Acute neurotoxicity in children with B-precursor acute lymphoid leukemia: An association with intermediate-dose intravenous methotrexate and intrathecal triple therapy - A Pediatric Oncology Group study
Acute neurotoxicity in children with B-precursor acute lymphoid leukemia: An association with intermediate-dose intravenous methotrexate and intrathecal triple therapy - A Pediatric Oncology Group study
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DOI：
10.1200/jco.1998.16.5.1712
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发表时间：
1998-05-01
影响因子：
45.3
通讯作者：
Camitta, B
中科院分区：
文献类型：
--
作者：
Mahoney, DH;Shuster, JJ;Camitta, B
目的：描述中剂量甲氨蝶呤（MTX）或分次口服MTX联合或不联合静脉注射（IV）巯嘌呤（MP）和延长鞘内三联疗法治疗的低风险B前体急性淋巴细胞白血病（ALL）儿童急性神经毒性（NT）的发生率。患者和方法：1991年1月11日至1994年9月1日，1304例患者进入儿科肿瘤组（POG）9005，一项随机III期试验。诱导缓解后，患者被随机分配至3个24周强化治疗方案中的一个：方案A，MTX 1，000 mg/m2静脉输注24小时，MP 1，000 mg/m2静脉输注6小时;方案B，低剂量MTX 30 mg/m2口服，每6小时一次，共6次，IV MP;或方案C，单独IV MTX。每2周强化一次，共12个疗程。CNS预防是年龄调整的鞘内MTX（ITM）。1992年8月，CNS预防改为年龄调整的三联鞘内治疗（TIT）。3级和4级急性NT的报告进行了reviewed.Results：急性NT报告在95 1,218（7.8%）合格的患者治疗FOG 9005。方案A的发生率为46/543例（8.3%）;方案8的发生率为13/354例（3.7%）;方案C的发生率为36/321例（11.2%）（P < .001）。大多数事件为癫痫发作，ITM或TIT后至首次发生症状性NT的中位天数为10 - 11天。在接受方案A和C治疗的有症状患者中，分别有75%和77.1%观察到与白质脑病（LE）一致的计算机断层扫描（CT）或磁共振成像（MRI）证据，无论是否存在脑钙化，但只有15.4%的有症状患者接受方案B治疗（P < .001）。与NT发生率增加相关的因素包括重复IV MTX累积暴露增加（方案A和C v B）、MTX-甲酰四氢叶酸（LCV）比值增加（方案A和C v B）以及TIT治疗的选择和时机。强化治疗期间使用IV MP似乎不会导致这些并发症。切换到TIT CNS预防与整体4年连续完全缓解（CCR）（P = 0.031）相比，ITM.Conclusion：在低剂量LCV救援设置与反复IV MTX强化与急性NT和LE的风险较高，特别是在接受伴随TIT的患者。受影响患者的长期后果仍然未知。(C)1998年，美国临床肿瘤学会。
Purpose: To describe the incidence of acute neurotoxicity (NT) in children with lower risk B-precursor acute lymphoid leukemia (ALL) treated with intermediate-dose methotrexate (MTX) or divided dose oral MTX with or without intravenous (IV) mercaptopurine (MP) and extended intrathecal triple therapy.Patients and Methods: Thirteen hundred four patients were entered onto pediatric Oncology Group (POG) 9005, a randomized phase III trial, between January 11, 1991 and September 1, 1994. After remission induction, patients were randomized to one of three 24-week intensification schedules: regimen A, MTX 1,000 mg/m(2) IV infused over 24 hours and MP 1,000 mg/m(2) IV infused over 6 hours; regimen B, low-dose repetitive MTX 30 mg/m(2) orally every 6 hours for six doses and IV MP; or regimen C, IV MTX alone. Intensification was given every 2 weeks for 12 courses. CNS prophylaxis was age-adjusted intrathecal MTX (ITM). In August 1992, the CNS prophylaxis was changed to age-adjusted triple intrathecal therapy (TIT). Reports of grades 3 and 4 acute NT were reviewed.Results: Acute NT was reported in 95 of 1,218 (7.8%) eligible patients treated on FOG 9005. The incidence by regimen was regimen A, 46 of 543 patients (8.3%); regimen 8, 13 of 354 patients (3.7%); and regimen C, 36 of 321 patients (11.2%) (P < .001). The majority of events were seizures and the median number of days to first occurrence of symptomatic NT after ITM or TIT was 10 to 11 days. Computed tomography (CT) or magnetic resonance imaging (MRI) evidence consistent with leuko-encephalopathy (LE), with or without the presence of cerebral calcifications, was observed in 75% and 77.1% of symptomatic patients treated on regimens A and C, respectively, but in only 15.4% of symptomatic patients treated on regimen B (P < .001). Factors associated with an increased incidence of NT included increased cumulative exposure with repeated IV MTX (regimens A and C v B), increased MTX-leucovorin (LCV) ratio (regimens A and C v B), and choice and timing of TIT therapy. The use of IV MP during intensification did not appear to contribute to these complications. The switch to TIT CNS prophylaxis was associated with an inferior overall 4-year continuous complete remission (CCR) (P = .031) when compared with ITM.Conclusion: Intensification with repeated IV MTX in the setting of low-dose LCV rescue was associated with a higher risk for acute NT and LE, especially in patients who received concomitant TIT. The long-term consequences for affected patients remain unknown. (C) 1998 by American Society of Clinical Oncology.