Jabbour Elias, Richard-Carpentier Guillaume, Sasaki Yuya, Konopleva Marina, Patel Keyur, Roberts Kathryn, Gu Zhaohui, Wang Feng, Huang Xuelin, Sasaki Koji, Short Nicholas J, Jain Nitin, Ravandi Farhad, Daver Naval G, Kadia Tapan M, Alvarado Yesid, DiNardo Courtney D, Issa Ghayas C, Pemmaraju Naveen, Garcia-Manero Guillermo, Verstovsek Srdan, Wang Sa, Khoury Joseph D, Jorgensen Jeffrey, Champlin Richard, Khouri Issa, Kebriaei Partow, Schroeder Heather, Khouri Maria, Mullighan Charles G, Takahashi Koichi, O'Brien Susan M, Kantarjian Hagop
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Lancet Haematol. 2020 Jul;7(7):e523-e533. doi: 10.1016/S2352-3026(20)30144-7.
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.
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.
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.
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.
Novartis.
在强化化疗中添加利妥昔单抗可改善B细胞急性淋巴细胞白血病患者的预后。奥法妥木单抗是一种抗CD20单克隆抗体，可与CD20的小细胞外环结合，并且在体外具有比利妥昔单抗更强的补体介导的细胞毒性。在本研究中，我们评估了奥法妥木单抗联合化疗在费城染色体（Ph）阴性、CD20阳性B细胞急性淋巴细胞白血病患者中的活性和安全性。
这是一项在美国德克萨斯州休斯顿市MD安德森癌症中心进行的单臂2期试验。新诊断的、Ph阴性B细胞急性淋巴细胞白血病或CD20表达至少1%的淋巴细胞淋巴瘤患者符合入选标准。患者接受多达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），在第1、3、5和7疗程使用，与高剂量甲氨蝶呤和阿糖胞苷在第2、4、6和8疗程交替使用。奥法妥木单抗在第1和第3疗程的第1天和第11天以及第2和第4疗程的第1天和第8天给药，共8剂。奥法妥木单抗的首剂为静脉注射300mg，所有后续剂量为静脉注射2000mg。患者接受30个疗程的维持治疗，使用6-巯基嘌呤、长春新碱、甲氨蝶呤和泼尼松（POMP），并进行4个强化疗程（第6-7和18-19疗程使用高剂量甲氨蝶呤加L-天冬酰胺酶以及hyper-CVAD加奥法妥木单抗）。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。该试验已在ClinicalTrials.gov注册，注册号为NCT01363128。
在2011年8月26日至2017年5月18日期间，69例患者（67例为B细胞急性淋巴细胞白血病，2例为B细胞淋巴细胞淋巴瘤；中位年龄41岁[四分位间距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44个月（26-53个月），4年无事件生存率为59%（95%CI 48-73）；18至39岁的青少年和年轻成人中为69%（54-87）。4年总生存率为68%（58-81）；青少年和年轻成人中为74%（60-91）。总缓解率为98%（65例患者中的64例）。最常见的3级或4级非血液学不良事件为感染（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%）在完全缓解期死于败血症（2例[3%]）、心脏骤停（1例[1%]）、治疗相关的急性髓系白血病（2例[3%]）和造血干细胞移植并发症（5例[7%]）。研究调查人员认为这些死亡均与奥法妥木单抗治疗无关。
hyper-CVAD加奥法妥木单抗的联合方案在Ph阴性CD20阳性B细胞急性淋巴细胞白血病成人患者中安全且有效。通过添加靶向CD19和CD22的新型单克隆和双特异性抗体构建体对该方案进行改良，可能会进一步改善预后，并允许降低化疗的强度和持续时间。
诺华公司。
