Rheingold Susan R, Tasian Sarah K, Whitlock James A, Teachey David T, Borowitz Michael J, Liu Xiaowei, Minard Charles G, Fox Elizabeth, Weigel Brenda J, Blaney Susan M
Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Division of Haematology/Oncology, Hospital for Sick Children, Toronto, ON, Canada.
Br J Haematol. 2017 May;177(3):467-474. doi: 10.1111/bjh.14569. Epub 2017 Mar 14.
The phosphatidylinositol 3-kinase (PI3K)/mammalian (or mechanistic) target of rapamycin (mTOR) signalling pathway is commonly dysregulated in acute lymphoblastic leukaemia (ALL). A phase 1 trial of the mTOR inhibitor temsirolimus in combination with UKALL R3 re-induction chemotherapy was conducted in children and adolescents with second or greater relapse of ALL. The initial temsirolimus dose level (DL1) was 10 mg/m weekly × 3 doses. Subsequent patient cohorts received temsirolimus 7·5 mg/m weekly × 3 doses (DL0) or, secondary to toxicity, 7·5 mg/m weekly × 2 doses (DL-1). Sixteen patients were enrolled, 15 were evaluable for toxicity. Dose-limiting toxicity (DLT) occurred at all three dose levels and included hypertriglyceridaemia, mucositis, ulceration, hypertension with reversible posterior leucoencephalopathy, elevated gamma-glutamyltransferase or alkaline phosphatase and sepsis. The addition of temsirolimus to UKALL R3 re-induction therapy resulted in excessive toxicity and was not tolerable in children with relapsed ALL. However, this regimen induced remission in seven of fifteen patients. Three patients had minimal residual disease levels <0·01%. Inhibition of PI3K signalling was detected in patients treated at all dose levels of temsirolimus, but inhibition at an early time point did not appear to correlate with clinical responses at the end of re-induction therapy.
磷脂酰肌醇3激酶（PI3K）/哺乳动物雷帕霉素靶蛋白（mTOR）信号通路在急性淋巴细胞白血病（ALL）中通常失调。一项mTOR抑制剂坦西莫司联合UKALL R3再诱导化疗的1期试验在ALL复发二次或更多次的儿童和青少年中进行。坦西莫司初始剂量水平（DL1）为10mg/m²每周×3剂。随后的患者队列接受坦西莫司7.5mg/m²每周×3剂（DL0），或因毒性而接受7.5mg/m²每周×2剂（DL - 1）。共纳入16例患者，15例可评估毒性。所有三个剂量水平均出现剂量限制性毒性（DLT），包括高甘油三酯血症、粘膜炎、溃疡、伴有可逆性后部白质脑病的高血压、γ-谷氨酰转移酶或碱性磷酸酶升高以及败血症。在UKALL R3再诱导治疗中添加坦西莫司导致毒性过大，复发ALL儿童无法耐受。然而，该方案在15例患者中有7例诱导缓解。3例患者的微小残留病水平<0.01%。在接受所有坦西莫司剂量水平治疗的患者中均检测到PI3K信号传导受到抑制，但早期抑制似乎与再诱导治疗结束时的临床反应无关。
