Adult Hematolymphoid Unit, Department of Medical Oncology.
Department of Medical Oncology.
Blood Adv. 2021 Sep 14;5(17):3436-3444. doi: 10.1182/bloodadvances.2020003368.
The expression of CD20 in precursor B-cell acute lymphoblastic leukemia (B-ALL) is associated with poor outcomes. The addition of rituximab to intensive chemotherapy in CD20+ ALL has led to improved outcomes in several studies. However, there is no clear evidence regarding the optimal number of doses and its benefit without an allogeneic stem cell transplant. Achieving measurable residual disease (MRD)-negative status postinduction would reduce the requirement for a transplant. Novel approaches are needed to induce a higher proportion of MRD-negative complete remission in patients with high-risk ALL. Given bortezomib's activity in relapsed ALL and its synergism with rituximab in B-cell lymphomas, the addition of bortezomib to rituximab and chemotherapy may provide an incremental benefit in CD20+ precursor B-ALL. We conducted a phase 2 study to test the activity of bortezomib and rituximab in combination with a pediatric-inspired regimen during induction therapy in newly diagnosed adolescents and adults (aged >14 years) with CD20+, Philadelphia-negative precursor B-ALL; bone marrow MRD negativity at the end of induction was the primary end point. From December 2017 through August 2019, a total of 35 patients were enrolled. End-of-induction MRD-negative status was achieved in 70.9% of patients, as opposed to 51.7% in the historical cohort treated with chemotherapy alone. MRD-negative rates improved to 87.5% post-consolidation. At a median follow-up of 21 months, event-free survival and overall survival rates were 78.8% (95% confidence interval, 66-94) and 78.7% (95% confidence interval, 65.8-94), respectively. There was no significant increase in toxicity with bortezomib and rituximab compared with the historical cohort. The incidence of neuropathy was 26% (all less than grade 3). The combination of bortezomib, rituximab, and a pediatric-inspired ALL regimen was active and well tolerated in de novo CD20+ Philadelphia-negative precursor B-ALL. This trial was registered with the Clinical Trials Registry-India as CTRI/2017/04/008393(http://ctri.nic.in/Clinicaltrials).
CD20 在前体 B 细胞急性淋巴细胞白血病（B-ALL）中的表达与不良预后相关。在 CD20+ALL 中加入利妥昔单抗联合强化化疗已导致多项研究中结局改善。然而，在没有异基因干细胞移植的情况下，最佳剂量及其获益尚不清楚。诱导后达到可测量残留疾病（MRD）阴性状态可减少移植的需求。需要新的方法来诱导高危 ALL 患者更高比例的 MRD 阴性完全缓解。鉴于硼替佐米在复发 ALL 中的活性及其在 B 细胞淋巴瘤中与利妥昔单抗的协同作用，在利妥昔单抗和化疗中加入硼替佐米可能会在前体 B-ALL 中为 CD20+患者带来额外获益。我们进行了一项 2 期研究，以测试硼替佐米和利妥昔单抗联合儿童诱导方案在新诊断的青少年和成人（年龄>14 岁）CD20+、费城染色体阴性前体 B-ALL 患者诱导治疗中的活性；诱导结束时骨髓 MRD 阴性是主要终点。2017 年 12 月至 2019 年 8 月，共入组 35 例患者。70.9%的患者达到诱导结束时的 MRD 阴性状态，而单独接受化疗的历史队列中为 51.7%。巩固治疗后 MRD 阴性率提高至 87.5%。中位随访 21 个月时，无事件生存和总生存分别为 78.8%（95%置信区间，66-94）和 78.7%（95%置信区间，65.8-94）。与历史队列相比，硼替佐米和利妥昔单抗并未显著增加毒性。周围神经病变发生率为 26%（均<3 级）。硼替佐米、利妥昔单抗和儿童诱导 ALL 方案联合在初治 CD20+费城染色体阴性前体 B-ALL 中具有活性且耐受性良好。该试验在印度临床试验注册中心（CTRI）注册，编号为 CTRI/2017/04/008393（http://ctri.nic.in/Clinicaltrials）。
