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Intravenous iron: From anathema to standard of care

Michael Auerbach,1* Dan Coyne,2 and Harold Ballard3

A growing body of literature supports the use of intravenous iron as a compliment to erythropoiesis stimu-
latory therapy and in a significant number of disease states where iron is necessary and oral iron is ineffec-
tive or not tolerated. The differences in efficacy, safety, and clinical nature of serious adverse events that
occur with the various iron preparations are poorly understood. Misinterpretation of adverse events leads
to underutilization of this important treatment modality. Understanding the history of the development and
use of intravenous iron is crucial to appreciate its importance in the management of anemias of dialysis,
cancer, and cancer chemotherapy and properly assess side effects and toxicity. The benefits seen with
intravenous iron therapy are independent of the pretreatment levels of serum ferritin, iron, total iron binding
capacity, and percent transferrin saturation. Intravenous iron has been shown to overcome hepcidin
induced iron restricted erythropoiesis in iron-replete patients. Available clinical and experimental data
suggest that increased utilization of intravenous iron should be considered. Am. J. Hematol. 83:580–588,
2008. V C 2008 Wiley-Liss, Inc.

Iron has been used by physicians throughout history. It Nonetheless, for over 50 years, recommendations for use
is believed that Sydenham, in 1681, was the first to rec- of parenteral iron have been supported by little more than
ognize the value of iron therapy in chlorosis [1]. This im- folklore. Today, despite numerous publications to the con-
portant insight had little impact on medical practice. trary, medical students around the world are routinely
Although it was well-known at the beginning of the eight- taught that oral iron is the method of choice for replenishing
eenth century that chlorosis represented a lack of hemo- iron. Standard texts advise against the use of parenteral
globin and that iron was present in hemoglobin, it was iron unless the situation is life threatening or severe malab-
not until the nineteenth century that a French physician, sorption is present [9]. Until recently IM iron was consid-
Pierre Blaud, introduced pills containing ferrous sulfate ered the standard method of administration of parenteral
and reported the cure of chlorosis [2]. Early clinical expe- iron, despite excellent data in the Indian literature support-
rience with parenterally administered iron (intramuscularly ing IV iron’s superiority [10]. IM iron is painful, associated
and subcutaneously) has been summarized by Stockman with gluteal sarcomas [11,12], causes permanent discolora-
[1]. Heath et al. [3] injected subcutaneous and intramus- tion of the skin, and has never been shown to be less toxic
cular (IM) iron solutions and noted increases in hemoglo- or more efficacious than IV iron; therefore, it should be
bin levels in hypochromic anemias. The increased synthe- abandoned [13].
sis of hemoglobin was proportional to the amount of iron Prior to 1992, Imferon, manufactured by Fisons Pharma-
delivered. ceuticals in Homes Chapel England, was the only paren-
Parenteral iron usage in the early twentieth century was teral product available in the United States. The drug was
extremely limited and thought to have prohibitive toxic marketed by Merrill in the United States and was consid-
reactions. To probe the safety issue, Goetsch et al. [4] ered a minor product. In 1980, Hamstra et al. [14] pub-
introduced intravenous (IV) infusions of colloidal ferric hy- lished a review of their experience with the usage of IV iron
droxide as therapy for patients with hypochromic anemias. dextran in a cohort of approximately 500 patients with iron
Toxic reactions were severe in most instances and led to deficiency and with no clinical reason to suggest that oral
the conclusion to ‘‘preclude its use for therapeutic pur- administration would not be adequate. The dose and
poses except under most unusual circumstances.’’ Subse- schedule varied from patient to patient. Virtually all patients
quent studies by Nissim [5] utilizing IV solutions of ele- achieved clinical benefit. Three serious acute and eight
mental iron as saccharide led to the conclusion that delayed adverse events occurred, none of which were fatal.
parenteral iron as saccharide could be administered with All acute reactions were classified as anaphylactoid even in
relative safety and was more suitable than the ferric
hydroxide for this purpose. Clinical use of parenteral iron
accelerated with the iron saccharides in the 1940’s and 1
Division of Hematology and Oncology, Private Practice Baltimore Maryland,
shortly thereafter with iron dextran. In 1954, a solution of Clinical Professor of Medicine, Georgetown University School of Medicine,
iron dextran (Imferon, Fisons pharmaceuticals) was intro- Washington, DC; 2Division of Nephrology, Professor of Medicine, Washing-
duced by Baird and Padmore [6] for the treatment of ton University School of Medicine, St. Louis, Missouri; 3Division of Hematol-
ogy and Oncology, Clinical Professor of Medicine, New York University
selective iron deficiency anemias by the IM route. Used School of Medicine, Harborview VA Medical Center, New York, New York
IM and occasionally IV, in divided doses, it soon gained
acceptance as it was associated with rapid hematologic *Correspondence to: Dr. Michael Auerbach, Private Practice Baltimore Mary-
land, Clinical Professor of Medicine, Georgetown University School of Medi-
responses and a low incidence of adverse events. Since cine, Washington, DC. E-mail: mauerbachmd@aol.com
the 1990’s, an upsurge in the clinical use of parenteral
Received for publication 12 October 2007; Revised 25 December 2007;
iron followed the introduction of recombinant human Accepted 2 January 2008
erythropoietin (EPO) for the correction of anemia in Am. J. Hematol. 83:580–588, 2008.
patients with renal failure. Two recent papers validate the Published online 29 January 2008 in Wiley InterScience (www.interscience.
safety and efficacy of IV iron in the management of wiley.com).
patients who are iron deficient [7,8]. DOI: 10.1002/ajh.21154

V
C 2008 Wiley-Liss, Inc.

American Journal of Hematology 580 http://www3.interscience.wiley.com/cgi-bin/jhome/35105

serious and unpredictable and opined that IV iron dextran should be used only when iron deficiency anemia cannot Clinical use of intravenous iron be treated adequately with oral iron. b DexFerrum [prescribing information]. Although characteristics of the IV irons relevant to therapeutic use. NY: American Regent Laboratories Inc. [19] reported that 125 mg of methyl- The different preparations all share the same metabolic prednisolone before and after TDI dramatically reduced the fate. In spite of the admonitions within the medical community ing protein. lular iron stores or is released to the extracellular iron bind. The total dose of iron dextran The adverse effects of bioactive free iron resulting from was diluted in 500 ml of normal saline and infused over 4–12 parenteral iron administration have been recognized for hr after a test dose of the diluted solution. 2001. Hamstra concluded that anaphylactoid reactions are ing the rate of release of bioactive iron. Amgen. Premedication with aspirin and gel. iron–carbohydrate complexes mix frequency and severity of arthralgias and myalgias (Table II). that they had been taught and pool. The currently the arthralgias and myalgias. This prompted the development of for. and the American Journal of Hematology 581 .000 265.TABLE I. of meningism [18] after a each other by the size of the core and the identity and den. d Ferrlecit [prescribing information]. a self-limiting harmless reaction that leaves no residua. believed had potentially life threatening complications. 2001. the FDA iron for hemoglobin synthesis. the product for those clinical situations where iron adminis- ing internalization of the iron transferrin complex supplies tration as a TDI was indicated. [17] published a study evaluating Imferon had a black box warning about the potential for an. in 1983. In 1998. transferrin.000 a INFeD [prescribing information]. tionship between the infusion rate and adverse event fre- mulations that shielded iron. Little did complexes characterized by specific carbohydrates used for anyone realize the role IV iron would play in managing complexing and shielding the iron. acute and delayed reactions in anemic patients with absence aphylaxis and a test dose was required. but generated little interest following the Lancet case The strengths of the iron complex affect pharmacokinetic report and Hamstra’s warning about IV iron therapy. NJ: Watson Pharma Inc. The package insert for In 1988. The specific carbohy. hypotension. based on small spheroidal iron–carbohydrate particles. minor arthralgia/myalgia syndrome with headache and neck lecular weight of the iron complex reflects the size of the stiffness and recovered without residua.d Low-molecular High-molecular Iron Ferric weight iron dextran weight iron dextran saccharate gluconate Test dose required Yes Yes No No Vial volume (mL) 2 1–2 5 5 Mg iron (mg/mL) 50 50 20 12. with plasma and are phagocytosed in the reticuloendothe. The currently available IV prep. slows the release of iron.c. One of 87 patients experienced an acute. Shirley.000 34–60. Morristown. quency or severity. iron is released from the erated. nonfatal.b. the stronger the complex the tory disorders was an exciting and unanticipated finding. approved recombinant human EPO for the correction of In summary. sity of the surrounding carbohydrate.000 289–440. IV iron preparations are iron–carbohydrate anemia in patients with chronic renal failure. TDI.000 mg. The mo. iron–carbohydrate complex into a low molecular weight iron albeit quite safe and effective. or respiratory dis. Currently Available Intravenous Iron Preparations [19]a. The toxicological implication major inference taken from the 1988 paper by the medical of this is that stronger complexes have a lower potential to community was the 50% incidence of arthralgias and myal- supersaturate transferrin with subsequent free iron toxicity gias. which delivers iron to the transferrin regarding the use of IV iron. Subsequently the more rapid rate was arations are all iron–carbohydrate complexes or colloids recommended. approved IV irons all share this structure but differ from a case report in Lancet. NJ: Watson Pharma Inc. Auerbach et al. the manufacturer of EPO. publication [17] recommended parenteral iron be given as a lecular weights vary according to method of measurement. During the conduct of this study. On June 1. Approximately half of the Each particle consists of a core made of an iron-oxyhydroxy patients developed arthralgias and myalgias within the first gel surrounded by a shell of carbohydrate that stabilizes the 48 hr following infusion. Doses Parenteral iron preparations ranged from 1. of bone marrow hemosiderin receiving a total dose infusion (TDI) of high molecular weight iron dextran (HMW ID).000 to 3. 1989. drate influences the strength of the iron complex determin- tress. Auerbach et al. The characteristics of A critical review of this article indicated that the patient had a the four available preparations are listed in Table I. 2001. Reported mo.5 Black-box warning Yes Yes No No Total-dose infusion (TDI) Yes Yes No No Premedication TDI only TDI only No No Preservative None None None Benzyl alcohol Molecular weight measured by manufacturer (Da) 165. There was no rela- more than 50 years. dose of IV iron led to a recall of the world’s supply of Imferon. Morristown. complete correction of hemoglobin deficit in a subset of The rate of release of bioactive iron is inversely related to seven of these patients with concomitant chronic inflamma- the strengths of the complex. anaphylactic reaction. NY: American Regent Laboratories Inc. Shirley. c Venofer [prescribing information]. The result. The subsequent iron core and the surrounding carbohydrate. and maintains the resulting diphenhydramine had no effect on the incidence or severity of particles in colloidal suspension [13. 2001. physicians had little need or interest in a product.15]. these patients. the absence of tachycardia. Within phagocytes. As oral iron was inexpensive and nearly always effective if tol- lial system. compared to the weaker complexes [16]. the slower the release of the iron. Fisons continued marketing receptors on the surface of erythroid precursors. After IV injections. This iron is either incorporated by ferritin into intracel.

7% following iron dextran administration. which recommended IV iron in product not commercially available at the time. mL. To prevent iron overload. each of which is able to cause severe cardiovascular ciency. Given the lack of efficacy surement of the reticulocyte hemoglobin content appears for pretreatment with aspirin and diphenhydramine to promising [21].TABLE II. rine. They preference to oral iron. between the efficacy of IV iron in these patients and the Of great interest was a description of what appeared to be potential for iron overload. or periorbital edema occurred. a chronic renal failure [27]. many investigators studied the role of IV iron as ber of patients on dialysis responding suboptimally to EPO a component of the management of anemia in dialysis administration could be reduced from 30–40% to less than patients. belief that extreme fatigue and exhaustion from severe ane- mia due to EPO deficiency could not be ameliorated with- out chronic transfusions.000 mg practice. medication with cimetidine. misconstrued as an anaphylactoid reaction prompting inter- Causes of EPO’s ineffectiveness were not well understood vention with drugs such as diphenhydramine and epineph- and were thought to be due to bleeding. the guidelines also rec- divided over 10 doses during sequential dialysis treatments ommended halting iron therapy if the transferrin saturation resulted in a rapid improvement of erythropoiesis and exceeded 50%. medical community also did not appreciate or anticipate the role of EPO in anemias related to cancer. these agents [13]. and considered a balance of approximately 0. of IV iron as an adjunct to EPO therapy came from the Fishbane et al. Fishbane. maintaining serum ferritin >100 ng/ showed that significant reductions in dosing and duration of mL. became an important area of research inter. mea. contradicted conventional hematology tion. began to carefully exam. In and rechallenging did not precipitate recurrence. usually considered the lower range for iron population due to poor compliance and impaired absorp. The availability of EPO should have generated enormous hopefulness in the dialysis popu. In a retrospective chart when ferritin was >800 ng/mL or transferrin saturation was review. In iron deficient patients receiving LMW ID preceded by pre- 1987. Odds ratio 5 3. the mean hemoglobin less reaction was unreported until the publication of a among US dialysis patients was still less than 10 g/dL. Fishbane noted a serious adverse event (AE) rate >50% were opinion-based. However.491. Subsequent to the pioneering studies of Hamstra and 1). They further concluded that IV iron given as 1. No serious events related to LMW ID were seen [26]. [24] published data on the safety and effi. with No. In 0. Functional iron deficiency.315–9. Subsequently. 2 years after EPO’s approval. including wheezing. or the presence of comorbid conditions (anemias of side effects. most AEs requiring therapy or ing to respond to EPO at standard doses of 50 U/kg thrice cessation of treatment were associated with the premedica- weekly despite serum ferritin values greater than 500 ng/ tion. [22] demonstrated the clinical effi. a situation Network guidelines suggest pretreatment with diphenhydr- where iron stores are present but not readily available for amine and acetaminophen to help reduce the risk of erythropoiesis. lead by the excellent reactions [17]. systemic collagen diseases. and diphen- cacy of 1. and not withholding iron as long as the serum ferritin therapy with EPO could be achieved by the addition of IV was <800 ng/mL. ten attributed to the injected iron. Dialysis patients had a life expect- ancy of less than 3½ years. and a host of other anemias associated with chronic disease states. but back pain without hypotension. 95% confidence inter- val: 1. Several studies have failed to an acute arthralgia and myalgia syndrome associated with identify a specific serum ferritin value in dialysis patients the test dose. adverse reactions [25]. short delay symptoms routinely abated without treatment lation. Effect of Methylprednisolone on Incidence of Reactions [19] No. They concluded that oral iron was not effective in this this ferritin level. This is corroborated by a study in 135 ine the use of IV iron in dialysis patients receiving EPO. this event continues to be many patients were not receiving EPO therapy [20]. This harm- 1991. Fishbane et al. these trials suffered from several design flaws. Eschbach et al. with no reaction (%) reaction (%) Total Saline 16 (59%) 11 (41%) 27 Methylprednisolone 15 (29%) 36 (71%) 51 Total 31 (40%) 47 (60%) 78 A statistically significant reduction in reactions is noted in the methyl- prednisolone treated group.000 mg of IV iron dextran in dialysis patients fail. Prompt increases in hemoglobin levels were seen (Fig. Although the National Comprehensive Cancer chronic disease).264. gastrointestinal disorders. 1987).3% of patients acute onset of chest and that was predictive of a lack of response to IV iron. Administration of IV iron to patients with iron. Hundreds of thousands of dialysis patients world-wide lived with the Figure 1. After a lack of a proper control group [28]. Functional iron deficiency induced in a patient by 50 U/kg of rHuEPO given three times weekly (Figure adapted from Eschbach et al.. but enthusiasm for its use was far from brisk. The recommendation to withhold IV iron replenishment of depleted stores. it is reasonable to avoid premedication with research of Eschbach and others. stridor. NKF-KDOQI Clinical Practice Guidelines for the anemia of cacy of low molecular weight iron dextran (LMW ID). tachypnea. In this study. the use of antihistamines can cause est. IV iron dextran boluses 582 American Journal of Hematology . reduce the incidence or severity of the arthralgia-myalgia The nephrology community. Currently there are no satisfactory tools to accurately vasoactive reactions that may be misinterpreted and are of- assess a state of functional iron deficiency. hydramine. Unfortunately. [23] showed that the num. overload states. tachycardia. The most important impetus to the increased use 10% when concomitant IV iron was administered. dexamethasone. and recent review [13]. absolute iron defi. In 1996.

Doses greater than 300 mg are not recom- uct. and concluded that the frequency of IV iron related had been published. age insert) and for iron sucrose. appetite. and either ferric gluconate or iron sucrose. No randomized trial com. Subsequently. cacy of safety of LMW ID and iron sucrose found no differ- ease [31]. 200 mg IV push or 300 Fisons. and Imferon was perma. This results American Journal of Hematology 583 . and others [46–50]. Pharmacosmos. Silverberg [35] Central to the development of the anemia of chronic dis- showed that approximately 20% of dialysis patients could ease (ACD) is disturbed iron homeostasis characterized by have anemia effectively treated with iron sucrose alone. et al. They noted a signifi. were in tryptase. In 1991. [41] reported a nearly 3-fold increase in Dexferrum not be used. FDA) in the number of serious with the use of HMW ID (Dexferrum) that could not be AEs reported to the US Food and Drug Administration. Similarly. a marker of mast cell degranulation [34]. and overall the rates Imferon in Nephrology. cognition. All of these trials will be discussed these papers were able to differentiate the reaction rate of later in the text. lar with an estimated incidence of <1:200. [33] found a very low in correcting anemia in patients with cancer or receiving reaction rate with ferric gluconate in 2. In a review of the US Food and Drug Administration bility of the dextran chains (personal communication with (FDA) database of spontaneous AE reporting. Denmark) conate is 125 mg IV push over 5–10 min (Ferrlecit pack- was approved for clinical use in the United States. time. study in ferric Schein Pharmaceuticals) and iron sucrose (Venofer. and ID used in the Fishbane et al. markedly affect the practice of IV iron administration. iron dextrans. Because of the perceived 0. In 1999. while no deaths were attributed to the non. placebo controlled.complementing EPO therapy became the standard of care increase serum ferritin to 200–400 lg/L and/or iron satura- in dialysis in the 1990’s. was a lower molecular weight iron dextran with less varia. these overall quality of life. A follow-up analysis [39] examined reactions to iron su- paring efficacy and toxicity of any of these three products crose. sexual activity. Ameri- gluconate naı¨ve patients. necessitating use of Dexferrum in many dialy. patients in a double-blind. and discovered that INFeD mended [37]. Glaspy. mg over 2 hr. Faich ison to historical controls or exposure of patients with prior and Strobos [32] compared the spontaneous reports to the allergies to these new agents [33. and this is believed to account for Imferon could be given with equal efficacy as TDI or dose and infusion rate dependent acute vasoactive reac- repeated boluses [29]. with INFeD being the major product were extremely low. None of pared to EPO alone. a contaminated batch of Imferon led tions to iron sucrose and ferric gluconate. were compared to LMW ID. INFeD became unavailable for a short pe. studies [49. First.52–54] proved that IV iron admin- true anaphylaxis. mous clinical benefits and improvements were seen in Black box warnings do not appear in the package inserts of energy. ences in efficacy or toxicity between the two iron prepara- The nondextran IV irons. A similarly low reaction rate has been reported in open Iron in anemias of chronic disease label studies of iron sucrose. and concluded that chemotherapy more than doubled the response rate com- ferric gluconate was much safer than iron dextran. Schein Phar. They also noted that patients hav. Third. among LMW ID. provided an alternative to INFeD. Subsequently. have been considered to have a markedly lower seri.534 hemodialysis cancer chemotherapy. Second.3% AE tion up to 25–35% before considering EPO. Henry. study (INFeD. and iron sucrose are simi- riod of time. [38] found no significant differences in life threatening tribution of Imferon was made. or fatal serious AEs when ferric gluconate and iron sucrose nently removed from the marketplace in 1992. These recent studies conflict with earlier claims of crose. highly insensitive in as much as they reflect only reported ceuticals) a HMW ID similar to Imferon was approved and events and under-estimate actual reaction rates many-fold. In explained by differences in patient or facility characteristics. Imferon. and TDI the average lifespan on dialysis improved to more than 4 because of little interest in nephrology except in patients years. Littlewood.6%) developed severe reactions the incidence of acute reactions for iron dextran believed to consisting of severe back and leg pain. ferric gluconate. Aronoff et al. Imferon. using molecular blueprinting. back pain. InFed and had no reactions. the LMW include low blood pressure. two products that had been ing reactions to ferric gluconate did not exhibit an increase used extensively in Europe and Asia for years.000. The current highest recommended dose for ferric glu- tionally known as Cosmofer. These nondextran irons bind iron utilized until 1991. to Schein’s INFeD. This suggests that Dexferrum 4 patients (28. three studies [42–44] comparing the effi- lished by Mamula in children with inflammatory bowel dis. An approved as parenteral iron supplements in the United increase in tryptase would be expected if reactions were States. ferric gluconate and iron su. be correct (0.’’ Similar conclusions were pub. Typical reactions to a total US recall of the drug. Gabrilove. During this time there was an 11-fold increase Fletes et al. the black box warning remained in the package insert [36] reported repeated doses of iron sucrose in 665 hemo- for all iron dextrans and a test dose was required. Fisons’ HMW ID was the product routinely on peritoneal dialysis. They also compared those results to the istered with EPO for the anemia of cancer and cancer published reaction rate to iron dextrans. Michael et al. Subsequently two of the four were given rate with LMW ID is far lower. a decision to cease US dis. can Regent Pharmaceuticals). In 2002. He decreased absorption and prevention of recycling of iron recommended administering sufficient iron sucrose to from the cells of the reticuloendothelial system. cantly higher rate of reactions and 31 deaths attributed to the work of Abels. showed that EPO was of great benefit dextran irons. and short. HMW versus LMW iron dextran preparations. abdominal discomfort. As a result. lower reactions rates to nondextran irons based on compar- ous acute event rate than the iron dextrans.3%) is related to the use of HMW ID and the ness of breath. 1998. noting ‘‘in 14 patients receiving AEs with HMW ID than with LMW ID. In 1997. tions. although these reports are In February 1996. Dexferrum (American Regent Pharma. US and European Drug agencies of serious reactions to In the last decade three events occurred that would iron dextrans and non-iron dextrans. In 1996. 80 patients (12%) considered intolerant to an iron dextran. [40] found an 8-fold higher AE rate associated (Freedom of Information. Case [30] published an article recommending that McCarthy et al.45]. Serendipitously. activity. rate. INFeD and Dexferrum replaced AEs with all products has decreased. in 1991. compared their prod. and resolve with cessation of the infusion and maceuticals––now Watson Pharmaceuticals––and interna. The reported incidence of serious AEs in use. urticaria. including Hundreds of thousands of dialysis patients derived enor. Chertow Fisons). For patients receiving EPO therapy two products have rapidly replaced iron dextran. At the same time it was shown that IV less avidly than dextran. dialysis patients receiving EPO was well tolerated. ferric gluconate (Ferrlecit. sis patients.

for the ITT population. and quality of life variables when IV iron was alpha upregulate DMT 1 expression resulting in an in. In the Auer- hepcidin levels and allows unimpeded iron absorption to bach study the only serious AE occurred in one of two occur [60]. and either no iron. oncology community. [61]. benefit from parenteral iron and that IV iron should be din is believed to be involved in the diversion of iron traffic given to all patients receiving EPO for chemotherapy- by decreasing duodenal iron absorption and blocking iron associated anemia. an iron regu. where a mutated HFE gene decreases patients with anemia of cancer chemotherapy. (Figs. yet IV iron. Further. Ferroportin. ferric gluconate as an adjunct to EPO therapy in cancer hemojuvulin. time to maximal gamma. In the iron treated patients there was a statistically Awareness of the degree of benefit IV iron had on anemia significant improvement in response compared to those in the nephrology population was generally lacking in the not receiving IV iron. in anemias of chronic diseases. not on chemother- The benefit of EPO in cancer patients is compelling apy. intensity of chemotherapy. (a) P < 0. Henry et al. for all intents and purposes. Hepcidin. There was little rea- are important contributors to the hypoferremia and anemia son to believe that IV iron would be less beneficial in can- seen in chronic diseases. quality of life. and tumor necrosis factor response.000 U/wk erythroid progenitor cells and impairment of their prolifera. The proinflammatory cytokines interferon response. and baseline release from macrophages is blocked [56]. Change in LASA scores from baseline to end point evaluation for the Figure 2. oral iron as 325 mg ferrous sulfate tion by negatively impacting on heme biosynthesis. 300 ng/mL with a percent saturation of transferrin of 19. Qol. This is supported by data in patients with hereditary increases the hematopoietic responses to EPO in cancer hemochromatosis. total dose infusion [51]. may act in concert with hepcidin to induce chemotherapy patients. However. When IV ferric gluconate (73%) than in those treated with oral inflammatory cytokines are not present. In this study. with positive marrow hemosiderin treated with epoetin [46–50]. hepcidin levels are iron (46%) and those not treated with iron (41%). patients receiving HMW ID when LMW ID was not avail- able. the increase showed that there was an increase in hemoglobin levels in inflammatory cytokines causes an increase in hepcidin of 2 g or more in significantly more patients treated with with a subsequent decrease in iron absorption. thrice daily or IV ferric gluconate 125 mg per week. Subsequently. TDI. lipopolysaccharide. Figure 3. Consequently iron type of cancer. In a study presented at the 2007 an- 584 American Journal of Hematology .01 versus no-iron group. is believed to be responsi. using release from macrophages. Responders were patients who achieved a maximal Hb lev- els 120 g/L or an increase in Hb of 20 g/L during the study. corroborated the previously pub- these changes [59]. given to patients receiving EPO for anemia of cancer creased uptake of iron into activated macrophages and chemotherapy when compared with oral iron or no iron also induces the retention of iron in macrophages by down. In the Henry study there were no serious AE’s attrib- utable to iron. a iron parameters (percent transferrin saturation and serum transmembrane exporter of iron. Because of a perception that many of the patients were portant role in the pathophysiology of ACD. anemias in cancer and can- in hypoferremia (low transferrin-bound iron) and resultant cer chemotherapy patients were not as severe as those in iron restricted erythropoiesis. Proinflammatory cytokines dialysis patients in the pre-EPO days. used in oncology patients until published data with iron port of ferrous iron by the protein divalent metal transporter dextran [51] reported a significant benefit in hemoglobin 1 (DMT 1) [55]. Expression of truly iron deficient this led to a criticism of the conclusions hepcidin is induced by lipopolysaccharide and interleukin 6 that baseline iron status was not predictive of who would and is inhibited by tumor necrosis factor alpha [58].01 versus oral iron group. These much lower and GI absorption of oral iron can more freely two studies clearly suggest that using IV iron therapy occur. Hepci. has been shown to have an im. ferritin). The conclusions of these two studies were Iron in the anemia of cancer and further supported by a recently published study in patients cancer chemotherapy with lymphoproliferative malignancies. These responses were independent of regulating the expression of ferroportin. 187 patients receiving chemo- iron homeostasis is a limitation of the availability of iron for therapy were randomized to receive EPO 40. Percentage of responders and nonresponders in each treatment group intent to treat population. was not through erythrophagocytosis and the transmembrane trans. They In summary. [52]. 2 and 3). latory acute phase protein. (b) P < 0. hematopoietic response. A recently identified gene. In chronic inflammatory states cer chemotherapy patients receiving EPO than in dialysis iron acquisition by macrophages takes place mainly patients. yet the transfer of this enthusiasm for EPO beta randomized to receive no iron or IV iron sucrose usage to the oncology community was slow to evolve. The net effect of these alterations in lished data. in this study the entry criteria required ble for the transfer of absorbed ferrous iron from duodenal a serum ferritin of less than 200 ng/mL or less than enterocytes into the circulation [57].

HMW ID dextran should not be used Iron is a pro-oxidant. [67] showed increased cellular uptake and subse- patients receiving darbepoietin every 3 weeks with either quent necrosis and decreased recovery of kidney cells in 200 mg of IV ferric gluconate or iron sucrose to darbe. This study was unique in its require. quality of life. decreased number of transfusions were reported in the IV Agarwal et al. These data are corroborated in a peroxidation with iron sucrose in CKD patients [16]. IV iron therapy. for IV iron as an adjunct to ESA therapy outside nephrol- sion requirements in patients receiving chemoradiation ogy. However. or Potential negative effects of intravenous iron iron sucrose. safely and effectively. there were no differences in tumor out. large databases. tines to absorb adequate iron from oral ingestion (Osler- ated with increased risk of infections. use of IV iron in institution of costly EPO therapy. surgical blood loss. A summary but avoid iron use if transferrin saturation approaches 50%. Pedrazolli et al. Randomized trial data have shown the efficacy of IV therapy. They concluded in patients with chemother. where intestinal blood loss exceeds the ability of the intes- arteriovenous grafts. 20). and immunosuppression were associ. obstet- the risks for infection in 998 hemodialysis patients over 6 rics and gynecology. iron preparations are needed. Small studies have found IV iron may improve There are three studies suggesting that iron sucrose and quality of life independent of improvements in anemia ferric gluconate may have more nephrotoxicity than iron [73. in all published trials with any of the other three available preparations can be utilized IV iron in oncology. Improving anemia in chronically ill patients improves point. Pinter et al. [66] prospectively examined small bowel malabsorption. indications for IV iron as sole that IV iron might increase oxidative stress. Those anemic at efits of iron repletion and repair of anemia. or even tumor growth. Sixty. In this trial. Erythropoietic stimulatory agents offer a more American Journal of Hematology 585 . In a variety of clini- mortality.31.61] in which hemoglobin response apy related anemia and no iron deficiency IV iron supple. showed significant increases in lipid peroxidation.74]. an important nutrient for many bac. who frequently have ele- patients with solid tumors and at least 12 weeks of planned vated ferritin from inflammation. Using a rat model. reliable predictors of a chemotherapy who were randomized to receive 150 mg of hematological response to IV iron have not been found subcutaneously administered darbepoietin weekly alone or [71].54. ferric gluconate. TDI of LMW ID is the pre- alone.65] in very transfusion need include: inflammatory bowel disease. data with tumor outcome as a primary or secondary end. theless.nual meeting of the American Society of Clinical Oncol. [69] compared nontransferrin bound iron was also given to those randomized to the IV iron arm not and markers of oxidative stress after single IV doses of iron anemic at onset but developing anemia during therapy. and has been shown to exacerbate sepsis in labora.’’ A recent comparative crossover study found or 540 mg of IV iron saccharate in 200 mL of normal 100 mg over 10 min of iron sucrose. showed stimulation of proteinuria and lipid iron arm (9 vs. as of this review. and INFeD respectively) (Fig. dextran.54] randomized 396 chemotherapy et al. and iron sucrose in patients were randomized patients to receive no therapy particular.72]. The IV iron can be administered either as a TDI of LMW ID or as repeated lower doses of LMW ID. In addition to optimizing efficacy of EPO in anemic dialy- tory animals. only ferric gluconate the patients in the IV iron arm were transfused. Pai et al. However. albeit underpowered.52. While tran- Patients were treated with platinum containing chemother. but not ferritin levels Weber-Rendu). even among patients with A soon to be published study lends support to the previ. Consequently. They concluded AEs with iron administration were not provided. 4). None. Lastly. Central venous catheters. 50% [61] and in patients with positive marrow hemosiderins bepoietin. Hoen et al. Human studies have cal settings use of IV iron alone is being investigated to shown transient increases in markers of oxidative stress reduce or eliminate red blood cell transfusions. Long nately. iron parameters consistent with an iron repletion state [28]. sient injury by iron sucrose may be outweighed by the ben- apy plus radiation therapy to the pelvis. without added toxicity. Unfortu. . As of this review there exist no clear practice guidelines tion of the benefit of IV iron alone in decreasing transfu. teria. nate. gastric bypass surgery. The nephrology literature is rife with publications with IV ferric saccharate administered as 125 mg per week showing IV iron reduces ESA dose even in patients with for the first 6 weeks. use of IV iron preparations in general. there are no prospective ferred method of IV iron administration. we believe it is reason- approved. anemia therapy are rapidly expanding. Entities in which IV iron dialysis patients has been associated with comparable or has great potential for treating anemia and ameliorating improved survival compared to no iron [64. ogy literature [51. greater nontransferrin bound iron appearance when com- four percent of the patients in the control arm and 40% of pared with iron dextran. rats receiving iron sucrose > ferric gluconate  iron dex- poietin alone or with oral iron. iron in epoetin-treated patients. raises the ques. but not ferric gluco- saline over an unspecified period longer than 30 min. however. Ferrlecit. or avoid with all forms of IV iron [63]. For these conditions. in those conditions months. elevated ferritin (500–1. ment that excluded patients with ferritins < 100 ng/mL and These data are corroborated by publications in the oncol- TSATs < 20%. infections. A statistically significant tran (Venofer. and in patients who are intolerant of or or total dose of IV iron administered. occurs in patients with transferrin saturations as high as mentation significantly reduces treatment failures with dar.71]. They study of 75 anemic patients receiving chemoradiation concluded ‘‘our study raises some concerns regarding the therapy for carcinoma of the cervix [53]. and iron sucrose. of these studies is listed in Table III. there were significant intragroup differences in this term studies assessing the risks and benefits of different IV study making interpretation of the results difficult. dextran in nondialysis settings. increasing in oncology but to date only iron dextran is and consistent with published data. induced proteinuria and albuminuria [68]. when one con- comes in those who received IV iron compared to ESAs siders cost and convenience. . [62] enrolled 149 [70. With the exception of HMW ID contradicted these data. [50. Zager ogy. Among dialysis patients. this study.200 ng/mL) with TSAT  25% ously cited studies. No study to date has unresponsive to oral iron. [13. In the absence of formal evidenced based guidelines. despite the extensive use and safety record of able to recommend that IV iron be added to ESA therapy ferric gluconate and iron sucrose in nephrology. concerns have been raised sis and oncology patients. history of bacteremia. The use of IV iron is [52]. None of iron sucrose and ferric gluconate were associated with the patients in either arm received an ESA agent. these results presentation and randomized to the IV iron arm received should question the abandonment of LMW ID as first line the IV iron infusion at the beginning of therapy. ferric gluconate.

No iron: iron: 3 pts. oral iron: 45%. no iron: 7 pts pts (10%).. began at 4 weeks while Hb QOL response was still similar between groups  No iron . activity. oral iron: 1. bolus IV iron: 68%. time to target Hb: 30 25%. no IV iron: 93%. Pts enrolled in study for at least 29 IV iron: 40% pts. no iron: iron: 41%.91 g/dL.87 units. no iron: 1. oral iron: 1.4 g/dL. dL. 2007 Kim et al. 2007 Hedenus et al. PP IV iron: 86%.5 g/ IV iron: 2. bolus IV iron: 2. SF < 800 ng/mL. activity and QOL in FACT-F score.000 U/wk Procrit no dose 40..5 g/dL. PP population and control groups no iron: 0. 2007 No. ITT population population Hb response TDI: 68%.5 g/dL. no/oral iron: 73%. oral iron: 5 of 6 pts. Nonmyleloid malignancy 8 weeks Cervical cancer receiving chemotherapy cycle of chemotherapy no chemotherapy of planned chemotherapy chemoradiotherapy Treatment arms IV iron versus oral iron versus no IV iron versus oral iron versus IV iron versus no iron IV iron versus no/oral iron IV iron versus no iron iron no iron Study period 6 weeks or until end bolus 9 weeks 16 weeks 16 weeks 6 weeks treatments Inclusion criteria Hb 10. no iron: 7 of 14 pts No: 3.58 units Energy/activity QOL  IV iron : LASA scores for Only IV iron group had significant : N/A % pt achieving FACT-F  3 points: N/A energy. 2004 Henry et al. Hb < 10 g/dL: pts in both groups were transfused Inclusion criteria SF  200 ng/mL or SF  300 SF  100 ng/mL or TSAT  15%.6 g/ IV iron: 2. Stainable iron in SF < 800 ng/mL N/A TSAT/SF ng/mL and TSAT  19% SF < 900 ng/mL and TSAT bone marrow <35% IV Iron dosing Iron dextran TDI or 100 mg to Ferric gluconate 125 mg QW for Iron sucrose 100 mg QW (week Ferric gluconate or iron sucrose Iron sucrose 200 mg if Hb calculated dose 8 weeks 1–6) 100 mg Q2W (week 8–14) 200 mg Q3W 10–12 g/dL ESA dosing 40. energy. N/A oral iron: 36%. evaluable population population median time to Median. no iron: 53%.5 g/dL <11 g/dL 9–11 g/dL <11 g/dL Hb measured prior to each chemotherapy cycle: Hb 10– 12 g/dL: pts in IV iron group received iron. oral IV iron: 11 pts (18%). ITT population achieve Hb response: 6 weeks days IV iron versus 43 days No/ IV iron versus 12 weeks no iron oral iron ESA No dose adjustment permitted N/A At Wk 15.000 U or 25% lower in IV iron than no iron group Transtusions TDI: 5 pts bolus IV iron: 4 pts. TABLE III.. Overview of Studies of IV Iron in Oncology 586 Auerbach et al. IV iron: 1. no iron: 14 pts (22%) no iron: 1 pt days: IV iron: 9%: no/oral iron: 64% pts Tx given after first 4 weeks: IV iron: 20% Mean transfusion volume: 2 of 11 pts. dose increase 30.. difference IV iron: 62%.000 U/wk neoRecormon dose 500 lg Q3W Aranesp dose None adjustments permitted after 4 weeks. QOL from baseline American Journal of Hematology . no/oral iron: 54%  Oral iron small : energy. dose adjustments permitted reductions permitted reduction permitted for safety Hb CFB TDI: 2. no iron: 1. IV iron: 73%.9 g/dL.5 g/ N/A Similar change between IV iron dL. ave difference was N/A N/A >10. activity. of Patients 157 187 67 398 75 Patient population Nonmyeloid malignancy receiving Nonmyeloid malignancy starting Lymphoproliferative malignancy. 2007 Pinter et al. evaluable dL.000 U/wk Procrit.4 g/dL.. oral iron: 6 IV iron: 2 pts.

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