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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).
Tasian, Sarah K; Silverman, Lewis B; Whitlock, James A; Sposto, Richard; Loftus, Joseph P; Schafer, Eric S; Schultz, Kirk R; Hutchinson, Raymond J; Gaynon, Paul S; Orgel, Etan; Bateman, Caroline M; Cooper, Todd M; Laetsch, Theodore W; Sulis, Maria Luisa; Chi, Yueh-Yun; Malvar, Jemily; Wayne, Alan S; Rheingold, Susan R.
Afiliación
  • Tasian SK; Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia; Philadelphia, PA, USA; Perelman School of Medicine at the University of Pennsylvania; Philadelphia, PA.
  • Silverman LB; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Division of Pediatric Hematology-Oncology, Boston Children's Hospital; Boston, MA.
  • Whitlock JA; Division of Haematology/Oncology, Hospital for Sick Children and the University of Toronto; Toronto, ON.
  • Sposto R; Department of Preventive Medicine, Keck School of Medicine, University of Southern California; Los Angeles, CA.
  • Loftus JP; Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia; Philadelphia, PA.
  • Schafer ES; Dan L. Duncan Institute for Clinical and Translational Research, Baylor College of Medicine and Texas Children's Cancer Center; Houston, TX.
  • Schultz KR; Division of Hematology/Oncology/Bone Marrow Transplant, British Columbia Children's Hospital; Vancouver, BC.
  • Hutchinson RJ; Division of Hematology/Oncology, CS Mott Children's Hospital; Ann Arbor, MI.
  • Gaynon PS; Division of Hematology/Oncology, Children's Hospital Los Angeles, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California; Los Angeles, CA.
  • Orgel E; Division of Hematology/Oncology, Children's Hospital Los Angeles, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California; Los Angeles, CA.
  • Bateman CM; Cancer Centre for Children, The Children's Hospital at Westmead; Westmead, NSW.
  • Cooper TM; Division of Hematology/Oncology, Seattle Children's Hospital Cancer and Blood Disorders Center; Seattle, WA.
  • Laetsch TW; Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia; Philadelphia, PA, USA; Perelman School of Medicine at the University of Pennsylvania; Philadelphia, PA.
  • Sulis ML; Department of Pediatrics, Memorial Sloan Kettering Cancer Center; New York, NY.
  • Chi YY; Division of Hematology/Oncology, Children's Hospital Los Angeles, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California; Los Angeles, CA.
  • Malvar J; Division of Hematology/Oncology, Children's Hospital Los Angeles, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California; Los Angeles, CA.
  • Wayne AS; Division of Hematology/Oncology, Children's Hospital Los Angeles, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California; Los Angeles, CA.
  • Rheingold SR; Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia; Philadelphia, PA, USA; Perelman School of Medicine at the University of Pennsylvania; Philadelphia, PA. rheingold@chop.edu.
Haematologica ; 107(10): 2295-2303, 2022 10 01.
Article en En | MEDLINE | ID: mdl-35112552
Phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling is commonly dysregulated in acute lymphoblastic leukemia (ALL). The TACL2014-001 phase I 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 on 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 of grade 4 pleural and pericardial effusions occurred in a patient treated at DL3. Additional dose-limiting toxicities were not seen in the DL3 expansion or DL4 cohort. Grade 3/4 non-hematologic toxicities occurring in three or more patients included febrile neutropenia, elevated alanine aminotransferase, hypokalemia, mucositis, and tumor lysis syndrome and occurred across all doses. Response and complete were observed at all dose levels 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. 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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Protocolos de Quimioterapia Combinada Antineoplásica / Leucemia-Linfoma Linfoblástico de Células Precursoras Límite: Adolescent / Child / Humans Idioma: En Revista: Haematologica Año: 2022 Tipo del documento: Article Pais de publicación: Italia

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Protocolos de Quimioterapia Combinada Antineoplásica / Leucemia-Linfoma Linfoblástico de Células Precursoras Límite: Adolescent / Child / Humans Idioma: En Revista: Haematologica Año: 2022 Tipo del documento: Article Pais de publicación: Italia