University of Liverpool, Liverpool, UK.
J Clin Oncol. 2012 May 10;30(14):1647-55. doi: 10.1200/JCO.2011.35.9695. Epub 2012 Apr 9.
In chronic lymphocytic leukemia (CLL), TP53 deletion/mutation is strongly associated with an adverse outcome and resistance to chemotherapy-based treatment. In contrast, TP53 defects are not associated with resistance to the anti-CD52 monoclonal antibody alemtuzumab or methylprednisolone. In an attempt to improve the treatment of TP53-defective CLL, a multicenter phase II study was developed to evaluate alemtuzumab and methylprednisolone in combination.
Thirty-nine patients with TP53-deleted CLL (17 untreated and 22 previously treated) received up to 16 weeks of treatment with alemtuzumab 30 mg three times a week and methylprednisolone 1.0 g/m(2) for five consecutive days every 4 weeks. Antimicrobial prophylaxis consisted of cotrimoxazole, itraconazole, and aciclovir (or valganciclovir for asymptomatic cytomegalovirus viremia). The primary end point was response as assigned by an end-point review committee. Secondary end points were safety, progression-free survival (PFS) and overall survival (OS).
The overall response rate, complete response rate (including with incomplete marrow recovery), median PFS, and median OS were 85%, 36%, 11.8 months, and 23.5 months, respectively, in the entire cohort and 88%, 65%, 18.3 months, and 38.9 months, respectively, in previously untreated patients. Grade 3 to 4 hematologic and glucocorticoid-associated toxicity occurred in 67% and 23% of patients, respectively. Grade 3 to 4 infection occurred in 51% of the overall cohort and in 29% of patients less than 60 years of age. Treatment-related mortality was 5%.
Alemtuzumab plus methypredisolone is the most effective induction regimen hitherto reported in TP53-deleted CLL. The risk of infection is age related and, in younger patients, seems only marginally higher than that associated with rituximab, fludarabine, and cyclophosphamide.
在慢性淋巴细胞白血病（CLL）中，TP53 缺失/突变与不良预后和对基于化疗的治疗的耐药性密切相关。相比之下，TP53 缺陷与抗 CD52 单克隆抗体阿仑单抗或甲基强的松龙的耐药性无关。为了尝试改善 TP53 缺陷型 CLL 的治疗，开展了一项多中心 II 期研究，以评估阿仑单抗和甲基强的松龙联合治疗。
39 例 TP53 缺失的 CLL 患者（17 例未经治疗，22 例先前治疗）接受了最多 16 周的治疗，每周 3 次给予阿仑单抗 30mg，每 4 周连续 5 天给予甲基强的松龙 1.0g/m2。抗菌预防包括复方磺胺甲噁唑、伊曲康唑和阿昔洛韦（或更昔洛韦治疗无症状巨细胞病毒病毒血症）。主要终点是终点审查委员会指定的反应。次要终点是安全性、无进展生存期（PFS）和总生存期（OS）。
在整个队列中，总缓解率、完全缓解率（包括不完全骨髓恢复）、中位 PFS 和中位 OS 分别为 85%、36%、11.8 个月和 23.5 个月，在未经治疗的患者中分别为 88%、65%、18.3 个月和 38.9 个月。3 至 4 级血液学和糖皮质激素相关毒性分别发生在 67%和 23%的患者中。总体队列中 51%和年龄小于 60 岁的患者中分别有 29%发生 3 至 4 级感染。治疗相关死亡率为 5%。
阿仑单抗联合甲基强的松龙是迄今为止报道的 TP53 缺失型 CLL 最有效的诱导方案。感染风险与年龄相关，在年轻患者中，与利妥昔单抗、氟达拉滨和环磷酰胺相关的风险似乎仅略高。
