Andrew E Place1, Yana Pikman1, Kristen E Stevenson2, Marian H Harris3, Melinda Pauly4, Maria-Luisa Sulis5, Nobuko Hijiya6, Lia Gore7, Todd M Cooper8, Mignon L Loh9, Giovanni Roti10, Donna S Neuberg2, Sarah K Hunt1, Sarah Orloff-Parry1, Kimberly Stegmaier1, Stephen E Sallan1, Lewis B Silverman1. 1. Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, Massachusetts. 2. Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts. 3. Department of Pathology, Boston Children's Hospital, Boston, Massachusetts. 4. Department of Pediatrics, Children's Healthcare of Atlanta/Emory University School of Medicine, Atlanta, Georgia. 5. Division of Pediatric Hematology, Oncology, and Stem Cell Transplant, Columbia University, New York City, New York. 6. Division of Hematology, Oncology, and Stem Cell Transplantation, Ann & Robert H. Lurie Children's Hospital/Northwestern University Feinberg School of Medicine, Chicago, Illinois. 7. Section of Hematology, Oncology, and Bone Marrow Transplantation, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, Colorado. 8. Cancer and Blood Disorders Center, Seattle Children's Hospital, Seattle, Washington. 9. Department of Pediatrics, Benioff Children's Hospital, University of California at San Francisco, San Francisco, California. 10. Department of Medicine and Surgery, University of Parma, Parma, Italy.
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 (≤10-3 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. 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.
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 (≤10-3 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. 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.
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