Advanced parameters offer faster, surer guidance to cancer care

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‘We need to educate physicians around what the RET-He means, how it can
help them.’ — Ellinor Peerschke, PhD, FAHA

“The FDA recently put out a guidance for blood collection centers to think about ways to identify repeat or frequent RBC donors to make sure they don’t become iron deficient. So we wouldn’t wait until the person’s hematocrit drops so low that they can no longer donate. Rather, we would look at their RET-He and follow up if it drops or becomes a concern. Then we would ask the donor to defer, recommend a longer interval between collections, so they have the ability to recover their red cell mass, and suggest iron supplements.”

This study is made possible because RET-He is a sensitive, rapid test of one of the earliest indicators of potential iron deficiency, Dr. Peerschke says. The RET-He test is also easier to perform than traditional iron studies, which would require another tube of blood for biochemical analysis of serum iron, ferritin, and transferrin saturation. Most important, RET-He is not subject to physiological variations that affect biochemical markers of iron status. “It’s a direct measure of the iron available for hemoglobin production in young red cells and provides more relevant information than looking at markers of iron deficiency in the peripheral blood, some of which are acute-phase reactants.”

“There is significant information on the use of RET-He and CHr, the RET-He equivalent on the Siemens Advia analyzer, in populations vulnerable to anemia, such as young children and elderly patients, with the goal to easily identify those in need of iron supplementation. At Memorial Sloan Kettering Cancer Center, we extended these studies to cancer patients,” she says.

The three major reasons why cancer patients become anemic are bone marrow suppression from chemotherapy, lack of iron utilization because of chronic disease, and iron deficiency, which may be nutritional or due to blood loss. In 2012, the hematology/oncology community issued a recommendation that cancer patients with hemoglobin levels less than 12 g/dL for males and 11 g/dL for females be investigated for anemia. But evaluating iron deficiency in cancer patients is notoriously complex, Dr. Peerschke notes.

Conventional markers are an imperfect gold standard and make interpretation of acutely ill patients’ hematology lab results more difficult, she points out. Ferritin, depending on the patient’s cancer, may be a tumor marker. Ferritin overexpression has been observed in hepatocellular carcinoma, Hodgkin’s disease, breast cancer, and pancreatic cancer, for example.

“Ferritin and transferrin levels may be affected also by liver dysfunction. So the iron deficiency may be masked.”

With a RET-He result, some conditions can be ruled out. “We can very rapidly say that a patient found to be anemic does not have iron deficiency, or poor iron utilization due to inflammation, and conclude perhaps the reason for the anemia is a production defect or the patient may be bleeding. So using this test is less about treatment and more about helping to guide further workups.”

Clinicians are still reluctant to use RET-He in isolation to screen for iron deficiency, she finds. “It’s not the standard of care, so if you have a low RET-He, clinicians need to go back and make sure they have further evidence of iron deficiency.” If the RET-He is elevated, however, iron deficiency can be pretty much ruled out and biochemical evaluations are probably not indicated. “But what we find here, and probably in other hospitals as well, is there are standard order sets for the evaluation of patients, and until those get changed, these workups in the clinical chemistry labs will persist.”

To cover some of the bases, Dr. Peerschke’s laboratory reports RET-He with an explanatory comment: “If your patient’s RET-He is greater than 32 picograms, iron deficiency is ruled out with a fairly high certainty (Negative Predictive Value of 98.5%).” This comment is based on Memorial Sloan Kettering’s experience. “It’s often the case with lab screening tests that the higher the sensitivity, the lower your specificity. It’s a tradeoff, so you need to ask what is your goal.” Each laboratory should define its own cutoff, she recommends. “I realize that’s burdensome, but if you look at the literature, the cutoffs that are quoted for RET-He and CHr vary. You really need to look at your population.”

Her laboratory also recommends that anyone with anemia and a RET-He below 32 pg be evaluated further, and that patients with a really low RET-He may be suspected of having a hemoglobinopathy. “Any time you have decreased red cell production like in alpha or beta thalassemia,” she says, “that will give you a low RET-He, often lower than 28 pg.”

What would be the impact of eliminating iron studies? “Every lab can look and see what it costs them to do iron studies,” Dr. Peerschke says. “Certainly, if you’re a very big place and you do a lot of iron studies that tend to be unnecessary, that’s a resource utilization issue.”

The actual patient impact should also be considered, she notes, because probably all of the patients who come into the outpatient clinic get CBCs drawn. “So we already have a tube of blood, and a reticulocyte count with RET-He is easy to add on. If a patient comes in with unexpected anemia, the clinician can very easily get that first piece of information to decide whether iron deficiency is an issue.”

She describes a recent case in which a RET-He helped in a rapid workup of a patient with unexpected anemia. She was a 72-year-old colon cancer survivor who came into the clinic for an annual checkup, and her hemoglobin was down to 10 g/dL compared with the previous year’s level of 12 g/dL, which was normal. “Given that she was a colon cancer survivor, there’s concern that the cancer has come back, but she denied any rectal bleeding. We were able to provide a RET-He level very rapidly that indicated she did have iron-deficient erythropoiesis. Then the clinician could start to think about how the patient became iron deficient. Is it dietary? Is she bleeding due to cancer but is unaware? The clinician could initiate a further workup pretty rapidly. Otherwise, if you are waiting for clinical chemistry test results to come back from our central laboratory, which take a few hours to come back, the patient would have to be called back for additional diagnostic studies.”

Hospitals need a robust education program to properly use RET-He, Dr. Peerschke believes. “We’re looking to change clinical practice. The laboratory isn’t the one ordering the tests, so we need to educate physicians around what the RET-He means, how it can help them, and, eventually, how it could affect the treatment of their particular patient population. That way, order sets can be rewritten with RET-He as a potential discriminator.”

But she is not a fan of rashly adopting a screening test. “We shouldn’t use screening tests blindly in the laboratory to prevent clinicians from ordering tests, unless the screening tests are so robust and they have a negative predictive value of 100 percent.” Instead, Dr. Peerschke recommends, the laboratory should say: “If you don’t have a clinical suspicion and you’re checking because it’s part of your standard protocol to check patients who are anemic with iron studies, then the RET-He may be very helpful in telling you where to focus your energy. If you have a very strong clinical suspicion, by all means do the more definitive tests, and use RET-He to help evaluate those complex patients with inflammation as it may help tease out what the iron studies mean.”

Institutions can develop their own diagnostic algorithms. For example, the RET-He could also be used to reflex to iron studies, hemoglobin electrophoresis, and perhaps even bone marrow analysis, depending on the result. That approach has reflected Memorial Sloan Kettering’s implementation of the parameter for a couple of years now, Dr. Peerschke says.

The general pattern, Dr. Hirsch-Ginsberg says, is that diagnostic tools often stay investigational for a long time before they’re as widely used as they could be. But she and Dr. Peerschke express confidence in the Sysmex advanced parameters’ robustness and their ability to diagnose or rule out hematologic conditions in many populations—the complex cancer population being one of the most important.
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Anne Paxton is a writer and attorney in Seattle.