Winkler U, Jensen M, Manzke O, Schulz H, Diehl V, Engert A
Department I of Internal Medicine, University of Cologne, Cologne, Germany.
Blood. 1999 Oct 1;94(7):2217-24.
Eleven patients with relapsed fludarabine-resistant B-cell chronic lymphocytic leukemia (CLL) or leukemic variants of low-grade B-cell non-Hodgkin's lymphoma (NHL) were treated with the chimeric monoclonal anti-CD20 antibody rituximab (IDEC-C2B8). Peripheral lymphocyte counts at baseline varied from 0.2 to 294.3 x 10(9)/L. During the first rituximab infusion, patients with lymphocyte counts exceeding 50.0 x 10(9)/L experienced a severe cytokine-release syndrome. Ninety minutes after onset of the infusion, serum levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) peaked in all patients. Elevated cytokine levels during treatment were associated with clinical symptoms, including fever, chills, nausea, vomiting, hypotension, and dyspnea. Lymphocyte and platelet counts dropped to 50% to 75% of baseline values within 12 hours after the onset of the infusion. Simultaneously, there was a 5-fold to 10-fold increase of liver enzymes, d-dimers, and lactate dehydrogenase (LDH), as well as a prolongation of the prothrombin time. Frequency and severity of first-dose adverse events were dependent on the number of circulating tumor cells at baseline: patients with lymphocyte counts greater than 50.0 x 10(9)/L experienced significantly more adverse events of National Cancer Institute (NCI) grade III/IV toxicity than patients with less than 50.0 x 10(9)/L peripheral tumor cells (P = .0017). Due to massive side effects in the first patient treated with 375 mg/m(2) in 1 day, a fractionated dosing schedule was used in all subsequent patients with application of 50 mg rituximab on day 1, 150 mg on day 2, and the rest of the 375 mg/m(2) dose on day 3. While the patient with the leukemic variant of the mantle-cell NHL achieved a complete remission (9 months+) after treatment with 4 x 375 mg/m(2) rituximab, efficacy in patients with relapsed fludarabine-resistant B-CLL was poor: 1 partial remission, 7 cases of stable disease, and 1 progressive disease were observed in 9 evaluable patients with CLL. On the basis of these data, different infusion schedules and/or combination regimens with chemotherapeutic drugs to reduce tumor burden before treatment with rituximab will have to be evaluated.
11例复发的氟达拉滨耐药B细胞慢性淋巴细胞白血病（CLL）或低度B细胞非霍奇金淋巴瘤（NHL）白血病变异型患者接受了嵌合单克隆抗CD20抗体利妥昔单抗（IDEC-C2B8）治疗。基线外周淋巴细胞计数从0.2至294.3×10⁹/L不等。在首次输注利妥昔单抗期间，淋巴细胞计数超过50.0×10⁹/L的患者发生了严重的细胞因子释放综合征。输注开始90分钟后，所有患者的血清肿瘤坏死因子-α（TNF-α）和白细胞介素-6（IL-6）水平均达到峰值。治疗期间细胞因子水平升高与临床症状相关，包括发热、寒战、恶心、呕吐、低血压和呼吸困难。输注开始后12小时内，淋巴细胞和血小板计数降至基线值的50%至75%。同时，肝酶、D-二聚体和乳酸脱氢酶（LDH）升高5至10倍，凝血酶原时间延长。首剂不良事件的频率和严重程度取决于基线循环肿瘤细胞数量：淋巴细胞计数大于50.0×10⁹/L的患者发生美国国立癌症研究所（NCI）III/IV级毒性不良事件的比例显著高于外周肿瘤细胞小于此值的患者（P = 0.0017）。由于首例接受1天375 mg/m²治疗的患者出现大量副作用，所有后续患者均采用了分次给药方案，第1天应用50 mg利妥昔单抗，第2天应用150 mg，第3天应用剩余的375 mg/m²剂量。虽然套细胞NHL白血病变异型患者在接受4×375 mg/m²利妥昔单抗治疗后实现了完全缓解（9个月以上），但复发的氟达拉滨耐药B-CLL患者的疗效较差：9例可评估的CLL患者中，观察到1例部分缓解、7例病情稳定和1例病情进展。基于这些数据，必须评估不同的输注方案和/或与化疗药物的联合方案，以在利妥昔单抗治疗前减轻肿瘤负荷。
