Children's Hospital of Wisconsin, Milwaukee, Wisconsin, USA.
Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
Pediatr Blood Cancer. 2022 Dec;69(12):e29999. doi: 10.1002/pbc.29999. Epub 2022 Oct 10.
Acute lymphoblastic leukemia (ALL) is the most common cancer diagnosed in childhood. Survival for patients following relapse remains poor, and achieving complete remission (CR) after relapse is the first critical step to cure. Carfilzomib is a proteasome inhibitor with an acceptable safety profile and clinical activity in adults with multiple myeloma but has not been assessed in children. The primary objective of this phase 1b study was to assess the safety and tolerability of carfilzomib combined with vincristine, dexamethasone, asparaginase, and daunorubicin (VXLD) in children with relapsed and/or refractory ALL.
Patients aged 1-21 years (n = 24) received 4-week induction therapy with carfilzomib at dose levels of 27 mg/m (n = 3), 36 mg/m (n = 7), 45 mg/m (n = 4), and 56 mg/m (n = 10) in combination with VXLD. Patients achieving stable disease were offered further consolidation chemotherapy. Analyses were based on the safety evaluable population.
Following dose escalation of carfilzomib, the recommended phase 2 carfilzomib dose was identified as 56 mg/m . Grade ≥3 hematological adverse events were common (83%, 20/24 patients), and serious treatment-emergent adverse events occurred in 58% (14/24) of patients. At the end of induction, CR/CR with incomplete platelet recovery (CRp)/CR with incomplete blood count recovery (CRi) was identified in 50% of patients (n = 12/24). By the end of consolidation, cumulative CR/CRp/CRi was identified in 58% of patients (n = 14/24).
These data support the use of carfilzomib in pediatric patients with relapsed and/or refractory ALL.
急性淋巴细胞白血病（ALL）是儿童中最常见的癌症。复发后患者的生存仍然很差，并且在复发后实现完全缓解（CR）是治愈的第一步。卡非佐米是一种蛋白酶体抑制剂，在多发性骨髓瘤成人患者中具有可接受的安全性和临床活性，但尚未在儿童中进行评估。这项 1b 期研究的主要目的是评估卡非佐米联合长春新碱、地塞米松、门冬酰胺酶和柔红霉素（VXLD）在复发和/或难治性 ALL 患儿中的安全性和耐受性。
年龄在 1-21 岁（n=24）的患者接受了 4 周的诱导治疗，用卡非佐米剂量水平为 27mg/m（n=3）、36mg/m（n=7）、45mg/m（n=4）和 56mg/m（n=10）联合 VXLD。达到稳定疾病的患者接受了进一步的巩固化疗。分析基于安全性可评估人群。
在卡非佐米剂量递增后，确定了推荐的 2 期卡非佐米剂量为 56mg/m。≥3 级血液学不良事件常见（83%，24 例患者中的 20 例），58%（24 例患者中的 14 例）的患者发生严重治疗后不良事件。在诱导结束时，50%（24 例患者中的 12 例）的患者达到完全缓解/不完全血小板恢复的完全缓解（CR/CRp）/不完全血细胞计数恢复的完全缓解（CRi）。在巩固结束时，58%（24 例患者中的 14 例）的患者达到累积 CR/CRp/CRi。
这些数据支持在复发和/或难治性 ALL 患儿中使用卡非佐米。
