Impairment of Longitudinal Growth By Tyrosine Kinase Inhibitor (TKI) Treatment - Data from a Large Pediatric Cohort with Chronic Myeloid Leukemia (CML)

Objectives: A decade after being licensed for treatment of CML in minors, the TKI imatinib (IMA) is well known for it's inhibitory “off-target” effects on activity and proliferative capacity of osteoclasts and osteoblasts resulting in impaired bone remodeling (Vandyke K et al 2010 Blood 115:766; Tauer JT et al Blood 2011:118). This causes longitudinal growth retardation in not outgrown individuals (Millot F et al 2009 Blood 114:863; Shima H et al 2011 Pediatrics 159:676; Bansal D et al 2012 Ped Blood Cancer 59:481) which can be aggravated by a disrupted growth hormone:IGF-I axis as a possible additional off-target effect exerted by TKI treatment (Ulmer A et al 2013 Klin Padiatr 225:120; Bansal D et al 2012 Ped Blood Cancer 59:481). Starting a pediatric trial in the year 2006 which recruits approx. 15 pediatric patients (pts) with CML annually, we investigated to what extend growth is impaired depending on sex, age, and pubertal stage at start of IMA treatment in a pediatric cohort.

Methods: 102 pts (54 male / 48 female; median age 12 years, range: 1-18 years) at diagnosis of CML receiving IMA as upfront treatment were enrolled retrospectively in this analysis from centers in Germany and participating countries during 02/2006 to 06/2014. Height standard deviation scores (SDS) were derived from WHO-AnthroPlus, version 1.04 software, a global growth-monitoring tool providing normal range values for the age cohorts from birth till 19 years. 81 out of 102 pts fulfilled the criteria for continuous assessment of growth scheduled at three months intervals during IMA exposure. 21 pts were analyzed at intervals ≠ 3 month. Pts excluded comprised individuals shifted to a 2^nd generation TKI, or cumulative interruptions of drug intake exceeding 4 weeks, or pts undergoing stem cell transplantation.

Results: The mean and median duration of IMA exposure was 12 months and 9 months, respectively (range: 0–98 month). 27/102 pts (13 male, 14 female) were prepubertal (age: <10 years) at initiation of IMA treatment while 46/102 pts were pubertal (age: 10-14 years; 23 male, 23 female), and 29/102 pts were in postpubertal stage (age: >14 years; 18 male, 11 female). In comparison to mean SDS at diagnosis a mean decrease in height of 0.48 SDS per year was observed in the total cohort during the first three years of treatment, being more pronounced in prepubertal pts. In pts diagnosed shortly before or at puberty a mean reduction of 0.75 SDS per year during the first three years were observed. Older teenagers revealed no change in body height z-score during TKI treatment compared to height z-score at diagnosis.

Discussion: Growth retardation is a significant adverse effect of IMA in children with CML affecting predominantly prepubertal children. Possible medical interventions still need to be investigated.

Acknowledgment: Supported by grant DFG SU122-3/1 to MS.

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