A phase 1 trial of temsirolimus and intensive re-induction chemotherapy for 2nd or greater relapse of acute lymphoblastic leukaemia: a Children's Oncology Group study (ADVL1114)

Susan R. Rheingold, Sarah J. Tasian, James A. Whitlock, David T. Teachey, Michael J. Borowitz, Xiaowei Liu, Charles G. Minard, Elizabeth Fox, Brenda J. Weigel, Susan M. Blaney

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

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/m2 weekly × 3 doses. Subsequent patient cohorts received temsirolimus 7·5 mg/m2 weekly × 3 doses (DL0) or, secondary to toxicity, 7·5 mg/m2 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.

Original languageEnglish (US)
Pages (from-to)467-474
Number of pages8
JournalBritish journal of haematology
Volume177
Issue number3
DOIs
StatePublished - May 2017

Bibliographical note

Funding Information:
We would like to thank Charlotte Ahern for her contributions to this work. Research reported in this publication was supported by National Institutes of Health/National Cancer Institute awards U01 CA97452 and UM1 CA097452 to the Children's Oncology Group and K12CA076931 and K08CA18441, the Rally Foundation for Childhood Cancer Research, the Leukemia & Lymphoma Society, the Cookies for Kids? Cancer Foundation and the Children's Oncology Group Foundation.

Publisher Copyright:
© 2017 John Wiley & Sons Ltd

Keywords

  • acute lymphoblastic leukaemia
  • clinical trials
  • mTOR inhibitor
  • pharmacodynamics
  • relapse

Fingerprint

Dive into the research topics of 'A phase 1 trial of temsirolimus and intensive re-induction chemotherapy for 2nd or greater relapse of acute lymphoblastic leukaemia: a Children's Oncology Group study (ADVL1114)'. Together they form a unique fingerprint.

Cite this