Cardiovascular & Hematological Agents in Medicinal Chemistry     Athanasios Tragiannidis 1,* and Elpis Mantadakis 2 1 Childhood & Adolescent Hematology Oncology Unit, 2 nd Paediatric Department, Faculty of Health Sciences, Aristotle University of Thessaloniki, AHEPA Hospital, Thessaloniki, Greece; 2 Department of Paediatrics, Paediatric Hematology/Oncology Unit, Democritus University of Thrace Faculty of Medicine, Alexandroupolis, Thrace, Greece Tyrosine kinase inhibitors (TKIs) have emerged as the primary treatment option for children with chronic myeloid leukemia (CML) and Ph+ acute lymphoblastic leukemia (Ph+ALL), as is the case in adults [1, 2]. Until the late 2000s, chemotherapy followed by allogeneic hematopoietic stem cell transplantation (aHSCT) represented the first line treatment for children with Ph+ leukemias. However, as aHSCT has limited donor availability and relatively high rates of morbidity and mortality, TKIs have recently become the gold standard of treatment. Nowadays, older and newer generation TKIs represent the optimal first line treatment option either alone (CML) or in combination with multiagent chemotherapy (Ph+ALL) [1, 2]. A R T I C L E H I S T O R Y Received: September 01, 2021 Revised: November 15, 2021 Accepted: November 15, 2021 DOI: doi: 10.2174/1871525719666211214114229 Nevertheless, many questions remain regarding the safety and long-term efficacy of TKIs in children because although they are approved for indefinite treatment, long-term safety data are still lacking. Questions about dosing, molecular resistance, intolerance, safe duration of treatment, and rare adverse events require further studies. Disturbances of bone metabolism and growth restrictions manifested with both clinical (growth impairment, musculoskeletal problems, pain, osteoporosis, osteonecrosis) and laboratory findings (decreased bone mineral density, disturbances of vitamin D, and other hormonal status deviations) have been described in children and adults receiving TKIs for CML and Ph+ALL [1, 3-5]. Imatinib (Glivec ® ) is a first-generation inhibitor of the BCR-ABL fusion gene that is present in children and adults with CML and Ph+ ALL, and of the related tyrosine kinases c-KIT and platelet-derived growth factor (PDGF) receptor. It has been approved for use in children by the European Medicines Agency (EMA) and the Federal Drug Administration (FDA), although indications slightly vary among the two agencies. EMA has approved imatinib for the treatment of paediatric patients with newly diagnosed CML for whom aHSCT is not an option, for paediatric patients with CML in chronic phase (CML-CP) after the failure of interferon-alpha therapy, or in accelerated phase or blast crisis, and finally in paediatric patients with newly diagnosed Ph+ALL, where the drug is integrated with conventional chemotherapy [6]. FDA has approved imatinib for newly diagnosed children with CML-CP, for children with recurrent disease after aHSCT or who are resistant to interferon-alpha therapy [7]. Imatinib has an indirect modulatory effect on both osteoblasts that form and osteoclast that resorb bone. More specifically, imatinib has been shown to inhibit PDGFR-receptor a and PDGFR receptor β expressed on immature osteoblasts and osteoclasts, respectively. Moreover, imatinib has an apoptotic effect on early-stage osteoclasts and suppresses osteoclast precursors by activating the macrophage-colony stimulating factor (M-CSF) [8]. Long-term results of imatinib use in children with CML from the Italian Registry have shown that among 47 treated paediatric patients, 9 (19%) developed musculoskeletal pain that resulted in discontinuation of therapy in one (2%) patient. Another study showed that among 32 children and adolescents treated for more than one year, seven presented longitudinal growth impairment and/or reduction of bone mineral density (BMD) [9]. Deng et al. evaluated 21 patients with CML < 18 years of age with a mean follow up time of 33.8 months and found that 42.9% of them had decreased BMD (z scores <-2.0) [8]. The EsPhALL 2010 study enrolled 155 paediatric patients with Ph+ALL in whom imatinib was prospectively evaluated. Although the results document the high efficacy of imatinib, the most common adverse events were infections in 39% of patients, followed by gastrointestinal disorders (6%) and osteonecrosis in eight patients (5%) [10]. In the previous EsPhALL study that also enrolled children and adolescents aged 1-18 years, two cases of osteonecrosis were registered, of whom one in the good risk imatinib group [11]. Millot et al., on behalf of the French Registry, reported data on the growth deceleration and bone metabolism of children with CML treated with imatinib. Growth velocity was reduced in both sexes during the first year of imatinib treatment in both prepubertal patients and adolescents [4]. Finally, a small study that included six children with CML-CP (median age 9.87 years) treated with imatinib and followed for a median time of 78.5 months showed that two patients (33.3%) developed decreased lumbar spine BMD, and this was related to a higher mean treatment exposure. Additionally, five of six patients had lower serum 25-hydroxyvitamin D levels [12]. *Address correspondence to this author at the Childhood & Adolescent Hematology Oncology Unit, 2 nd Paediatric Department, Faculty of Health Sciences, Aristotle University of Thessaloniki, AHEPA Hospital, Thessaloniki, Greece; E-mails: atragian@auth.gr, atragian@hotmail.com 1875-6182/22 © 2022 Bentham Science Publishers Editorial Cardiovascular & Hematological Agents in Medicinal Chemistry, 2022, Vol. 20, No. 3 175 EDITORIAL Effects of Tyrosine Kinase Inhibitors on Growth and Bone Metabolism in Children with Haematologic Malignancies