Randomized phase III trial of fludarabine plus cyclophosphamide with or without oblimersen sodium (Bcl-2 antisense) in patients with relapsed or refractory chronic lymphocytic leukemia
Randomized phase III trial of fludarabine plus cyclophosphamide with or without oblimersen sodium (Bcl-2 antisense) in patients with relapsed or refractory chronic lymphocytic leukemia
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DOI：
10.1200/jco.2006.07.1191
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发表时间：
2007-03-20
影响因子：
45.3
通讯作者：
Rai, Kanti R.
中科院分区：
文献类型：
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作者：
O'Brien, Susan;Moore, Joseph O.;Rai, Kanti R.
目的Bcl-2蛋白表达与慢性淋巴细胞白血病（CLL）化疗耐药及生存期降低有关。我们评估了oblimersen是否会改善复发或难治性CLL患者对化疗的反应。患者和方法患者既往至少接受过一种含氟达拉滨方案，并根据既往氟达拉滨反应、既往方案数量和对上次既往治疗的反应持续时间进行分层。患者被随机分配到28天的周期，氟达拉滨25mg /m(2)/d加环磷酰胺250mg /m(2)/d静脉注射3天，有或没有oblimersen 3mg /kg/d作为7天连续静脉输注（化疗前4天开始），最多6个周期。主要终点是达到完全缓解（CR）或结节性部分缓解（nPR）的患者比例。结果在随机分配的241例患者中，oblimersen组120例患者中有20例（17%）达到CR/nPR，单纯化疗组121例患者中有8例（7%）达到CR/nPR （P = 0.025）。CR/nPR的实现与进展时间延长和生存相关（P < 0.0001）。在对氟达拉滨仍然敏感的患者中，oblimersen与CR/nPR率增加4倍和显著的生存获益相关（P = 0.05）。Oblimersen常与血小板减少症有关，很少与肿瘤溶解综合征和细胞因子释放反应有关；两组的机会性感染和二次恶性肿瘤发生率相似。结论氟达拉滨+环磷酰胺联合奥布莫森治疗可显著提高复发或难治性CLL患者（尤其是氟达拉滨敏感患者）的CR/nPR率，并可显著延长达到CR/nPR的患者的缓解时间。
Purpose Expression of Bcl-2 protein is associated with chemotherapy resistance and decreased survival in chronic lymphocytic leukemia (CLL). We evaluated whether oblimersen would improve response to chemotherapy in patients with relapsed or refractory CLL.Patients and Methods Patients had received at least one prior fludarabine-containing regimen and were stratified on the basis of prior fludarabine response, number of prior regimens, and duration of response to last prior therapy. Patients were randomly assigned to 28-day cycles of fludarabine 25 mg/m(2)/d plus cyclophosphamide 250 mg/m(2)/d administered intravenously for 3 days with or without oblimersen 3 mg/kg/d as a 7-day continuous intravenous infusion (beginning 4 days before chemotherapy) for up to six cycles. The primary end point was the proportion of patients who achieved complete response (CR) or nodular partial response (nPR).Results Of 241 patients randomly assigned, CR/nPR was achieved in 20 (17%) of 120 patients in the oblimersen group and eight (7%) of 121 patients in the chemotherapy-only group (P = .025). Achievement of CR/nPR was correlated with both an extended time to progression and survival (P < .0001). In patients who remained sensitive to fludarabine, oblimersen was associated with a four-fold increase in the CR/nPR rate and a significant survival benefit (P = .05). Oblimersen was frequently associated with thrombocytopenia and, rarely, tumor lysis syndrome and cytokine release reactions; the incidence of opportunistic infections and second malignancies was similar in both groups.Conclusion The addition of oblimersen to fludarabine plus cyclophosphamide significantly increases the CR/nPR rate in patients with relapsed or refractory CLL (particularly fludarabine-sensitive patients), as well as response duration among patients who achieve CR/nPR.