For the first time in the history of either the American Society of Hematology (ASH) or the American Society of Clinical Oncology (ASCO) annual meetings, an education session was devoted to the clinical use of intravenous (IV) iron.  Furthermore, three abstracts were presented in the supportive care poster session on Saturday, June 2.  

For decades the use of IV iron has been limited by a quagmire of folklore surrounding poorly characterized and misinterpreted adverse events.  Since the early 1990s, IV iron has become part of the standard of care in dialysis associated anemia, providing synergy with erythropoietic stimulatory agents (ESAs) in raising hemoglobin, improving quality of life, cognition, sexual function, energy, activity and even survival. Decreased costs with ESA dose sparing is so profound that IV iron has become an integral part of the practice guidelines for dialysis outlined in the Dialysis Outcomes Quality Initiative (DOQI) of the National Kidney Foundation.  Despite several publications in respected peer reviewed journals demonstrating its safety and efficacy, concern about IV iron’s use continues throughout other areas of medicine.[1],[2],[3],[4]   In the following summary, the pertinent details of the data presented at ASCO will be reviewed and an overview of the Meet the Professor session provided.  

IV Iron Supplementation and Responses to Darbepoetin Alfa

Tamas Pinter, et al presented final data on a previously presented study delivered preliminarily at ASH, 2006.[5] This unique study randomized 396 patients to either 500 ug of darbepoetin injected subcutaneously every three weeks alone (oral iron could have been provided at the discretion of the investigator) or with 200 mg of IV iron administered with darbepoetin or as two 100 mg boluses over the three week period.  The intravenous iron preparation used was either ferric gluconate (Ferrlecit) or iron saccharate (Venofer).  The two groups were similar in age and pre-randomization iron parameters consisted of percent transferrin saturation and serum ferritin and baseline hemoglobin levels.  

The results were striking.  As in other studies, statistically significantly more patients in the IV iron arm achieved the target hemoglobin of 11 g/dL.  This was even more pronounced in those with starting hemoglobins less than 10 g/dL. Furthermore, the investigators were able to show a statistically significant decrease in the number of transfusions in the IV iron treated group compared to the group receiving darbepoetin alone. This is the first study outside of nephrology to demonstrate a statistically significant decrease in number of transfusions with the use of supplemental iron with an ESA.

To avoid the criticism that the IV iron was benefiting overtly iron deficient patients, the investigators excluded patients at entry if the patient's baseline ferritin was <10ng/ml or percent transferrin saturation <15.  Mean ferritin levels were between 262.8 and 299.8 ng/ml in all four groups (IV iron or no IV iron, baseline Hb < or >10 grams/dl).  Nonetheless, as of this writing, the investigators were unable to provide a stratification of iron status among the responders and non-responders as well as transfused and non-transfused patients.  These data will be forthcoming in the publication of this important study.  Of note, no significant difference in toxicity was reported between the group receiving IV iron and the group receiving darbepoetin alone.  The authors were able to corroborate that those receiving IV iron had more hematopoietic responses, more target hemoglobins, more target hemoglobins in a shorter time, and more improvements in fatigue using FACT-F scores.  For the first time, these investigators demonstrated a decrease in transfusions, providing the first proven synergy with ESAs for their indicated use of decreasing blood transfusions.  

IV Iron vs No Iron: A Phase III Randomized Study

In another unique presentation, Bellet et al presented the results of 375 patients randomized to receive ESAs given subcutaneously as either epoetin alfa 40,000 U weekly, darbepoetin 100 ug weekly or 200 ug every other week alone or with three planned doses of 500 mg of IV iron saccharate (Venofer).[6] Unlike other studies using iron saccharate, these investigators gave higher than the recommended maximum dose of iron saccharate or 300 mg.[7] In order to circumvent the acute toxicity associated with higher doses of iron saccharate, the authors slowed down the iron infusion to two hours from two to five minutes.  Dose reductions were made as necessary, resulting in an average dose of iron saccharate of 1200 mg across the treatment groups.  Four serious adverse events were noted consisting of two episodes of hypotension, one episode of chest pain and one episode of hypersensitivity.  It should be noted that in the latter patient, paclitaxel had been administered prior to the IV iron and differentiation between the two agents as the cause of hypersensitivity was not possible.  Seven additional minor adverse events attributable to the IV iron saccharate were noted.  All events were self-limited and without residual symptoms.  There were no deaths.  An observation that the adverse events were more common in patients weighing less than 50 kilograms was made.  

The uniqueness of this trial was in the design.  Unlike other studies that showed synergy with IV iron given at the start of ESA therapy, these investigators treated all patients with ESAs without IV iron for eight weeks and then randomized to eight more weeks of ESA alone or with IV iron saccharate as described above.  No benefit was seen for four weeks but in the following four weeks there were more hemoglobin and hematopoietic responses in the groups receiving IV iron.  As in other studies, there were no baseline differences among the treatment groups in hemoglobin levels, serum ferritins or percent transferrin saturations.  Mean serum ferritins at baseline ranged from 243.6 to 457.1 ng/ml across the treatment groups.  These data corroborate prior studies which showed that baseline iron status does not predict responsiveness to IV iron therapy.  The results showed that iron saccharate plus ESA compared to ESA alone resulted in greater mean maximum hemoglobin levels and a greater number of patients who achieved hemoglobin increases > 2 and 3 grams/dl in both ESA prior responders and non-responders.  The magnitude of the hemoglobin responses with IV iron was independent of prior ESA responsiveness or non-responsiveness.  

The dose of iron saccharate that was used in this study appears to be suboptimal due to inconvenient infusion and more related adverse events.  A two hour infusion for less than total iron replacement, which should only be done with low molecular weight (LMW) iron dextran, is inconvenient and probably unnecessary, since responses to IV iron are independent of the method or rate of iron administration.  Further, adverse events, albeit self-limiting, were serious in 2% of patients and more frequent than in other published trials.  However, this study provides us with the extremely important and useful information that prior ESA unresponsiveness does not predict for a subsequent response to IV iron nor the magnitude of the response.           

IV Iron’s Effect on Fatigue Score

In what is surely to be the most intriguing of the three excellent presentations, Henry et al showed that improvements in hemoglobin and hematopoietic responses and fatigue using the FACT-F subscale were statistically significantly higher in patients receiving IV ferric gluconate (Ferrlecit) given as a 125 mg bolus with epoetin alfa given subcutaneously as 40,000 U per week compared to similar patients receiving epoetin alfa with no iron or oral iron as ferrous sulfate given as 325mg thrice daily.[8] However, what was most unique about this study compared to other previously published trials showing similar benefits was that the improvements in fatigue scores were seen at week four and that this improvement (measured on visits on weeks 5 and 10) was independent of hemoglobin response and sustained throughout the duration of the trial.  No significant differences in fatigue using the FACT-F subscale were seen in the IV iron, no iron or oral iron groups at baseline.  As in other studies, this study corroborated that these responses were independent of the baseline iron parameters serum ferritin and percent transferrin saturation.  The mean serum ferritin among the three groups was 421 ng/ml.  These data provide us with new food for thought that iron repletion corrects fatigue independently from its role in raising hemoglobin concentration.  The only possible criticism of these most intriguing results is that the IV iron infusion could be due to a placebo effect.  Considering that all of these patients were receiving intravenous chemotherapy, that appears unlikely. 

Review of Clinical Use of IV Iron

The Meet the Professor Session titled “The Use of Intravenous Iron in the Treatment of Anemia in Patients with Cancer” was a review of the clinical use of intravenous iron.  The session was fully subscribed and contained a lively discussion about the side effects of IV iron, especially iron dextran.  The key points stressed were that in all prior and current clinical trials using IV iron as an adjunct to ESA therapy, clinically significant improvements in hemoglobin and hematopoietic responses are seen with IV iron and not oral iron and no iron.  

It was stressed that premedication, especially with diphenhydramine, prior to the administration of IV iron, is inappropriate and can confound the side effect profile as the premedication agents have significant hemodynamic reactions of their own. An exception to this is the administration of IV methylprednisolone before and after giving IV iron dextran as a single total dose infusion of the entire iron deficit, which has been shown to abate and ameliorate the arthralgia/myalgia syndrome associated with this method of IV iron administration. 

 Also stressed was that there are two different preparations of iron dextran; high (Dexferrum) and low (InFed) molecular weight, and virtually all serious adverse events described with iron dextran are due to the high molecular weight (HMW) product.  In addition session emphasized that there are three nearly completely safe preparations, LMW iron dextram, iron saccharate (Venofer) and ferric gluconate (Ferrlecit) with an estimated SAE rate of <1:200,000, and that to date all three preparations have been shown to have equal safety and efficacy.  If there was a single message  intended for the attendees to take home, it was that there is a significant inappropriate underutilization of intravenous iron in medicine and that the proscription against its use is due to misinformation and misinterpretation of the incidence and clinical nature of serious adverse events.[9] And, lastly and most importantly, when HMW iron dextran is excluded, there is no substantially increased risk with the administration of IV iron. 

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