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.

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.

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

Deferiprone (L1) was originally designed, synthesised and screened in vitro and in vivo in 1981 by Kontoghiorghes G. J. following his discovery of the novel alpha-ketohydroxypyridine class of iron chelators (1978-1981), which were intended for clinical use. The journey through the years for the treatment of thalassaemia with L1 has been a very difficult one with an intriguing turn of events, which continue until today. Despite many complications, such as the extensive use of L1 suboptimal dose protocols, the aim of chelation therapy-namely, the complete removal of excess iron in thalassaemia major patients, has been achieved in most cases following the introduction of specific L1 and L1/deferoxamine combinations. Many such patients continue to maintain normal iron stores. Thalassemia has changed from a fatal to chronic disease; also thanks to L1 therapy and thalassaemia patients are active professional members in all sectors of society, have their own families with children and grandchildren and their lifespan is approaching that of normal individuals. No changes in the low toxicity profile of L1 have been observed in more than 30 years of clinical use and prophylaxis against the low incidence of agranulocytosis is maintained using mandatory monitoring of weekly white blood cells' count. Thousands of thalassaemia patients are still denied the cardioprotective and other beneficial effects of L1 therapy. The safety of L1 in thalassaemia and other non-iron loaded diseases resulted in its selection as one of the leading therapeutics for the treatment of Friedreich's ataxia, pantothenate kinase-associated neurodegeneration and other similar cases. There are also increasing prospects for the application of L1 as a main, alternative or adjuvant therapy in many pathological conditions including cancer, infectious diseases and as a general antioxidant for diseases related to free radical pathology.

Liver iron and serum ferritin levels are misleading for estimating cardiac, pancreatic, splenic and total body iron load in thalassemia patients: factors influencing the heterogenic distribution of excess storage iron in organs as identified by MRI T2*.

A comparative assessment of excess storage iron distribution in the liver, heart, spleen and pancreas of ß-thalassemia major (ß-ΤΜ) patients has been carried out using magnetic resonance imaging (MRI) relaxation times T2*. The ß-ΤΜ patients (8-40 years, 11 males, 9 females) had variable serum ferritin levels (394-5603 µg/L) and were treated with deferoxamine (n = 10), deferiprone (n = 5) and deferoxamine/deferiprone combination (n = 5). MRI T2* assessment revealed that excess iron is not proportionally distributed among the organs but is stored at different concentrations in each organ and the distribution is different for each ß-ΤΜ patient. There is random variation in the distribution of excess storage iron from normal to severe levels in each organ among the ß-ΤΜ patients by comparison to the same organs of ten normal volunteers. The correlation of serum ferritin with T2* was for spleen (r = -0.81), liver (r = -0.63), pancreas (r = -0.33) and none with heart. Similar trend was observed in the correlation of liver T2* with the T2* of spleen (r = 0.62), pancreas (r = 0.61) and none with heart. These studies contradict previous assumptions that serum ferritin and liver iron concentration is proportional to the total body iron stores in ß-ΤΜ and especially cardiac iron load. The random variation in the concentration of iron in the organs of ß-ΤΜ patients appears to be related to the chelation protocol, organ function, genetic, dietary, pharmacological and other factors. Monitoring of the iron load for all the organs is recommended for each ß-ΤΜ patient.

Efficacy, compliance and toxicity factors are affecting the rate of normalization of body iron stores in thalassemia patients using the deferiprone and deferoxamine combination therapy.

The international committee on chelation (ICOC) of deferiprone (L1) and deferoxamine (DFO) combination therapy was the first protocol reported to have achieved normal range body iron store levels (NRBISL) in ß-thalassemia major (ß-TM) patients. A follow-up study in eight ß-TM patients has been designed to investigate the factors affecting the rate of iron removal leading to NRBISL. The patients had variable serum ferritin [mean ± SE (standard error) =1692 ± 366, range 539-3845 µg/L)] and magnetic resonance imaging (MRI) T2* relaxation times cardiac (mean ± SE =11.1 ± 2.5, range 4.5-24.2 ms) and liver (mean ± SE = 4.3 ± 1.8, range 1.4-14 ms). Organ function, blood and other biochemical parameters were regularly monitored for toxicity. The ICOC L1 (80-100 mg/kg/day) and DFO (40-60 mg/kg, at least 3 days per week) combination therapy caused an increase in cardiac (mean ± SE =30.2 ± 2.3, range 22-41 ms) and liver (mean ± SE =27.6 ± 2.8, range 9.1-35 ms) T2* and reduction in serum ferritin (mean ± SE = 158 ± 49, range 40-421 µg/L) to within the NRBISL. The rate of normalization was variable and in one case was achieved within 9 months, whereas the longest was about 3 years. The initial iron load, the rate of transfusions, the combination dose protocol and the level of compliance were the major factors affecting the rate of normalization of the iron stores. No serious toxicity was observed during the study period, which lasted a total of 24.7 patient years.

Reduction of body iron stores to normal range levels in thalassaemia by using a deferiprone/deferoxamine combination and their maintenance thereafter by deferiprone monotherapy.

BACKGROUND: Iron overload and toxicity is the major cause of morbidity and mortality in thalassaemia patients. New chelating drug protocols are necessary to treat completely transfusional iron overload and eliminate associated toxicity. Appropriate deferiprone/deferoxamine combinations could achieve this goal. METHODS: A single-centre, single-armed, proof-of-concept study of the combination of deferiprone (75-100 mg/kg/d) and deferoxamine (40-60 mg/kg, at least 3 d per week) was carried out in eight patients with thalassaemia major (four men and four women) for 21-68 months. The patients were previously treated with deferoxamine and had variable serum ferritin [geometric (G) mean ± SD = 1446 ± 1035 µg/L] and magnetic resonance imaging relaxation times T2* cardiac (Gmean ± SD = 10.32 ± 6.72 ms) and liver (G mean ± SD = 3.77 ± 4.69 ms). The use of deferiprone (80-100 mg/kg/d) continued for 7-26 months in seven of the eight patients following the combination therapy. Organ function, blood and other biochemical parameters were monitored for toxicity. RESULTS: The deferiprone/deferoxamine combination caused an absolute value increase in cardiac (G mean ± SD = 29.6 ± 6.6 ms, P < 0.00076) and liver (G mean ± SD = 25.9 ± 8.07 ms, P < 0.00075) T2* and reduction in serum ferritin (G mean ± SD = 114.7 ± 139.8 µg/L, P < 0.0052) to within the normal body iron store range levels. In two cases, normalisation was achieved within a year. Deferiprone monotherapy was sufficient thereafter in maintaining normal range cardiac (G mean ± SD = 31.4 ± 5.25 ms, P < 0.79) and liver (G mean ± SD = 26.2 ± 12.4 ms, P < 0.58) T2* and normal serum ferritin (G mean ± SD = 150.7 ± 159.1, µg/L, P < 0.17) in five of the seven patients. No serious toxicity was observed. CONCLUSION: Transfusional iron overload in patients with thalassaemia could be reduced to normal body iron range levels using effective deferiprone/deferoxamine combinations. These levels could be maintained using deferiprone monotherapy.

Risk/benefit assessment, advantages over other drugs and targeting methods in the use of deferiprone as a pharmaceutical antioxidant in iron loading and non iron loading conditions.

Tissue damage caused by oxidative stress is a common characteristic of many conditions involving different major organs such as the brain, heart, liver and kidneys. The treatment of such conditions using classical antioxidants is not in most cases sufficient or effective because it lacks specificity and has a low therapeutic index. Increased evidence from in vitro, in vivo and clinical studies suggest that deferiprone (L1) can be used as a potent pharmaceutical antioxidant by mobilizing labile iron and copper and/or inhibiting their catalytic activity in the formation of free radicals and oxidative stress in tissue damage. The high therapeutic index, tissue penetration, rapid iron binding and clearance of the iron complex, and the low toxicity of L1, support its application as an antioxidant pharmaceutical for adjuvant, alternative or main therapy, especially in conditions where other treatments have failed. Substantial clinical improvement and reversal in most cases of the tissue damage has been observed in cardiomyopathy in thalassemia, diabetic nephropathy and glomerulonephritis in kidney disease, Friedreich's Ataxia and Fanconi Anemia patients. In contrast to L1, both deferoxamine (DFO) and deferasirox (DFRA) have major disadvantages in their use in non iron loading conditions due to toxicity implications. Further studies in the above and other conditions and optimization of the L1 therapy in each individual will increase the prospects of the application and role of L1 as a universal antioxidant pharmaceutical.