Growth Retardation and Adult Height in Children with Chronic Myeloid Leukemia Treated with Tyrosine Kinase Inhibitors
Authors: Shima Haruko , Tono Chikako , Tanizawa Akihiko , Ito Masaki , Watanabe Akihiro , Yuza Yuki , Hamamoto Kazuko , Muramatsu Hideki , Okada Masahiko , Saito Shoji , Goto Hiroaki , Imamura Masaru , Saito Akiko M , Adachi Souichi , Ishii Eiichi , Shimada Hiroyuki 
Published: December 2024

Background: Tyrosine kinase inhibitors (TKIs) are known to have an impact on growth in children with chronic myeloid leukemia (CML). While these patients show catch-up growth during puberty, the extent of catch-up and the long-term impact of TKI exposure on adult height remain poorly understood.
Methods: We prospectively collected data from children diagnosed with chronic phase CML enrolled in the Japan Pediatric Leukemia and Lymphoma Study Group (JPLSG) CML-08 study. Height data were collected annually beginning two years before diagnosis. Adult height was defined as the maximum height measured when the height increase velocity was &lt;1 cm/year. Height-standard deviation scores (SDS) were adjusted using age- and sex-adjusted Japanese norms. Puberty was defined as a testicular size ≥3 mL for males and breast Tanner 2 for females. Peak height velocity was defined as the increase in height velocity during the growth spurt, and age at peak height velocity was calculated from the growth curves. Parental height data were collected to calculate target height (TH) and target range (TR).
Results: Sixty-four patients were eligible for inclusion in our study. The median ages at CML diagnosis and analysis in this study were 11 (range, 1-15) years and 18 (range, 8-24) years, respectively. Forty-two patients were males, and 32 patients were prepubertal at diagnosis. The median follow-up duration was 71 (range, 45-103) months. Among the 53 patients with height data prior to TKI initiation, a significant decrease in height-SDS was evident post-TKI initiation in both prepubertal and pubertal patients. In addition, a significant decrease in height-SDS before CML diagnosis was observed in prepubertal patients, and some pubertal patients also showed severe growth retardation before TKI initiation. Among the 46 patients reaching adult height post-TKI initiation, 42, whose TH could be calculated, were eligible for adult height analysis. The cohort was divided into “in or above TR” and “below TR” groups based on their TR. The height-SDS at diagnosis was significantly correlated with adult height-SDS. Of the 42 patients, we next focused on 14 who were prepubertal at TKI initiation. TKI exposure until the age of peak height velocity was correlated with a decrease in height-SDS during TKI exposure. Notably, due to the later onset of the pubertal growth spurt in males compared to females, males had significantly longer TKI exposure periods before reaching peak height velocity, resulting in more pronounced growth retardation. Among the 42 patients, adult height fell below the TR in 10 patients (23.8%). Except for one patient, all were male. The female patient had an adult height 0.7 cm below the TR, while the 9 males had a median adult height of 3.8 (range, 0.9-16.9) cm below the TR. This finding suggests that males are at higher risk of not reaching TR, possibly due to longer TKI exposure periods before reaching peak height velocity in prepubertal patients. Unexpectedly, half (n=5) had already entered puberty upon TKI initiation. Given that growth velocity dramatically decreased soon after TKI initiation, TKI initiation may have interfered with pubertal growth spurt, resulting in adult height below the TR in these pubertal patients.
Conclusion: Approximately one-quarter of our cohort exhibited adult height below the TR, including patients who would not be considered as “short stature”. Catch-up growth is likely not complete, especially in prepubertal patients with prolonged TKI exposure before reaching peak height velocity. The reduced height-SDS before TKI initiation indicates that not only TKI but CML itself may cause growth retardation. Further studies are required to confirm the generalizability of these findings regarding growth retardation in children with CML.