Growth deceleration in a girl treated with imatinib

Abstract

Imatinib is an inhibitor of tyrosine kinase as well as BCRABL, platelet-derived growth factor receptor (PDGF-R) and c-kit, and is becoming a first-line treatment for chronic myeloid leukemia (CML). In children, the long-term toxic effects related to the inhibition of tyrosine kinase are not yet well understood. A 6-year-old girl was diagnosed with BCR-ABL positive CML in the chronic phase in June 2003. After receiving imatinib (400 mg/m per day), molecular remission was achieved and persisted for 4 years without major side-effects. At the beginning of imatinib administration, the patient was aged 6 years, and her height was 114 cm (-0.7SD). Her growth rate decreased during these 4 years, and her height was 121 cm (-2.7SD) when she was aged 11 years. The patient followed the normal growth pattern since birth she had normal body proportions and appearance, no family history of short stature. Following extensive tests, she reached the normal GH peak after two stimulatory tests and other systemic diseases (endocrine disorder, renal failure, inflammatory disorders) were excluded. Additionally, we identified delayed bone age on X ray of her wrists at the age of 11 years (bone age was 7 years) and low bone mineral density was demonstrated on dual-energy X ray absorptiometry of the lumbar spine (0.576 g/m Z score less than -2.5SD for chronological age). Bone formation markers (serum osteocalcin, 8.5 ng/ml and bone specific alkaline phosphatase BAP, 30.0 U/L) were lower than those of age-matched healthy girls (reference range; osteocalcin 36–93 ng/ml, BAP 66–137 IU/l) and bone resorption marker (urinary deoxypyridinoline 5.8 nM/mMCre) was also lower (reference range 28–42 mM/mMCre), suggesting that effect of decreased bone formation exceeded that of decreased bone resorption. Because she had not been exposed to a long-term immunosuppressive steroid treatment and there were no other risk factor of inhibition of bone formation, we strongly suspected that imatinib treatment may have been associated with the low mineral density in this patient. After confirming the absence of detectable BCR-ABL trasnscript, imatinib was discontinued in October 2007, which subsequently resulted in gradual growth acceleration. However, because BCR-ABL transcript in her peripheral blood reappeared, she was prepared for allogeneic stem cell transplantation. We noted increased bone formation markers (BAP 110.9 U/L, osteocalcin 22.9 ng/ml) 8 months after discontinuation of imatinib, as well as an increased growth rate (6.2 cm over 8 months) (Fig. 1). The possibility that imatinib restrains bone resorption (by inhibiting c-Fms on osteoclasts) and stimulates bone formation (by inhibiting PDGF-R on osteoblats) has been reported in vitro [1–3], and adult CML patients actually have increased bone volume after long-term imatinib therapy [4]. Although bone metabolism in our patient differed from that in adults receiving imatinib, we suspect that growth deceleration and low bone mineral density in our patient were associated with imatinib administration. In September 2008 (11 months after discontinuation of imatinib), the patient has successfully achieved complete donor chimerism from an unrelated cord blood donor following reduced intensity conditioning with the expectation that she would achieve puberty and accelerated growth. T. Kimoto (&) M. Inoue K. Kawa Department of Hematology/Oncology, Osaka Medical Center and Research Institute for Maternal and Child Health, 840 Murodo-cho, Izumi, Osaka 594-1101, Japan e-mail: tomiko@mch.pref.osaka.jp