Bcr-abl tyrosine kinase inhibitors in the treatment of pediatric cml

The therapeutic approach to Chronic Myeloid Leukemia (CML) has changed since the advent of the tyrosine kinase inhibitor (TKI) imatinib, which was then followed by the second generation TKIs dasatinib, nilotinib, and, finally, by ponatinib, a third-generation drug. At present, these therapeutic options represent the first-line treatment for adults. Based on clinical experience, imatinb, dasatinib, and nilotinib have been approved for children even though the studies that were concerned with efficacy and safety toward pediatric patients are still awaiting more specific and high-quality data. In this scenario, it is of utmost importance to prospectively validate data extrapolated from adult studies to set a standard therapeutic management for pediatric CML by employing appropriate formulations on the basis of pediatric clinical trials, which allow a careful monitoring of TKI-induced adverse effects especially in growing children exposed to long-term therapy

β‐Dystroglycan Restoration and Pathology Progression in the Dystrophic mdx Mouse: Outcome and Implication of a Clinically Oriented Study with a Novel Oral Dasatinib Formulation

ROS‐activated cSrc tyrosine kinase (TK) promotes the degradation of β‐dystroglycan (β‐ DG), a dystrophin‐glycoprotein complex component, which may reinforce damaging signals in Duchenne muscular dystrophy (DMD). Therefore, cSrc‐TK represents a promising therapeutic target. In mdx mice, a 4‐week subcutaneous treatment with dasatinib (DAS), a pan‐Src‐TKs inhibitor approved as anti‐leukemic agent, increased muscle β‐DG, with minimal amelioration of morphofunctional indices. To address possible dose/pharmacokinetic (PK) issues, a new oral DAS/hydroxypropyl(HP)‐β‐cyclodextrin(CD) complex was developed and chronically administered to mdx mice. The aim was to better assess the role of β‐DG in pathology progression, meanwhile confirming DAS mechanism of action over the long‐term, along with its efficacy and tolerability. The 4‐week old mdx mice underwent a 12‐week treatment with DAS/HP‐β‐CD10% dissolved in drinking water, at 10 or 20 mg/kg/day. The outcome was evaluated via in vivo/ex vivo disease‐relevant readouts. Oral DAS/HP‐β‐CD efficiently distributed in mdx mice plasma and tissues in a dose‐related fashion. The new DAS formulation confirmed its main upstream mechanism of action, by reducing β‐DG phosphorylation and restoring its levels dose‐dependently in both diaphragm and gastrocnemius muscle. However, it modestly improved in vivo neuromuscular function, ex vivo muscle force, and histopathology, although the partial recovery of muscle elasticity and the decrease of CK and LDH plasma levels suggest an increased sarcolemmal stability of dystrophic muscles. Our clinically oriented study supports the interest in this new, pediatric‐suitable DAS formulation for proper exposure and safety and for enhancing β‐DG expression. This latter mechanism is, however, not sufficient by itself to impact on pathology progression. In‐depth analyses will be dedicated to elucidating the mechanism limiting DAS effectiveness in dystrophic settings, meanwhile assessing its potential synergy with dystrophin-based molecular therapies