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Helping children with growth failure due to tyrosine kinase inhibitor drugs requires knowledge of the pathogenesis of the problem

The recent review by Samis et al.1 confirms that imatinib and dasatinib inhibit longitudinal growth of children. The prevention of this important complication, ignored by the official documentation of these drugs,2 requires clarification of its causes. The authors raise the possibility that osseous andmetaphyseal dysfunctionmaybe themain cause of this complication, suggesting the failure of the growth hormone– insulin-like growth factor 1 (GH–IGF-1) axis as the potential mechanism. In our view, the available data do not support this hypothesis. Decreased recruitment and activity of chondrocytes in the growth plate, closure of this structure, and low bone density3,4 are side effects that may account for the early decline of growth in the majority of treated children. However, osseous and metaphyseal disorders often appear as different conditions: children with poor growth have a moderate delay in bone maturation, but they do not show bone or cartilage abnormalities. In addition, the chronology of both afflictions is different: slow growth is observed in the first months of treatment with TKIs,5 and persists (if the treatment does) throughout prepubertal life. Bone and growth plate abnormalities are late in pubertal age.4 Further, children with growth failure experience a sharp growth spurt during puberty (although they do not reach their genetic height), with the progressive closure of the growth plate. Metaphyseal disorders seem toworsen at this age.6 Children on treatment with TKIs suffer from disruption of the GH– IGF-1 axis, a combination of growth hormone deficiency and insensitivity, with inhibition of IGF-1 production and downstream signal transmission.7 This complex condition can account for the growth disorder of these patients,7,8 who, nevertheless, experience an unexplained pubertal growth improvement. The pubertal growth spurt is due to the action of sex steroids, along with more extensive, intense, and numerous GH pulses than during prepubertal age. Samis et al.1 hypothesize that the outbreak of pubertal growth in children treated with TKIs may be due to increased production of GH, which overcomes the resistance induced by drugs. The disruption of the GH–IGF-1 axis by TKIs is more complex than amere GH resistance. Growth reactivation at puberty is more likely to be due to increased steroid production. Activation of sex steroidmembrane receptors and cross-talk between nuclear steroid receptors and membrane-bound G protein receptors (steroid nongenomic actions) activate the drug-inhibited pathways.9 Each of the cited mechanisms suggests different therapeutic measures. However, withdrawal of the TKIs is not an option. Likewise, the risk of administering recombinant somatropin to patients with active cancer may not be advisable, but administration of sex steroids with limited androgenic action carry a much lower therapeutic risk. In any case, controlled clinical trials are necessary.