Temsirolimus 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)

Abstract

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.

A phase 2 and pharmacological study of sapanisertib in patients with relapsed and/or refractory acute lymphoblastic leukemia

“…DLTs included mucositis, hypertriglyceridemia, elevated liver enzymes, hypertension, and sepsis. In a subsequent study, r/r pediatric ALL patients were treated with cyclophosphamide, etoposide, and temsirolimus 43 . Among 15 patients, one DLT (grade 4 pleural and pericardial effusion) was observed.…”

Novel pharmacological and dietary approaches to target mTOR in B-cell acute lymphoblastic leukemia

“…Dephosphorylation of 4E-BP1 reactivates its ability to disrupt the eIF4F translation initiation complex and suppress cap-dependent translation of mRNAs with key roles in proliferation and survival (35)(36)(37). Clinical studies of rapalogs added to chemotherapy have not clearly improved outcome in B-ALL (38)(39)(40)(41). Second generation ATP-competitive mTOR inhibitors that completely inhibit both mTORC1 and mTORC2 (mTOR kinase inhibitors; TOR-KI) are more effective at causing dephosphorylation of 4E-BP1 to restore inhibition of eIF4F assembly (Figure 1B).…”

Children's Oncology Group blueprint for research: Acute lymphoblastic leukemia

“…The remarkable improvement in EFS and OS of children with Ph+ ALL when TKI is added to multiagent chemotherapy 33–36 has established a new paradigm for clinical investigation of precision medicine therapies for other high‐risk “boutique” subtypes of ALL. Several early‐phase clinical trials have studied mTOR inhibition in children with relapsed B‐ALL or T‐ALL given general constitutive activation of PI3K pathway signaling and/or PTEN mutations, 37,38 although toxicity of these drugs in combination with specific chemotherapy agents has been reported 39–41 . Preclinical data have suggested therapeutic potential of JAK inhibition in T‐ALL and Down syndrome (DS)‐associated B‐ALL, 42,43 BTK or SRC/ABL inhibition in TCF3::PBX1 B‐ALL, 38,44 FLT3 inhibition in TCF3 :: ZNF384 B‐ALL, 45,46 BCL‐2 and Aurora kinase A inhibition in TCF3::HLF B‐ALL, 47,48 and BCL‐2 inhibition in hypodiploid B‐ALL, 49 although such approaches have been variably studied in the clinic.…”

“…Several early-phase clinical trials have studied mTOR inhibition in children with relapsed B-ALL or T-ALL given general constitutive activation of PI3K pathway signaling and/or PTEN mutations, 37,38 although toxicity of these drugs in combination with specific chemotherapy agents has been reported. [39][40][41] Preclinical data have suggested therapeutic potential of JAK inhibition in T-ALL and Down syndrome (DS)-associated B-ALL, 42,43 BTK or SRC/ABL inhibition in TCF3::PBX1 B-ALL, 38,44 FLT3 inhibition in TCF3::ZNF384 B-ALL, 45,46 BCL-2 and Aurora kinase A inhibition in TCF3::HLF B-ALL, 47,48 and BCL-2 inhibition in hypodiploid B-ALL, 49 although such approaches have been variably studied in the clinic. Although subclonal NRAS and KRAS mutations are common in various ALL subtypes at both diagnosis and relapse, 50,51 it is unknown whether MEK inhibitors will influence clinical outcomes substantially.…”