Effect of the tyrosine kinase inhibitors on the growth in children with Philadelphia chromosome–positive acute lymphoblastic leukemia: a case–control study

Abstract

First-generation ABL-targeted tyrosine kinase inhibitor (TKI) imatinib is known to retard growth in children but it is not known if the second-generation ABL-targeted TKI dasatinib has the same effect. We aimed to determine the impact of the first- or second-generation TKI on the growth of children treated for Philadelphia chromosome-positive (Ph+) childhood acute lymphoblastic leukemia (ALL). We evaluated the longitudinal growth changes in 140 children with Ph+ALL treated with imatinib or dasatinib in additional to intensive cytotoxic chemotherapy and 280 matched controls treated with the same intensity of cytotoxic chemotherapy without TKI on Chinese Children's Cancer Group ALL-2015 protocol between 2015 and 2019. We retrospectively reviewed the height data obtained during routine clinic visits at 4 time points: at diagnosis, the end of therapy, 1 year and 2 years off therapy. Height z Scores were derived with the aid of WHO Anthro version 3.2.2 and WHO AnthroPlus version 1.0.4, global growth monitoring tool. This study consisted only patients who have completed all treatment in continuous complete remission without major events, including 33 patients randomized to receive imatinib, 43 randomized to receive dasatinib, and 64 assigned to receive dasatinib. Similar degree of loss of height z scores from diagnosis to the end of therapy was observed for the 33 imatinib- and the 107 dasatinib-treated patients (median △=-0.84 vs.-0.88, P=0.41). Adjusting for height z score at diagnosis, puberty status, and sex, there was no significant difference in the longitudinal mean height z scores between patients treated with imatinib and those with dasatinib (0.08, 95% CI,-0.22 to 0.38, P=0.60). The degree of loss of height z scores from diagnosis to end of therapy was significantly greater in the 140 TKI-treated patients than the 280 controls (median △=-0.88 vs.-0.18, P<0.001). The longitudinal mean height z scores in the TKI-treated patients were significantly lower than those of the controls (-0.84, 95% CI,-0.98 to-0.69; P<0.001). These data suggest that dasatinib and imatinib have the similar adverse impact on the growth of children with Ph+ALL. This study was supported by the National Natural Science Foundation of China (grant 81670136 [JCai and JT]), the fourth round of Three-Year Public Health Action Plan (2015-2017; GWIV-25 [SS]), Shanghai Health Commission Clinical Research Project (202140161 [JCai]), the US National Cancer institute (CA21765 [C-H Pui]), and the American Lebanese Syrian Associated Charities (CC, JJY, and C-HP). The content of this paper is solely the responsibility of the authors and does not necessarily represent the official views of the US National Institutes of Health.