Exjade - first oral treatment for iron overload - will make life easier for patients needing regular blood transfusion

New data presented at the American Society of Hematology meeting in Atlanta this month suggest the problems associated with iron overload in frequently-transfused patients can now be managed simply with an oral treatment rather than continuous infusions of several hours duration. 

Iron was removed from the blood and tissues of patients just as safely and effectively with the novel once-daily oral chelator treatment deferasirox (Exjade) as with the standard older injectable iron chelator deferoxamine. The finding is predicted to have major implications for boosting the rate of compliance with treatment.

Dr Elliott Vichinsky, Director of Hematology/Oncology at Oakland Children’s Hospital and Research Center compared the oral iron chelator Exjade with deferoxamine in a randomised controlled trial of 195 patients with sickle cell disease, 98 of whom were under 16. Dosing was based on baseline liver iron concentrations (LIC), as determined by SQUID (superconducting quantum interference device) measurements. The mean dose of oral Exjade treatment was 17.3mg/kg/day and of deferoxamine was 36mg/kg/day. Efficacy was measured by LIC and serum ferritin over one year.

 “Both agents showed a statistically significant reduction in LIC from baseline and serum ferritin values were consistent with LIC by the end of the study”, said Dr Vichinsky. The oral therapy also induced negative iron balance, ie, removed more iron than was added by transfusions indicating that accumulated iron was being excreted and total body iron reduced, he noted.

Side effects experienced with deferasirox were most frequently mild to moderate gastro-intestinal effects -  nausea, vomiting, diarrhoea, abdominal pain and in a few cases skin rash.  Increases in serum creatinine were seen but these were usually within the normal range, he said.

Patients with thalassaemia, sickle cell disease and rare myelodysplastic syndromes need lifelong regular transfusions from an early age. Transfused blood leads to excess iron that can accumulate in body organs such as the lungs, liver, heart and brain, he explained.   Iron chelator therapy is considered vital for reducing total body iron before it has time to cause potentially fatal cardiomyopathy, or damage to liver and to endocrine glands, including the thyroid, parathyroid and pituitary glands.  “The number one cause of death resulting from iron overload is diabetes resulting from damaged endocrine glands.”

Deferoxamine requires an eight to 12-hour overnight subcutaneous infusion, five to seven nights a week. Both drugs bind to iron and allow it to be excreted.  “But iron-chelating drugs have to remain in the circulation for hours in order to soak up iron from the tissues” explained Dr Vichinsky.  With deferoxamine this means a continuous infusion of several hours and this causes problems with compliance.  “Survival is directly related to compliance,” he added.

With overnight subcutaneous infusion therapy, the cost of providing home care nursing can be expensive running into 10s of thousands of dollars per patient per year.  Deferasirox has a long half-life of 8 to 16 hours and so needs only to be administered once a day as a drink (tablets are dispersed in juice or water).It will remove the need for a home nursing care infrastructure, he suggested.

The study above showed over three quarters of previously deferoxamine-treated patients preferred oral treatment with Exjade to the subcutaneous infusion, he said.  More than 85 per cent receiving oral therapy opted to stay on it.  “A once-daily pill obviously scores over injectables in popularity.”

Heart benefits from therapy now demonstrable

Preclinical studies presented at ASH also demonstrated evidence of deferasirox’s ability to remove excess iron from the heart which affects a subsection of high-risk sickle cell and other patients.  Professor John Porter of University College Hospital, London, said a new MRI cardiac imaging test T2* had made it possible to estimate the iron content of the heart over time.  In a small study of 30 patients randomised to Exjade or deferoxamine, changes in T2* indicated an improvement in left ventricular function after chelation treatment.

 “Iron accumulates in cardiac myosites, the heart muscle cells, generating harmful free radicals which decrease the heart’s pumping ability.”  The change in T2* measurement indicates improvement in heart function as the iron content of the heart is decreased after therapy. A T2* score below 20 milliseconds is a signal for excess cardiac iron.  As the cardiac iron burden reduces, the T2* score is increased. “Along with the removal of liver iron, this is very encouraging,” said Professor Porter.

In an analysis of 22 patients with thalassaemia and anaemias receiving deferasirox for one year, mean MRI T2* scores improved from 18 to 23.1 milliseconds and correlated with significant reductions in liver iron and serum ferritin – additional measures of stored body iron.

The software for the T2* MRI technique, developed by cardiologists at the Royal Brompton Hospital, London, UK, is still being validated but is now being made available to five centres in the US and will be rolled out to other centres over the next five years, he noted.

Deferasirox was fast-tracked to meet the need for an oral iron chelator therapy and is currently available in the US and Switzerland.  It is awaiting licensing approval in other countries and further clinical trials are in progress.

To see more features by Olwen Glynn Owen follow this link to his first feature article and scroll to the end for a list:
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