Jan 15, 2013 - evaluate GH dynamics in children with CML receiving imatinib. The purpose .... IGF-1 and IGFBP-3 levels were evaluated by enzyme linked.
Pediatr Blood Cancer 2013;60:1148–1153
Growth Failure in Children With Chronic Myeloid Leukemia Receiving Imatinib Is Due to Disruption of GH/IGF-1 Axis Karthik R. Narayanan, MBBS,1 Deepak Bansal, MD, DNB, MNAMS,1* Rama Walia, MD, DM,2 Naresh Sachdeva, PhD,2 Anil Bhansali, MD, DM,2 Neelam Varma, MD, FISHTM,3 and R.K. Marwaha, MD, MNAMS, FIAP, FRCPCH1 Background. The frontline treatment for chronic myeloid leukemia (CML) is tyrosine kinase inhibitor therapy. There is increasing evidence that imatinib results in growth failure in children; etiology is unclear. Procedure. The cross-sectional study was conducted from January 2011 to June 2012 in a pediatric oncology unit. Patients with chronic-phase CML, receiving imatinib for more than 6 months were enrolled. Growth hormone (GH): Insulin like growth factor-1 (IGF-1) axis was evaluated by GH stimulation test by insulin tolerance and clonidine stimulation test, among other hormonal assays. Results. Eighteen patients with a median age of 12.9 years (range 6.5–17) completed the study. The mean duration of imatinib therapy was 43.7 32.8 months. The height-for-age zscores at the start of imatinib and at enrollment were 1.07 0.88
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and 1.8 0.98, respectively (P < 0.001). Seven (39%) patients were GH deficient and lacked a sufficient response to either of the two stimulation tests. Majority, 16 (89%) patients had IGF-1 zscores less than the mean. IGFBP-3 levels were below the mean in all patients. Every patient had deficiency of either GH, or IGF-1, or both. Bone age was delayed in 7 (39%). Conclusions. This study demonstrates that imatinib results in growth failure in children with CML by disturbing the GH:IGF-1 axis. GH stimulation test and serum IGF-1 levels should be performed in children on treatment with imatinib who have growth retardation. Future studies should evaluate the role of recombinant GH therapy for ameliorating the adverse effect on growth. Pediatr Blood Cancer 2013;60:1148– 1153. ß 2013 Wiley Periodicals, Inc.
FSH; LH; puberty; sexual maturity rating; stunting; Tanners scale; thyroid function tests; TKI
INTRODUCTION Chronic myeloid leukemia (CML) is rare in childhood and accounts for 2–3% of all leukemias [1]. The prognosis has drastically improved following the availability of tyrosine kinase inhibitors (TKI) [2]. Imatinib mesylate is a first generation TKI that has become standard therapy for children and adults with CML [2]. However, allogeneic stem cell transplantation (SCT) remains the only proven curative modality. The recommended frontline therapy for pediatric CML in chronic phase is TKI therapy [2]. Patients in accelerated/blast crisis or who fail to reach landmarks on TKIs should pursue SCT [2]. While cytogenetic/molecular responses to imatinib are encouraging, information regarding long-term adverse effects in children is now emerging. For instance, there is increasing evidence that imatinib results in growth failure in children [3–12]. Growth retardation has been earlier documented in a cohort of 20 patients with CML from our institute (Post Graduate Institute of Medical Education and Research, Chandigarh, India) [6]. The etiology is unclear. It has been postulated that growth hormone (GH) deficiency and disturbances in bone remodeling are responsible, but these have not been proven [7–12]. The aim of the study was to evaluate GH dynamics in children with CML receiving imatinib. The purpose was to identify a plausible etiology for the growth retardation, so that remedial measures can be considered.
SUBJECTS AND METHODS The cross-sectional observational study was conducted from January 2011 to June 2012. The inclusion criteria included children (age 6 months. The exclusion criteria were accelerated/blast phase of disease, height-for-age standard deviation score (SDS)
