Salles Gilles, Gopal Ajay K, Minnema Monique C, Wakamiya Karen, Feng Huaibao, Schecter Jordan M, Wang Michael
Hématologie, Hospices Civils de Lyon and Université de Lyon, Lyon, France.
Department of Medicine, University of Washington, Seattle, WA.
Clin Lymphoma Myeloma Leuk. 2019 May;19(5):275-284. doi: 10.1016/j.clml.2018.12.013. Epub 2019 Jan 2.
Daratumumab is a CD38 monoclonal antibody approved for treating relapsed/refractory and newly diagnosed multiple myeloma. Preclinical daratumumab studies demonstrated cytotoxic activity and reduced tumor growth in B-cell non-Hodgkin lymphoma (NHL) subtypes, including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and mantle-cell lymphoma (MCL).
This was a phase 2, open-label, multicenter, 2-stage trial. Patients with relapsed/refractory DLBCL, FL, or MCL with ≥ 50% CD38 expression were eligible for stage 1. Daratumumab (16 mg/kg; 28-day cycles) was administered intravenously weekly for 2 cycles, every 2 weeks for 4 cycles, and every 4 weeks thereafter. Overall response rate was the primary end point. Pharmacokinetic and safety were also evaluated. Stage 2 was planned to further assess daratumumab in larger populations of NHL subtypes if futility criteria were not met. The study was registered with ClinicalTrials.gov (NCT02413489).
The trial screened 138 patients resulting in accrual of 15 patients with DLBCL, 16 with FL, and 5 with MCL. Median CD38 expression across treated patients was 70%. Overall response rate was 6.7%, 12.5%, and not evaluable in DLBCL, FL, and MCL cohorts, respectively. The most common grade 3/4 treatment-emergent adverse event was thrombocytopenia (11.1%), and 4 (11.1%) patients discontinued treatment because of treatment-emergent adverse events. Infusion-related reactions occurred in 72.2% of patients (3 patients with grade 3; no grade 4).
In NHL, the safety and pharmacokinetics of daratumumab were consistent with myeloma studies. Screen-fail rates were high, prespecified futility thresholds were met in 2 cohorts, and the study was terminated. Studies in other hematologic malignancies and amyloidosis are ongoing.
达雷妥尤单抗是一种已获批用于治疗复发/难治性及新诊断多发性骨髓瘤的CD38单克隆抗体。临床前对达雷妥尤单抗的研究表明，其在B细胞非霍奇金淋巴瘤（NHL）亚型中具有细胞毒性活性并能抑制肿瘤生长，这些亚型包括弥漫性大B细胞淋巴瘤（DLBCL）、滤泡性淋巴瘤（FL）和套细胞淋巴瘤（MCL）。
这是一项2期、开放标签、多中心、两阶段试验。复发/难治性DLBCL、FL或MCL且CD38表达≥50%的患者符合1期入组条件。达雷妥尤单抗（16mg/kg；每28天为一个周期）静脉给药，第1个2周期每周1次，接下来4周期每2周1次，之后每4周1次。总缓解率是主要终点。同时评估了药代动力学和安全性。如果未达到无效标准，计划在2期对更多NHL亚型患者进一步评估达雷妥尤单抗。该研究已在ClinicalTrials.gov（NCT02413489）注册。
该试验筛查了138例患者，最终纳入15例DLBCL患者、16例FL患者和5例MCL患者。所有接受治疗患者的CD38表达中位数为70%。DLBCL、FL和MCL队列的总缓解率分别为6.7%、12.5%和不可评估。最常见的3/4级治疗中出现的不良事件是血小板减少（11.1%），4例（11.1%）患者因治疗中出现的不良事件而停药。72.2%的患者发生了输液相关反应（3例3级；无4级）。
在NHL中，达雷妥尤单抗的安全性和药代动力学与骨髓瘤研究结果一致。筛查失败率很高，2个队列达到了预先设定的无效阈值，该研究因此终止。针对其他血液系统恶性肿瘤和淀粉样变性的研究正在进行中。
