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.