Benefits and Risks in Polypathology and Polypharmacotherapy Challenges in the Era of the Transition of Thalassaemia from a Fatal to a Chronic or Curable Disease

Abstract

Beta thalassaemia major (TM), a potentially fatal haemoglobinopathy, has transformed from a fatal to a chronic disease in the last 30 years following the introduction of effective, personalised iron chelation protocols, in particular the use of oral deferiprone, which is most effective in the removal of excess iron from the heart. This transition in TM has been achieved by the accessibility to combination therapy with the other chelating drugs deferoxamine and deferasirox but also therapeutic advances in the treatment of related co-morbidities. The transition and design of effective personalised chelation protocols was facilitated by the development of new non-invasive diagnostic techniques for monitoring iron removal such as MRI T2*. Despite this progress, the transition in TM is mainly observed in developed countries, but not globally. Similarly, potential cures of TM with haemopoietic stem cell transplantation and gene therapy are available to selected TM patients but potentially carry high risk of toxicity. A global strategy is required for the transition efforts to become available for all TM patients worldwide. The same strategy could also benefit many other categories of transfusional iron loaded patients including other thalassaemias, sickle cell anaemia, myelodysplasia and leukaemia patients.

Iron Load Toxicity in Medicine: From Molecular and Cellular Aspects to Clinical Implications

“…Similarly, the rate of RBC transfusions may also vary, with transfusion frequency every 1–4 weeks in TM and a much lower rate for many TI patient categories. Further variations on RBC transfusions and rate of iron loading may be related to the underlying disease, individual and other factors such as hypersplenism, hemolysis, and RBC antibodies [ 39 ].…”

“…The level of excess iron in the body of iron-loaded patients can be diagnosed and monitored using a number of diagnostic techniques, most of which are also generally used for the monitoring of other diseases of iron metabolic imbalance. In addition to monitoring iron level parameters, regular clinical and biochemical assessment is also widely used in order to evaluate organ function and the extent of damage caused by iron overload, as well as other complications of the underlying disease [ 1 , 39 , 89 ].…”

“…The physiologic non-toxic levels of iron are usually characterized by the normal range of serum ferritin values (male 40–340 μg/L and female 14–150 μg/L), transferrin saturation (25–35%), and serum iron (10–40 μmol/L). In rare cases, urinary iron excretion in response to chelating drugs such as DF and L1 may also be used [ 39 , 89 ].…”

“…Liver iron concentration levels, equivalent to not more than 2 mg iron per g liver dry weight, are considered as the maximum normal physiologic levels in the assessment of liver biopsies, whereas higher levels of iron concentration have been classified to various grades of liver iron load, with the higher grades being associated with liver cirrhosis and fibrosis [ 1 , 7 , 9 , 104 , 105 ]. Furthermore, the use of histochemical techniques of the liver biopsy samples can lead to the identification of the non-heme iron concentration and the level, as well as the pattern of iron deposition in hepatocytes and Kupffer cells [ 39 , 89 , 104 , 105 ]. However, a drawback of the iron load estimation by this method is that the distribution and concentration of iron in liver and spleen biopsy samples is not uniform ( Figure 3 e,f) [ 104 ].…”

“…The concentration of excess iron in the heart was, until recently, impossible to identify by using biopsies or other methods. Furthermore, the introduction of the MRI T2 and T2* techniques have successfully been used for estimating the level of iron loading not only in the heart but also in the liver, spleen, pancreas, and other organs ( Figure 3 d) [ 39 , 96 , 100 , 104 , 108 , 109 , 110 ].…”