ESAs and IV iron: a perfect match?

Five randomized trials have shown that IV iron improves the response to erythropoietin treatment.

Shortly after epoetin alfa was approved by the FDA in 1989 for the treatment of anemia related to chronic kidney disease, data emerged that indicated IV iron supplementation improved the response to epoetin.

According to Michael Auerbach, MD, IV iron has been the standard of care since 1994 for patients with chronic kidney disease who are assigned erythropoiesis-stimulating agents.

Auerbach, a clinical professor of medicine at Georgetown University who is in private practice in Baltimore, argues diligently that IV iron should also be standard in the hematology/oncology setting.

It has not caught on yet, despite safety concerns and reimbursement issues surrounding ESAs that have left many hematologists/oncologists struggling to keep their patients from requiring transfusions.

“We are in the middle of this storm because of our failure to embrace a therapy that now has 15 years of experience in the nephrology community, with no long-term toxicity and virtually no short-term toxicity,” Auerbach told HemOnc Today.

In the past four years, data from five randomized trials have demonstrated that IV iron was beneficial to patients with chemotherapy-induced anemia who are assigned ESAs.

According to results from these trials, IV iron appears to improve hemoglobin response when it is added to ESA treatment in patients with chemotherapy-induced anemia. The benefit is seen in both iron-deficient and iron-replete patients.

John Glaspy, MD, a professor of medicine in the division of hematology/oncology at the University of California, Los Angeles Medical School, said it is unfortunate that hematologists and oncologists have been slower to appreciate the potential of IV iron to enhance response.

“With all of the other issues that have arisen with regard to safety of ESAs in hematology/oncology, we have lost our opportunity to integrate this into practice,” Glaspy told HemOnc Today. “It would have been better for the patients if we had recognized sooner the value of IV iron to overcome resistance to ESAs and lower the ESA dose.”

Dangerous iron preparation

John Glaspy

According to George Rodgers, MD, a professor of medicine at the University of Utah, the different iron products may be a contributing factor to the hesitancy of oncologists to implement routine IV iron use.

The iron product that is FDA-indicated for patients with chemotherapy-induced anemia in the United States is iron dextran, which comes in two forms: high-molecular weight iron dextran (Dexferrum, American Regent) and low-molecular weight iron dextran (InFed, Watson).

“Many people think these are equivalent drugs, but high-molecular weight iron dextran is associated with significant toxicities,” Rodgers told HemOnc Today. “Physicians may be confusing the toxicity of high-molecular weight iron dextran with all iron dextran products. Low-molecular weight dextran is actually a very safe drug.”

In 1980, Hamstra et al published research in the Journal of the American Medical Association that demonstrated the use of iron dextran resulted in three life-threatening anaphylactoid reactions and eight severe delayed reactions. The product used was the high-molecular weight iron dextran, ImFeron (Fisons), which is no longer available.

In an editorial published in the Journal of the American Society of Nephrology, Rodgers and Auerbach et al outlined the dangers surrounding high-molecular weight iron dextran.

Michael Auerbach, MD, is a proponent of using IV iron in the hematology/oncology setting. Photo by Dr. HuzefaBahrain

At least nine studies have demonstrated higher rates of adverse events associated with high-molecular weight iron dextran, they wrote. They recommended that the FDA withdraw the formulation from the market in the United States. The drug has been taken off the market and the black triangle warning removed from low-molecular weight iron dextran in Europe.

According to Rodgers, who is chairman of the Cancer and Chemotherapy Anemia panel of the NCCN, the NCCN guidelines recommend against using high-molecular weight iron dextran for iron supplementation in chemotherapy-induced anemia because of toxicity.

In a 2006 study of patients on dialysis receiving parenteral iron, Chertow et al found that among patients receiving high-molecular weight iron dextran, the incidence of serious adverse events was 11.3 per million doses. This is compared with 3.3 per million doses of low-molecular weight dextran.

Auerbach said, however, that because of an equal distribution of events attributed to iron dextran when the iron type could not be identified, the data from this study underestimated the number of adverse events with high-molecular weight iron dextran and overestimated the number of events with low-molecular weight iron dextran.

Despite the anaphylactic reactions and toxicities associated with high-molecular weight iron dextran, the FDA has allowed the drug to remain on the market, Auerbach said. The FDA black box warning on iron dextran does not distinguish between the products, he said.

“Low-molecular weight iron dextran is probably the least toxic iron available, but it carries a black cloud over its head because of the safety issues with high-molecular weight iron dextran,” Auerbach said. “An overwhelming majority of hematologists and oncologists are not aware that two different iron dextran products exist. Whenever the high-molecular weight iron dextran causes an anaphylactic reaction, it is wrongly assumed that both iron dextran products are dangerous.”

Auerbach said that pharmacists often substitute high-molecular weight iron dextran for low-molecular weight iron dextran because it is less expensive. He said this has led to life-threatening toxicities and death in several patients.

“This drug needs to be taken off the market,” Auerbach said.

Safe for patients

In addition to low-molecular weight iron dextran, two other iron preparations, iron sucrose (Venofer, American Regent) and ferric gluconate (Ferrlecit, Watson), are also available but not yet indicated for patients with chemotherapy-induced anemia.

In the Chertow study, the risk for serious adverse events was 0.6 per million doses for iron sucrose and 0.9 per million doses for ferric gluconate.

In a systematic review published in 2007 in Transfusion Alternatives in Transfusion Medicine, researchers identified little difference in the safety and efficacy among iron sucrose, ferric gluconate and low-molecular weight iron dextran in dialysis patients. However, a savings of $120,000 per dialysis unit per year was achieved when low-molecular weight iron dextran was substituted for either of the salts.

“Within the panoply of drugs that we administer in cancer practice, there is no doubt that IV iron is relatively safe, especially when high-molecular weight iron dextran is avoided,” Glaspy said.

In all five studies, IV iron was well-tolerated. The rate of adverse events was similar among patients in all groups. According to Auerbach, one of the most common effects related to IV iron administration is arthralgia/myalgia syndrome, but this can be prevented.

“When you pretreat patients with medications such as steroids or acetaminophen, most adverse events can be ameliorated,” Rodgers said. “The advantages of using IV iron far outweigh the potential disadvantages, most of which can be prevented.”

There have been five randomized trials that demonstrated the efficacy of the IV iron preparations in patients with chemotherapy-induced anemia who are assigned ESAs.

Auerbach et al conducted the first trial, the results of which were published in the Journal of Clinical Oncology in 2004. One hundred fifty-seven patients, all of whom were receiving 40,000 U of epoetin alfa (Procrit, OrthoBiotech; Epogen, Amgen) weekly, were randomly assigned to no iron, oral iron, repeated iron dextran 100 mg bolus or iron dextran total-dose infusion.

Although patients in all the groups had an increase in hemoglobin, the increases were greater in both of the IV iron groups: 68% for both groups vs. 25% for no iron and 36% for oral iron.

In 2007, data from a study of iron sucrose conducted by Hedenus et al were published in Leukemia. Sixty-seven patients with positive marrow hemosiderin and lymphoproliferative malignancies who were not receiving chemotherapy were randomly assigned to 30,000 IU of epoetin beta (NeoRecormen, Roche-Europe) weekly with or without IV iron supplementation.

The results indicated that 93% of patients who received IV iron had a mean hemoglobin increase of >2 g/dL, compared with 53% of patients in the no-iron group. They also demonstrated that the total ESA dose was lower in patients who received IV iron resulting in a $100 per patient per week savings.

This study was the first to show a true clinical benefit of adding IV iron, according to Glaspy.

“Each of the five trials has shown that IV iron enhances hemoglobin response to ESAs,” Glaspy said. “The question is, ‘what is the benefit of that?’ The two most important benefits are a reduced ESA exposure for patients — while we work out the ESA safety issues — and a further reduction in transfusion rates compared to ESAs alone.”

Decreased transfusion rates were observed in a study conducted by Bastit et al, published in 2008 in the Journal of Clinical Oncology. The researchers randomly assigned 396 patients with nonmyeloid malignancies and a hemoglobin level <11 g/dL to darbepoetin alfa (Aranesp, Amgen) with or without IV iron (ferric gluconate or iron sucrose).

The hematopoietic response rate among patients who received IV iron was 86% vs. 73% in the darbepoetin alone group. Nine percent of patients who received IV iron required a red blood cell transfusion vs. 20% of patients in the darbepoetin alone group.

In 2007, Henry et al published data in The Oncologist from a trial of 187 patients receiving 40,000 U epoetin alfa weekly for chemotherapy-induced anemia; patients were randomly assigned to ferric gluconate with epoetin alfa, oral iron or no iron. The hematopoietic response rate among patients who received IV iron was 73% vs. 46% for those who received oral iron and 41% for those who received no iron.

Lastly, in 2008, data from a study of 149 patients conducted by Pedrazzoli et al indicated that among iron-replete patients who received ferric gluconate with darbepoetin, the hematopoietic response rate was 76.7% vs. 61.8% among patients who received darbepoetin alone. These data were published in the Journal of Clinical Oncology.

Case-by-case basis

Jerry Spivak

There are downsides to giving IV iron routinely to every patient with chemotherapy-related anemia who is receiving ESAs, according to Jerry Spivak, MD, a professor of medicine and oncology at Johns Hopkins University School of Medicine.

Spivak said that giving IV iron to all patients would add additional costs and physician visits and would be inconvenient for many patients. He also said that although the latest iron preparations are safer than before, there is still a chance for a reaction.

In the IV iron studies, Spivak said there were some imbalances between the groups that may have affected the outcome of IV iron administration. For example, more women received the iron than men, or the patients who received iron were generally healthier. He also said it is difficult to determine whether the patients who were deemed iron-replete were indeed iron-replete.

“I am not convinced that IV iron is necessary in everybody,” Spivak told HemOnc Today. “There are some people who would benefit, including those with definite signs of iron deficiency, women who are premenopausal and some patients with gastrointestinal malignancies. But an otherwise healthy patient does not need an additional drug.”

He said that if there is no response to ESA therapy after five to six weeks, there are two options: Give iron or increase the ESA dose. At this point, it is patient preference whether to take oral or IV iron. He did say that patients with anemia of cancer might not absorb oral iron and that IV iron would work faster.

In the ASH/ASCO guidelines published earlier this year on the use of ESAs in patients with cancer, it was stated that instituting iron repletion may be indicated in some patients. They recommend baseline and periodic monitoring of iron, total iron-binding capacity, transferrin saturation and ferritin levels.

Alan Lichtin, MD, a staff physician at the Cleveland Clinic Foundation and a member of the guideline committee, said IV iron should be used only in patients who are iron deficient and who cannot tolerate oral iron.

“It does not make sense to give IV iron to everyone, especially if they’re not iron deficient,” Lichtin told HemOnc Today. “Each patient’s iron status is so different, but these studies have used a blanket approach to the patients. The appropriate thing to do is assess the individual and direct iron therapy as necessary.”

The NCCN guidelines also recommend monitoring the patient’s iron, total iron-binding capacity, transferrin saturation and ferritin levels. The guidelines state that for functional iron deficiency, IV iron appears superior.

Future directions

Because the combination of iron and ESAs appears to lower dose requirements, this may be a solution to the current safety issues related to ESA administration. However, Glaspy said that experts are unsure whether the safety risks observed with ESAs are a dose-related phenomenon.

“Given the safety issues that have been raised with ESAs, especially the effect on survival and tumor progression, clinical trials are necessary,” Glaspy said. “That has nothing to do with IV iron, but it does have a major effect on the future of anemia treatment in hematology/oncology. Whatever happens with ESAs will have an effect on the use of IV iron.”

Rodgers said concomitant IV iron administration could lower the necessary ESA dose and thus, lead to a significant cost savings. He also said that some patients who were confined to chronic transfusions may be salvaged with the combination treatment.

Both Auerbach and Rodgers said that physicians need to be made aware of the research, and implementing more frequent IV iron use is going to mean overcoming an educational or informational barrier.

“Either ASH or ASCO need to have an educational session on this topic at the annual meetings,” Auerbach said. “The data are there. It just requires more educational effort.” – by Emily Shafer

Harry S. Jacob

Using IV iron in patients recieving ESAs: perspective from HemOnc Today’s chief medical editor

Having reviewed the articles referenced in this piece and the physician comments therein, I come down on the side of those proposing liberal use of intravenous iron in patients receiving ESAs. The notion that one needs documentation of iron deficiency before undertaking IV iron seems ill-considered. Usual assays of such deficiency are probably not relevant in predicting whether patients can appropriately utilize their endogeneous stores for acute, intensively-stimulated erythropoiesis. This caveat seems especially germaine in patients with cancer and other chronic diseases with their attendant disordered iron delivery to the erythron. Moreover, numerous studies in uremic patients have demonstrated that far more efficient erythropoiesis results in ESA-treated patients who are provided intravenous, rather than oral, iron supplementation — regardless of serum iron, iron-saturation and/or ferritin levels. Finally, I agree with Dr. Auerbach that this subject deserves further exploration at a future ASH or ASCO meeting.

– Harry S. Jacob, MD

Professor of Medicine at the University of Minnesota.

Should IV iron be given to every patient with chemotherapy-induced anemia assigned ESA therapy?

For more information:

• Auerbach M, Ballard H, Trout JR, et al. Intravenous iron optimizes the response to recombinant human erythropoietin in cancer patients with chemotherapy-related anemia: A multicenter open-label, randomized trial. J Clin Oncol. 2004;22:1203-1307.
• Bastit L, Vandebroek A, Altinta S, et al. Randomized, multicenter, controlled trial comparing the efficacy and safety of darbepoetin alfa administered every 3 weeks with or without intravenous iron in patients with chemotherapy-induced anemia. J Clin Oncol. 2008;26:1611-1618.
• Chertow GM, Mason PD, Vaage-Nilsen O, Ahlmén J. Update on adverse drug events associated with parenteral iron. Nephrol Dial Transplant. 2006;21:378-382.
• Critchley J, Dundar Y. Adverse events associated with intravenous iron infusion (low-molecular weight iron dextran and iron sucrose): a systematic review. Transfusion Alternatives in Transfusion Medicine. 2007;9:8-36.
• Hamstra RD, Block MH Schocket AL. Intravenous iron dextran in clinical medicine. JAMA. 1980;243:1726-1731.
• Hedenus M, Birgegård G, Näsman P, et al. Addition of IV iron to epoetin beta increases hemoglobin response and decreases epoetin dose requirement in anemic patients with lymphoproliferative malignancies: a randomized multicenter study. Leukemia. 2007;21:627-632.
• Henry DH, Dahl NV, Auerbach M, et al. Intravenous ferric gluconate significantly improves response to epoetin alfa versus oral iron or no iron in anemic patients with cancer receiving chemotherapy. Oncologist. 2007;12:231-242.
• Pedrazzoli P, Farris A, Del Prete S, et al. Randomized trial of intravenous iron supplementation in patients with chemotherapy-related anemia without iron deficiency treated with darbepoetin alfa. J Clin Oncol. 2008:26:1619-1625.
• Rizzo JD, Somerfield MR, Hagerty KL, et al. Use of epoetin and darbepoetin in patients with cancer: 2007 American Society of Clinical Oncology/American Society of Hematology clinical practice guideline update. J Clin Oncol. 2008;26:132-149.
• Rodgers GM, Auerbach M, Cella D, et al. High-molecular weight iron dextran: A wolf in sheep’s clothing? J Am Soc Nephrol. 2008;19: 833-834.