Open AccessTemsirolimus combined with cyclophosphamide and etoposide for pediatric patients with relapsed/refractory acute lymphoblastic leukemia: a Therapeutic Advances in Childhood Leukemia Consortium trial (TACL 2014-001)
Author(s) -
Sarah K. Tasian,
Lewis B. Silverman,
James A. Whitlock,
Richard Sposto,
Joseph P. Loftus,
Eric S. Schafer,
Kirk R. Schultz,
Raymond J. Hutchinson,
Paul S. Gay,
Etan Orgel,
Caroline M. Bateman,
Todd M. Cooper,
Theodore W. Laetsch,
Maria Luisa Sulis,
YuehYun Chi,
Jemily Malvar,
Alan S. Wayne,
Susan R. Rheingold
Publication year - 2022
Publication title -
haematologica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.782
H-Index - 142
eISSN - 1592-8721
pISSN - 0390-6078
DOI - 10.3324/haematol.2021.279520
Subject(s) - medicine , temsirolimus , etoposide , mucositis , gastroenterology , cyclophosphamide , leukemia , leukopenia , pharmacology , pi3k/akt/mtor pathway , toxicity , chemotherapy , biology , apoptosis , biochemistry , discovery and development of mtor inhibitors
PI3K/mTOR signaling is commonly dysregulated in acute lymphoblastic leukemia (ALL). The TACL2014-001 phase 1 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 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 (DLT) of grade 4 pleural and pericardial effusions occurred in a patient treated at DL3. Additional DLTs were not seen in the DL3 expansion or DL4 cohort. Grade 3/4 non-hematologic toxicities occurring in ≥3 patients included febrile neutropenia, elevated alanine aminotransferase, hypokalemia, mucositis, and tumor lysis syndrome and occurred across all DLs. Complete responses were observed at all DLs 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. Responses were observed across all DLs. 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.