Side effects of tyrosine kinase inhibitor (TKI) treatment vary in children and adults with chronic myelogenous leukemia (CML). As children have a much longer life expectancy than adults, TKI therapy may continue for decades and with long-term consequences that differ from adults. Children may develop endocrinopathies related to "off-target" effects of TKIs, such as delayed growth, changes in bone metabolism, thyroid abnormalities, and effects on puberty and fertility. These endocrinopathies present additional challenges for pediatric patients with CML. This review critically evaluates the literature on long-term endocrine side effects of TKIs in the pediatric CML population and provides suggested recommendations.

The phase 2, open-label study (DIALOG) of nilotinib in pediatric patients with Philadelphia chromosome-positive chronic myelogenous leukemia (CML) met its coprimary end points, showing sustained nilotinib efficacy in patients with newly diagnosed (ND) or imatinib/dasatinib resistant/intolerant (R/I) CML. This update assessed growth and safety profiles in patients who had completed ≥48, 28-day treatment cycles of nilotinib 230 mg/m2 twice daily, or previously discontinued the study. Height was assessed regularly and reported using standard deviation scores (SDSs) based on World Health Organization growth charts. All data were summarized descriptively (cutoff, 6 March 2019). Overall, 33 patients in the R/I cohort and 25 patients in the ND cohort received nilotinib. Each cohort showed a negative slope in height SDS over the course of the study, indicating attenuated growth rates during nilotinib treatment: overall median change from baseline in height SDS after 48 cycles was −0.54 SDS (range, − 1.6 to 0.4) and −0.91 SDS (−1.4 to −0.1) in R/I and ND cohorts, respectively. Patients in the R/I cohort were shorter at baseline than those in the ND cohort, and remained so throughout the study. The most common all-cause adverse events were increased blood bilirubin (53.4%), headache (46.6%), pyrexia (37.9%), and increased alanine transferase (36.2%). Apart from the impact on growth, the safety profile of nilotinib was generally consistent with previous reports. This study was registered on www.clinicaltrials.gov at #NCT01844765.

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Background:Tyrosine kinase inhibitors (TKIs) have dramatically altered the treatment landscape for managing pediatric CML‐CP. In the largest prospective trial (CA180–226/NCT00777036) in children with CML‐CP, we previously reported that dasatinib was associated with clinically relevant early, deep, and durable responses, with a safety profile similar to that of treated adults with no cases of pleural effusion (Gore 2018). Reports have documented growth retardation and reduction of bone mineral density in pediatric patients (pts) with CML‐CP treated with imatinib (Millot 2014; Giona 2015); impaired growth from imatinib use has mainly been observed in prepubertal versus pubertal pts (Shima 2011). There remains limited understanding about the impact of 2nd‐generation TKIs such as dasatinib on growth and endocrine function in this pt population.Aims:To assess growth outcomes and endocrine function in a retrospective analysis of pts from the phase 2 CA180–226 study.Methods:CA180–226 was an open‐label, nonrandomized phase 2 trial enrolling pts <18 years with CML‐CP who were newly diagnosed (ND) or imatinib resistant/intolerant (IM‐R/I; 1 and 3 pts also received previous stem cell transplant and chemotherapy, respectively). IM‐R/I pts received 60 mg/m2 dasatinib tablets once/day (QD, n = 29), and ND pts received either 60 mg/m2 tablets or 72 mg/m2 of dasatinib in powder for oral suspension (PFOS) QD; the tablet and PFOS groups were pooled for this post hoc analysis (ND, n = 84). Change in z‐scores from baseline for pt height, dual‐energy X‐ray absorptiometry (DXA) L‐spine, and body mass index (BMI) were assessed over time. Predicted adult height (PAH) was determined from actual height and bone age at each assessment via the Greulich and Pyle method. Height z‐scores were stratified by Tanner stage.Results:Median change in height z‐scores from baseline demonstrated a slight decrease at ≤1, >1‐≤2, and >2‐≤3 years in the ND cohort (−0.16 [n = 73], −0.33 [n = 71], and −0.43 [n = 65]) and the IM‐R/I cohort (−0.1 [n = 22], −0.30 [n = 18], and −0.35 [n = 17]), respectively. Prepubertal pts (Tanner stage 1) in the ND cohort had greater differences in median height z‐score (−0.35 [n = 23], −0.62 [n = 22], and −0.73 [n = 21]) compared to ND pts in Tanner stages 2–4 (−0.02 [n = 36], −0.22 [n = 35], and −0.33 [n = 31]) at ≤1, >1‐≤2, and >2‐≤3 years, respectively. Median change in BMI z‐score from baseline in the ND cohort was minimal at ≤1 year (0.46 [n = 84]) and stable thereafter at >1‐≤2 years (0.46 [n = 81]) and >2‐≤3 years (0.42 [n = 68]). Minimal z‐score changes were also observed in the IM‐R/I cohort (−0.01 [n = 28], −0.08 [n = 23], and −0.26 [n = 19]) at ≤1, >1‐≤2, and >2‐≤3 years, respectively. Data collected for up to 5 years (including both on‐ and off‐treatment assessments) showed median DXA z‐scores unchanged in both cohorts (Figure). Detailed additional data on PAH and endocrine assessments, including thyroid and reproductive hormone profiles, will be presented.Summary/Conclusion:In this retrospective analysis of the phase 2 CA180–226 study, dasatinib was found to have minimal or no impact over time on BMI and bone densitometry in both the ND and IM‐R/I cohorts; this contrasts with previously reported growth results with imatinib. Based on the minimal changes in height z‐scores, the effect of dasatinib on growth appears to be minimal in ND pubertal pts. However, as in previous reports with imatinib, ND prepubertal pts still showed altered growth velocity. Continued and more extensive monitoring will be required to assess the long‐term impact of dasatinib use in this pt population.image