Guest Editor: Raffaella Origa IRON TOXICITY AND HEMOPOIETIC CELL TRANSPLANTATION: TIME TO CHANGE THE PARADIGM.

Abstract

The issue of iron overload in hemopoietic cell transplantation has been first discussed in the field of transplantation for thalassemia. Thalassemia major is characterized by ineffective erythropoiesis and hemolysis leading to anemia in the majority of patients. Patients require regular blood transfusion therefore they develop iron overload causing organ damage and hematopoietic cell transplantation (HCT) is a consolidated reliably curative option. In this category of patients an important issue for transplant outcome is the iron burden before transplant and in the long-life post-transplant. Nevertheless, today the concept of the impact of iron overload / toxicity on the outcome of HCT) has been extended to other diseases characterized by periods of variable duration of transfusion dependence Recent preclinical data has shown how increased production of reactive oxygen species (ROS) resulting under iron overload condition, could impair the stem cells clonality capacity, proliferation and maturation. Also, microenvironment cells could be affected through this mechanism. For this reason, iron overload is becoming an important issue also in the engraftment period post-transplantThe aim of this review is to update consolidated knowledge about the role of iron overload/iron toxicity in the HCT setting in non-malignant and in malignant diseases introducing the concept of exposition of free toxic iron forms and related cellular damage in the different stage of transplant.

Beta Thalassemia: New Therapeutic Options Beyond Transfusion and Iron Chelation

“…However, peculiar features of hemoglobinopathies, namely splenomegaly and thrombophilia, may represent risk factors for adverse events [32][33][34][35]. Moreover, in adult thalassemia patients, iron overload and consequent oxidative stress, the suppressive effect of long-term transfusions and chelation on the stem cell compartment, and the "aged" stem cells, could compromise the safety and success of HSC procurement [36]. Among the other compounds available, Plerixafor represents a good alternative.…”

“…Plerixafor has proved to be safe and effective in mobilizing HSC in thalassemia patients [24,25,37]. Hydroxyurea has been evaluated as an agent to be administered prior to mobilization; however, it reduces the amount of circulating CD34+ [38], is associated with myelosuppression, and did not show any beneficial effect in thalassemia patients [36,39]. 3.…”

The History of Deferiprone (L1) and the Complete Treatment of Iron Overload in Thalassaemia

“…Similar controversies apply in the risk/benefit assessment for the use of chelating drugs not only in transfusion-dependent thalassemia (TDT) but in patients with non -transfusion dependent thalassaemia (NTDT) intermedia, idiopathic haemochromatosis, myelodyplasia, sickle cell disease, post-transplanted sickle cell disease and thalassaemia as well as many other categories of patients. 78,[104][105][106][107][108][109][110] With regards to personalised medicine, the characterisation of the iron metabolic or toxicity or other related targets is necessary for designing the appropriate therapeutic strategies in each condition and each patient, which can result in the optimisation of chelating drug protocol or other therapeutic interventions. [111][112][113][114][115][116][117] In this context, the mechanisms of iron release from ferritin and haemosiderin, as well as other molecular or cellular mechanisms are of particular interest.…”

Novel genetic therapeutic approaches for modulating the severity of β‑thalassemia (Review)

“…Among these drugs, hydroxyurea is a good and cost-effective drug that normalizes the activity of several signalling pathways resulting in augmented HbF production, which ultimately results in reduction in the frequency of blood transfusions required (24). Allogenic (hemopoietic cell) transplantation is a promising cure for thalassemia; however, there are several hurdles preventing its use: Limited availability of Human Leukocyte Antigen (HLA)-identical donors, graft rejection in certain cases and the role of iron toxicity in haematopoietic stem cell transplantation (HSCT) rejection or failure (25). Lentiglobin gene therapy is the latest method for cure without any mortality, graft rejection and clonal dominance issues.…”