Bone Abstracts

Background: The tyrosine kinase inhibitor (TKI) imatinib is applied as front-line treatment in adult and pediatric patients with chronic myeloid leukemia (CML) in order to selectively inhibit the causative oncogenic BCR-ABL1 tyrosine kinase. However, TKIs exhibit off-target effects on further kinases involved in the regulation of bone metabolism. As consequence, pediatric patients display longitudinal growth retardation while on imatinib treatment. As CML is a rare disease in children, growth experiences are limited so far (Millot F 2009 Blood; Shima H 2011 Pediatrics). Therefore, we examined longitudinal growth in a pediatric CML cohort and also established a juvenile rat model to investigate side effects of long-term TKI exposure on the growing skeleton.

Methods: 102 CML patients (54♂/48♀) receiving upfront imatinib were enrolled in growth analysis using height SDS. The animal model comprises male Wistar rats which starting at the age of 4 weeks (w) were continuously or intermittently exposed to TKI at varying dosages over 10w. After defined time intervals of exposure (after 2w, prepubertal stage; 4w, pubertal stage; 10w, postpubertal stage, respectively), rats were sacrificed and bone parameters and osseous metabolism were investigated.

Results: A mean decrease in height of 0.48 SDS per year (y) during the first 2 years of imatinib treatment was observed, with prepubertal patients being more severely affected (−0.75 SDS/y) compared to pubertal teenagers (−0.02 SDS/y). The juvenile animal model demonstrated altered osseous parameters (bone length, trabecular BMD, bone strength) predominantly in long bones compared to vertebrae. Dose-dependently decreased osteocalcin- and TRAP-serum levels were observed. Intermittent treatment minimized osseous and biochemical changes.

Conclusion: Growth retardation is a significant adverse effect of TKI treatment in pediatric patients, which could be uniformly modeled in juvenile rats. In addition, high-dose, long-term TKI exposure in rats predicts an increased fracture risk. Skeletal side effects were reduced by intermittent treatment thus possibly reflecting a new therapeutic option. Ongoing investigations on next-generation TKI revealed identical osseous alterations with dasatinib, whereas bosutinib exhibited milder changes. Presently, TKI administration is considered a life-long treatment thus requiring regular monitoring of skeletal side effects under long-term exposure.

Acknowledgement: Funded by DFG-grant SU122-3/1.

Disclosure: The authors declared no competing interests.