As early diagnosis and treatment of thalassemia are improving the prognosis of pediatric
and young adult thalassemia patients, the major cause of illness and mortality has shifted from the
problems of hemoglobin-deficient anemia to iron overload associated with chronic blood transfusion
therapy. Heart, liver and other organ failure due to iron toxicity is the leading cause of death for
thalassemia patients in the developed world. In chronically-transfused thalassemia patients, the body is
receiving large amounts of exogenous iron and, having no mechanism to excrete the extra iron, stores it
primarily in the spleen, liver, endocrine organs, and heart. Iron storage is further compounded by
increased iron absorption from food as a way to combat anemia.

Aggressive monitoring of body iron burden is key to the survival and well-being of a chronically-
transfused patient. There are several methods of iron assessment. The easiest, most affordable, least
reliable and most common method is a serum ferritin test. This involves drawing a small sample of blood
and testing for its ferritin content, which is an important iron-storage protein. Ferritin tests are useful
for measuring gross iron overload or dramatic reduction in iron levels, but are limited when attempting
to finely measure actual organ storage of iron. Several factors can affect test results: inflammation or
infection of the liver, liver disease (such as fibrosis or hepatitis), hemolysis or breakdown of red blood
cells during the blood draw or due to rough handling of the sample, vitamin C deficiency, or even too
much alcohol the night before a test. Ferritin tests remain an approximation rather than an accurate
indicator of iron stores.

A second method of measuring body iron burden is the liver biopsy, a direct sampling of burdened
tissue, during which a small piece of liver tissue is removed and examined for iron fall between storage.
The method is an invasive procedure, sometimes involving a short hospital stay. As a result, many
patients are reluctant to get a liver biopsy and are worried about its safety. However, a study from Italy,
where thalassemia is extremely prevalent, showed that of 1000 patients biopsied over 5 years, no
complications occurred. This is due in part to improved ultrasound technology which allows physicians
to see the liver before the procedure.

Dr. Nancy Olivieri of Toronto and Dr. Gary Brittenham of Cleveland studied several patients and found
that after a specific threshold - 7 mg of hepatic (liver) iron per gram dry weight - a patient will
experience increased risk of illness and death. Those with iron levels over 15 mg/g dry weight
experience substantial risk for death. Conversely, levels under 3 mg/g dry weight, while considered
normal for non-transfused people, should be avoided for transfused patients because of the associated
risks of Desferal toxicity. These include growth problems, pulmonary toxicity, kidney dysfunction, spinal
and bony changes (crucial for the growing child), auditory problems (tinitus or ringing in the ears), and
ocular abnormalities. Thus it is important for thal patients to keep their body iron levels between a
specific range of 3 - 7 mg/g dry weight for optimal health. Dr. Olivieri recommends annual liver biopsies
at the same time every year. For patients with steady levels, the time between biopsies can increase 1
1/2 to 2 years.

One of the best ways to rid the body of extra iron is through daily infusions of desferrioxamine or
Desferal. Desferal actively binds iron that it encounters in the body and excretes it in urine and stool.
A study conducted by Sir David Weatherall et al showed that optimal iron chelation occurred when
Desferal was infused 24 hours a day every day, while 12 hours of infusion was 80% as effective as a 24-
hour infusion. For most patients' lifestyles, though, this amount of therapy is inconvenient. Many people
do not allot twelve hours every evening for Desferal therapy. However, the longer a patient uses
Desferal, the better for their health. If, for example, a person returns home at two in the morning, he
should not forego the night because of reduced treatment time. Nor should he double the amount of
Desferal, since concentrated doses are irritating to the body. Dr. Olivieri suggests patients think about
maximizing the amount of Desferal time over a week rather than day to day. This way, hours clocked in,
no matter when or where, work toward chelating iron.

Chelation should begin one year after the start of chronic transfusions if a biopsy records a hepatic
(liver) iron of higher than 3.2 mg/g dry weight. A baseline assessment of height and a spinal X-ray should
be taken to monitor growth, and the daily dose of Desferal should not exceed 35 mg/kg dry weight
during the first three years. After that, dose should not exceed 50 mg/kg.

Vitamin C is a supplement patients can take to help Desferal do its job. Supplements of 100-200 mg
should be taken concurrent with Desferal use, for example 1/2 hour after the start of one's daily
therapy. A word of caution: excessive Vitamin C can exacerbate existing heart and liver problems by
increasing the amount of iron circulating in the blood.

One of the most difficult problems associated with Desferal use is compliance. Nightly infusions of the
medicine can be emotionally taxing and frustrating, especially for a patient entering their teen years.
The effects of Desferal are not immediately felt, nor are the effects of iron overload, so teens often stop
therapy for long periods of time. It is important to develop mentor programs and peer support groups
early on to encourage good habits and regular use of Desferal. Only with consistent use of
desferrioxamine can the damaging effects of iron overload be averted.

Iron overload and chelation therapy

Patients with significant iron overload

Some patients have particularly high iron loads, a high presence of cardiac iron, or other organ toxicity
that may require more aggressive treatment. There are many ways to approach these patients, and
treatments need to be tailored to achieve reduction of iron in a way that is acceptable to each patient.
With the availably of several chelators, a number of new approaches have been suggested. There is no
extensive experience with any of them. Some are presented below.

High-dose, continuous deferoxamine

An aggressive chelation regimen is recommended when liver iron is greater than 20 mg/g dry weight, or
cardiac T2* is less than 20. A higher—but not a toxic—dose of deferoxamine is recommended.
Intensification of treatment can be accomplished by administering continuous intravenous
deferoxamine (via a central intravenous line, if possible) in the hospital or in an outpatient/day unit. A
minimum of 72 hours continuous, one to two times a month, in addition to regular use of subcutaneous
deferoxamine has been recommended to increase iron removal. The continuous regimen alone may
control liver iron concentration but will allow development of cardiac iron. Intravenous treatment is
given at 50 to 100 mg/kg per day (with a maximum dose of 6 g per day). This regimen should be
continued until the ferritin level is less than 2,000 ng/mL on two consecutive occasions. Alternative
regimens include daily intravenous administration of deferoxamine, or continuous deferoxamine via
percutaneous line or an indwelling venous access device. In all such treatment, high-dose, continuous
treatments require careful monitoring for signs of toxicity.

Combination therapy: deferoxamine and deferasirox

Combination therapy of deferoxamine and deferasirox is presently being studied in North America. In
over 30 patients followed for over one year, combination therapy appeared safe and effective in
lowering body and cardiac iron. Larger multicenter trials are now underway.

Combination therapy: deferoxamine and deferiprone

Combination therapy with deferoxamine and deferiprone is increasingly being used worldwide.
Treatment protocols include both sequential and simultaneous administration of both drugs. Pilot
studies show that sequential therapy (for example, three days of deferoxamine and four days of
deferiprone) appears to improve compliance and maintain iron levels. Simultaneous therapy (both drugs
daily) improves cardiac function better than either drug alone. Careful monitoring for increased side
effects is imperative.