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.

Conclusion:

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.

Zusammenfassung

Hintergrund:

Tyrosinkinase-Inhibitoren (TKIs) verursachen eine Störung des Knochenwachstums, welche entweder durch eine unzurei­chende Wirkung von Wachstumshormon (GH) oder eine Störung des Knochen-„Remodelling“ hervorgerufen wird.

Methoden:

Die Körperlänge und die Parameter Insulin-like growth factor 1 (IGF-1) und Insulin-like growth factor-binding protein 3 (IGFBP-3) wurden über 2 Jahre wiederholt bei 21 pädiatrischen Patienten mit CML bestimmt, die stan­dardisiert mit Imatinib behandelt wurden. Im Tiermodell erhielten 4 Wochen alte Wistar Ratten in unterschiedlichen Konzentrationen mit dem Trinkwasser über 10 Wochen Imatinib, Dasatinib oder Bosutinib. Im präpubertären, pubertären und Erwachsenenalter wurden IGFBP-3 bestimmt.

Resultate:

Unabhängig von der Therapiedauer fanden sich im Vergleich zu altersbezogenen Kontrollen bei den Patienten IGF-1 und IGFBP-3 Serumspiegel durchweg im sehr niedrigen unteren Normalbereich. Im Tierversuch fanden sich im Vergleich zu den Kontrolltieren bei den exponierten Ratten die IGFBP-3-Serumspiegel signifikant erniedrigt.

Schlussfolgerungen:

Neben ungerichteten Effekten am wachsenden Skelett verursachen TKIs auch eine Absenkung der Serumspiegel von IGF-1 und IGFBP-3. Ein juveniles Rattenmodell präjudiziert diese Nebenwirkung für Dasatinib und Bosutinib. Aus diesem Grund sind das Längenwachstum und GH-assoziierte Parameter bei Kindern mit CML unter TKI-Behandlung zu überwachen.

Key words

CML - children - imatinib - growth hormone - growth - juvenile rat model

Schlüsselwörter

CML - Kinder - Imatinib - Wachstumshormon - Längenwachstum - juveniles Rattenmodel

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