Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia; Philadelphia, PA, USA; Perelman School of Medicine at the University of Pennsylvania; Philadelphia, PA.
Department of Pediatric Oncology, Dana-Farber Cancer Institute and Division of Pediatric Hematology-Oncology, Boston Children's Hospital; Boston, MA.
Haematologica. 2022 Oct 1;107(10):2295-2303. doi: 10.3324/haematol.2021.279520.
Phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling is commonly dysregulated in acute lymphoblastic leukemia (ALL). The TACL2014-001 phase I trial of the mTOR inhibitor temsirolimus in combination with cyclophosphamide and etoposide was performed in children and adolescents with relapsed/refractory ALL. Temsirolimus was administered intravenously (IV) on days 1 and 8 with cyclophosphamide 440 mg/m2 and etoposide 100 mg/m2 IV daily on days 1-5. The starting dose of temsirolimus was 7.5 mg/m2 (DL1) with escalation to 10 mg/m2 (DL2), 15 mg/m2 (DL3), and 25 mg/m2 (DL4). PI3K/mTOR pathway inhibition was measured by phosphoflow cytometry analysis of peripheral blood specimens from treated patients. Sixteen heavily-pretreated patients were enrolled with 15 evaluable for toxicity. One dose-limiting toxicity of grade 4 pleural and pericardial effusions occurred in a patient treated at DL3. Additional dose-limiting toxicities were not seen in the DL3 expansion or DL4 cohort. Grade 3/4 non-hematologic toxicities occurring in three or more patients included febrile neutropenia, elevated alanine aminotransferase, hypokalemia, mucositis, and tumor lysis syndrome and occurred across all doses. Response and complete were observed at all dose levels with a 47% overall response rate and 27% complete response rate. Pharmacodynamic correlative studies demonstrated dose-dependent inhibition of PI3K/mTOR pathway phosphoproteins in all studied patients. Temsirolimus at doses up to 25 mg/m2 with cyclophosphamide and etoposide had an acceptable safety profile in children with relapsed/refractory ALL. Pharmacodynamic mTOR target inhibition was achieved and appeared to correlate with temsirolimus dose. Future testing of next-generation PI3K/mTOR pathway inhibitors with chemotherapy may be warranted to increase response rates in children with relapsed/refractory ALL.
磷酸肌醇 3-激酶（PI3K）/哺乳动物雷帕霉素靶蛋白（mTOR）信号在急性淋巴细胞白血病（ALL）中通常失调。TACL2014-001 期试验是在复发性/难治性 ALL 患儿和青少年中进行的 mTOR 抑制剂替西罗莫司联合环磷酰胺和依托泊苷的研究。替西罗莫司于第 1 天和第 8 天静脉内（IV）给药，环磷酰胺 440mg/m2 ，依托泊苷 100mg/m2 每日 IV 给药于第 1-5 天。替西罗莫司的起始剂量为 7.5mg/m2（DL1），递增至 10mg/m2（DL2）、15mg/m2（DL3）和 25mg/m2（DL4）。通过磷酸化流式细胞术分析治疗患者的外周血标本来测量 PI3K/mTOR 通路抑制。入组了 16 例预处理过的患者，其中 15 例可评估毒性。1 例患者在 DL3 时发生了 4 级胸腔和心包积液的剂量限制毒性。在 DL3 扩展或 DL4 队列中未观察到其他剂量限制毒性。在 3 例或更多患者中发生的 3/4 级非血液学毒性包括发热性中性粒细胞减少症、丙氨酸氨基转移酶升高、低钾血症、黏膜炎和肿瘤溶解综合征，所有剂量均发生。在所有剂量水平均观察到缓解和完全缓解，总缓解率为 47%，完全缓解率为 27%。药效学相关研究表明，所有研究患者的 PI3K/mTOR 通路磷酸化蛋白均呈剂量依赖性抑制。替西罗莫司联合环磷酰胺和依托泊苷的剂量高达 25mg/m2，在复发性/难治性 ALL 儿童中具有可接受的安全性。实现了药效学 mTOR 靶标抑制，并且似乎与替西罗莫司剂量相关。为了提高复发性/难治性 ALL 儿童的缓解率，可能需要进一步检测下一代 PI3K/mTOR 通路抑制剂联合化疗。
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