Introduction
Beta-thalassemia is an inherited hemolytic anemia that is associated with reduced or absent ß-globin synthesis. In severe cases imbalanced accumulation of α-globin chains and the formation of its aggregates impairs terminal erythroid maturation. Beta-thalassemia major (TM) is characterized by early onset, significant changes in the ratio of hemoglobin fractions (HbF > 50%, HbA2< 4%) and profound anemia.1-4
To date allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative therapy. HSCT in TM is associated with increased rate of graft failure and transplant-related complications.5-8
Ineffective erythropoiesis (IE) is the most prominent feature of TM, which in severe cases leads to extramedullary hemopoiesis with hepatosplenomegaly and skeletal deformities. Splenomegaly leads to an increase in red blood cell (RBC) transfusion requirement, as a large proportion of the circulating RBC are eliminated by an enlarged spleen. This results in subsequent complications such as accumulation of alloantibodies and iron overload.9-12
It is thought that prominent expansion of IE, seen in TM, exerts a negative effect on engraftment and graft function. In view of this fact highly intensive myeloablative conditioning regimens are used in these patients. On the other hand, most of the patients with TM have a severe iron overload, which is the strong risk factor for transplant-related complications and mortality. Therefore, in heavily transfused patients with TM accompanied by drastic IE, the outcomes of HSCT are often inferior.7-9 In the recent years several studies aiming to improve outcomes in patients with class 3 TM, including well-tolerated pre-transplantation treatment have been published.7-9,13,14
The JAK-STAT signaling pathway is one of the key regulators of normal hematopoiesis which is mediating signals transduction from a variety of cytokines and hematopoietic growth factors in hematopoietic stem cells and precursors.15 It was shown that inhibition of JAK1 impairs cytokine production and modulate dendritic cell function.16-18 Ruxolitinib as JAK-1/JAK-2-inhibitor, has shown its efficacy in suppressing IE and immune system.19-23
Ruxolitinib treatment effectively reduces spleen size in patients with polycythemia vera, essential thrombocythemia and myelofibrosis.19-23 The similar effect has been demonstrated in adults with TM and ruxolitinib appeared to be safe and well tolerated.23 However, a long-term ruxolitinib treatment could lead to severe adverse events (AE) such as infectious complications and hematological and solid tumors.24-26
The aim of our study is to evaluate the efficacy and safety of ruxolitinib in IE suppression as a short-term pre-transplantation treatment for pediatric patients with TM.