Irreversible growth plate fusions in children with medulloblastoma treated with a targeted hedgehog pathway inhibitor

// Giles W. Robinson 1 , Sue C. Kaste 2 , Wassim Chemaitilly 3 , Daniel C. Bowers 4 , Stephen Laughton 5 , Amy Smith 6 , Nicholas G. Gottardo 7 , Sonia Partap 8 , Anne Bendel 9 , Karen D. Wright 10 , Brent A. Orr 11 , William C. Warner 12 , Arzu Onar-Thomas 13 and Amar Gajjar 1 1 Department of Oncology, Division of Neuro-Oncology, St. Jude Children’s Research Hospital, Memphis, TN, USA 2 Department of Radiological Sciences, Division of Diagnostic Imaging, St. Jude Children’s Research Hospital, Memphis, TN, USA 3 Department of Pediatric Medicine, Division of Endocrinology, St. Jude Children’s Research Hospital, Memphis, TN, USA 4 Division of Pediatric Hematology and Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA 5 Starship Blood and Cancer Centre, Starship Children’s Hospital, Auckland, NZ, USA 6 Division of Pediatric Hematology/Oncology, The Haley Center for Children’s Cancer and Blood Disorders at Arnold Palmer Hospital, Orlando, FL, USA 7 Department of Haematology and Oncology, Princess Margaret Hospital for Children, School of Paediatrics and Child Health, Telethon Kids Cancer Centre, Telethon Kids Institute, University of Western Australia, Perth, Western Australia, Australia 8 Department of Neurology, Division of Child Neurology, Lucile Packard Children’s Hospital at Stanford, Stanford University, Palo Alto, CA, USA 9 Cancer and Blood Disorders Program, Children’s Hospitals and Clinics of Minnesota, Minneapolis, MN, USA 10 Pediatric Medical Neuro-Oncology, Dana-Farber Boston Children’s Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA, USA 11 Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN, USA 12 Department of Orthopedic Surgery, Campbell Clinic, University of Tennessee College of Medicine, Germantown, TN, USA 13 Department of Biostatistics, St. Jude Children’s Research Hospital, Memphis, TN, USA Correspondence to: Giles W. Robinson, email: // Keywords : premature physeal fusion, medulloblastoma, hedgehog inhibitor, targeted therapy, childhood toxicity Received : August 16, 2017 Accepted : August 21, 2017 Published : September 01, 2017 Abstract The permanent defects in bone growth observed in preclinical studies of hedgehog (Hh) pathway inhibitors were not substantiated in early phase clinical studies of vismodegib in children. Consequently, vismodegib advanced into pediatric trials for malignancies suspected of being driven by aberrant activation of the Hh pathway. In one multicenter phase II trial, vismodegib was added to the therapy regimen for newly diagnosed Hh pathway activated medulloblastoma. Herein, we report on 3 children (2 on trial and one off trial) treated with vismodegib who developed widespread growth plate fusions that persist long after cessation of therapy. Currently, all 3 patients exhibit profound short stature and disproportionate growth, and 2 subsequently developed precocious puberty. Notably, the growth plate fusions only developed after a prolonged exposure to the drug (> 140 days). These findings resulted in a major trial amendment to restrict the agent to skeletally mature patients as well as a product label warning and update. Moreover, these findings alter the risk-benefit ratio of Hh inhibitors and underscore the importance of careful study of targeted agents in children.