期刊
BRITISH JOURNAL OF HAEMATOLOGY
卷 177, 期 3, 页码 467-474出版社
WILEY
DOI: 10.1111/bjh.14569
关键词
acute lymphoblastic leukaemia; mTOR inhibitor; clinical trials; pharmacodynamics; relapse
类别
资金
- National Institutes of Health/National Cancer Institute [U01 CA97452, UM1 CA097452]
- Children's Oncology Group [K12CA076931, K08CA18441]
- Rally Foundation for Childhood Cancer Research
- Leukemia & Lymphoma Society
- Cookies for Kids' Cancer Foundation
- Children's Oncology Group Foundation
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 10mg/m(2) weeklyx3 doses. Subsequent patient cohorts received temsirolimus 75mg/m(2) weeklyx3 doses (DL0) or, secondary to toxicity, 75mg/m(2) weeklyx2 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 <001%. 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.
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