Hyper-CVAD regimen in combination with ofatumumab as frontline therapy for adults with Philadelphia chromosome-negative B-cell acute lymphoblastic leukaemia: a single-arm, phase 2 trial
Hyper-CVAD regimen in combination with ofatumumab as frontline therapy for adults with Philadelphia chromosome-negative B-cell acute lymphoblastic leukaemia: a single-arm, phase 2 trial
复制标题
DOI：
10.1016/s2352-3026(20)30144-7
复制
发表时间：
2020-07-01
影响因子：
24.7
通讯作者：
Kantarjian, Hagop
中科院分区：
文献类型：
--
作者：
Jabbour, Elias;Richard-Carpentier, Guillaume;Kantarjian, Hagop
在强化化疗中加入利妥昔单抗可改善B细胞急性淋巴细胞白血病患者的预后。奥法木单抗是一种抗CD 20单克隆抗体，与CD 20的细胞外小环结合，体外补体介导的细胞毒性大于利妥昔单抗。在这项研究中，我们评估的活动和安全性ofatumumab联合化疗患者费城染色体（Ph）阴性CD 20阳性B细胞急性淋巴细胞leukemia.Methods这是一个单臂，2期临床试验在MD安德森癌症中心（休斯顿，得克萨斯州，美国）。新诊断的Ph阴性B细胞急性淋巴母细胞白血病或淋巴母细胞淋巴瘤且CD 20表达至少为1%的患者有资格入选。患者在疗程1、3、5和7接受最多8个疗程的hyper-CVAD方案（超分割环磷酰胺、长春新碱、多柔比星和地塞米松）治疗，在疗程2、4、6和8交替接受高剂量甲氨蝶呤和阿糖胞苷治疗。奥法木单抗在疗程1和3的第1天和第11天以及疗程2和4的第1天和第8天给药，共给药8次。奥法木单抗的首次剂量为300 mg静脉注射，所有后续剂量均为2000 mg静脉注射。患者接受了30个疗程的6-巯基嘌呤、长春新碱、甲氨蝶呤和泼尼松（POMP）维持治疗，4个强化疗程（第6-7和18-19个疗程的高剂量甲氨蝶呤+L-天冬酰胺酶和hyper-CVAD+奥法木单抗）。主要终点为无事件生存期、总缓解率和总生存期。所有入组患者均纳入主要分析和安全性分析。该试验注册于ClinicalTrials.gov，NCT 01363128。结果在2011年8月26日至2017年5月18日期间，69例患者（67例患者患有B细胞急性淋巴细胞白血病，2例患者患有B细胞淋巴细胞淋巴瘤;中位年龄41岁[IQR 32-50]）入组并接受治疗，其中33例（48%）年龄在18至39岁之间。33例患者中有9例（27%）患有Ph样急性淋巴细胞白血病。中位随访时间为44个月（26-53），4年无事件生存率为59%（95% CI 48-73）; 18-39岁青少年和年轻人为69%（54-87）。4-年总生存率为68%（58-81）;青少年和年轻人为74%（60-91）。总有效率为98%（64/65例患者）。最常见的非血液学3级或4级不良事件是感染（诱导期65例患者中有35例[54%]，巩固期68例患者中有53例[78%]）。69例患者中有10例（14%）死于败血症（2例[3%]）、心脏骤停（1例[1%]）、治疗相关急性髓性白血病（2例[3%]）和造血干细胞移植并发症（5例[7%]）的完全缓解。研究者认为这些死亡均与奥法木单抗治疗无关。解释hyper-CVAD加奥法木单抗的组合在患有Ph阴性CD 20阳性B细胞急性淋巴细胞白血病的成人中是安全和有效的。通过添加靶向CD 19和CD 22的新型单克隆和双特异性抗体构建体对该方案进行修改，可能会进一步改善结局，并减少化疗的强度和持续时间。版权所有（c）2020 Elsevier Ltd.保留所有权利。
Background The addition of rituximab to intensive chemotherapy improves outcomes in patients with B-cell acute lymphoblastic leukaemia. Ofatumumab is an anti-CD20 monoclonal antibody that binds to the small extracellular loop of CD20 and has greater in vitro complement-mediated cytotoxicity than rituximab. In this study, we assessed the activity and safety of ofatumumab in combination with chemotherapy in patients with Philadelphia chromosome (Ph)-negative CD20-positive B-cell acute lymphoblastic leukaemia.Methods This was a single-arm, phase 2 trial done at the MD Anderson Cancer Center (Houston, TX, USA). Patients with newly diagnosed, Ph-negative B-cell acute lymphoblastic leukaemia or lymphoblastic lymphoma with CD20 expression of at least 1% were eligible. Patients were treated with up to eight courses of the hyper-CVAD regimen (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) on courses 1, 3, 5, and 7 alternating with high-dose methotrexate and cytarabine on courses 2, 4, 6, and 8. Ofatumumab was administered on days 1 and 11 of courses 1 and 3 and on days 1 and 8 of courses 2 and 4 for a total of eight doses. The first dose of ofatumumab was 300 mg intravenously and all subsequent doses were 2000 mg intravenously. Patients received 30 courses of maintenance therapy with 6-mercaptopurine, vincristine, methotrexate, and prednisone (POMP), with four intensification courses (high-dose methotrexate plus L-asparaginase and hyper-CVAD plus ofatumumab on courses 6-7 and 18-19). The primary endpoints were event-free survival, overall response, and overall survival. All enrolled patients were included in the primary and safety analyses. The trial is registered with ClinicalTrials.gov, NCT01363128.Findings Between Aug 26, 2011, and May 18, 2017, 69 patients (67 patients had B-cell acute lymphoblastic leukaemia and two had B-cell lymphoblastic lymphoma; median age 41 years [IQR 32-50]) were enrolled and treated, including 33 (48%) aged between 18 and 39 years. Nine (27%) of 33 patients had Ph-like acute lymphoblastic leukaemia. With a median follow-up of 44 months (26-53), 4-year event-free survival was 59% (95% CI 48-73); 69% (54-87) in adolescents and young adults aged 18-39 years. 4-year overall survival was 68% (58-81); 74% (60-91) in adolescents and young adults. The overall response rate was 98% (64 of 65 patients). The most common non-haematological grade 3 or 4 adverse events were infections (35 [54%] of 65 patients during induction and 53 [78%] of 68 patients during consolidation). Ten (14%) of 69 patients died in complete remission from sepsis (two [3%]), cardiac arrest (one [1%]), therapy-related acute myeloid leukaemia (two [3%]), and haematopoietic stem-cell transplantation complications (five [7%]). None of these deaths were considered related to ofatumumab treatment by the study investigators.Interpretation The combination of hyper-CVAD plus ofatumumab is safe and active in adults with Ph-negative CD20-positive B-cell acute lymphoblastic leukaemia. Modifications of this regimen with the addition of novel monoclonal and bispecific antibody constructs targeting CD19 and CD22 might further improve outcomes and allow reduction in the intensity and duration of chemotherapy. Copyright (c) 2020 Elsevier Ltd. All rights reserved.