Carlo Brugnara (00:06):
I'm Carlo Brugnara and I'm happy to provide a summary of a Medscape live event that took place at the ASH 2020 meeting. And
this was a title involving the standard of care, and rethinking the treatment paradigm for iron deficiency anemia. A key issue
on iron metabolism is understanding the particular metabolism of iron in man, and the iron cycle. This slide highlights the
defining characteristic of iron metabolism that is the recycling of iron, and the contribution of iron absorption to make
up the daily losses of iron. But, as you see, most of the iron is being recycled. With this in mind, iron deficiency is a
condition in which this recycling mechanism gets disturbed to the point that the iron acquired through the diet is unable
to sustain the requirement of metabolism and erythropoiesis.
Carlo Brugnara (01:37):
There are several symptoms of iron deficiency that are worth considering and I outline in this slide. There's some very frequent
ones. There's obviously fatigue, paleness, dyspnea, and headache, and some frequent ones that are restless leg syndrome, glossitis,
dry and rough skin, dry and damaged hair, and then some rare ones. All together, these symptoms may be accompanied by signs
of iron deficiency, as shown in this slide, that include pallor due to the anemia, decreased population of the tongue, and
some mucosal changes, like hair losses, and some nail bed defects, as again outlined in this slide here. Now, what are the
defining laboratory features of iron deficiency?
Carlo Brugnara (02:42):
For absolute iron deficiency, certainly the biochemical parameters have been studied for a long time and ferritin, along with
the biochemical parameter, is informative if this value is below the cutoff. We will describe in the next slide what is the
appropriate cutoff. This is accompanied by low serum iron, and decreased transferrin saturation, increased transferrin, and
possibly add markers that are not measured routinely, but serum transferrin receptor, EPO and hepcidin. The hematological
changes are classic to an iron deficient data proteases, and so they have a reduction with MCV, in MCH, and in MCHC. Increase
of the [inaudible 00:03:41], increase of hypochromic red cells, and reduction in the reticulocyte hemoglobin count and measure
as CHr or RET-HE, as well as increased zinc protoporphyrin.
Carlo Brugnara (03:53):
The reticulocyte count is usually reduced for the degree of anemia and iron deficiency compared with other types of anemia.
I mentioned the serum ferritin cutoffs, the cutoff by the WHO is 15, but papers have been publishing showing that increasing
the cutoff to 30 may increase the sensitivity to diagnose iron deficiency and still maintain excellent specificity. In the
presence of inflammation, this cutoff varies and can be 100%, but also can be 300%... I'm sorry, 300 nanograms in congestive
heart failure, and 500 nanograms in chronic kidney disease. At times, the decision point for this cutoff, accompanied by also
decision point from transferrin saturation, so that for a 500 cutoff in chronic kidney disease, and it is less than 30% that
will still prompt possibly iron therapy decisions.
Carlo Brugnara (05:14):
Again, the cutoff of ferritin is very much dependent on the clinical situation, as shown here in this slide. For repeated
blood donors, the cutoff of 30 nanograms per ML of ferritin has been used as a prompt to lengthen the donation interval to
more than 56 days, and so reduce the number of times that the donor was unable to donate due to the low hemoglobin. I mentioned
the inflammation because anemia of inflammation is certainly a very common feature that the physician has to deal with. This
slide outlines the pathophysiology of the anemia of inflammation, that there's both iron restriction, of the suppression of
[inaudible 00:06:17] due to a variety of cytokines, and also of strong red cell survival. It is seen in a variety of conditions
that include autoimmune disease infections, but also malignancies as well as chronic kidney and pulmonary disease, as well
as obesity.
Carlo Brugnara (06:38):
What are the laboratory features of the anemia chronic disease? The ferratin can be normal or much more often is elevated.
The serum iron may be normal or low, and transferrin may be low, and transferrin separation might be reduced. The reticulocyte
count is reduced and there are inappropriately high serum and urinary hepcidin values, as well as changes in red cell and
what they call [inaudible 00:07:09]. Inflammatory markers may be elevated, but there is no consensus about what is the most
improper inflammatory marker, but CRP or IL-6 might be elevated. I have mentioned hepcidin, and again, this is a central regulator
of iron metabolism. We have seen how it can be activated in conditions in which the iron stores are repleted, or in consequence
of red cell transfusion, or in a variety of inflammatory diseases. It can be reduced in conditions in which there is an expanded
[inaudible 00:07:56] or anemia.
Carlo Brugnara (07:58):
Overall, hepcidin measurements are diagnostic for iron refractory, iron deficiency, anemia, the IRIDA, that is a genetic form
of iron deficiency. They're also helpful in the anemia chronic disease because they can show elevated values. And that is
mostly driven by the inflammation. And one area that has shown promise is the prediction of responsiveness to oral iron therapy,
as shown in this slide by work that was published in blood a few years ago. Low hepcidin value is associated with increased
iron incorporation, when you look at patient that had been treated with oral iron due to iron deficiency anemia. And while
elevated hepcidin levels are associated with low incorporation of iron, and low response to oral iron therapy. So some conclusions
for the section are we have to be careful about how we define normal hemoglobin values.
Carlo Brugnara (09:18):
We have to be careful about that there's no magic biomarker. And so we had to address the methodological and biochemical parameters
cap off to the particular condition of the patient. The pathophysiology of [inaudible 00:09:36] is certainly complex and multifactorial
when dealing with chronic disease. And hepcidin is a promising marker for both IRIDA, and for predicting the response to iron
replacement therapy. And these are some suggested readings. For the treatment side, it's clear what are the indication for
oral iron and for IV iron therapy. And they're outlined here in this slide. It's certainly, for IV iron therapy, intolerance
or unresponsiveness to oral iron, and also conditions that require rapid replacement, or after bariatric surgery or condition
in which we know the oral iron absorption is poor. There are several approved formulation of iron, this slide outlines the
ones that are approved for total iron replacement, as well as the appropriate dosing.
Carlo Brugnara (10:36):
And so in both iron dextran as well as ferumoxytol, ferric carboxymaltose, and iron isomaltoside, are approved for a dose
that can provide a total iron replacement, and the references for some of these are outlined below in this slide. What are
the adverse events for iron supplementation? For oral iron, pretty clear that there is a high frequency of constipation, less
often is diarrhea, but also nausea, cramping, and problem with stools. Intravenous iron, there are infusion reactions that
are usually mild in trends, and severe hypersensitivity is a rare event. In the oral iron therapy, there have been some new
findings that are associated with the timing of oral iron administration and the associated changes in hepcidin. So studies
have shown that a single oral dose of iron induces a rise in hepcidin. And as you know, hepcidin is a negative regulator by
metabolism. So this increased hepcidin turns off the absorption of oral iron. So the concept has emerged that the next oral
iron administration should be timed when this peak in hepcidin subsides.
Carlo Brugnara (12:24):
And so studies have actually shown the alternate dosing of iron is much more efficient in promoting iron absorption than the
daily dose, and the advantage of this alternate dosing is not only to have more iron absorption, but also to reduce the side
effect associated with oral iron administration, especially with the GI. So I think the field is moving toward a shifting
from daily to alternate daily oral iron supplementation. What about the IV iron safety? Multiple trials had been performed,
and this work in the Mayo clinic proceeding, look at pool data from more than 10,000 patients, treat them with IV iron, comparing
them with oral iron, a placebo, or no iron. And overall, there was no increase in the risk of severe adverse event with IV
iron compared to control. And also there was no difference in either efficacy or toxicity among the formulation that there
was studied in this retrospective study.
Carlo Brugnara (13:50):
However, the highest quality of evidence come from randomized clinical trial that are designed to compare and to assess the
incidence of a severe hypersensitivity reaction. And when these are becoming now pre-specified primary or secondary end points.
So these studies have more power than retrospective studies in answering the question about the incidents of severe hypersensitivity
reaction. Iron sucrose has consistently shown to have a low risk of hypersensitivity. And from a regulatory authority perspective
has been considered the benchmark for comparing a different iron formulation. Again, when one looks at hypersensitivity reaction.
So I'm going to briefly outline some clinical trials that have tried to answer this question in a randomized clinical fashion.
This study, it's actually two trial, was powered to look at the incidents of serious and severe hypersensitivity reaction
for iron isomaltoside compared with iron sucrose.
Carlo Brugnara (15:18):
And then this trial showed actually that there was no significant difference in the frequency of patient with serious or severe
hypersensitivity reaction between the two groups. So this was a study showing, that basically the two formulations were equivalent.
When you look at severe sensitivity reaction, this study, the first study again, was a randomized multicenter double-blind
trial, comparing ferric carboxymaltose for the treatment of iron deficiency and was designed to formally investigate the rates
of hypersensitivity reaction. This study took place in over 129 sites in the U.S., and Europe, and Canada and included adults
with iron deficiency, or virus etiology, were mostly GI disorder, as well as chronic kidney disease and also women with abdominal
uterine bleeding, and the study compare, ferric carboxymaltose with ferumoxytol in a one-to-one fashion and allow the administration
of two doses of these IV iron preparations.
Carlo Brugnara (16:43):
So they had the slightly different total dose, but both were total iron replacement. And the primary endpoint for these two
compounds were the moderate or severe hypersensitivity reactions, and the study basically showed that there were no statistically
significant difference for any of these endpoints. And as well as that the main change of hemoglobin from baseline to week
five was similar for the two preparations. And so basically this study shows no difference in these severe hypersensitivity
reactions, this third, a large trial, again, composed of two identical design, an open label trial compare a single infusion
of a hundred milligram of one iron preparation, versus two infusion of ferric carboxymaltose. And again, the studies show
no differences in the hypersensitivity reactions between these two compounds.
Carlo Brugnara (18:09):
So overall we can say that the risk difference, and the risk of adding a severe hypersensitivity reaction, is not different
between all these preparations. And so they're equally safe and equally likely to have, or not have, a severe hypersensitivity
reaction. Also, worth mentioning is pregnancy, because I think pregnancy is becoming now an area which IV iron is becoming
more accepted and more investigated. And so the more studies showing or examining the benefit of IV iron replacement in pregnancy,
the last area that I'd like to address is the one of hypophosphatemia. And this is based on the fact of the description of
severe hypophosphatemia in a patient being treated with the ferric carboxymaltose, and has been highlighted in the updated
label from the AMA for this practice.
Carlo Brugnara (19:32):
I'd like to briefly review the studies and the evidence that brought about this change in labeling. And this is based on the
central role that FGF23 has in the regulation of phosphate metabolism. And as shown in this slide, FGF 23 is a very powerful
stimulator of phosphaturia, at the same time that it inhibits phosphate production. And the unique feature of FGF23 is it's
cleavage, after it is being postulationally modified, and the two different postulation modification of this hormone, either
glycosylation or phosphorylation. But the key is that the hormone can be cleaved, and be divided into an N-terminal fragment
and a C-terminal fragment. And based on the assays that are used to detect this compound, this form, intact FGF assay will
pick the intact molecule. While a C-terminal FGF23 assay will pick up both intact molecule, it will also pick up the cleavage
site.
Carlo Brugnara (21:12):
So studies have shown that after an administration of iron, there's a substantial reduction in the C-terminal FGF23 assay
data. But if we look at the intact FGF23, the iron dextran and ferric carboxymaltose gave very different results. And as you
see here with ferric carboxymaltose, we have a substantial increase in the intact FGF23. So these two compounds have two totally
different behaviors when we look at the total molecule. While they seem similar when you look at the C22 terminal, and this
translates into quite different physiological responses because the intact terminal is associated with obviously the development
of hypophosphatemia. And as you see here in the two groups, the behavior for phosphatemia is quite different for dextran and
for ferric carboxymaltose, and as well as in the behavior for a 25, 125 vitamin D, calcium, and peptide hormone.
Carlo Brugnara (22:53):
So the third trial is a trial that compare ferumoxytol versus ferric carboxymaltose. Specifically looking at some of these
endpoints for phosphate metabolism. As shown in the other trial, the ferric carboxymaltose was associated with a very significant
change in the FGF intact, while again, the C-terminal value were the similar for the two groups. And there was a very substantial
portion of patients who develop a hypophosphatemia with the ferric carboxymaltose at both one week, and two weeks, and also
five weeks. And this was present both in patient who had chronic kidney disease, and much more so in patient who did not have
chronic kidney disease. And so the effect was more pronounced with normal kidney function, but was present in patients with
chronic kidney disease. These other trials were two identical design trial, again, randomized to either iron isomaltoside
or ferric carboxymaltose, and the primary endpoint was incidence of hypophosphatemia.
Carlo Brugnara (24:36):
The hypophosphatemia was much more prevalent with the use of ferric carboxymaltose compared with the other iron form, as shown
in this slide. And as well as the changes in intact FGF value, in serum phosphate, and in urinary fractional excretion of
phosphate, they were all substantially different in the ferric carboxymaltose versus the iron. And as you see here, the inactive
25, they are dosing Vitamin D, in the third panel was substantially higher in the patient taking ferric carboxymaltose, as
well as the intact peptide hormone, and the alkaline phosphatase value, and the ionized calcium. So what's the bottom line
from all these studies? Ferric carboxymaltose does replete iron store, but induces high rate of hypophosphatemia.
Carlo Brugnara (25:50):
And this IV iron induced hypophosphatemia is an under-reported and underappreciated side effect. The mechanism involved acute
increases in intact FGF 23, and the effect is magnified in patients with normal kidney function. But is present even in patients
with chronic kidney disease. So more studies are needed to precisely define the mechanism that this distribution and duration
of hypophosphatemia and what are the potential consequences of this hypophosphatemia in either a patient with heart failure
or with, or without chronic kidney disease. And we still don't know, and we should study what is the long-term effect of single
or multiple episodes of hypophosphatemia on muscle health. And this is the end of my summary. Thank you so much for listening.
