20%), and 8 (8%) pts had low, intermediate, and high Sokal risk score. Among the 102 CP pts who were not in CHR at the start, 100 (98%) achieved CHR (one discontinued after 2 weeks without adverse events). Among 73 CP pts followed for at least 12 mo, 69 (95%) achieved a complete cytogenetic response (CCyR). MMR at 18 mo has been achieved in 51 (89%) pts, including 30 (52%) with a complete molecular response (CMR)(Table 1). The median time to achieve CCyR, MMR was 6 mo each. Grade 3–4 thrombocytopenia, neutropenia, and anemia occurred in 9%, 12%, and 6% pts. The most frequent non-hematologic toxicities were rash (62%), pain (57%), and elevated transaminases (45%) and bilirubin (42%). However, grade 3–4 non-hematologic adverse events (possible, probable or suspected relationship only) were rare, including: pain and increased bilirubin (4% each), elevated lipase, fatigue, and elevated transaminases (2% each), and hyperglycemia (1%). One (1%) pt experienced QTc prolongation (grade 2; QTc prolonged from 444msec to 483msec), not associated with arrhythmias and resolved after a brief treatment interruption. Forty-five (45%) pts had transient treatment interruptions (median days off-nilotinib 7 [range 1–68]) and 27 (27%) had dose reductions. Of the patients that were dose reduced, their current or last known dose was either 200mg daily (n=7), 200mg twice daily (n=14), or 400mg daily (n=6). Nineteen (19%) pts terminated nilotinib therapy due to toxicity (n=7), personal reasons or loss to follow-up (n=7), loss of MCyR (n=2), progression to BP (n=2), or death (n=1). Of the pts who discontinued therapy, 3 were tested for BCR-ABL1 mutations; 2 were found to have mutations (F359C and Y253H). The 48 mo probability of EFS (event= loss of CHR, loss of MCyR, AP/BP, or death) is 88%. The annual rate of events during the first 48 mo of follow-up was 4%, 0%, 2%, 5%, and 0% and the rate of transformation 2%, 0%, 0%, and 0%, respectively. The best response achieved on nilotinib by the 2 pts that transformed to BP was CCyR and PCyR, respectively. The overall survival at 48 mos is 96%. One pt died due to stroke, unrelated to nilotinib. No other vascular events have been observed to date. Conclusion: Nilotinib 400 mg twice daily induces CCyR in 78% of pts as early as 3 mo and MMR in 86% at 12 mo after the start of therapy, with very low rates of progression to AP/BP and a mild toxicity profile. Disclosures: No relevant conflicts of interest to declare.