Growth retardation and adult height in pediatric patients with chronic-phase chronic myeloid leukemia treated with tyrosine kinase inhibitors

Abstract

Although tyrosine kinase inhibitors (TKIs) have substantially improved chronic myeloid leukemia (CML) prognosis, long-term TKI exposure remains a major concern, especially among children. One critical challenge specific to the treatment of children with TKIs is growth retardation [1,2,3,4]. Recently, both first-generation TKI imatinib and second-generation TKI dasatinib were reported to impact growth in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia [5]. We have previously reported growth retardation in children with CML treated with imatinib, particularly those treated before reaching puberty [3]. Although patients often experience catch-up growth during puberty, the extent of this catch-up and the long-term impact of TKI exposure on adult height remain poorly understood.

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, starting two years before diagnosis. Adult height was defined as the maximum height measured when the height increase velocity was <1 cm/year. Height-standard deviation scores (SDS) were adjusted using age- and sex-adjusted Japanese norms [6], with data from 17 years and six months of age used for adult height-SDS. 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 [7]. The duration of TKI exposure before the growth spurt was defined as the duration of TKI exposure until peak height velocity. Parental height data were collected to predict adult height and range. Target height (TH), representing a child’s predicted adult height from parental heights, and target range (TR), a 95% confidence interval of target height, were calculated as follows (cm): males, TH = (mother’s height + father’s height + 13)/2, TR = TH ± 9; females, (mother’s height + father’s height − 13)/2, TR = TH ± 8 [8].