Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA.
Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA.
Clin Lymphoma Myeloma Leuk. 2024 Oct;24(10):724-731.e1. doi: 10.1016/j.clml.2024.05.017. Epub 2024 Jun 15.
BV is an antibody-drug conjugate directed against CD30 and is safe and effective in relapsed/refractory (R/R) Hodgkin lymphoma (HL). Most patients with r/r cHL respond well to BV monotherapy; however, the large of majority of them eventually progress on this drug, and BV-resistant HL remains an unmet need. Preclinical data suggest that BV resistance is mediated at least in part by increased drug efflux associated with increased expression of multidrug resistance pump 1 (MDR1) while CD30 expression appears to be preserved in BV resistant cell lines and patient samples. We conducted a phase 1 study evaluating BV + cyclosporine (CsA) in BV-refractory HL and previous reported results in the dose finding cohort. Here we report the final results from the phase 1 study.
This was a phase I trial of BV + CsA in patients with r/r HL with dose-finding and dose escalation cohorts. Eligibility criteria included age ≥ 18 years with r/r HL after at least 1 prior line of therapy. Treatment consisted of 1.8 mg/kg BV intravenously on day 1 and CsA 5 to 7.5 mg/kg PO twice daily on days 1 to 5; cycles were 21 days long. Patients in the expansion cohort had to have cHL refractory to BV. The primary objectives were to evaluate safety and tolerability and to determine MTD of BV + CsA; the secondary objective was to determine efficacy of this combination.
29 patients were enrolled onto the study, 14 in the dose finding cohort and 15 in the dose expansion BV refractory cohort. Study accrual was terminated before target accrual due to unacceptable toxicity. 62% of patients were male, and the median age was 36 years (range: 20-69). The median number of prior therapies was 5 (range: 3-12); all patients had prior BV, and 93% had PD-1 directed therapy, and 93% were BV-refractory. Of 22 evaluable patients, CR rate was 27% and ORR 64%; median DOR 4.9 months. Treatment-related deaths occurred in 3 patients, and another patient died during cycle 1 due to cardiac arrest deemed unlikely related to be protocol therapy. All grade GI toxicity was seen in 90% of patients (G3+ in 24%); other common adverse events were nausea (90%), hypertension (90%), nausea (90%), hypertension (90%), anemia (86%), fatigue (76%), neutropenia (76%), leukopenia (76%), hypomagnesemia (76%), anorexia (66%), and hyponatremia (66%).
BV + CsA demonstrated modest activity in BV-refractory r/r HL; however, toxicity is substantial.
BV 是一种针对 CD30 的抗体药物偶联物，在复发/难治性（R/R）霍奇金淋巴瘤（HL）中安全且有效。大多数接受 r/r cHL 治疗的患者对 BV 单药治疗反应良好；然而，他们中的大多数最终都会对这种药物产生耐药性，BV 耐药性 HL 仍然是一个未满足的需求。临床前数据表明，BV 耐药性至少部分是由与多药耐药泵 1（MDR1）表达增加相关的药物外排增加介导的，而在 BV 耐药细胞系和患者样本中 CD30 表达似乎保持不变。我们进行了一项评估 BV + 环孢素（CsA）在 BV 耐药 HL 中的疗效的 1 期研究，并报告了剂量发现队列的先前结果。在这里，我们报告了 1 期研究的最终结果。
这是一项评估 r/r HL 患者中 BV + CsA 的 1 期试验，包括剂量发现和剂量递增队列。入选标准包括年龄≥18 岁，接受至少 1 线治疗后复发/难治性 HL。治疗包括第 1 天静脉注射 1.8mg/kg BV 和第 1 天至第 5 天口服 5 至 7.5mg/kg CsA，每日 2 次；周期为 21 天。扩展队列中的患者必须对 BV 耐药。主要目的是评估安全性和耐受性，并确定 BV + CsA 的最大耐受剂量；次要目的是确定该联合的疗效。
共有 29 名患者入组，14 名入组剂量发现队列，15 名入组 BV 耐药扩展队列。由于不可接受的毒性，研究入组在目标入组前终止。62%的患者为男性，中位年龄为 36 岁（范围：20-69 岁）。中位治疗线数为 5 条（范围：3-12 条）；所有患者均接受过 BV 治疗，93%的患者接受过 PD-1 靶向治疗，93%的患者对 BV 耐药。22 名可评估患者的 CR 率为 27%，ORR 为 64%；中位 DOR 为 4.9 个月。3 名患者发生治疗相关死亡，另 1 名患者在第 1 周期因心脏骤停死亡，据认为与方案治疗无关。90%的患者出现了全级别的胃肠道毒性（G3+占 24%）；其他常见的不良反应包括恶心（90%）、高血压（90%）、恶心（90%）、高血压（90%）、贫血（86%）、疲劳（76%）、中性粒细胞减少症（76%）、白细胞减少症（76%）、低镁血症（76%）、厌食症（66%）和低钠血症（66%）。
BV + CsA 在 BV 耐药的 r/r HL 中显示出适度的疗效；然而，毒性很大。
