Spontaneous Alleviation Of Growth Impairment In Tyrosine Kinase Inhibitor-Treated Chronic Myeloid Leukemia Children

Although tyrosine kinase inhibitor (TKI) is popular in controlling chronic myeloid leukemia in the chronic phase (CML-CP), its long-term adverse effects in children are an issue of concern. One such concern is the negative impact on growth in these children. We previously demonstrated that growth impairment was a major adverse effect in imatinib-treated CML children. However, severity of impairment was not completely elucidated because of the short follow-up period.

The Japanese Pediatric Leukemia/Lymphoma Study Group CML committee reviewed the clinical records of 107 Japanese children diagnosed with CML-CP (<18 years of age) between 2001 and 2011, and treated with TKI for more than a year with no history of hematopoietic stem cell transplantation. Concurrent hydroxyurea administration was permitted (n = 7). Cumulative change in height was assessed using the height standard deviation score (height-SDS) and converted height data from age- and sex-adjusted Japanese norms. Children who reached final height at the time of diagnosis (n = 5), those afflicted by a chronic disease (n = 10), those treated for a disease that could affect growth (n = 7), and those without height data (n = 8) were excluded.

In total, 77 children (47 boys and 30 girls) met these criteria. Median age at diagnosis was 10 years (2 to 15 years) and median observation period was 38 months (12 to 119 months). Median height-SDS at diagnosis and during the study was −0.14 SD (−2.3 to 2.3 SD) and −0.75 SD (−3.2 to 1.9 SD), respectively. Decrease in height-SDS (change in height-SDS from initiation of TKI till last follow-up point) was observed in 84.4% of children, which was >1 SD in 21 children (27.2%). Decrease in height-SDS was more severe in prepubertal children than in pubertal children (0.85 vs. 0.36, p< 0.01). However, in prepubertal children median annual change in height-SDS significantly decreased 2 years after TKI initiation, and was<0.1 SD 3 years after TKI initiation. There was no significant difference in median height-SDS at 3 years and thereafter from TKI initiation. Similar tendency was observed in pubertal children, with median annual change in height-SDS shifting to an increasing trend since 3 years after TKI initiation.

Because of the possibility of TKI discontinuation, growth impairment is assumed to be a huge issue particularly in children who are inevitable of prolonged exposure to TKI. We previously discussed the possibility that growth velocity may recuperate in prepubertal children as they reach pubertal age, suggesting that imatinib had less impact on growth during puberty. However, this updated study data demonstrated that period of TKI treatment may influence alleviation of growth impairment by TKI to a greater extent than puberty. We suggest that severity of growth impairment could be mitigated 2 years after TKI initiation. Thus, therapeutic intervention, such as reduced-intensity hematopoietic stem cell transplantation and discontinuation of TKI, may not be necessary for improvement of growth in TKI-treated CML children.