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Place, Andrew E.; Pikman, Yana; Stevenson, Kristen E.; Harris, Marian H.; Pauly, Melinda; Sulis, Maria‐Luisa; Hijiya, Nobuko; Gore, Lia; Cooper, Todd M.; Loh, Mignon L.; Roti, Giovanni; Neuberg, Donna S.; Hunt, Sarah K.; Orloff‐Parry, Sarah; Stegmaier, Kimberly; Sallan, Stephen E.; Silverman, Lewis B.

Phase I trial of the mTOR inhibitor everolimus in combination with multi‐agent chemotherapy in relapsed childhood acute lymphoblastic leukemia

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  • Medientyp: E-Artikel
  • Titel: Phase I trial of the mTOR inhibitor everolimus in combination with multi‐agent chemotherapy in relapsed childhood acute lymphoblastic leukemia
  • Beteiligte: Place, Andrew E.; Pikman, Yana; Stevenson, Kristen E.; Harris, Marian H.; Pauly, Melinda; Sulis, Maria‐Luisa; Hijiya, Nobuko; Gore, Lia; Cooper, Todd M.; Loh, Mignon L.; Roti, Giovanni; Neuberg, Donna S.; Hunt, Sarah K.; Orloff‐Parry, Sarah; Stegmaier, Kimberly; Sallan, Stephen E.; Silverman, Lewis B.
  • Erschienen: Wiley, 2018
  • Erschienen in: Pediatric Blood & Cancer
  • Sprache: Englisch
  • DOI: 10.1002/pbc.27062
  • ISSN: 1545-5009; 1545-5017
  • Schlagwörter: Oncology ; Hematology ; Pediatrics, Perinatology and Child Health
  • Entstehung:
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  • Beschreibung: <jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>We sought to determine the feasibility of co‐administering everolimus with a four‐drug reinduction in children and adolescents with acute lymphoblastic leukemia (ALL) experiencing a first marrow relapse.</jats:p></jats:sec><jats:sec><jats:title>Procedure</jats:title><jats:p>This phase I study tested everolimus with vincristine, prednisone, pegaspargase and doxorubicin in patients with marrow relapse occurring &gt;18 months after first complete remission (CR). The primary aim was to identify the maximum tolerated dose of everolimus. Three dose levels (DLs) were tested during dose escalation (2, 3, and 5 mg/m<jats:sup>2</jats:sup>/day). Additional patients were enrolled at the 3‐ and 5 mg/m<jats:sup>2</jats:sup>/day DLs to further evaluate toxicity (dose expansion).</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Thirteen patients enrolled during dose escalation and nine during dose expansion. During dose escalation, one dose‐limiting toxicity occurred (grade 4 hyperbilirubinemia) in six evaluable patients at DL3 (5 mg/m<jats:sup>2</jats:sup>/day). The most common grade ≥3 adverse events were febrile neutropenia, infections, transaminitis, hyperbilirubinemia, and hypophosphatemia. Two of the 12 patients treated at DL3 developed <jats:italic>Rothia mucilaginosa</jats:italic> meningitis. Nineteen patients (86%) achieved a second CR (CR2). Of those, 13 (68%) had a low end‐reinduction minimal residual disease (MRD) level (≤10<jats:sup>−3</jats:sup> by polymerase chain reaction–based assay). The CR2 rate for patients with B‐cell ALL treated at DL3 (n = 12) was 92%; 82% of these patients had low MRD.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Everolimus combined with four‐drug reinduction chemotherapy was generally well tolerated and associated with favorable rates of CR2 and low end‐reinduction MRD. The recommended phase 2 dose of everolimus given in combination with a four‐drug reinduction is 5 mg/m<jats:sup>2</jats:sup>/day. This promising combination should be further evaluated in a larger patient cohort.</jats:p></jats:sec>