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Introduction
Chronic myeloid leukemia (CML) is a rare hematologic disease with low incidence but increasing prevalence (1). This progressive, hematopoietic neoplasm is characterized by the presence of the BCR-ABL1 hybrid gene that is localized on the-so called Philadelphia (Ph+) chromosome [t(9;22) (q34;q11)] (2)-which leads to the constitutively active tyrosine kinase (TK) BCR-ABL1 causing leukemic cell transformation (3–5). As the oncogenic TK BCR-ABL1 is responsible for initiating the disease process (6), selective TK inhibitors (TKI) such as imatinib (IMA; Glivec®/Gleevec®: Novartis, Basel, Switzerland) were developed. Since 2001, (7–12) IMA has become the standard front-line therapy for the treatment of CML in adults (13). For pediatric patients with CML, IMA was approved in Germany in 2003. However, due to the increasing resistance or intolerance of leukemic cells to IMA therapy (14), second-generation TKIs like nilotinib (NIL; Tasigna®; Novartis, Basel, Switzerland) were developed. NIL, an aminopyrimidine-derivative based on imatinib mesylate (15), has a 20- to 50-fold higher inhibitory activity in IMA-sensitive cells and a 3 to 7 times higher inhibitory activity in IMA-resistant cells due to its higher potency and selectivity for the BCR-ABL1 TK (16). Based upon its efficacy, NIL was approved for the treatment of adult patients with CML in chronic and advanced phases after IMA failure or intolerance in 2008 (1).
However, both TKIs show off-target effects on further TKs such as PDGFR and CSF1R (c-FMS), which are involved in the bone remodeling cycle. Especially for IMA it is known that under prolonged treatment, adult CML patients revealed hypophosphatemia and an increased bone mineralization whereas pediatric CML patients develop growth retardation in up to 72.9% of the cases (17–22).
Reports of growth retardation due to a long-term application of IMA and related TKIs are increasing (13,17,21,23,24) and are even more prominent in those patients, who started IMA therapy at a prepubertal age. Additionally, pediatric patients display reduced serum levels of 25-hydroxy-vitamin D3 (25-OH-VD3; calcidiol) and 1.25-dihydroxyvitamin D3 (1.25-(OH)2-VD3; calcitriol) (25) under IMA treatment. At least, the effects for NIL are expected to have a similar potential for skeletal effects compared to IMA.
Vitamin D3 (VD3) synthesis is initiated by UVB-induced photolysis of 7-dehydrocholesterol (7-DHC) into previtamin D3 (26)...