Background: 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. Procedure: This phase I study tested everolimus with vincristine, prednisone, pegaspargase and doxorubicin in patients with marrow relapse occurring >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/m2/day). Additional patients were enrolled at the 3- and 5 mg/m2/day DLs to further evaluate toxicity (dose expansion). Results: 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/m2/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 Rothia mucilaginosa meningitis. Nineteen patients (86%) achieved a second CR (CR2). Of those, 13 (68%) had a low end-reinduction minimal residual disease (MRD) level (≤10−3by 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. Conclusions: 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/m2/day. This promising combination should be further evaluated in a larger patient cohort.

Phase I trial of the mTOR inhibitor everolimus in combination with multi-agent chemotherapy in relapsed childhood acute lymphoblastic leukemia / 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.. - In: PEDIATRIC BLOOD & CANCER. - ISSN 1545-5009. - 65:7(2018), p. e27062. [10.1002/pbc.27062]

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

Roti, Giovanni;
2018-01-01

Abstract

Background: 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. Procedure: This phase I study tested everolimus with vincristine, prednisone, pegaspargase and doxorubicin in patients with marrow relapse occurring >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/m2/day). Additional patients were enrolled at the 3- and 5 mg/m2/day DLs to further evaluate toxicity (dose expansion). Results: 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/m2/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 Rothia mucilaginosa meningitis. Nineteen patients (86%) achieved a second CR (CR2). Of those, 13 (68%) had a low end-reinduction minimal residual disease (MRD) level (≤10−3by 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. Conclusions: 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/m2/day. This promising combination should be further evaluated in a larger patient cohort.
Phase I trial of the mTOR inhibitor everolimus in combination with multi-agent chemotherapy in relapsed childhood acute lymphoblastic leukemia / 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.. - In: PEDIATRIC BLOOD & CANCER. - ISSN 1545-5009. - 65:7(2018), p. e27062. [10.1002/pbc.27062]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11381/2849499
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