Bone Metabolism and Endocrine Function in Children with Chronic Myeloid Leukemia (CML) Treated with Imatinib during Puberty.
Authors: Giona Fiorina , Mariani Stefania , De Vellis Annalisa , Moleti Maria Luisa , Testi Anna Maria , D’Angiò Mariella , De Masi Bruna , Foa Robert , Gnessi Lucio 
Published: October 2019

Abstract
Imatinib, a BCR-ABL tyrosine kinase inhibitor, is an effective treatment for adults and children with CML. However, the in vivo inhibition of the PDGF receptor and c-kit in normal cells may have clinical side effects: altered bone and mineral metabolism, reduction of testosterone and gynecomastia have been reported in adults treated with imatinib. To evaluate bone and mineral metabolism and puberal development, we studied 4 consecutive prepuberal patients (median age 10.6; range 9–12 years) with Ph+ CML treated with imatinib (340mg/sqm/day) in complete cytogenetic response. To evaluate puberal development we used the Tanner staging and serum concentrations of follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone (T), free testosterone (fT), inhibin-B, progesterone (P), 17a-hydroxyprogesterone (17a-OH-P) dihydrotestosterone (DHT), prolactin (Prl), growth hormone (GH), insulin-like growth factor-1 (IGF-1); to evaluate mineral metabolism, we tested osteocalcin levels, C-terminal telopeptides of type I collagen (CTX), parathyroid hormone (PTH), serum and urinary calcium, serum and urinary phosphate levels; bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry (DEXA). Table 1 reports the serum concentration results at different time points during treatment. The bone resorption marker CTX was up to 2.6 times over the highest reference interval for age matched normal boys and was accompanied by a reduction of BMD for chronologic age (mean z-score -1.3). The longitudinal growth, between the 50th and the 10th percentile before imatinib, slowed below the 10th percentile, although TSH, GH and IGF-1 were within the normal range. All males had progesterone and 17a-OH-P above the highest cut-off point and one (case 2) developed gynecomastia, pubertal delay, low BMD for chronologic age (z-score -2.9), serum calcium in the upper normal limits, urinary calcium higher than normal (896 mg/day, n.v. 100–300 mg/day), while serum PTH, 25-OH-D, urinary phosphate, BAP and osteocalcin were within the normal range. This patient during therapy presented an increase of FSH with a simultaneous decrease of inhibin-B; the decrease inhibin-B/FSH ratio is predictive of a spermatogenesis failure. In conclusion, the reduced BMD, the growth swiftness delay, gynecomastia and the inhibin-B/FSH ratio in our adolescents are probably due to imatinib. To better understand the safety profile of imatinib, it is important to investigate larger series of CML children treated with targeted therapies involving the PDGF receptor and c-kit.
FSH LH T Inhibin-B P 17a-OH-P CTX Age(yrs)/Imatinib (mos) mlU/ml(1–14) mlU/ml(1.5–9.2) ng/ml(2.4–8.2) pg/ml(50–250) ng/dl(0.1–0.9) ng/dl(0.4–3.6) ng/ml(0.23–1.7) Case 1(male) 13.9/20 4.1 4 1.61 183 1 1.9 2.55 14.9/32 4.8 4.6 3.82 177 1.07 4.6 3.58 16.1/46 1.7 6.0 4.49 103 261 3.7 3.55 Case 2(male) 13.0/17 4.4 1.9 <0.1 77 0.59 0.49 1.83 15.0/41 3.9 3.1 3.15 57 1.57 2.9 4.45 16.0/53 13.4 1.5 3.40 9 4.2 4.6 3.22 Case 3(male) 10.5/17 4.3 1.9 0.12 80 0.72 0.55 1.34 11.5/29 4.2 2.4 0.62 159 1.12 2.3 1.48 12.6/42 2.6 3.7 2.67 69 1.52 3.2 2.35 Case 4(female) 11.5/17 6 1.1 <0.1 39 0.26 0.42 1.94 12.6/30 5.9 1.6 <0.1 51 0.5 0.35 1.75 14.1/46 7.2 1.1 1.07 23 0.75 0.68 1.62