These are the educational objectives of the meeting. After attending, it is hoped that people will gain further insight into a number of areas.
Participants should be able to explain the pathogenesis and sequelae of iron overload in general terms. Another objective is to understand in greater detail the key issues involving iron overload in different conditions.
A lot of the information hitherto has been on thalassemia. That is what we know most about, in terms of iron overload and its treatment. As iron chelation becomes more available, and hopefully, easier to take, then we will need to know the limitations. The meeting will cover the risks and treatments of sickle cell disease and myelodysplasia.
Recently there have been new approaches to following iron overload, using a variety of techniques, including MRI. Gary Brittenham will speak about noninvasive and invasive techniques for assessing and managing iron overload.
Participants should obtain further insight into current responses to standard treatment practices. We also expect to learn about emerging new treatments. By the end of the meeting, participants should be able to describe the impact of new developments in the treatment of these diseases. Participants will also learn how therapies might be integrated to maximize therapeutic outcome.
These are the objectives of the symposium.
This is an overview of iron overload and its treatment. This talk is going to be divided into three broad sections. First, I will briefly talk about hematological causes of iron overload. We are not going to be talking about genetic hemochromatosis here, because this primarily can be treated with venesection. We will focus on iron overload, which results from blood transfusion, although issues of iron absorption will obviously be relevant.
I will discuss the sequelae of iron overload, the way in which iron causes damage to cells, and the systemic effects of organ damage.
Finally, I will review the status of standard treatment. I will talk about the general goals and principles of chelation treatment. I will review the changing pattern of morbidity and mortality over the last three decades, using desferrioxamine.
Iron overload from blood transfusion is seen in a wide variety of clinical conditions. The best known and most predictable is thalassemia major. This is because it starts with blood transfusion early in life and it is very well documented as to how rapidly iron accumulates. Also, there is a lot of information about the impact of chelation therapy on survival.
With a whole variety of other conditions, blood transfusion is less predictable. Thalassemia intermedia can range from something which is rather like thalassemia minor—with just slightly worse anemia—to something which is almost as bad as thalassemia major. The transfusion can be sporadic or may start continuously in the teens or twenties.
Sickle cell disorders are equally unpredictable in transfusion requirement. Most patients do not actually require regular transfusion. However, about 50% of patients will receive transfusion at some point in their lives. Approximately 5 to 10% of patients are on a chronic transfusion regimen.
There are highly variable requirements for blood transfusion in myelodysplasia. Peter Greenberg will address that topic. Some hemolytic anemias—such as paravac highs [phonetic] deficiency in the severe forms—require transfusion from childhood. Diamond-Blackfan and Fanconi anemias can require transfusion from early in life. Patients who undergo multiple myeloablative chemotherapy regimes can often accumulate over 100 units of blood during their various forms of treatment.
Iron turnover in the body is required for production of new red cells, about 20 or 30 mg a day, delivered by transferrin and circulation. A roughly equivalent amount is broken down in macrophages every day. The old red cells become effete, with 30 mg released under transferrin. In health, about 30% of the transferrin binding sites are saturated. This is the main flux of iron turnover in the body. Approximately 2 to 3 mg is taken into the parenchyma, mainly into the hepatocytes. This is a two-way process, so it is taken up in iron loading and released in terms of iron deficiency. Each day, 1 to 2 mg of iron is absorbed, and equivalent loss in the skin and the gut.
In iron overloading from transfusion, one unit of blood contains about 200 mg of iron, or 0.47 mg iron/ml of whole blood, equivalent to 1.16 mg iron/ml of “pure” red cells. This is quite a useful thing to know. If you know the hematocrit of the donor units that you are giving, and the volume, then you can predict exactly how much iron is being received from the transfusion regimen.
In a thalassemia major patient who has had the spleen removed and who maintains a mean hemoglobin of 12 g/dl, 300 ml of blood/kg body weight/annum will be given, on average. This is equivalent to 0.4 mg iron/kg body weight/day. This turns out to be 1 to 4 mg in addition to the absorption of the gut. Consequently, the total net positive balance is 0.4 to 0.5 mg/kg/day. This is actually even greater variability than that estimate.
If you add the transfusion to the previous scheme I have showed, you are adding, in adults, something like 20 to 30 mg/day, 0.4 mg/kg a day. The transferrin mechanism becomes saturated. Transferrin cannot cope with this. The iron released from the macrophages has to bind to other moieties. Nontransferrin outbound iron is found in the plasma. Nontransferrin iron is not a single entity. It is a heterogeneous group of iron citrate and iron albumin complexes. These are poorly understood.
The pattern of uptake in nontransferrin iron is very different from that of transferrin. It appears to be taken up into parenchyma—such as hepatocytes, heart, anterior pituitary, and pancreatic B-cells—much more rapidly than transferrin iron. This is what is probably responsible for the distribution of iron in transfusional overload.
Iron gets into cells by the initial process of the breakdown of red cells and macrophages. In normal homeostasis, the major pathway is as follows: transferrin by receptor-mediated endocytosis through the transferrin receptor, on to red cell precursors, hepatocytes, and proliferating cells in S phase.
In iron overload, nontransferrin iron is found in plasma. This is taken into cells. We know a little bit more about the uptake mechanisms such as the divalent metal cation transporter (DMT 1). Recently, a paper in Nature Medicine showed an L-type voltage-dependent Ca2+ channel (LVDCC) transporter that was important for iron uptake. These two are probably responsible for the pattern of uptake into hepatocytes, heart cells and anterior pituitary.
Early in transfusional overload, we see the iron mainly in macrophages. Very soon, we get spilling over of iron into the parenchyma, in the liver, the endocrine glands and the anterior pituitary. There is remarkably little in brain and skeletal muscle. This may have something to do with the distribution of the receptors I mentioned just now.
Liver iron predominates and correlates with the units of iron transfused. Consequently, we can get a very good estimate of overall iron buildup by measuring liver iron concentration. This is from early work by Modell in post mortem thalassemia patients. It shows the concentration in different organs in patients who died from the effects of iron overload. There are very high concentrations in some endocrine glands such as the liver, an important storage organ. These patients all died of heart failure. The concentration of iron in the heart is less than in the liver. There is very little in the skeletal muscle. This represents the whole stain of the liver and the heart in one of these patients.
This has been the best study, in terms of mortality from iron overload in thalassemia. This is from a paper in the late 1980s. Heart disease is the major cause of death in these patients. Most patients are not affected by heart disease before their second decade. Infection is an important cause of death in iron overload. It is not just the hyposplenic state; there seems to be an increased susceptibility to infection. Liver disease is the other major cause of death and morbidity.
In thalassemia patients today, we still see problems with growth failure, mainly due to hypogonadism from hypogonadotrophic hypogonadism. There are problems with sexual development and fertility, diabetes, hypothyroidism, hypoparathyroidism, and osteoporosis. It is not clear whether the osteoporosis is directly related to iron overload or a secondary effect of hypogonadism. Certainly it is related to that, but there are probably other causes, as well.
Iron induces damage through nontransferrin iron in plasma. The actual evidence that nontransferrin iron is important for toxicity is a bit indirect. We know that levels in the blood correlate inversely with antioxidant depletion measured in the blood. We know that we can use NTBI to generate lipid peroxidation in various in vitro models. It is not clear which species of NTBI are toxic. Is it the citrate forms? Is the rapidly chelatable forms? Are the redox active forms important? There needs to be more understanding of this. We are not sure how to use this in a clinical setting.
There is the concept of the labile intracellular iron pool. Most iron in cells is not chelatable, being present as ferritin and hemosiderin. This is broken down on a regular basis in the low molecular weight pool. When it exceeds a certain concentration, probably 3 to 5 micromolar, it can induce lipid peroxidation and organelle damage.
We know from clinical evidence that heart performance can improve very rapidly with intravenous Desferal. This can happen within a few days in patients who are in incipient heart failure. If you measure cardiac iron over this process, albeit indirectly, using MRI techniques, that does not change over a period of weeks or months. This fits in with the concept of the toxic labile iron pool within heart cells.
One of the reasons iron is so ubiquitous in biology is its facility to redox cycle between the Fe2 and Fe3 state. In this process, it can generate free radicals, particularly in iron overload. The hydroxyl radical is the radical which has been most closely associated with iron-induced toxicity. There are probably other species which are important, such as the peroxynitrite. The Haber-Weiss reaction with the generation of hydroxyl radicals is catalyzed first by the reduction of Fe3 to Fe2 and the subsequent oxidation of Fe2 to Fe3. This produces hydroxyl radicals, a highly reactive species. They will interact with a whole variety of molecules they come in close contact with. The classic scheme is with the peroxidation. In this example, the hydroxyl radical attacks the lipid to extract hydrogen. There are some molecular rearrangements—oxygen update with production of peroxyl radical. A chain reaction then occurs with the end production of a lipid hydroperoxide which will compose. We can detect that in a variety of ways. The classic way is by malondialdehyde (MDA).
We have increased free iron. This could be NTBI. Other possibilities are LIP within cells, generating hydroxyl radicals, increasing lipid peroxidation, causing organelle damage directly. This can lead directly to cell death. We can have indirect threats in which cytokines are released—such as TGF-ß1, which has been shown to increase collagen synthesis—so we get fibrosis.
The duality of cell death and fibrosis is seen in a number of cell types, in response to iron overload. The next question is what levels of iron are associated with pathology. The data we have is remarkably complete. We have associations of serum ferritin with survival in thalassemia patients. If the ferritins are consistently above 2,500, this is associated with a much worse cardiac free survival. Brittenham looked at the association between liver iron and survival over a 10-year period, in 53 thalassemia patients. All of the patients who developed cardiac disease had liver irons of about 15 mg/g dry weight.
However, there are a lot of uncertainties. We don't know the relationship between the concentration of iron in other tissues, or the prognosis in the heart. We don't know the relative importance of storage versus labile iron to tissue toxicity. There is a paradox of improvement in heart function with short exposure to Desferal, even though the storage iron did not increase very much. We need to understand that relationship further.
We do not know the effect of duration of iron loading on risk. This is very relevant to the age at which patients start treatment. We often start transfusing sickle patients at 10 or 20 years of age. How does the duration relate to risk, given the level of iron loading? Are there differences in different disease states? Elliott Vichinsky will be addressing some of the potential differences between thalassemia and sickle.
We do not know how the duration of exposure to chelator, the so-called protection time, relates to protection from iron toxicity. If you give chelator 24 hours a day, or it is present in the bloodstream 24 hours a day, you might anticipate that toxicity in the labile pool would be reduced. We do not have respective studies looking at that.
This scheme incorporates the idea of 15 mg/g dry weight as a cardiac threshold. This is not set in stone but clearly acts as a guide when we are trying to think about new chelation treatments. We know that heterozygotes with hemochromatosis can reach levels of up to 7 mg/g dry weight, without apparent problems. Therefore, we should aim to keep the liver iron somewhere in this range. If you never get iron overload, if you never build up iron in the liver, you are unlikely to spill iron out into other tissues.
We want to get iron balance with 'safe' tissue levels. This is 0.4 to 0.5 mg/kg/day excretion, total, either in the urine or in the feces. This is going to be a slow process; there are finite chelatable pools. We need to detoxify the iron, and we need the chelation to be safe. This is a balancing act, because we know the effects of excess iron. Excess chelator can result in inhibition of metalloenzymes, neurotoxicity and growth failure in the case of Desferal. Excess chelator can cause bone marrow toxicity in the deferiprone.
This is a scheme of how Desferal works, based largely on the work of Tom Hirschco [phonetic]. An old red cell is broken down in macrophage of the iron release. As the iron is released, if the transferrin is saturated, then the iron will become available for Desferal. Chelation of iron results in iron excretion in the urine. This occurs with hexagon technology which wraps in one-to-one coordination with iron. The iron that is released from the breakdown of red cells is excreted almost entirely in the urine, in the case of Desferal.
The storage iron pool is very important. This becomes available as it is broken down in lysosomes. We know that Desferal gets into hepatocytes relatively easily and can chelate this pool. This is excreted almost exclusively in the feces. By this scheme, half the iron is excreted in the urine and half in the feces, but they come from different iron pools.
At the cellular level, we have a cell taking up transferrin iron by receptor-mediated endocytosis. We have nontransferrin iron being taken up either by the DMT 1 or the LVDCC mechanism, entering the iron pool and making it larger. When it reaches a critical mass, we have the risk of generating free radicals and causing organelle damage. What we are trying to do with the chelators is to mop up these various pools as they enter the cell as a labile iron. This is to prevent ferritin synthesis and to chelate iron as it is broken down from lysosomal degradation of ferritin. We do not want to inhibit the production of essential proteins in cells.
Desferal is the best-known chelator. It is a hexadentate molecule. It has six teeth. It wraps around one molecule. The absorption features the use of smaller molecules which bind either in a 3:1 or 2:1 ratio. These will be better absorbed, but they may be inherently less stable. We have a balancing act between stable, fully absorbed molecules and possibly less-stable, smaller molecules.
Desferal has been around for three decades. It was first given as bolus doses, either IM or IV, and subsequently, subcutaneously. It became apparent in the early 1970s that intramuscular boluses of Desferal stabilized hepatic iron and fibrosis. Important work by Propper and coworkers showed that 24-hour infusions gave iron balance. This was followed up by subcutaneous studies by the same group that showed that you could get iron balance with subcutaneous treatment. Subsequently, Pippard and others showed that you only needed to give a 12-hour infusion to get iron balance. Pippard showed that half the iron came out in the urine and feces. His study defined some of the things that affect the variability in that.
The first evidence that Desferal prolonged survival came from the early IM work and was published by Modell. In the early 1980s, there was increasing evidence that Desferal was good at improving asymptomatic cardiac disease. The evidence also showed Desferal reversed cardiac failure and had a long-term effect on reducing cardiac disease. It was shown that if you give high dose IV Desferal, you could reverse heart failure in some patients. It also became clear that a number of the other complications, such as hypogonadism, became less frequent. While we still see patients with hypogonadism, the frequency is undoubtedly dropping.
Long-term compliance issues became clearer in the 1990s. We showed that long-term survival can be very good in patients—even though they have had previous heart failure—provided you continue the regimen.
In summary, Desferal prevents cardiac disease and it can reverse cardiac disease. It can prevent hepatic fibrosis. It can decrease diabetes, hypothyroidism, hypoparathyroidism, and hypogonadotrophic hypogonadism, but all of these conditions still occur. The benefits of survival are clear if the patient is compliant.
On the other hand, there are problems with prognosis, mainly due to problems with parenteral administration and compliance. When we give high doses there is oto and retinal toxicity, related to high dose and low iron loading. Bone toxicity will result from high doses, particularly in children. The short plasma half life leads to a very short protection time. Protection is only present during infusion of the drug. Morbidity persists in some patients, despite good compliance.
This shows the rapid recurrence of NTBI after stopping an infusion. It makes the point that ideally, we need a drug which is present in the blood all the time. This study from Antonio Piga's group shows the relationship of compliance to prognosis. If you are able to do infusions five times a week or more, then the prognosis is good. If you fail that, your prognosis slips away markedly.
A paper in Lancet a couple of years ago, reviewing the overall UK data, was very disappointing. It showed only 50% survival beyond 35 years in patients as a whole. This, however, is unusually gloomy. In the UK, you can see that survival is very much better. We have no deaths at all in patients born after 1975. We have an overall survival rate of 78% at 40 years of age. We can attribute this to the interest of specialists. In the treatment of iron overload, there is a message for specialists. It is important that patients are seen by someone who has an interest in iron overload, and who will work very carefully on the aspects of monitoring and compliance.
We need to improve the monitoring and delivery of current treatment, to maximize the outcome and minimize the complications. A number of new chelators in development will be discussed later this morning; I will not expand upon these now.
We need to understand more about the optimal use of chelation in other groups of patients with thalassemia. We need to understand how sickle cell disease differs from thalassemia, for example, so that we can make clear recommendations about when chelation is indicated.
It is not just what we know, but also what we do not know. First, we know that conventional treatment with Desferal works, provided the patient takes it. Not enough doctors work with patients to ensure that they take it. We can learn from that. The survival is really very good, if people take it.
With emerging new chelation treatments, we need to understand how to monitor treatment properly. To do that, we need to understand the factors that affect iron toxicity. We covered the various iron pools which affect iron toxicities, such as nontransferrin iron and labile intracellular iron. We looked at how that relates to total levels of iron loading in the body.
I covered storage iron, which we can measure quite effectively by liver biopsy or with certain noninvasive techniques, such as SQUID and MRI. I looked at the difference between storage iron and labile iron, which is toxic, which we do not really have a handle on. We know that if we can mop that up with chelation treatment, we can reverse things like heart failure quite effectively. This would not have any demonstrable effect on things we measure, other than organ function. I explained that we do not understand everything fully. That is a challenge when we have new chelation regimes available with oral chelators. What do we actually measure? How do we test how well we are doing? It is important to be able to control body iron, but there were other things, such as iron toxicity, which we need to get a handle on, as well.
For the last three decades, knowledge of how to use Desferal has increased. If it is used, it is effective and has tolerable toxicity. The problem is, it is a difficult treatment to take. Many patients will not take it unless they have a lot of help in specialist centers. Oral chelators potentially extend iron chelation to patient groups who have difficulty in taking it at the moment, particularly patients with sickle cell disease. It also has secondary effects, because it may alter the way we treat some diseases. In sickle cell disease, we are often inhibited from using chronic transfusion regimes, because of the fear of iron overload. If we have a safe and effective oral chelation treatment, we may end up transfusing more patients. Therefore, on balance, the quality of life will be better.
Myelodysplasia is a heterogeneous group of conditions. There is iron overload, which affects older patients. There is myelodysplasia, which affects older patients. Patients get overloaded in their sixties and seventies. Often, iron overload is not the cause of death. There are other patients who start needing transfusions much earlier in life. It is the latter group who are going to be impacted most, in terms of effective chelation.
One study shows that iron chelation does improve hemoglobin values in some minor myelodysplasia in patients, which is intriguing. If it is true and it is confirmed by other studies, it may be that we can do two things at once in groups of patients who may not be dangerously iron overloaded yet. If we can treat incipient iron overload, then we may be able to improve the hemoglobin and the well-being of the patients. That is an intriguing possibility.
Treatment implications: If we have effective and safe chelation, we will get better survival and less morbidity from iron overload. We talk about survival, with heart failure improving. A substantial proportion of patients still get hypothyroidism and hypoparathyroidism. Such patients also have problems with the anterior pituitary gland, which affects growth, sexual development and fertility.
With these emerging strategies, if we have chelators which are more effective from an earlier age, then in principle, we could reduce morbidity. We could have a higher proportion of patients growing properly, having full sexual maturity, and being able to have families, without any help. There are a lot of advances we can make in effective treatment with these new strategies.
We are looking at a number of oral chelators in patients. Deferiprone, the oral chelator which has been around for the longest time for the greatest number of patients, has a number of drawbacks. In particular, as a monotherapy, it does not control liver iron in enough patients. I hope the new ICL670 will be better at controlling body iron, and it will have an acceptable toxicity profile. It is too early to say that is definitely the case. However, the results so far look encouraging.
This is a typical smear. It is the original smear from Walter Noel, a dental student who was the first to be diagnosed with this disease in the U.S. The red cell contains mostly sickle hemoglobin. When the hemoglobin is oxygenated, the hemoglobin remains in the aqueous solution as tetrameric hemoglobin S molecules. This allows the cells to be soft and to behave pretty much like normal cells. When these red cells are deoxygenated, the hemoglobin S deoxygenated begins to form polymers. These polymers force the cell to become sickle cell. This process can go back and forth, and the cell changes shape and consistency. The disease changes the cell, through damage to the cell's membrane. Interaction between these damaged cells and the endothelium leads to abnormal adhesion. The interaction also causes destruction of these cells, most of it intravascularly. That accounts for much of the pathophysiology of sickle cell disease.
In general, we can think of the complications we see in sickle cell disease under three broad categories. One is the anemia that is common to all of the severe forms of sickle cell disease. Then, there is occlusion at the micro and macro level. Chronic organ damage is caused by the combination of this chronic anemia and either persistent microvascular occlusion or acute macrovascular complications.
Anemia in sickle cell disease is a very common feature. Usually we ignore the anemia itself, as a pathology. Much of our therapy is not directed toward correcting the chronic anemia in sickle cell disease. The anemia in most patients with SS type of sickle cell disease ranges between 6 and 8-1/2. A few of them are outliers. It is a chronic intravascular hemolysis. For most patients, it is a steady state. On top of that, patients can develop acute anemia.
Here are three of the most common reasons patients may develop acute anemia. The first—and probably the most common—is red cell aplasia caused by provirus. This probably accounts for over 90% of the red cell aplasia we see in sickle cell patients. Young children with SS and older patients with milder forms of sickle cell disease can have acute splenic sequestration. This can threaten their lives, because of a rapid drop in the hemoglobin and blood volume, as the spleen sequesters blood. In certain circumstances, patients appear to be hemolyzing a little faster than they normally do. In the areas of the world where malaria is common, this is the most common cause of death. In children with sickle cell disease, acute hemolysis is caused by malaria. In other areas, in patients who have acute chest syndrome, there is a slight drop in their hemoglobin. This is not very well understood.
The vasoocclusive complications of sickle cell disease are well known. A clinically silent microvascular occlusion occurs in sickle cell patients all the time, with the loss of capillaries throughout organs. Most of us are aware of the episodic complications patients have. We attribute these to occlusion of several beds of small vessels—or, most likely, large blood vessels—that lead to pain episodes, stroke and priapism. This occlusion also leads to acute chest syndrome, renal papillary necrosis of splenic infarction, and probably many other complications of the disease.
The first organ that is damaged in most children with sickle cell disease is the spleen. That puts these patients at very high risk for bacterial infections, particularly pneumococcus. There is progressive dysfunction of several organs as patients age.
We can think of why red cell transfusion in sickle cell patients may be important. Think of how many of our patients, at any one time, have received transfusion as part of their therapy. The cooperative study of sickle cell disease—which was organized in the 1970s and 1980s by the National Heart, Lung and Blood Institute—at its peak had about 4,000 patients. When the patients were entered into the study between 1978 and 1983, half of all of the patients had received at least one transfusion. Sixty percent of those had SCD-SS of the most severe type. At that time, about 5% of the SS patients were on chronic transfusion therapy.
To show how things may have progressed or changed since then, we can look at the children at the Children's Hospital of Philadelphia (CHOP), where I work. This is our chronic transfusion application in sickle cell disease patients. We have 415 SS patients as of this past month. Seventy-five of them, or 18%, are on chronic transfusion therapy.
These are the reasons for chronic transfusion therapy in our population: Thirty-seven percent of them are being transfused because they have had a stroke. They are being transfused to prevent the recurrence of stroke. Thirty-one percent, or 23 of them, have been transfused because they have been identified as having repeatedly abnormal TCDs. Eight of them, or 11%, were transfused for recurrent acute splenic sequestration. Transfusion was needed for acute management. Seven patients have been transfused because they have chronic, severe, debilitating pain. That is, it interferes with their lives. Six of them, or 8%, were transfused acute chest syndrome, also on a recurrent basis.
These are the major reasons why we transfuse patients. Originally stroke, and its prevention, seemed to be the main reason to transfuse these patients. More and more, other reasons are being found to place patients on chronic transfusion.
Some of the major clinical issues that we have to think about in deciding whom to transfuse in sickle cell patients are, of course, the indications:
· The methods that we use to deliver the blood, and what types of blood we give our patients
· Issues of alloimmunization
· Blood safety and infection, in general
· Iron overload, which is the topic of the day
The indications are clear in some instances and not very clear in others. Much of this information also comes from a session that was held two or three years ago. A group of hematologists met to try to determine transfusion practices in sickle cell disease.
We use episodic transfusion quite a lot in the management of complications of sickle cell disease. In episodic transfusion, we give one or a few transfusions for acute illness, or short-term preventive therapy. Then there is chronic transfusion therapy, where patients receive blood regularly, in much the same way as thalassemics do. These patients receive blood either for a limited term or for a long, open-ended term, to prevent complications from occurring.
Commonly we use episodic transfusions to treat anemia. Over and beyond the steady state anemia, acute splenic sequestration can be life-threatening. Transient red cell aplasia is caused by parvovirus, in most cases. So-called hyperhemolysis is clearly seen in the malaria world. There is also anemia associated with acute chest syndrome. Apoxia may be related to it. These are often resolved in episodic transfusion. There is also anemia that may be induced by other infections.
Sometimes we give blood to correct the anemia and improve the oxygen-carrying capacity during other acute illnesses of sickle cell disease. We would do this when the patient is hypoxic from acute chest syndrome, or when the patient has a severe infection. Even though there may not be a clear indication for the blood, it is often given when the patient is seriously ill. Transfusion helps them to be less hypoxic, and it helps patients to recover.
When patients have an acute stroke, we often given them red cell transfusions, either as a simple transfusion or as an exchange transfusion. We do this even though the reasons and the outcome of this practice have not been carefully studied. There is a syndrome of acute multiorgan failure. This is seen in adults who often present just with pain crisis and rapidly deteriorate, with several organs failing. In that setting, exchange transfusions primarily have been used for management.
Often we use transfusions to prevent what we see as potential acute complications. When patients have been prepared for surgery, or for general anesthesia, they are given blood transfusions. The indications are not always very clear. However, in a study that was done a number of years ago, comparing different ways in which patients are prepared by transfusion, a standard has been developed. Consequently, patients facing general anesthesia for prolonged procedures need to have the hemoglobin raised to about 10 prior to the procedure. Pregnancy is a controversial area. In the past, people believed that transfusion of sickle cell pregnant women throughout the pregnancy would give a better outcome. In other studies comparing just high risk management of the pregnancy, without necessarily given regular blood transfusions to pregnant women, resulted in the same outcome. When patients have developed either acute vasoocclusive complications, or other complications during pregnancy, often obstetricians and hematologists who manage them have used chronic transfusion therapy for the duration of the pregnancy.
There are controversial areas in the use of episodic transfusion. We will go through a few of them. Most hematologists managing large numbers of sickle cell patients agree that transfusions actually do not have much of a role when a patient presents with acute complications such as a painful episode, or acute priapism. Also, there is the area of transfusing—or, in some cases, exchange transfusing—patients to prepare them for high ionic contrast media, prior to the procedure. These are controversial areas.
Traditionally, chronic transfusion therapy had been used for stroke patients in a long-term or indefinite-term application. There, we primarily want to prevent the recurrence of stroke. Recently the TCD study showed clearly that one can prevent primary stroke by transfusing patients who have abnormally high blood flow velocity in the major intracranial vessels. Consequently, this has become part of standard care of patients in several centers. Patients who have recurrent acute chest syndrome are often placed on chronic transfusion as a preventive measure. Adult patients, in particular, who have developed chronic hypoxic lung disease are also managed with chronic transfusion. Chronic transfusion is used for chronic severe pain. Patients who have developed chronic renal failure maintain very low hemoglobin levels. Consequently, they are often placed on chronic transfusion therapy. Patients in chronic heart failure are treated with chronic transfusion therapy. This helps them to maintain a higher baseline level of hemoglobin. It also reduces the stress on their hearts.
In limited-term chronic transfusion therapy, clinicians may decide that they will treat a patient for six months or a year for a particular reason. Clinicians maintain the patient with a close-to-normal hemoglobin with fewer red cells that can sickle. The rationale is that this may somehow either prevent deterioration of the condition or prevent a particular complication from occurring. This has been used for management of pain and for acute chest. When patients have recurrent splenic sequestration, often they are transfused at centers such as ours. This is done for a year or two, until they are a little bit older. At that point, a decision about splenectomy can be made. Recurrent severe priapism has been managed by limited-term transfusion, although the value of it has not been clearly established. Limited-term transfusion is also used for leg ulcers and for pregnancy.
In chronic transfusion, there are areas where there may be clear indications. There are several applications that have not been shown to be efficacious.
The issues involved here are the blood products to use, and the method of administration. The goal of the transfusion is often not very clearly stated. The interval between transfusions must be considered. We must also consider how we monitor patients on transfusion.
Most patients who are placed on transfusion for prevention of chronic complications are treated with a particular goal in mind. Generally, the advice is to try to limit the hemoglobin level that you achieve in patients to less than 10 g/dL. This would be the goal if you are using simple transfusions, unless the hemoglobin S percentage is higher than 70%. It is recommended that we use exchange transfusion when we want to keep the hemoglobin higher than 10. An exchange also is recommended for chronic transfusion therapy, when this can be managed. It is important to track the red cell phenotypes and alloimmunization rate in sickle cell patients. It is also important to keep track of the volume of blood transfused. In many of the older teen and adult patients we see for episodic transfusions for sickle cell disease, there is no clear record of how much blood they have actually received. Often they are not considered as patients who may have acquired enough iron to require some intervention. In some institutions where there are large numbers of patients, special red cell transfusion units may be required for the management of sickle cell patients.
In planning transfusion therapy for a patient who is facing chronic transfusion, it is recommended, if it is available, that patients initially receive extended red cell phenotyping. In some centers, this has become part of standard management of sickle cell patients. Patients enroll in the centers as babies because they are likely to have transfusions. It is prudent to do the red cell phenotyping from the start.
It is recommended, where available, that patients receive prestorage leukodepleted blood. This is particularly needed for patients who have been managed in Western European countries and in the United States. In these areas, most of the patients with sickle cell disease are of African background and most of the donors may be of European background. The blood that they receive needs to be matched for ABO for C, D, E and K antigens.
Where possible, we recommend that special efforts be made to recruit donors who may present red cells that are more similar to the patient population. This reduces the risk for alloimmunization. In general, we avoid sickle cell trait blood when we are transfusing patients with sickle cell disease. There is not anything wrong with sickle cell trait blood. We monitor the level of hemoglobin S blood in these patients as part of the outcome. Transfusing them with AS often will create confusion in the monitoring.
The problem of alloimmunization has been well characterized in sickle cell disease patients. This is from a report by Elliott Vichinsky in the early 1990s. Vichinsky compares the SS patient and the red cell antigens that are common in patients who likely have African background with donors in the U.S. who are largely of European background. The ones that are highlighted in yellow are where there are enough differences—sometimes not major—so that they may present as antigens for which the recipients may develop antibodies. In the preoperative study that was led by Elliott Vichinsky, this is a report on patients who developed antibodies prior to enrollment. A percentage of these patients developed new antibodies to these offending antigens while they were on the study. Overall, about 7% developed new alloantibodies. The patients in this study were grouped into those who were aggressively transfused and received many more units, and those who received only enough blood to raise their hemoglobin up to about 10. Clearly, those who were exposed to more red cells developed more antibodies.
This shows Group 1, aggressively transfused patients, in the green bars, and Group 2, less aggressively transfused. Clearly, though, the number of transfusions that one was exposed to is related to the percent of patients who developed new antibodies. Therefore, the more transfusions you get, if you do not get the right type of blood, the more likely that you develop antibodies.
Issues of blood safety and infection in sickle cell patients are similar to others. As we will hear later on, issues of iron overload may be similar to what we know about other patients, but there may be some special differences. I am not addressing those here.
I wanted to go back to the issue of anemia in sickle cell disease. I mentioned that in general, we have ignored anemia as a pathology that, in itself, needs to be addressed. I am not sure whether this is right or not. The fact that most of our patients are quite anemic is accepted as part of standard sickle cell management. As long as the patients are not developing severe, acute complications, we tend to accept the anemia.
The cooperative study of sickle cell disease, following a large number of patients, tried to establish the risk factors for several complications that are typically seen in sickle cell disease. These are the effects of anemia and some of these clinical complications. Clearly, anemia was related to increased mortality in children. Anemia is related to an increased incidence of leg ulcers. Anemia in sickle cell disease may sometimes just mean that the patient has a worse form of sickle cell disease. You may not be able to separate the sickling complications from the fact that there is anemia.
We show that those who are more anemic within the SS genotype are more likely to get stroke. Also, patients who are more anemic develop more silent infarcts—brain infarcts that have not been related to clinical stroke. In comparison, patients in the same genotype, who are less anemic, develop fewer silent infarcts.
Small-for-gestational age (SGA) babies are more common in patients who develop acute anemia during pregnancy. Also, there is a lower rate of sickle cell disease-related postoperative complications when patients receive transfusion prior to surgery. Cardiac chamber dimensions and wall thickness are improved in those with higher hemoglobin. There is only one complication for which anemia seems to be somewhat protected: Those who are anemic seem to have a lower rate of acute chest syndrome.
There is a summary on the pathologic effects of anemia, not in sickle cell patients, but in renal patients. The issue is whether anemia in these chronically ill patients is an innocent bystander or not. It is in the June 23, 2003 edition of the Archives of Internal Medicine. It is very good reading, because it makes us wonder whether patients who are very anemic are actually healthy or not.
This is a study from Styles and Vichinsky, looking at the unintended benefits of chronic transfusion. The patients who were transfused mostly for stroke showed a lower hospitalization rate and a lower rate of vasoocclusive crises. The patients also showed lower rates of acute chest syndrome, of bacterial infections, and even of the febrile illnesses for which children are admitted.
In a very significant way, patients who are placed on chronic transfusion seem to have lower complications of all sickle cell disease. One might leave you with this question: Might red cell transfusion therapy be the best available overall treatment for sickle cell disease?
Because of concerns about iron overload and alloimmunization and other things, this question has not been adequately addressed. As we consider the potential complications of iron overload, the use of red cell transfusion in managing sickle cell disease may change.
I see the role of oral iron chelators as affecting the treatment of people with iron overload. In sickle cell patients, there are many times when we know that blood transfusion will help. Many times, when considering the problem of iron overload, we do not use the option of chronic transfusion therapy. This is because of the difficulty of implementing subcutaneous Desferal for these patients. An oral iron chelator that is effective and safe will open up the possibilities of transfusing many more patients. It will have a very significant impact in the management of these patients.
The role of oral iron chelators in influencing transfusion in sickle cell disease will be tremendous. Many programs around the country have been unable to implement automated erythrocytapheresis. This is one mechanism by which we can reduce the rate at which sickle cell patients accumulate iron. Patients who are placed on chronic transfusion therapy eventually develop iron overload. The transfusions are often discontinued because of the threat of what the iron overload may lead to. If there is a very effective oral iron chelator that patients can take and maintain low iron levels, then it opens up the possibility of maintaining them on a very, very effective chronic transfusion program.
The key take-away concepts from my presentation involve transfusion and oral chelation. There are some indications for transfusion therapy in sickle cell disease patients. There are some other clinical situations where transfusions are probably not beneficial, and those should not be implemented. Since increasingly we are placing younger and younger sickle cell patients on chronic transfusion therapy, we must take very serious measures to address the eventual problem of iron overload. This certainly could include oral iron chelators when they become available. Until then, we should really design our programs to include exchange transfusion or, where available, automated erythrocytapheresis, as part of the management.
The most promising development in the treatment of iron overload is the development of oral chelators. That is the most promising change. We have been using parenterally administered Desferal for 30 or 40 years. I have been looking for an oral chelator that would make it possible for us to open up chronic transfusion for many patients. If oral chelators become available, this will clearly be the most important development.
We have used a lot of transfusions for sickle cell patients. The clinical implications of these evolving strategies will be that we can face transfusion as a therapeutic measure for fundamentally changing the course of sickle cell disease. This is possible if we know that we can assure that the patients will not develop iron overload.
Up to this point, we have been unwilling to consider transfusion therapy on a chronic basis as fundamental therapy for sickle cell disease, because we know we would be giving the patients on such therapy chronic iron overload from the chronic transfusion. If we are able to have effective oral chelators that can manage the iron overload, it would change the way that we manage sickle cell patients.
I hope to review some of the issues that relate to that, with recommendations. I will also review some new data from a number of sources. In addition, I will cover recommendations from the consensus group on iron overload and sickle cell, which was published in Seminars of Hematology. I will review the California consensus on hemoglobinopathies and standard of care, and a number of other important recommendations from consensus meetings.
Iron overload is really changing. In fact, the diseases are really changing. While thalassemia major in one of my adult patients was actually a great leader in the area, it was next to a younger patient. What we are seeing now, in California and in other areas, is mixtures of sickle cell and Thal, hemoglobin SC and other kinds of disorders. The diseases are blending on several levels, and transfusion is one of them. They share many problems. One of them is clearly a high rate of iron overload.
Blood, obviously, is made up of iron. People get iron overload well before the physicians get involved in it. In fact, Olivieri and others have shown that you can have liver fibrosis as early as six months. After 10 transfusions, you can actually show significant changes as well.
Another important area involves the hemoglobinopathies that are now occurring in North America. These are structural mutations and b Thals and α Thals, some of the sickle cell, and others. Now that we are quantifying liver iron, we are seeing clinically significant iron overload in nontransfused patients, or in intermittent transfused patients. I will show you some of that information.
Normally, antioxidants in the body provide a major counterbalance to this. As important work is being done by people I work with, Dr. Ames and others, we know that the antioxidant system is depleted in these disorders. This happens, in part, because of the iron and, in part, because of the diseases themselves. Clearly, the lack of vitamin E and antioxidants affects the disease. I will show you some data about its impact on NTBI.
We do not know everything about iron overload. What we now are learning is that the disorders and abnormalities in patients that we did not pay attention to, in terms of iron overload, are linked. Neurocognitive abnormalities, brain atrophy, and pulmonary function abnormalities are now being recognized in asymptomatic iron overload patients. This is happening in both sickle cell and thalassemia patients.
Most importantly, we know what to do, and we actually can tell who needs it. However, in the United States, in North America and in the world, we have not been able to implement the therapy that these patients need. Transfusions are here to stay. With the development of fetal hemoglobin agents and transplants, patients are living much longer. They are living longer because of better clinical care, and transfusions make up a major part of that. Each complication, in general, seems to involve the role of transfusion.
This slide demonstrates the power of a transfusion. This is from a paper I published in the New England Journal of Medicine a couple of years ago, on acute chest syndrome. We took the patients who were deteriorating and becoming acutely hypoxic. Before they were transfused, we measured on room air their oxygen and their pulmonary functions. Then we measured their oxygen immediately after transfusion, or within a 12-hour period. Consistently, we were able to reverse the hypoxia in patients with a transfusion. Transfusions are very powerful, too, in the acutely ill patient, and they are also powerful in a preventive role.
We have now been working on pulmonary hypertension, which has become a major issue in both sickle cell and thalassemia. That is a talk in itself. What we are finding is, as we screen the children, we are seeing the kind of foundation for the data that Castro and others have published on sickle cell, and on people with Thal. About one-third to 40% of these patients, as they get older, develop clinically significant pulmonary hypertension. This is an early predictor of death. Pulmonary hypertension occurs in the asymptomatic patient, sometimes with no clinical history. This is a strong predictor of death, as indicated in findings recently published by Castro.
Since we are seeing so much of this in our own program, we are screening everybody. What we are finding is that if you can diagnose this early enough, you can reverse it with transfusion therapy. Other therapies are arginine under the leadership of Dr. Morrison in our group, and others, have really been dramatic, as well. There is even work that shows that the standard prostacyclins have an acute role. Chronic transfusions improve these patients' outcome. This is also true in the thalassemia intermedia group. Therefore, look in your patients for pulmonary hypertension. I would recommend you treat it early.
Transfusions are used for a lot of things. Some of them are proven; some of them will never be proven because they are accepted. In the consensus report, many experts came to a consensus meeting and agreed, which was not easy, on the indications for transfusion. I have summarized these. Transfusion is indicated for most serious acute events that have clinical symptoms, and for many chronic things. The list of indications is growing. As the transcranial Doppler study has shown, elective transfusions can prevent progression to stroke in patients who have normal MRI, with an abnormal Doppler. Now we are seeing multicenter trials showing that patients who have watershed lesions may be prevented from going on to full stroke. Work in our group, under Dr. Styles, has been able to show that we can abruptly stop the progression of acute chest syndrome in patients who have elevated PLA2. That will be presented at this meeting.
Transfusions are a powerful tool. Ninety-one percent of sickle cell SS patients have been recurrently transfused by age 21, according to the cooperative study. These patients are iron overloaded. As the data from Brittenham showed you a moment ago, you can correlate the degree of iron overload in these patients, on liver biopsy, with the amount of total body iron. This could be accomplished if you do phlebotomy studies on selected patients. There is a problem with liver biopsy here. If it is done correctly, when you get enough tissue, you could really show a strong correlation with the total body iron stores, as well as with the amount of blood the patients received. There is a growing amount of information and there have been some changes. I thank Drs. Olivieri and Brittenham, who demonstrated this a decade ago. They kept pointing out that the ferritin does not work.
This is from the cooperative study that we are doing now, a multicenter trial, which I will show you. It illustrates very nicely that if you look at the liver iron and the serum ferritin, they are unpredictable. This is despite having a 2,000 range in Thals, which is the range of most sickle cell patients. Their liver irons are all over the map. We know this now. The question is, what are we going to do about it? They need liver biopsies. My recommendation is, if you cannot get a SQUID, you need to do a liver biopsy. I will go over the MRI issues briefly.
This data came from a multicenter trial of thalassemia disorders. I show this because it illustrates a growing problem in the United States and North America. That is, there is a growing number of thalassemia intermedias. This may be difficult for you to see; there are four groups here—the Thal majors, the Thal intermedias, E Thal and hemoglobin H Constant Spring disorders. This data shows that if you look at the X marks on the graph, patients who have Thal intermedia, E Thal and HH have a dramatic discrepancy between their ferritins and their liver iron. While it is unreliable in Thal major and sickle cell, the liver iron is consistently much higher in these nontransfused groups. What this translates to the clinical community is: You will have nontransfused, or occasionally, transfused Thal intermedia patients—E Thals and HH—who are having serum ferritins of 1,000 or less. These results are not on transfusions. These patients will have liver irons of 15 or above 7.5. This means, this patients will suffer from end organ failure as they get older. So, being intermittently or being not being transfused at all does not mean anything in preventing iron overload. This relates to the intermittently transfused sickle cell patients as well.
Oxidative injury is very active in the development of many of the problems that affect both disorders. In this study, we were measuring malondialdehyde (MDA) levels in patients. What we have been finding across the board, as others have, is that sickle cell and Thal patients have significant oxidative damage, reflected by MDA. In sickle cell patients, the damage is actually much greater. We are now using other techniques, as well, to show that these patients have ongoing oxidative injury. They need a counterbalance for that. The body's natural counterbalance is depleted in these disorders.
This data is from a recent study on vitamin E as it correlates with NTBI in sickle cell. The toxic form of nontransferrin bound iron may be a key factor in the development of cardiac and other organ injury. The study showed that vitamin E levels correlate very nicely, particularly in the sickle cell study done here, with the amount of transfusion the patients received. Vitamin E was inversely related to NTBI. The lack of antioxidants most likely causes damage in these patients. It is much worse in the transfused group.
One way to protect this is pheresis. All patients with sickle cell should have the option of undergoing pheresis. In this day and age, you can prevent iron overload with pheresis, by and large. Good programs that are set up, as they are for other services, can have venous access, and it is successful. It is dramatic in eliminating iron overload. There is no reason a sickle cell patient should not have access to this—not health insurance or any other reason. It works.
Alloimmunization [unable to verify in references] is a problem, but it is not necessarily the reason patients should not be transfused. Clearly, it is not the reason patients should not be chelated. Given phenotypically matched blood, I showed, can overcome this problem. The data we are using, with PEG coated red cells, seems to abort the antigen action. It is very exciting.
This is brief report on the multicenter trial we are doing. Under the leadership of people in these centers—Ellen Frangin and Paul Harmatz—we are comparing sickle cells patients and thalassemia patients who are heavily iron overloaded. We want to see if they differ in how they acquire iron overload. Do they differ in the biology of it? Most importantly, do they differ in organ injury? You will hear a presentation by Dr. Fong on the data.
I am going to show you some key points. There are now about 200 to 300 sickle cell patients in the sickle arm, 200 in Thal, and they are matched for age. Obviously, the Thals are Asian and Caucasian, and the sickle cell patients are African-American. Their transfusion history is different, but they all have been transfused for 10 years or more. We have enough sickle cell patients now to match the two groups. This helps to answer the questions related to iron overload. Even in the very long-term groups, there are enough sickle cell patients to compare to Thal, which is what we were hoping for.
The key data is that these patients underwent liver biopsy and serial ones. Look at this data. The dry weight iron is 20 or greater as the mean in the sickle cell patients. This is extremely high. While the Thal patients, over time, are dropping, the sickle cell patients clearly are not.
This slide compares how many patients ever receive chelation—not once a month, but do their doctors use chelation? Only 70 percent of the patients in this study, who have to be heavily iron overloaded by liver biopsy, are getting chelation. Of that group, probably only half are getting compliant chelation. This means chelation is not being used in sickle cell. That is resulting in a rising ferritin in the sickle cell population, over time, and a falling one in thalassemia. The result is growing morbidity.
Look at the data on antioxidants. The Thal community gives antioxidants to patients they feel are indicated at a much higher rate than the sickle cell community does. There is a lot of data that shows sickle cell patients are antioxidant-depleted. I think that is because the Thal community realizes, historically—because of transfusion history—that this is an important role. We are particularly interested in what role cardiac disease plays in sickle cell injury. I think death in sickle cell is a very difficult problem to sort out, since it is acute. Most deaths in sickle cell remain acute.
Ongoing iron-induced organ injury plays an important role in the eventual death of patients from sickle cell. The underlying injury to heart, adrenals, or lung, adds to and amplifies the complication of hypoxic injury that occurs with pain or stroke, and causes death. It is going to be difficult to sort out. Consequently, this data, which will be reported this week, was very different for me. It shows that the echocardiograms—these people had to have abnormal ejection fractions—is growing in the sickle cell transfused population. Thirteen percent of the sickle cell patients, at one year, have cardiomyopathy. This is compared to 16% percent of the Thal patients. This is very high.
We are also seeing diabetes and thyroid disease. This correlates with liver iron. Consequently, sickle cell patients are having the problems thalassemia patients have. The death rate in the sickle cell group, over the first year, was very high. We had 10 deaths and only 3 in the Thal group. These patients are dying. The role iron plays in that needs to be determined.
In summary, this is a big problem. We need to do better in taking care of these patients. We need to have a plan. The plan would be—when sickle cell or Thal patients come in—knowing what to do and having it standardized in a protocol. When patients come in to be transfused, they need a plan that includes DNA typing, HLA typing, and extended phenotyping. We need to do baseline organ staging for liver, heart, endocrine, and others. This is what the Thal community does.
We need to use an extended red cell phenotype. Even if patients are not transfused, if you look at the data in the last year or so, you can do red cell phenotyping now, using DNA techniques. If patients all receive E, C, Kell blood, the chances of alloantibodies are quite small. However, if they do get further antibodies, they will need to be matched. Alloantibodies can be managed. Most importantly, patients need to be transfused in a program that can monitor, between hospitals and blood banks, the phenotypes and antibodies. Most deaths from transfusions, acutely, are related to mislabeling. The patients need to be in programs with professionals who know what they are doing and who have seen a lot of these patients.
The ferritin does not work. I am not going to go over the data that was shown before; but, it just does not work. You cannot use it. You can get trends for groups, but you cannot make good clinical decisions. You are stuck with what you need to do.
Liver biopsy is here, unless you have equipment. The MRI reminds me of the Doppler study. When the Doppler study came out and showed that it can predict stroke, a lot of hospitals in my area started using the duplex Doppler to look at risk of stroke. Initially, 75% of patients had an abnormal Doppler. That was because the duplex could not be correlated, at that time, with the unipolar Doppler. Therefore, rather than using peaks or averages, they used different means. You cannot adapt the machine to the use, unless it is validated. It will be, but it is not now.
Consequently, we need to follow these patients serially. We need to chelate them early, but carefully. The consensus meeting tried to come up with a guideline on when to start chelation. Clearly, the liver iron is the best method. Other methods used by people who will not do biopsies include 120 cc/kg, or the high ferritin, or a number of years of transfusions. We have to remember that if the liver iron is above 7, the patient begins to get clinical morbidity. If it is above 15, the patient is, most likely, going to die. Therefore, those patients need aggressive treatment. Infants or young children who start out on Desferal get Desferal toxicity. These things need to be taken into account.
I will mention splenectomy quickly. It is a double-edged sword. It does decrease the transfusion requirements. However, there is pretty good data that shows it causes pulmonary hypertension and a thrombotic state. In our own program, we anticoagulate splenectomized patients.
Phlebotomy can be used in episodically transfused patients—specifically, those on hydroxyurea. It is an effective tool in those patients. They need endocrine studies early. We have an abstract being presented on osteoporosis. It shows how common osteoporosis is in teenagers with sickle cell disease, and this surprised us. It happens. You need to look for it.
Cardiac disease kills these patients. We believe, if you pick up cardiac disease early, you can reverse it, as with the Desferal data I showed.
You can reverse the injury in sickle cell and Thal if you detect it. However, you need to detect it. We have tools to do that. We just need to do it.
Today's symposium integrated very well some advances in the treatment of people with iron overload diseases. The basic laboratory and clinical needs were assimilated to present a picture that should help us understand how to treat patients better, and why. In my opinion, the biggest problem we have with iron overload is the lack of implementation of existing therapy. Therefore, if you have a therapy that works, and people do not use it, then you are not doing any good.
The sickle cell community—and, to a lesser extent, the thalassemia community—suffers a great deal from that problem. That is, sickle cell patients have increasingly been shown to suffer the laboratory and clinical morbidity of iron overload. Yet, the patients themselves are not being treated. This is related to a historical lack of interest in chelation in sickle cell, because most patients die very young. The causes of death are usually catastrophic, acute events. Therefore, the physician has been less concerned about the chronic problem of iron overload. I hope to change that perspective. My goal is to have providers recognize their responsibility. With medical knowledge to help them, providers can be guided regarding how early to treat the patient.
Iron overload is a complex problem. We are talking about, in large part, transfusion-induced iron overload. I see three problems as paramount. First is the development and utilization of effective drugs that eliminate iron from the body. Second is the availability of testing to monitor patients for that level of iron therapy. Third is a program that is funded—in terms of health insurance—and physicians who will carry out the implementation. Those, and advances, are the key things.
What we have now are the answers to all three of those things. First, we have therapy that can effectively eliminate iron toxicity. Desferal is a very effective drug. It is the most effective drug. It works, and it has a very good safety panel. Newer drugs are being made, including Novartis' therapeutic oral medication, that will improve chelation. Therefore, we have opportunities to offer patients effective treatment, whether it be with Desferal or with oral medication.
I also showed data that was very important for the person who takes care of the older patient—whether it be MDS, sickle cell or Thal. Aggressive treatment will reverse cardiac failure and prolong life. I think effective therapy exists and is improving. Physicians need to know about it, and I think they do.
Second we have the issue of implementation of this knowledge. We had a wonderful attendance at the meeting. I think a better infrastructure is now in place for the improvement of the physician-patient relationship. This infrastructure particularly involves hemoglobins and MDS., so that patients will have access to this. It has taken a while, a decade or more, but with a multifocal approach, the medical community is becoming more geared to effective treatment of these patients.
Third, related to that, blood safety and availability, and methods of using blood are improved. We know that transfusion is a lifesaving in thalassemia, but the data that others and I have presented, and the work I have done, have shown that transfusions actually are given to 90% of patients and, in fact, they can reverse, or cure, problems.
Now, with the alloimmunization problem being under control with phenotypically matched units, with the availability of pheresis and better testing of units, blood safety is a very small issue. At least, it is not a small issue but a well-controlled issue. I am optimistic that the world will change in caring for these people. We can treat people with medications that work, whether it be desferrioxamine or an oral agent, such as Novartis' product. We will have blood available that is safe. We will finally have a synergistic relationship between the care provider and the patient. We need a health insurance program that will be able to deliver that historically difficult product to those in need.
A drug is only as good as the way it works. Therefore, oral chelators are extremely important, if they are to be effective in chelating patients. What makes a drug effective is the ratio of efficacy versus toxicity. Therefore, the first role of all chelators is: does the drug chelate people, and is it safe to use? If that is true, and you have a drug that can chelate iron and be relatively safe, it will make a huge difference in the outcome of iron overload, and in the quality of life of patients. This will occur on two levels. An oral chelator—even if it is not as effective as desferrioxamine in terms of iron excretion studies—will dramatically change survival because it has the potential to work sequentially or in combination with desferrioxamine.
Consequently, I think we are very close to expanding the lifespan to almost-normal for some iron-overloaded patients. I have 50-year-old thalassemia patients now. If we had better chelation by either combination, or better compliance, people would live a much fuller life.
Oral chelation does improve compliance. There is no question. That is the big holy grail for the patients and the activist groups. People want a simple answer. One pill will not change iron overload. It is one part of a multidisciplinary program. It will go a long way toward making some improvement in the quality of life.
Over the last 20 years, I have been involved in setting up prospective trials to evaluate the efficacy of transfusion as well as evaluate the risks of transfusion. This has been a difficult research undertaking, because so many patients were erratically transfused. However, over the last 10 years, other investigators and I have increasingly shown that transfusions can prevent and reverse the disease of sickle cell, and obviously, in thalassemia. In fact, the utilization of blood has continued to increase. The NIH has funded several preventive trials to prevent stroke with transcranial Doppler. Now there is an NIH-funded study to prevent stroke by MRI. I have a large NIH grant to see if I can improve neurocognitive functioning in adults with memory loss. From the data I have recently gathered, I believe that adults with sickle cell have an undiagnosed vascular dementia caused by hypoxia. Therefore, my study is looking at transfusions and reversing or preventing that.
The medical community has come to the realization that transfusions are profound in improving life. As Dr. Ohene-Frempong mentioned at today's meeting, we are really at a stage in which preventive transfusions could be studied right at the time of diagnosis, or older. That has not been done, in large part, not because the drug does not work, but because the physicians and community do not want to chelate, or are afraid of it.
The indications and the randomized trials are increasingly showing the same thing: Transfusions are, in some ways, the holy grail in sickle cell, but their toxicity is a limiting factor.
If you had a chelator that worked and, in fact, was safe, and it was an oral pill, it would have substantially increased use for chronic transfusion and sickle cell already. Especially as the lifespan continues to increase—initially 21 in 1971 or 1972, and in the mid 1990s, 42; and now, probably in the 50s. Most of these patients are suffering from end organ chronic illness. Transfusions will only increase in the later life of these patients. I am optimistic: If a pill works, and it is safe, it will only increase the use of transfusions.
MDS is a heterogeneous disorder, one in which the dominant clinical problems generally devolve into two regions. One is the potential for evolution to acute myeloid leukemia. The other is that cytopenia may dominate the clinical course, and its management is critical. I will focus on the management of these individuals, the potential pathogenesis of this disease, and the possible role and contribution of iron overload for these disorders.
II. MDS: Dilemmas
Heterogeneity is a watchword in MDS, and there are early and advanced stages. Cytopenias occur in most of these individuals; 60 to 80% of patients are anemic. A high proportion of these individuals require transfusions. Acute monocytic leukemia (AML) evolution occurs predominantly in the more advanced stages. What we are required to do is to find ways to treat these diseases effectively.
I have listed +/- iron chelation. A recent informal poll of individuals treating MDS indicated that perhaps no more than 10 to 20% of patients who could use chelation receive it. One reason this is so rarely used is because of logistical issues with the use of Desferal.
It has been a major challenge to refine the risk analysis, so that we know which patients require what form of therapy. Most of these individuals are elderly. The median age is 65 to 70; patients' comorbidities may play major roles in their management. They have a poor response to standard treatment, so we need to modify such treatment for their tolerance. Within their marrow, there are inherent abnormalities of their stem cells and stroma, with poor responses to standard therapy. Therefore, attempts at biologically selective treatment have been used.
These combined challenges lead to the fact that there is uncertainty in the management of these individuals—for physicians as well as patients. We need to answer questions about where we go from here. Clinical trials are certainly the center of trying to manage these people.
III. Classification
The French-American-British (FAB) Classification, which was generated in 1982, stood in good stead for a prolonged period of time. Refractory anemia with ringed sideroblast had a relatively good prognosis. Patients with refractory anemia with excess blasts, and those with transformation, had somewhat variable problems. As a result, this was used initially, looking at the proportion of blasts in the marrow.
However, it was quite clear that other features played a major role in the outcome of individuals with MDS. An international workshop was convened and generated a series of features that may be better at indicating outcome. These included marrow blasts, cytogenetics, and the number of cytopenias. Because of this combination of features, a refinement of the risk prognostic score occurred. The International Prognostic Scoring System (IPSS) has evolved. There are now four groups: low, intermediate-1, intermediate-2, and high. These groups appear to better refine the outcome of individuals with MDS, both for survival and for freedom from acute myeloid leukemia.
Age plays a role as well, particularly in individuals who have relatively low-risk disease. Those with low and intermediate-1 do much better if they're less than 60, compared to those over the age of 60. Those who are in the poor risk categories, either intermediate-2 or high, do poorly despite ages younger or older than one or the other. I mention this because 60 is often a cutoff for transplantation. People in the lower risk groups do relatively well, without transplantation or major intervention. However, certainly major impact is required in individuals with higher risk categories.
In addition to blasts, cytogenics and cytopenias, risk factors include blast immunophenotype, marrow cell apoptosis, neovascularity within the marrow, and a number of molecular abnormalities. These are all covered within the IPSS scoring system. We won't have time to go over these in great detail, but it is important to realize that further refinement of the IPSS is going to be necessary.
The National Comprehensive Cancer Network is a group of 19 institutions around the United States that has attempted to come up with practice guidelines for a number of malignancies, including MDS. The guidelines suggest considering several features when viewing patients with MDS: the IPSS risk score, age and performance status. Those three features play a major role in the type of treatment these individuals will have.
Therapeutic options are excessive. I say excessive because we have many possibilities. However, the standard of care still remains transfusion support, as well as the potential for iron chelation, suboptimal though it may be. Growth factors are certainly used, and erythropoietin is one that has been used in a high proportion of such individuals. In low-risk individuals, perhaps 20% of patients may respond to high dose erythropoietin therapy. Often, this can be doubled with the use of granulocyte colony-stimulating factor (G-CSF), but a number of patients still are refractory to erythropoietin. I have listed a number of other possible therapies that can be used.
Here is a way of stratifying individuals for the type of therapy that might be useful. In addition to erythropoietin, they include a number of agents that are now in clinical trials. Different types of treatment for low-risk and high-risk individuals seem to be potentially useful. We are still in the midst of a number of phase II and phase III clinical trials, trying to determine which agents are best, and what their limitations and risks are.
We know there is heterogeneity, as well as complexity, of pathogenetic mechanisms in patients with MDS. They include a Δ of apoptosis. I use the word Δ because of the fact that it changes over time. In individuals with early stage disease, there is a high degree of apoptosis in the hemopoietic precursors. As the disease evolves, that may diminish, with expansion of an abnormal clone crowding out relatively normal hemopoietic cells. Angiogenesis may be increased. Tumor-related genes and mutations will occur, as well as immune modulation, in some patients with MDS.
You can separate the pathogenic mechanisms into those that are endogenous within the stem cell, and those that are within the stroma. Within the endogenous stem cell, there are oncoprotein levels that may change; increased pro- to anti-apoptotic mechanisms will occur early in the disease. As the disease evolves, a decrease or a change occurs. There is a decrease in the pro-apoptotic mechanisms, with expansion of the abnormal clone. There are many mechanisms for deranged signaling. Oxidant stress susceptibility of the stem cell is something we have known for years. It is now becoming more applicable, particularly in the issue regarding iron overload. Mitochondrial dysfunction and gene mutations also contribute to this issue.
Within the stroma of patients with MDS, there are a number of inhibitory cytokines that are released endogenously, in paracrine ways, within the marrow. These include tumor necrosis factor (TNF), tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), Fas Ligand, interferon, transforming growth factor beta (TFGβ), and vascular endothelial cell growth factor (VEGF). A diminishing of normal hemopoiesis may occur as a result.
In addition, stimulatory cytokines such as granulocyte cell-stimulating factor (GCSF) and erythropoietin (Epo) may be decreased in individuals as the growth advantage of normal cells may diminish. Toxic oxidants may play a role, as earlier speakers have alluded to. Nontransferrin-bound iron and other oxygen radicals present within the marrow milieu may play a major role in providing a very harmful microenvironment for normal stem cells.
There are many mechanisms for the movement of iron within the erythron through the RE system. These include iron binding to transferrin, going to the liver, and going back to the erythron. Iron transport certainly is a critical mechanism. We know how transfusions will add to that and markedly increase the situation, causing iron overload.
Nontransferrin-bound iron becomes rife as soon as the transferrin-binding situation is overloaded. Adding to this is the issue of hepcidin. This is a newly discovered protein that has two major roles. Recent reviews in Blood have described this in detail, indicating that it will decrease RE cell transport, and decrease uptake in the gut. Normally, this will be altered by both anemia and iron overload. On the other hand, if conditions such as MDS or thalassemia both occur, you have both anemia and iron overload. In this situation, anemia trumps iron overload. Normally there will be a decrease in hepcidin production when iron overload occurs; if anemia is present, that will not occur. As a result, iron transport may be modified in an abnormal way.
There are a number of mechanisms whereby the consequences of oxygen free radical generation cause damage within the marrow stroma. Superoxide generation will cause lipid peroxidation and organ damage. There is a review by Bowen and colleagues recently that presented this very nicely. This certainly is playing a role within the marrow of individuals who have iron overload and nontransferrin-bound iron in excess.
Recently, a paper by Deng, et. al. indicated that B-cell lymphoma 2 (Bcl2), an anti-apoptotic protein, increases the production of enzymes that metabolize some of the superoxide radicals. Consequently, that mechanism can modify mitochondrial areas as well as other areas of iron overload and toxicity.
Within the hemopoietic cell, nontransferrin-bound iron may also play a major role in toxicity. Therefore, genotoxic damage can occur to the mitochondria and DNA. This DNA damage may contribute further to pathogenesis of the disease. With many other mechanisms, it now appears that nontransferrin-bound iron (NTBI) does play a role, and needs to be alluded to when we are dealing with this illness.
In 1981, Andy Shafer, Frank Bunn [phonetic] and others studied adult transfusion overload and the clinical effects in a small number of mainly MDS patients. They found that these were individuals who had multiple prior transfusions, 110 at median. The patients had increased serum ferritins and liver iron biopsies. These individuals showed organ dysfunction—hepatic, cardiac and endocrine. Hepatic dysfunction with inflammation was shown by iron biopsy. The patients had liver dysfunction, left ventricular (LV) dysfunction, supraventricular tachycardias, and a number of endocrine abnormalities. Adults with transfusion overload clearly demonstrated these abnormalities.
In 1996, Jensen reported a study of a small group of patients. Sadly, there has been no followup of these individuals, or subsequent studies, but they are provocative. Jensen studied 11 MDS patients with multiple prior transfusions—the median number of transfusions was 90. The patients had an increase in serum ferritin and an increase in liver iron, by biopsy and by MRI. These individuals showed marrow dysfunction. They had thrombocytopenia and neutropenia as well as anemia. A number of these individuals had thrombocytopenia with platelet counts less than 20,000, and neutrophils less than 1,000. They treated these individuals with Desferal for a median of about two years—anywhere from a year and a half to three and a half years. They demonstrated a number of changes that occurred after such chelation. These changes included a decrease in liver iron and serum ferritins. That finding appeared to be relatively consistent in individuals who had relatively good chelation therapy.
This is a slide that indicates several individuals who responded, to your left, and one person who did not respond. Individuals whose hemoglobin, platelets and white cells rose during therapy are demonstrated in the two panels on the left. There were some patients in whom no such change occurred. Generally, it took a year and a half before this happened. The solid bars at the bottom indicate those individuals who did not have any chelation thereafter, but who had a further rise in the blood counts after the chelation had been ended.
A review of the study indicates that 7 of 11 patients who had this long-term chelation, had a decrease in transfusion requirement. Four out of 4 patients with less than 20,000 platelets had improvement in that. Neutrophils increased in 6 of the 6 patients with less than 1.8 neutrophils. This was best related to the effectiveness of iron chelation therapy.
When they looked in the marrows, there was no change in marrow iron or FAB morphologic patterns. This suggests other things were going on, rather than iron moving out of the RE cells. However, liver iron and serum ferritins did decrease in most of these individuals.
This is a study by Oliveri et al. in which she demonstrated that the more effective individuals were chelated, in chelation therapy in patients with thalassemia. That is, the more effective individuals had serum ferritin levels less than 2500 for a substantial period of time. Their overall cardiac outcomes were much better, and their survival was better.
Jensen and colleagues again did studies of MDS patients, looking at their cardiac MRIs. The object was to see whether there would be any correlation between the MRIs and the overload the patients had with iron transfusions. These individuals had a very high median number of transfusions and high serum ferritins. Liver iron and cardiac iron were increased. Desferal was used for one to four years. They found that there was a decrease in cardiac iron in these individuals. The greatest benefit that occurred with cardiac iron release was when these individuals showed effectiveness of chelatable iron by NTBI as well as by other measurements.
These results show the relationship between myocardial iron concentration and iron indices. Individuals who had the most effective iron chelation showed a drop in serum ferritin, liver iron and urinary iron excretion.
Cortelezzi and colleagues looked at other measures of nontransferrin-bound iron in patients with MDS. They looked at 33 patients and found that there was an increase in plasma nontransferrin-bound iron in these individuals. The increase showed up particularly in individuals who had low-risk, rather than high-risk, disease. This was associated with an increase in mononuclear cell apoptosis of the marrow and an increase in serum malondialdehyde. The increase in serum malondialdehyde is another measure of lipid peroxidation damage, which you heard about earlier in the symposium.
Recently the group in Israel has demonstrated that there is another way of measuring nontransferrin-bound iron. As you have heard, NTBI is heterogeneous and has a number of ways of being measured. Labile plasma iron appears to be the most effective and the most redox-active form. It can now be measured by a redox reading fluorophore that will permit one to analyze the level of this after treatment. A group of thalassemia patients was treated. The effect of the treatment on the labile plasma iron was measured and was shown to decrease markedly. This shows that when using the fluorophore for looking at the redox-potentially-active material, there certainly appeared to be an effective decrease.
This table shows you a comparison of red cell transfusion dependent states. I have used thal major and MDS as a way of comparing the two. Ineffective erythropoiesis is certainly a measure in both. Intramedullary hemolysis and ++ to ++++ is something that varies. Early in MDS, there is a very high degree of ineffective erythropoiesis. That effectiveness changes with the disease evolution. Mitochondrial dysfunction occurs in both. Again, it is variable, depending on the stage of MDS. Apoptosis within the marrow of these individuals certainly is increased in both and it changes with the disease. Oxidative damage by nontransferrin-bound iron is present in MDS. However, there are also changes within the stroma. TNF and pyrimidines have a major impact on the oxidative damage. The cellular target is also different in MDS, as compared to thalassemia. The erythroid progeny and the hematopoietic stem cell are altered.
Looking further, genetic lesions differ, in that there are globin abnormalities in thal. However, there are multiple genetic abnormalities in MDS, many of which lead to the potential for AML evolution. Leukemic potential is certainly quite strikingly different, depending on the disease evolution that exists in MDS and not in thal. Oxidative damage may play a role in this, for reasons that I have mentioned earlier. Stromal abnormalities also appear to be present in MDS compared to thal. Although there are similarities and differences in individuals with these two iron overloaded states, the potential problem is altered. There is inherent damage and difference within the stem cell and stroma of these diseases.
Suboptimal chelation therapy is being used in MDS. What should we use? You have heard of the inaccuracy of serum ferritins. Certainly, that is an experience that we have all had. One approach is to consider the number of transfusions. In individuals who have had at least 20 to 40 transfusions—that is, 5 to 10 grams of iron on board—we have heard about potential hepatic and cardiac damage. Consequently, the use of chelation therapy at that stage makes sense and should be considered very strongly.
In addition, there are individuals with early stage MDS who have had symptomatic anemia. If they have lengthy further need—that is, mainly the individuals who have low or intermediate-1—they may need further transfusion therapy. For this subgroup of patients, certainly some form of chelation therapy would be quite reasonable.
In addition, some patients have if they have cardiac, hepatic or endocrine evidence of organ dysfunction. Iron overload may be adding to the dysfunction, and those are issues that certainly need to be considered. Measuring serum ferritin is a surrogate, which is not very effective. Liver iron content is not something that can be readily done by biopsy. MRIs should be considered for this purpose.
One treatment is Desferal subcutaneously, with or without vitamin C. However, the logistical impediments and cost difficulty for patients are huge. There are ongoing clinical trials with oral iron chelators, both ICL670 and L1, which should be joined. These are attempts to determine which would be the most effective use.
Trial designs for oral iron chelators should certainly consider the safety profile of these agents, and the toxicity tolerance. Efficacy assessment should include hepatic and cardiac iron evaluation. You have heard about the limits as well as the potential for the use of superconducting quantum interference device (SQUID), MRI and liver biopsy. Certainly MRI and its evolution will be an important tool for monitoring these individuals.
Looking at nontransferrin-bound iron, this is certainly another measure that could be very useful and helpful. In looking at hepatic, cardiac, endocrine and hematologic function—will blood counts change? Realize that it may take a year and a half before you see that. However, certainly it may play a role in diminishing the impact of the disease on the cytopenias. Of course, quality of life is something that needs to be considered in these patients.
The highlights today were discussion of the global nature of the overall problem, and new approaches to trying to deal with it. Now that there are oral agents, a more comprehensive approach is likely to be used.
In my presentation, the issue was where iron overload fits into the pathogenesis and complications of MDS. It is clear that it does play a role. Oxidant radicals play a major role in causing stromal and stem cell damage. Correction of that may improve hemopoiesis.
The new developments that will be helpful will be the use of oral iron chelators, either alone or in combination with Desferal. The two agents that are there will be L1, or deferiprone, and ICL-670. Clinical trials are ongoing to try and determine their role.
If iron chelation is more effective, it is likely organ damage may diminish, and hematologic improvement may occur. The role of oral iron chelators will be that they will be more frequently used than the subcutaneous drugs. Consequently, they will likely be more effective and have more patient compliance. I don't see that there will be much change in the use of transfusions unless they diminish the need for transfusion for sickle cell disease.
Clearly, MDS patients are suboptimally chelated at the moment. Oral iron chelators may be effective in improving hemopoiesis and, theoretically, may decrease the need for transfusion.
A study by Jensen, suggests that subcutaneous iron chelators have been useful in unloading iron from patients. Jensen's study also showed improvement of hemopoiesis and blood counts. If that is substantiated, then it will have a major implication for management of these patients.
It is likely that iron toxicity is not the whole story. However, it may be part of the story as to why there is a problem with blood counts in these people.
The serious limitation of compliance prevents a significant number of patients from being properly chelated. The thrust of the research is on compounds, mainly iron compounds. It is almost mandatory to lower the molecular weight of the compound. In other words, the aim is to lose the hexadentate way of chelating an atom of iron. Surely that would have some disadvantages.
Deferiprone is a bidentate that chelates three molecules to strongly bind one atom of iron. It is now approved in many countries but not in the U.S. and Canada. It is, at most, a second-line treatment for patients who are contraindicated for desferrioxamine. These are individuals who have serious problems with desferrioxamine. Desferrioxamine is orally active and is given in two doses. This is the range of the dose that has been used. The characteristics of this compound are these: The variability in the effect, using the mean dosage of 75 mg/kg/day, is definitely high. In this example, in a patient with a wonderful response to cilium blue, the serum ferritin level and the liver iron concentration drop over the long term. On the contrary, with this patient, there was no significant change in serum ferritin. Otherwise, there was an important rise in liver iron concentration. The most important point in the safety profile is that this compound may cause neutropenia and agranulocytosis.
In this example, a patient on long-term deferiprone developed mild neutropenia. There was interruption of the drug, then rechallenge of the drug. After a couple of months, you see severe agranulocytosis, requiring hospitalization and treatment with granulocyte colony-stimulating factor (GCSF). This compound requires close monitoring. Therefore, every patient who is taking this drug must have a blood count, ideally every week, to prevent serious consequences of the side effects.
A recent interesting point is that there are data showing that ICL670 may have some advantage in comparison with desferrioxamine in the method and in the effect of chelation. In a paper we published recently, we retrospectively analyzed patients on long-term chelation—more than four years on desferrioxamine or on deferiprone. These two groups were matched for age and iron stores. The two groups had a significantly different chance of developing new cardiac disease. The groups had a significantly different chance of pre-existing cardiac disease. There are also many individual observations in this study, but this is not evidence.
There are now some prospective randomized controlled trials that are trying to answer this very interesting characteristic.
ICL670 is a tridentate compound. Its short two molecules are able to bind the iron. It is orally active. The phase I results of the study on thalassemia major patients showed a good relationship between the dose administered and the plasma concentration of the drug. This was a single administration of the drug.
An important phase I trial showed liver confirmation of plasma concentration, on multiple doses. It also showed that the iron excretion is within the therapeutic range we saw previously. This is in transfusion-dependent patients ranging from 0.1 to 0.5 mg of iron/kg/day. Unfortunately, this compound is almost completely excreted with the feces. Consequently, there are many implications. One practical implication is that the monitoring of the effect of this compound is not easily addressed. The serum ferritin—as you can see here in three groups of patients taking two different doses of the compound—is compared with standard treatment of Desferal. You see that the serum ferritin trend in patient groups is not so informative. Therefore, for the phase II studies on this compound, SQUID biomagnetic susceptometry has been used to monitor the effect of liver iron concentration.
This has been the core study for phase II development of this compound. You see three groups of patients taking the drug for 12 months. Then there is a potential crossover from Desferal to oral chelation. The liver iron concentration is assessed every three months. We could see that this compound, at the dose of 20 mg at peak, has an efficacy that is equivalent to the standard treatment with desferrioxamine. This is very important. One year is a short time in terms of iron chelation.
There is confirmation of good dose-dependent pharmacokinetics of this compound. This means that in the peak level of difference, there is no trend toward accumulation of this compound, over time, with once a day administration.
The safety profile is interesting examination of important issues. With the oral agent, there is nausea and vomiting, but generally these symptoms are transient. No patient had to interrupt or discontinue the treatment due to these effects. Less than 1% of patients had skin rashes of this type. Again, these are transient and most patients can continue the treatment, with the rash disappearing without consequences.
The renal safety profile is significant because there is some increasing urinary ß-2 microglobulin, with a minor increase in N-acetyl-ß-d-glucosaminidase (NAG). There is also slight proteinuria. However, there is no increase in serum creatinine over the long term. The meaning of these findings is not so clear, at least in thalassemia. There are several papers that show proximal renal dysfunction without regard to extra evaluation and treatment.
This set of these results on ICL670 gave this compound the status of orphan drug in Europe and in the U.S., and also Fast Track status in the U.S. It may be that if the results of these developments continue to be so positive, we will have conventional registration within a shorter-than-average time. Now this compound is fully in development in phase II trials. These trials include patients with sickle cell disease, thalassemia, other genetic chronic anemia, acquired anemias, and myelodysplasias. In many countries, these trials are now limited to 1,000 patients. Possibly, registration will be here in 2005.
Another new advance in iron chelation is the potential of combining different iron chelating drugs. That is, we hope to find an additive effect or, in some patients, a synergistic effect. At the end, we hope to have greater efficacy. Obviously, it is possible to alternate the drug as may be done in a standard way, using desferrioxamine by night and an oral chelator by day, such as deferiprone. Alternatively, one could try to have a concomitant presence of the two drugs in the plasma. We hope to find an additive or synergistic effect.
Here you have an example of urinary iron excretion in one patient taking desferrioxamine alone, deferiprone alone, and then the alternate way of taking the two drugs, or combining them. You see that on the average, in these individual patients, the additive effect is taking place, at least for urinary iron excretion, and maybe for some synergistic effect.
Today it is very difficult to decide what to do when a patient such as this one—with a severe iron overload condition—has the onset of severe heart disease that is life-threatening. In this patient, you also have MRI evidence that the signal in the myocardium is indicating a severe iron load. Consequently, you may use continuous intensive intravenous treatment with Desferal, which we know is effective. There is evidence of this. However, we do not know the timeline for Desferal to have a clinical effect. We do not know the amount of time it takes to save a patient, or to significantly reduce the chance that a patient to die.
Combination therapy may be an alternative. It is not a registered approach today. Here you have another example, a patient who presented to us with a severe iron overload, indicated by the liver iron concentration. The MRI indicated a severe load too. The patient was on Desferal. At the same time, we started combination therapy with this treatment, subcutaneous desferrioxamine, taken 24 hours a day, and deferiprone orally. After a few months, we had incredible results. You see with MRI that the gray signal is evident. It did change. You see that the numbers are very different. Look at the iron load that is incredibly low. It is close to iron deficiency. We continue to give iron chelation to this patient orally, with good results.
Other compounds: Dr. Vichinsky mentioned starch desferrioxamine. It has been on the borderline of being clinically developed for some years. It may be that now there will be a new effort to try to understand if this compound could be clinically useful in the future.
I would like to mention GT56-252. Again, it is an oral iron chelating agent that is tridentate. It is a novel new compound that shows—at least in iron overload animal models—interesting results in terms of efficiency of chelation, both parenterally and orally. In animals, it has an acceptable safety profile. It is now fully developed in phase I trials. We will soon see the results.
Another compound that is interesting is PIH. This is an oral compound that is orally active. It has been left behind; the efficacy is relatively poor. Now there are several derivates of this compound that show interesting characteristics, at least in vitro. Maybe they will be fully developed.
This recent, interesting paper by Link demonstrates the use of a shadowing effect. That is, giving this compound, at least the 108-109 compounds, with desferrioxamine, leads to an additive effect. This additive effect is achieved by shuttling the iron from this compound to desferrioxamine molecules.
We have had to manage iron chelation with a single drug. We have learned how to use this drug to have a more efficient chelation, with reduced side effects. We have now at least two compounds that are out of the door and maybe other compounds will be found. At this point, we may be very close to the ideal of tailoring iron chelation to optimize effectiveness and reduce side effects.
I treat pediatric hematologic diseases such as thalassemia and sickle cell disease. The most promising treatment for iron overload is the development of new iron chelators that may be taken by mouth. Nonreactive iron chelators may change the life of patients with iron overload condition. The standard treatment is given with a needle, subcutaneously, every night, all night long, and every day of the patient's life. Therefore, an oral chelator is extremely important.
There are new, very interesting developments involving chelators. There is a new compound, ICL670, that is very promising for potentially being an ideal chelator. If an oral chelator is available soon, and is effective and safe, it could change the attitude of physicians in regard to transfusion, mainly for sickle cell disease. Consequently, transfusion may be used more frequently, with advantages for this type of patient, because the iron chelation could be done more easily. These evolving treatment strategies may ideally optimize this treatment. Ideally, in the near future, it will be possible to individually tailor these treatments for each individual patient. Each patient would have the best personalized treatment. Over the long term, this will not only improve the quality of life but will improve the duration of life.
This symposium had several highlights. One was an in-depth discussion of the mechanisms of iron toxicity and of the natural history of iron overload. Understanding the differences among important diseases in iron overload was also significant. Consideration of iron chelation methods in thalassemia, sickle cell disease and myelodysplasia was a dominant theme. In the end, there were some important highlights for the future: new advances in iron chelation therapy.
MDS disease is changing, because life expectancy continues to increase. Physicians are paying more attention to treating the condition of iron overload. It is very important, in this disease, to have long-term perspectives. It is very important to give iron chelation where it is needed.
Participant
I have a number of questions for Gary, relating to management of iron overload.
Participant
First, is there any correlation of iron content with SQUID measurements, with liver biopsy, and is this reliable? My experience has been with our system, and we do find an excellent correlation, but there are ongoing a number of studies that are examining both the correlation of SQUID and of MRI with liver biopsies.
There is another related question. How much variation is there in liver irons measured in various laboratories through the world? It is not as straightforward as it might seem. There once, in fact, were efforts to try to send samples around to various labs to see how well they do. It is quite true that there is some variation in the laboratory. You need to have both the collection and the processing rigorously maintained, free of iron contamination, especially when you are measuring very small samples of tissue. Tiny amounts of iron, even from cutting it with stainless steel, can produce real problems. Standardization of processes and protocols is very important as liver iron studies become more widely used.
Are we recommending liver biopsy in all patients in whom there are signs of iron overload? No, it certainly needs to be tempered by clinical judgment. However, liver biopsy certainly needs to be a consideration. I think Elliott Vichinsky, for example, showed patients who normally would be considered to be doing very well, who have really high liver irons. They need to have at least some sort of assessment, so you really know how much iron overload you are dealing with.
Participant
Elliott, you had a number of questions to you there.
Elliott Vichinsky, MD
The first question involves a 14-year-old child with sickle cell anemia. The liver iron, I assume, is 30 mg of dry weight, which is obviously extremely high. There is a history of stroke, with an abnormal MRI. How would I manage this patient? The patient is already getting subcutaneous Desferal 12 hours a night and is already on Epo.
It is a good question. First of all, I think I would manage them effectively. I mean, I think each family needs a special approach about how you are going to get their iron down. There are two mechanisms to do that.
One, I would clearly implement cytapheresis, if it is not being done. In multi-patient programs that have cytapheresis, it is rare that a patient cannot be pheresed. I think pheresis needs to be part of the program.
Secondly, programs can go down to a very young age, even three years of age. In larger programs, it is very rare that the patient needs to have deep lines placed. If the liver iron is high, it must be validated. I have seen problems with the handling of liver iron samples. We did not go over this, but the biopsy sample has to be large enough. Otherwise, it is very unreliable.
In patients who are at risk, we admit them to the hospital and we give them continuous Desferal in a method that is suitable for the family. I would consider that an indication for your patient, as I would transfusions for stroke.
Participant
There is a question here about transfusing patients with sickle cell disease who have priapism that is associated with stroke. There were, I think, at least two reports that specifically linked the two conditions. The reports showed automated erythrocytapheresis in patients who have been managed with acute priapism, who develop CNS complications like stroke. These were mostly in the 1980s. There have not been any more reports. There was never a good explanation for why that particular setting would lead to any CNS complications. Obviously, there are many patients who have been pheresed for many different complications of sickle cell disease. Pheresis was done either acutely or on a chronic basis. For these patients, stroke was neither an indication nor has been a complication of the procedure. Even though there were reports of so-called association of sickle cell disease, priapism, exchange transfusion and neurological events (ASPEN) syndrome, there is no good explanation for it.
I think one might also say that probably erythrocytapheresis in the context of acute priapism may not achieve much clinical benefit. I think that needs to be said. There is not a lot of information that it works.
There is another question about what practical difficulty
you expect to see in offering erythrocytapheresis to all sickle cell patients
who are on chronic transfusion therapy, at all ages? There are some
limitations, which are mostly access limitations, in offering erythrocytapheresis
therapy.
If you place patients on erythrocytapheresis and you do it effectively, with
the goal of maintaining them at a negative iron balance, then you may have
other concerns. You may have patients who have a high reticulocyte count and a
lower hemoglobin level than normal. The high reticulocyte count may itself
predispose them to have a more vasoocclusive phenomenon. Clinically, this has
not been proven, but I think with the goal of lowering iron overload, that this
is a very effective therapy. The limitations are investment in the time and
interest of the physicians and the hospitals managing these patients. I think,
as has been stressed today, if you are going to manage a large number of sickle
cell patients on chronic transfusion therapy, this should be considered an
important part of their management, because it works. If you place patients on
chronic transfusion therapy on erythrocytapheresis, you will reduce the rate of
iron overload to the point where many of them will never need chelation, as long
as they continue it. So it is a very important investment to make.
Participant
There are a couple of questions on the use of intravenous Desferal—what the best regime is. There isn't time to describe it in great detail. I think the general point is that you can get very good survival and reversal of cardiac disease without using very high doses, if you use it continuously. In fact, you don't need to give it intravenously. You can get very good results using 24-hour subcutaneous treatment in those who will tolerate it, even if they have got heart disease.
Participant
There is a question on the use of bolus subcutaneous Desferal that I showed on a slide but did not explain. There are a few studies showing that subcutaneous bolus Desferal in 10 ounces of water, given once or twice a day, in the same dose as a low subcutaneous infusion, may have the same effect in times of urinary iron excretion. This is true and it may be a good approach, mainly with naïve patients, naïve in terms of iron chelation. They may accept more easily this type of prescription. For patients who have been a long time on iron chelation, by slow infusion or subcutaneous, there is no important difference for the patient.
This type of treatment is interesting in itself. It may be that the bolus subcutaneous injection may give a higher plasma peak level of desferrioxamine. In the long term, this could be important in the iron removal from tissues like the heart.
Participant
There are several questions on what you do with patients who have been iron overloaded in the past, who have a transplant procedure, or are cured of another disease. What should be done in terms of phlebotomy and removal? It is fairly clear that there is a benefit in removing the iron and often, you can remove that with simple phlebotomy.
Participant
I will quickly summarize these answers and questions. First is the question of thal intermedia, iron overload and anemia, without being transfused. The best correlation with iron overload in the non-transfused patients is the correlation with the degree of ineffective erythropoiesis. The correlation would not necessarily be with anemia; I think Stan Schreier [phonetic] has some information. You cannot just go by hemoglobin level; it is really the level of intramolecular pheresis.
The second question, which I thought was really good, was pulmonary hypertension's relationship to just hyperactive sickle cell dynamic circulation. I was very skeptical at the same point. Mark Gladwin [phonetic] published a nice paper on cardiac catheterization in JCI and recently published a series in respiratory journals. He didn't find a correlation with anemia. He looked at pre- and post-transfusion, which we did. I think a hyperactive dynamic state plays a role, but once it is established, it is irreversible and transfusion is not the sole factor in it.
Liver iron variability in the world, by biopsy—that is an issue. It is an issue of getting a big enough sample and having a lab that does quantitative liver irons well. There are only a few that I know of.
Kwaku Ohene-Frempong, MD and I have a question on hydroxyurea for the treatment of pulmonary hypertension, stroke versus transfusion. Do you want to comment about that?
Participant
The hydroxy study showed that there was improvement in pain rates, acute chest syndrome rates and transfusion requirements, but not for these other indications. Therefore, one cannot really make a recommendation. There is an ongoing study that is looking at using hydroxyurea in patients who have had a stroke, to prevent recurrence. There is not any information on using hydroxyurea, instead of transfusion, to prevent primary stroke in patients who have abnormal TCD studies. These cannot be recommended.
There is a related question about how long to continue transfusion in patients on transfusion for abnormal TCD. That also is not determined. There is Stop 2 trial which is looking at that question. In that trial, patients have been randomized to continue or discontinue the transfusion. The patients under study have normalized their TCD, they do not have MRI or MRA abnormalities, and they do not have vasculopathy of the brain. Until that study shows that it is safe to discontinue transfusion, for those not participating in the study, my advice would be to continue the transfusion; manage the iron overload as best as you can, until that study is completed.
Peter Greenberg, MD
One question relates to the patient who had been heavily transfused for malignant disease and then had transplant and post transplant graft-versus-host (GVH). Following that, GVH resolved. What to do? If one needed to determine the iron status of this individual, it would be reasonable to either get an effective MRI or SQUID, or a liver biopsy. As demonstrated, the outcome certainly is quite different when you have effective chelation. Individuals with high iron probably should be chelated until their iron levels decrease.
Participant
I have a question on combination therapy, that there is a need to modify the drug dosage.
Participant
The answer depends on the aim. The answer is no if the aim is to chelate more iron than possible. Today, there is no evidence of a rise of toxic effects in this combination therapy. The answer may be yes if the aim is to lower the toxicity of one or both of the chelators. Again, there are no results from a randomized controlled trial on this topic today.