title: TK inhibitor treatment disrupts growth hormone axis: clinical observations in children with CML and experimental data from a juvenile animal model.
abstract: BACKGROUND
  Long-term treatment of chronic myeloid leukemia (CML) with tyrosine kinase inhibitors (TKIs) exerts off-target effects on bone growth by either impaired growth hormone (GH) action or osseous modelling impairment.
  
  
  METHODS
  Body height and the GH-related parameters insulin-like growth factor 1 (IGF-1) and insulin-like growth factor-binding protein 3(IGFBP-3) were determined repetitively 3-monthly over 2 years in 21 pediatric CML-patients on standardized imatinib treatment. In an animal model 4-week-old male Wistar rats were exposed over 10 weeks to imatinib, dasatinib, or bosutinib at varying concentrations via the drinking water. Blood was collected at prepubertal age, pubertal age, and at adult age, respectively, and animals' serum levels of IGFBP-3 were measured.
  
  
  RESULTS
  Independent from treatment duration patients exhibited IGF-1 and IGFBP-3 levels almost exclusively in the very low range when compared to age-matched references. No clear pattern of rising or falling IGF-1 and IGFBP-3 levels was observed. In rats, compared to controls, serum IGFBP-3 was significantly lowered for all TKIs tested, at all concentrations applied, and at all ages under investigation.
  
  
  CONCLUSIONS
  Besides direct off-target effects on the growing skeleton, TKI treatment also results in lowered blood levels of IGF-1 and IGFBP-3.A juvenile rat model predicts this side effect for dasatinib and bosutinib. Thus, growth and GH- related parameters should be monitored regularly in pediatric patients with CML on TKIs.
authors.affiliation: Pediatric Hematology and Oncology, Department of Pediatrics, University Hospital "Carl Gustav Carus", Dresden, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Ulmer
authors.forename: J
authors.initials: J
authors.lastname: Tabea Tauer
authors.forename: I
authors.initials: I
authors.lastname: Glauche
authors.forename: R
authors.initials: R
authors.lastname: Jung
authors.forename: M
authors.initials: M
authors.lastname: Suttorp
mesh_terms: D000293:Adolescent; D000818:Animals; D000831:Animals, Newborn; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use*; D001549:Benzamides / Q000009:adverse effects* / Q000627:therapeutic use*; D001827:Body Height / Q000187:drug effects; D001846:Bone Development / Q000187:drug effects; D002648:Child; D004195:Disease Models, Animal; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D000068877:Imatinib Mesylate; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000097:blood*; D007334:Insulin-Like Growth Factor I / Q000502:physiology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000503:physiopathology*; D008297:Male; D010879:Piperazines / Q000009:adverse effects* / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use*; D011743:Pyrimidines / Q000009:adverse effects* / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; C515497:IGFBP3 protein, human; D018972:Insulin-Like Growth Factor Binding Protein 3; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D007334:Insulin-Like Growth Factor I; D000068877:Imatinib Mesylate