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I'm gonna lay down my burden....

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Bergit Korschan-Kuhle

28 February 2018

No, no chance to lay down my burden of iron overload somewhere.

Our organism does not have any biochemical or physiological pathway to remove excess iron. Instead the excess iron accumulates mainly in the liver, joints, pancreas, bone marrow and at the worst in the heart, causing organ and tissue damage in the long run.

We’re talking about transfusion related iron overload. I have been a Myelodysplastic Syndrome (MDS) patient for more than 12 years and I regularly need blood.

The main cause of iron overload is transfusion therapy. Each unit of blood transfused delivers 200–250mg of iron. After only 20 units of transfused blood, 4,000–5,000 mg of iron will have been delivered to the body. At this iron-loading, the serum ferritin level rises to about 1,000μg/l. When this level is about to be reached, the doctor suggests iron chelation for transfusion dependent patients like me.

I have never had a wealth of medical expertise on iron overload. I have accepted  the most important fact: excess iron does harm to my vital organs, so chelation is necessary. Everything went according to plan. I trusted the medication, not giving too much thought to the issue.

I have been tolerating the iron chelator Deferasirox without significant side effects for 10 years now.  I only had an uncomfortable rash in the beginning, which disappeared after two weeks and never ever came back. - The ferritin level reliably has descended and always has stayed below 1,000μg/l. So I felt safe from life-threatening organ iron deposition. I was as compliant as can be and always, always took my pills or my suspension even when travelling. Not only once I prepared and swallowed the suspension in an airport ladies‘ room. -  Finally I have built confidence in my ferritin level, which was fluctuating a little from time to time. But what the heck, my hematologists have been content with 400-700 μg/l and I have never been experiencing any discomfort.

I have been lucky with my iron-chelator Defirasirox, being free from side-effects. Whereas in MDS webforums and in my work with patients,  I met with various people suffering from all kinds of bearable or unbearable side-effects, mainly such as all stages of gastrointestinal disorders.

There was – or shall I say – there is a lot of debating about the correct timing of the tablet intake, the dosage, stop and possible re-start of the therapy out of all kinds of reasons, efficacy, ferritin levels and repeatedly drug intolerance.

Discussion has evolved since there has been a new formulation since 2016, a shift from suspension to pills. The pills are supposed to be easier to digest, because they don’t contain lactosis any more, and to be more efficient in relation to the dosage. The available statistics seem to confirm these benefits, but as always there is variability in individual cases. For me the pills are not as efficient as the suspension was. Unfortunately the suspension has already disappeared from the market. „Not as efficient“ means in my case the ferritin level remains in the 700 μg/l, but does not drop beyond anymore, although I am not transfused more frequently.

People, relying on long-term medication intake, tend to give up compliance  even for minor side-effects. Only from then on they are lulled  into a false sense of security: iron overload does not hurt, until it hurts.

This  may take years and may have the consequence of irreparable damage. Some patients are not aware of the causal corelation between compliance and efficacy. Some of them stop the therapy, because the ferritin decrease takes too long. The reasons of non-adherence are manifold. When the physician asks his patients about their adherence, most of them answer they take their medication regularly. This has been proved by different surveys in different countries.

Although everything is being explained in detail in the package leaflet, it obviously is not sufficiently perceived or understood by patients. The package leaflet, however, cannot be changed due to legal regulations. The patient’s compliance is a major issue for the pharmaceutical company, defining the medication’s success in the market. As a patient advocate I have worked in the company‘s national and international patient ad-boards to discuss additional printed material with graphics, illustrations, using lay language in the descriptions.  Thus our concern was to draw the patient‘s awareness and understanding to the dangers of iron overload and to the medication’s mode of action. Regular educational workshops are being organized for patients in many countries.

For me years of chronic transfusion dependance went by and I counted my blessings: more than 530 units of blood in total since 2008, with a stable transfusion interval of 10-18 days since 2010.

My treating professor initiated an invitation for me to a special clinic, where I  underwent an MRI in autumn 2017. They scanned my heart, liver, pancreas and my bone marrow. The results were devastating. My view on iron overload broke with the medical report.  I still have not fully recovered from what I was told. I would be very lucky, the radiologist said, that my heart was still free of iron. But my liver and my pancreas show a five-fold iron overload, also my bone marrow is full of iron. Another obstacle for haematopoiesis in addition to my blood disorder. Where do we go from here? Heading diabetis, liver cirrhosis or even hepatic cancer? My heart is iron-free, yes, but the pancreas is strongly loaded. No reason for long-lasting joy as the pancreas takes up similar iron species as the heart, only earlier. Iron overload of the pancreas serves as an early and robust marker of prospective cardiac risk.

It is neither an option for me to increase the dosage of the iron chelator – this could be toxic for my kidneys for instance - nor to reduce the number of transfusions – this would destroy my qualitiy of life and would send me into severe aemia.  I’m stuck.

As so often in the course of my disease there is a diagnosis without any therapeutic consequences. That’s frustrating.

On the medical report I more recently can read „severe hemosiderosis of the pancreas and the liver“ amongst my other serious health problems. However, my liver values (GPT, GOT) are not yet elevated. Not yet?

I am anxious and confused: that's the patient's perspective.

Only now I am finding out that for any one patient, the predictive value of ferritin is quite poor. Two patients with identical total body iron burdens can have vastly different serum ferritin levels. Many factors affect the relationship between iron overload and serum ferritin levels. But still the ferritin level  g e n e r a l l y correlates with both, total body iron stores and clinical outcomes. Serum ferritin therefore remains the most commonly used metric to monitor iron chelation therapy. Mainly because its measurements are inexpensive in comparison to  MRI.  However, the biology of circulating ferritin is poorly characterized and hardly comprehensible for non-physicians and non-scientists.

Iron homeostasis relies on a regulated network of systemic and cellular mechanisms for the acquisition, transportation and cellular utilization of the metal. I very well understand that these metabolisms are completely disturbed in case of strong iron overload.

AT THE END OF MY ARTICLE I WANT TO MAKE CLEAR ONE THING:

the outcomes of chelation therapy in Myelodysplastic Syndromes are not bad. There is a positive impact on survival, without doubt. I probably would not be alive any more without Defirasirox. There are retrospective studies clearly indicating a significant improved survival in patients who received regular iron chelation. Transplant outcomes are also far better after iron chelation therapy. And in case there is a cure, high iron stores can be drained or at least reduced by a most effective phlebotomy therapy.

So yes, there are definitely some solutions for iron overload, if you are in the right cohort.

But we urgently need more innovative iron chelation therapies.

 

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