May 2010
Feature Story

Anne Paxton

When a male patient arrived recently at the Diggs Kraus Sickle Cell Center with severe joint pain, elevated liver enzymes, and a serum ferritin level of 10,000 µg/L, there wasn’t much doubt about the diagnosis, says Patricia Adams-Graves, MD, director of the Memphis-based clinic. It was a classic case of iron overload.

As part of treatment for his sickle cell disease in a previous rural hometown, the 29-year-old patient had received more than 100 blood transfusions in his lifetime—but he had never been given treatment for accumulation of excess iron.

“He was not just iron-burdened, he was iron-toxic,” reports Dr. Adams-Graves, whose center provides outpatient treatment for some 400 adult sickle cell patients. Fortunately, this one was immediately placed on che­lation therapy and has responded well. But the case serves as a reminder of a critical fact: More than two decades after transfusion-related iron overload became a treatable condition, and despite the availability of effective iron-chelating therapies, for a variety of reasons many patients at risk for the condition are not being treated. In fact, for the nation’s population of sickle cell patients in their early to mid-30s, iron overload is now the No. 1 cause of mortality, Dr. Adams-Graves says.

Patients with iron overload often go undetected. Many of those who have received a critical burden of iron from transfusions are not being recognized for that risk, and many are not getting appropriate clinical monitoring and followup. “It’s not something really obvious, but particularly over time, with increasing numbers of transfusions, patients can develop severe hepatic or cardiac conditions that may be very difficult to turn around in the later stages,” says James AuBuchon, MD, president and CEO of the Puget Sound Blood Center, Seattle. “There is a growing but incomplete awareness—even among transfusion medicine physicians—of the importance of this problem.”

People have known about iron overload for a number of years, says Morey Blinder, MD, associate professor, hematology division, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis. “There are early studies back in the 1960s showing it can cause problems in the liver and heart, but a lot of patients back then who were at risk didn’t live long enough to develop complications of iron overload.” Now, many people who might have died as adolescents or young adults 30 years ago are in their adult years and becoming iron overloaded.

Iron overload can stem from hereditary conditions—it’s called hemochromatosis. But the acquired version of iron over­load, known as hemosiderosis, is a long-term complication of repeated red blood cell transfusion. It occurs because of a hard fact of physiologic arithmetic: Every pint of blood transfused adds 200 to 250 mg of iron into the body but the body can only excrete about one or two milligrams of iron a day. Without treatment, even someone who is getting just one transfusion a month of two units of red cells—a common therapy for aplastic anemia, myelo­dysplastic syndromes (MDS), thalassemia, and sickle cell disease—will soon become iron-burdened.

“Iron is conserved very rigidly in the body because it’s useful in so many processes,” explains Cage Johnson, MD, a hematologist and director of the Comprehensive Sickle Cell Center at USC Keck School of Medicine, Los Angeles. As red cells break down, the body normally stores the iron they release in the liver, spleen, and bone marrow. Too much iron may accumulate in these sites, however, and in others, including the pancreas, the joints, the pituitary, the thyroid and adrenal glands, and the heart.

“You can get diabetes from iron over­load in the pancreas, you can get arthritis from iron loading in the joints, and the biggest problem is iron loading in the heart leading to cardiomyopathy with heart failure or dysrhythmia,” says Dr. Johnson. “And by the time patients get symptomatic, it’s too late to do anything.”

For people with hereditary hemochromatosis, phlebotomy is a realistic treatment and provides a generally good prognosis. It can be a relatively mild disease anyway; many people who have it never become clinically ill. But the problem with myelodysplastic syndrome and sickle cell patients is they are anemic already, so phlebotomy would only make them worse. “Anemia is why you’re transfusing them, so taking out blood is not an option,” Dr. Blinder says.

Leading blood organizations and the Food and Drug Administration have recognized that treatment for iron overload is essential. A blood product circular authored jointly by the American Red Cross, America’s Blood Centers, and the AABB, with approval by the FDA, provides information about iron overload as a long-term complication of repeated red blood cell transfusion and recommends treatment for those at risk. The International Symposium on MDS Syndrome, through the MDS Working Group on Transfusional Iron Overload, also issued a similar consensus statement in 2008.

Ira Shulman, MD, director of the Transfusion Medicine Service Group and professor of pathology at the University of Southern California Keck School of Medicine, and a former chair of the CAP Transfusion Medicine Resource Committee, says the LAC–USC Medical Center has begun to look at its transfusion database very carefully to identify patients at risk of excessive iron exposure who might not yet have been plugged into a serum ferri­tin monitoring scheme. At present, when a blood unit is ordered for a chronically transfused patient, “there’s no ‘Here’s your 23rd unit.’ It’s just: ‘Here it is.’ Unless somebody asks, ‘Well, how many is that?’ they wouldn’t have that information.”

A systematic review of data, just completed at USC and being readied for discussion at hospital quality review committees, looked at more than 32,000 transfused patients over a 10-year period. “We found that five percent of our transfused patients were chronically transfused, that about 300 of the chronically transfused patients received some of their transfusions during 2009, and that a dozen of those active patients had hematologic conditions requiring transfusion, but no evidence of serum ferritin testing. The good news is there are not legions of patients being missed who might benefit from serum ferritin monitoring. We have discussed these findings with our clinical hematology group, and they have asked us to repeat the data analysis every six months.”

Clinics of a few hospitals have adopted iron overload monitoring protocols, according to Novartis. The company’s Iron Overload Nurse Ambassador Program provides tools and guidance to help hospitals scan patients’ transfusion history through a medical record, identify patients who appear to be getting repeated transfusions, and then introduce the patients to iron overload educational materials, make sure ferritin levels are being assessed, and encourage action depending on the iron level.

“The hematologists that I’ve come into contact with who are treating sickle cell disease or thalassemia are well aware of the dangers of iron overload,” Dr. AuBuchon says, though he notes that some patients treated outside of major medical centers might have general practitioners who might not be as cognizant of the risks. A more significant problem, in his view, is the inherent disconnect between those who have the information about the number of transfusions administered and those who are caring for the patient.

“The clinicians caring for the patient are going to be interested in delivering therapy; the transfusion medicine physician doesn’t see the patient and the clinical problem, and he has to cast a very broad net to create an algorithm that looks at a large number of transfusions for a very small fraction that are going to be related to iron overload.” For progress to be made, he thinks, physicians who are treating chronically transfused patients like those with sickle cell disease are going to have to bring the issue to the attention of the transfusion medicine physicians.

“I suppose with increasing use of the electronic medical record that it’s feasible to have either the EMR or LIS programmed to query the record of all transfusion recipients to determine whether hemorrhage is one of the diagnoses, and if not, then alert the transfusion service that a person receiving more than a given number of red cell units has a positive iron balance,” Dr. AuBuchon says. “I’m not aware that anyone has developed such an algorithm, but it’s theoretically possible.”

“There’s a little tension between clinicians and blood bankers about whose responsibility it should be,” says Stuart Goldberg, MD, chief of the Division of Leukemia, Hackensack (NJ) University Medical Center. “We don’t have a national tracking system. Our patients move from hospital to hospital. Our blood bank says it can’t be responsible for telling how many units these mobile patients have received. While the clinicians say: Can’t you give us a little help?”

Patients do slip through the net because they go to different locations, says Kathleen Sazama, MD, medical officer, LifeSouth Community Blood Centers, Gainesville, Fla. “It’s probably not as unusual as you might think. Because of lifestyles and the way we migrate around for jobs, or don’t have jobs, it’s not that uncommon for a person to get therapy at some different sites.” Unless there is an acute crisis for a sickle cell patient, for example, chances are the transfusions are happening in an outpatient setting. Physician offices or group practice settings are other areas where records aren’t integrated with the comprehensive record.

As an interim measure, one option might be a kind of “transfusion passport” that patients could use to keep track of how many transfusions they have received, Dr. Sazama suggests. Although not a solution that’s been proposed formally, it could allow each patient to log transfusions, note when ferritins are done, and chronicle therapies. “It could be a kind of chronology of events surrounding your diagnosis to help clinicians know where to intervene.”

To be fair, Dr. Sazama says, most hospital transfusion services are handling trauma, surgery, and cardiac patients, and occasionally pregnancies. “This isn’t going to be the No. 1 focus for many of them, unless they happen to have either a high number of hemoglobinopathy or oncology ­patients or patients being treated by a hemato-oncology group.”

“I think CAP could be a very strong voice” on the need for tracking and flagging, Dr. Sazama says. “Nobody gets transfused without somebody issuing blood, and typically that’s the hospital transfusion service, which is overseen almost exclusively by pathologists.” If the goal is improving awareness and treatment of iron overload, she maintains, “I think that’s exactly where the push should come from.”

There are only two approved medications for treating iron overload in the U.S., both made by Novartis: Desferal (deferoxamine) and Exjade (deferasirox). In Europe there is a third medication, Ferriprox (deferiprone), made by ApoPharma, but the FDA has not yet approved it, says Dr. Goldberg of Hackensack University Medical Center. Additional oral iron chelators are in pilot studies in Europe, and there may be other drugs coming down the pike, he adds.

Deferoxamine, a chelating agent, was the first drug developed. Long the standard treatment, it works by binding with iron in the body and excreting it through urine and feces. But it has significant problems that limit its usefulness: It is administered subcutaneously by continual infusions, in addition to having a range of side effects.

“It’s a little pump you wear like a cell phone, and a syringe, and you can walk around and let it run or sleep with it at night. It’s a burden and it’s frustrating to patients. But you’re not going to get a good chelation unless you’re running that for 10 to 18 hours. The longer the infusion, the better the chelation,” Dr. Adams-Graves says.

Since 2007, Novartis has offered Exjade (deferasirox), an alternative chelation therapy that is taken orally in the form of a pill and has proved far more acceptable to patients. At the USC’s clinic, for example, Dr. Johnson says, “There were a couple of patients whom we didn’t switch because they were comfortable with the injection regimen.” But most patients have reacted positively to replacing the injection with the oral drug. “The side effects aren’t really that different.”

Deferoxamine was a difficult drug to use because of how it had to be administered, Dr. Blinder says. “It really took a motivated provider and a motivated patient to get that drug going.” Moreover, as Dr. Johnson notes, the cost is significant: “The subcutaneous agent with all of the supplies needed probably costs on the order of $40,000 per year,” he estimates.

As an indication of the problem with compliance, Dr. Blinder describes a survey he took at Washington University Medical Center. “We looked at our sickle cell population, and we had 32 patients who I thought were eligible for deferoxamine based on the old criteria of iron overload. We tried to prescribe deferoxamine in 17. But of those 17, we could find only three who I would say were compliant by taking their medication.”

The new oral drug—while it has side effects including gastrointestinal upset and diarrhea—makes treatment much easier, and compliance has improved over the past couple of years since Exjade has been available. But patients who have never had chelation therapy before are not as appreciative of the Exjade oral pill, Dr. Adams-Graves notes. “They start taking it and it causes diarrhea or GI symptoms; then they’re likely to slow down or stop and say, ‘I can’t stand this.’ But a lot who have been switched off the needle that they have to stick in their belly or their leg subcutaneously every day, they do appreciate it, and they are the ones who are most compliant.”

Her clinic has placed a strong emphasis on patient education, she says, noting that many cases of noncompliance emerge only when serum ferritin levels start creeping up.

Another problem with both chelation therapies is that they chelate not only iron, but also other divalent cations such as calcium and manganese, Dr. Johnson points out, thus creating a whole laundry list of potential toxicities such as renal disease and hearing loss. “Those effects are quite common. I’ve observed them myself. Some of these trace metals are necessary for certain biologic processes, and if you deplete them, hearing loss is one of the potential side effects.”

Although the oral medication Exjade works in broad terms by the same mechanism as deferoxamine, by binding to iron, it does have major drawbacks, says S. Gerald Sandler, MD, a member of the CAP Transfusion Medicine Resource Committee and professor of medicine and pathology and director of transfusion medicine at MedStar Georgetown University Medical Center, Washington, DC.

“On my desk I have FDA announcements dated 2007, 2009, and most recently February 18, 2010—each informing health care providers that in post-marketing surveillance, fatal renal, fatal hepatic, and fatal GI bleeding events have occurred, and that persons taking this more convenient approach to removing iron overload need to be informed about the toxic profile.”

The FDA also found that, compared with the infusion treatment deferoxamine, “in all six categories there were more adverse reactions occurring with the new medication Exjade.” The early clinical trials on this drug, in fact, showed a tendency toward increased adverse reactions, and as is common, the post-licensure period has brought out even more. “So on the one hand you have a way for some of the patients to get a major benefit from taking a pill every day as opposed to a 12-hour infusion. But on the other hand, the people who need it the most, the ones who are sickest, are those at higher risk for complications.”

A younger person without accumulated organ damage is in pretty good shape with this drug, he says, while older people with a lifelong history of transfusions could be at higher risk. “There’s a long list of contraindications, warnings, and precautions in the packet insert, so pretreatment evaluation is an extremely important part of planning a program and making sure a person qualifies for this treatment.”

“This makes it clear that basically there is no quick fix to the longstanding problem of iron overload,” Dr. Sandler says. “It also reinforces the need for conservative use of transfusions.”

To minimize the number of blood transfusions that a given patient needs, he notes, there are two strategies that work well with sickle cell disease. “One is to treat with the chemotherapeutic agent hydroxyurea, which increases the percentage of hemoglobin F. The second strategy is to manage the need for transfusion by using red cell exchange or erythrocytapheresis. You take out four or five units with a cell separator, and give the patient back four or five units, so he ends up having his blood that doesn’t cause a sickling problem and he has not had a net increase of iron.” For older patients with MDS who need chronic transfusion, the strategy is to take advantage of chemotherapy that’s available for this category of patient to increase their hemoglobin, he says.

The standard laboratory test for iron overload, serum ferritin, is not a perfect indicator but does correlate reasonably well with the degree of iron overload. “Serum ferritin has a number of confounding effects because it’s also sensitive to inflammation,” which makes the level go up independent of the iron load, says Dr. Johnson. “So you need serial values of ferritin, usually two or three times a year, to really detect a trend.

“It’s really difficult to interpret; you get all kinds of noise, and sometimes clinicians order it too often. You have to get the test at the proper time and when the patient is relatively asymptomatic. It requires some thoughtfulness rather than a reflex acquisition of data— but when you draw a curve and follow the patient, you can see if a number shouldn’t count because it was affected by something else.”

Better MRIs are being developed to test for iron levels as well, Dr. Blinder says. “Since we’re talking about iron, which is attracted to magnets at a very simple level, you can get a rough idea of iron overload based on the intensity of the signal of the MRI, and there are ways being developed with software to try to quantitate that, to get a measure that is potentially more exact than ferritin.”

Unfortunately, a patient’s iron burden is not truly measurable in all systems of the body that might be affected, Dr. Adams-Graves points out. “A liver biopsy may show four plus iron; that’s the most burden you can have. But if it’s in the heart or endocrine glands, we can’t cut into those areas. There are new CT scans that look at the liver and heart but basically that’s the gray zone. Right now, there’s no good formula that’s reliable.”

One of the improvements she would like to see is more CT scan machines. “I would be hard-pressed to say we have more than three to five of those special CT scanners that can do quantitative analysis in the nation. We need more of these testing devices to diagnose this horrible complication.”

She also believes the clinical laboratory can help. “When you get a ferritin that’s over 1,000, that should be an alert value. In trauma cases, you see a lot of ferritins that are off the chart, and it may not be an accurate way to evaluate patients. But if there were an alert, it could be coupled with the clinician’s knowledge of whether the person is in an inflammatory situation.”

The percent saturation should be a part of the laboratory report as well, she adds. “That figure needs to be reimplemented into iron profile studies. Now we just do TIBC, but we need to start recalculating the saturation, because we know if it’s over 50 percent then the patient is iron burdened.”

There are two main stories in iron overload treatment, says Hackensack University’s Dr. Goldberg. The best known is the progress since the development in the 1980s of deferoxamine in markedly increasing the life expectancy of children with iron overload through use of chelation therapy. “This was due to a big movement by pediatric doctors who take care of thalassemia and sickle cell patients to get them on some type of chelation process.”

The other story is in the adult world, which is where he cares for patients. “We’ve known about advances in iron chelation from our pediatric patients, but didn’t pay attention to elderly MDS patients who had bone marrow failure. We were keeping them alive with transfusions, yet they were dying early, possibly from complications of the iron. We weren’t bothering to do the research and studies to find out, because even if we did, the adults wouldn’t wear the pumps.”

“With the development of the more convenient pill about five years ago, there’s been interest in reexamining iron overload issues in older adults, including following the amount of transfusions they’ve received, their ferritin levels, and then when they hit a certain level starting them on treatment for iron overload. That’s where we are right now,” Dr. Goldberg says.

Another issue in the hematology world, since children with these diseases are living into adulthood, is transitioning them from pediatric hematologists to adult hematologists. “We’re spending a lot of time in the meetings I go to asking how we can be sure somebody remembers ‘okay, now we have to start the chelating process.’”

In a study published in the Journal of Clinical Oncology, Dr. Goldberg and colleagues looked at MDS patients and followed them to see the impact of chronic transfusions on comorbid outcomes. “We asked for all the bills for the U.S. Medicare population for 2003 and we looked to see who was diagnosed with MDS in 2003.”

After tracking these several hundred patients over the next three years of records, they found that people with MDS developed heart attacks and congestive heart failure at much higher rates than people without MDS. They also found that MDS patients who were getting transfused had even more heart attacks and heart failure. They found, in addition, higher rates of diabetes, hepatic disease, and infections—all potential complications of iron overload. A related finding of the study is that there are many more new cases of MDS in the U.S. per year than what is commonly assumed. Rather than 10,000, it may be more like 45,000 per year, he says.

The endpoint of most studies is not the percentage of people who would get sick and die of iron overload if they did not get chelation, Dr. Blinder notes, but just how many are not iron-overloaded. To actually look at the mortality of people chelated might be useful but would take a lot of patients over a long time, he points out. “That’s why we use surrogate biochemical markers; we make a leap of faith that if you’re not overloaded, your survival might be better.” However, a large international study sponsored by Novartis is poised to begin a head-to-head, randomized, placebo-controlled trial of chelation versus no chelation in MDS patients. “That’s the question we all want to answer,” Dr. Goldberg says.

Dr. Goldberg, who believes that for the most part Exjade is a safe medication, points out that statistically, the biggest safety issue is that a third of patients on Exjade will reduce their kidney function, measured by creatinine, by about one-third. “Fortunately it’s reversible in most patients; it’s usually manageable by just watching and changing the dose. But in rare cases there is permanent kidney damage and hemodialysis.”

The other big issue, he says, is whether Exjade actually hurts blood counts themselves. “With MDS patients, the question is if the bone marrow fails anyway, how do you know it was due to the Exjade and not just due to the underlying disease?”

Progress in treating sickle cell disease has been incremental. “There haven’t been any home runs,” Dr. Blinder says. “Transfusions have helped, and there are certainly hopes for newer medications, but they’re not reality yet.” The growing role of stem cell transplant treatment could have important implications for iron overload. “It’s very early, but there is some data to show that if a patient is undergoing a stem cell transplant, they will do better if their iron level is lower. They will have fewer infections and fewer complications from their transplants.”