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Answered Questions:
1. Is there any effect of Deferasirox on bones or any bony lesions have been found with the drug use in thalssemia major?
According to Dr. Taher and Dr. Cappellini, both experts in the fields of iron metabolism and iron chelation, there have been no reports of adverse effects on bone associated with deferasirox. Moreover, there is no mention of effects on bone associated with deferasirox in the October 2010 Swiss PI or the EMEA's update site. It should be noted, however, that bone loss and altered bone architecture have long been known to be associated with iron overload.1
1. Hershko C. Blood 2010;116:2405-2406.
2. What are the neurodegenerative diseases associated with excess iron?
Response from John B. Porter, MA, MD, FRCP
Transfusional iron overload and genetic HFE haemochromatosis, conditions in which total body iron is increased, are not typically associated with neurodegenerative disease. This occurs when the distribution of iron rather than total body iron content are the cause of neuro-pathology. Examples of this are Freidrichs Ataxia and Acaeruloplasminaemia.
In Friedreich ataxia, decreased iron-sulphur cluster and heme formation leads to mitochondrial iron accumulation and ensuing oxidative damage that primarily affects sensory neurons, the myocardium, and endocrine glands. Freidrichs Ataxia is caused by the abnormal expansion of a GAA repeat in intron 1 of the FRDA gene on chromosome 9, which encodes a 210 amino acid protein called frataxin.
In aceruloplasminaemia, patients typically present in adulthood with neurological symptoms such as chorea and cognitive decline, due to iron accumulation in the brain, predominantly in the globus pallidus. Increased iron deposition in the liver and other organs such as the pancreas also occurs. Caeruloplasmin is a plasma oxidase that regulates the efficiency of iron efflux from cells and catalysies the oxidation of Fe(2+) to Fe(3+) thereby promoting Fe(3+) binding to transferrin. Caeruloplasmin also stabilizes ferroportin membrane expression. In the brain, GPI (glycosylphosphatidylinositol)-linked Cp is the predominant form.
In both Friedreich ataxia (Boddaert . Blood , 110, 2007) and acaeruloplasminaemia (Skidmore , J Neurol Neurosurg Psychiatry, 2008) there evidence of syympotmatic improvement with oral iron chelation therapy.
3. I have a young patient who has hereditary haemochromatosis and beta thalassaemia trait (Hb around 9-10). He has been on weekly venesection for past year but his iron saturation remains >95%, ferritin around 300. I can't intensify venesection as he becomes symptomatic with his anaemia. Is it any role to add oral iron chelator deferasirox?
- The residual iron excess can be considered as minor, given that serum ferritin is only slightly increased (it would be interesting to know the initial ferritin levels and the total number of weekly venesections performed in order to reach a serum ferritin level of approximately 300). Moreover, it is likely that the increase of transferrin saturation is partly due to hemolysis (through increased serum iron).
- Therefore, I would not propose deferasirox therapy, in so far as side-effects of iron chelation are expected to be more important when body iron overload is only very moderate.
- I would keep on venesection therapy, on a lower schedule (if weekly venesections turn out to be poorly tolerated), with, for instance, one 300 mL venesection every month (or every 3 weeks), with the goal that ferritin eventually reaches around 100 and transferrin saturation becomes lower than 75% (above this threshold, potentially toxic plasma non-transferrin bound iron may appear in the plasma).
4. In compliant patients who do not achieve a satisfactory response to DFO, what factors would suggest moving to a combination of DFO and DFP and what factors would prompt you to switch to DFX?
Although the combination of DFO (twice weekly SC) plus DFP (three times/day orally) significantly increases the probability of achieving a response, this regimen may be difficult for some patients to adhere to. Advantages offered by DFX are the efficacy of this agent and the convenience of a once-daily oral regimen, particularly in patients who are having difficulty with SC administration. Of course, the side effect profiles of the two regimens also impact the choice of therapy. Neutropenia and, less frequently, agranulocytosis, have been observed with DFO + DFP, whereas side effects most commonly associated with DFX are gastrointestinal disturbances and rash.
5. What is the first step you would take in assessing non-response?
Since the primary reason for drug failure with any regimen is the patient's failure to take the drug, the first thing is to ascertain the patient's adherence to therapy. Following that, you should determine the patient's transfusion loading rate, try an alternate measure of response, and see if there are other issues, such an inadequate dose requiring dose titration, comorbid diseases that may confound the assessment of response, or the timing of oral dosing with food intake, etc, that may be a factor.
6. Are there similar issues with bioavailability of DFO and DFP that have been observed with DFX?
It's important to note that data on interpatient differences in bioavailability are scanty even in terms of DFX, and exactly what accounts for patient differences in bioavailability of DFX is unclear. With the exception of oral absorption, which is not an issue with an agent administered SC, patient differences in distribution, metabolism, and excretion could exist with all chelators. At this point, we don't know.
7. Do patients take advantage of peer support groups/family groups in your experience?
As mentioned, these groups are part of a larger program to improve adherence that includes disease education, medication diaries, and positive reinforcement from the staff for good compliance. Patients and their families derive considerable benefit from the support groups and the program has had a positive impact. But compliance still remains a problem.
8. Should the initial starting dose of chelation be based on a combined calculation of transfusion rate and body iron stores or should one start at the recommended initial dose and adjust accordingly depending on response?
This issue was only investigated for the oral chelator deferasirox. The current recommendation is a fixed starting dose based on iron intake from ongoing blood transfusions and current iron burden with subsequent individual dose titration every 3 months according to serum ferritin levels and safety markers. One important question to answer during dose assignment is whether the target is to reduce or maintain body iron levels.
