Blood bank: On guard against daratumumab interference

“Blood bank technologists need to look out for daratumumab, so if they find a patient with panreactivity, they should flag the case for review or dig around in the electronic medical record, if they have access, to see if the patient has multiple myeloma and the blood bank wasn’t told about the drug order,” she recommends.

Dr. Delaney and many other blood banking experts consider systematic notification to be the most effective approach in dealing with daratumumab interference. “If your hospital hasn’t set up a way to be communicating, for providers or pharmacists to tell you that that patient is going on the drug, that process should be set up.” An automatic alert to the blood bank, when a patient is put on a drug therapy, would be more of an error-proof way to give the blood bank a heads-up, she adds. Many hospitals in the Seattle area have introduced such alerts or other ways of flagging that a patient is on daratumumab, she notes.

But automatic notification to the blood bank about a patient’s drug treatment has never been proposed before, Dr. Delaney says, and while pathologists’ awareness of this need is growing, that awareness is still inadequate. “We had protocols for the drug because our blood bank was a center that was used in the study. When the FDA approved the drug, I got inundated with questions about how to handle this from all different kinds of blood banks—big, medium, and small.” The need for awareness could broaden further if the drug is used in cases of lymphoma or other diseases.

Following the first testing of daratumumab in Europe, Dana-Farber Cancer Institute, which has a large multiple myeloma research group, was part of the phase one and phase two trials of the drug, and became the first site in the U.S. to start using it, says Dr. Kaufman. Brigham and Women’s Hospital adult transfusion service, where he is medical director, serves as Dana-Farber’s blood center.

Early on, he had discussions with the oncologists engaged in the trials. “There was a little bit of language in the consent form for this research study, saying that there can be some blurring of the antibody screen in the blood bank. It wasn’t clear what that meant or how often you’d see it. But we decided a couple of things. If we saw anything, we’d let oncology know, and we asked for a baseline type and screen before putting anyone on this new drug.”

The first time a patient from the trial appeared and there was this interference, “the techs got really frustrated trying to adsorb it out, and they weren’t able to.” More patients followed “and with all of them, the blood center saw interference. There was basically panreactivity on the antibody screen, so an AHG crossmatch was always incompatible.”

“One thing that was interesting is that we saw some positive DATs [direct antiglobulin tests] and some negative DATs, and other labs started to see this same problem over time,” Dr. Kaufman recalls. “It turned out that most of the time, even though we know the problem is the drug is binding red cells’ CD38, the DAT is negative.”

Neutralizing or using DTT-treated red cells began looking like two ways to address the interference, Dr. Kaufman says. Before Dana-Farber’s experience, a European institution had been working on the interference issue in Utrecht, the Netherlands, and eventually both Dana-Farber and the Dutch group published side-by-side papers on it in Transfusion (Chapuy CI, et al. 2015;55[6 Pt 2]:1545–1554; Oostendorp M, et al. 2015;55[6 Pt 2]:1555–1562).

The Dutch group had been trying a couple of different ways to neutralize the antibody in solution, Dr. Kaufman continues. “One way was to take soluble CD38 protein and mix it in with the patient’s plasma, and the anti-CD38 would bind to that and take care of the problem.” A second approach was to take an anti-idiotype, an ITG antibody specific for the F(ab) (fragment antigen-binding) portion of daratumumab. “And that antibody could be mixed up with the plasma. It would bind up the daratumumab and get rid of the interference.” He started to believe the problem was most likely that CD38 was expressed at very low levels on red cells.

The normal dose for patients on daratumumab—16 mg/kg—is quite high, Dr. Kaufman notes. “So the idea is that for patients on daratumumab, if the drug is in the plasma, then it will basically stick to the reagent red cells that are used in the antibody screen. Then when you add in immunoglobulin, you get a positive result, usually a weakly positive result. You can’t get rid of it as you can an antibody.”

“Normally you would use red cells to pull out the antibody so it could adsorb out. The problem with daratumumab is there is really very little CD38 expressed on the red cells, and the ZZAP is what most labs use to do their adsorption—a mixture of dithiothreitol and papain. And we now know that DTT will really efficiently denature CD38.”

“So the adsorptions were failing. It was driving people crazy, because in the lab you don’t know the patient is on daratumumab. It really can look like an autoantibody or a chemical. You don’t know what it is, but you can’t get rid of it.”

Based on older studies, his blood center ended up using DTT to denature CD38. “Using that approach, we showed you could treat red cells with DTT and get rid of the interference.” Trypsin enzyme treatment also works, he adds, but not as well and not as easily. “The main advantage of the DTT method is it is pretty easy and it’s very, very cheap.” While you can certainly use soluble CD38, he says, “it costs a few hundred dollars to just do the antibody screen, whereas with DTT you can do it and the reagent costs pennies.”

However, when the blood center developed this method, conditions were somewhat artificial because the trial was underway. “It was really just the patients on this one study, so we were informed about all patients on daratumumab.” Since then, things have changed now that the drug is licensed. “Sometimes we know the patient is on the drug and sometimes we don’t. And it can be very frustrating, not just for us but for everyone, if you don’t know the patient is taking it.”

The laboratory technologists, Dr. Kaufman says, are getting used to daratumumab’s quirks. “If they’re seeing a weird interference, then they’ll just start asking, ‘Does this patient have multiple myeloma? Is the patient on daratumumab?’” But the problem won’t end there, since daratumumab is now being studied in other diseases. “There are a huge number of clinical trials that are being sponsored by the manufacturer,” he points out.

Extended matching”—giving patients cells that are matched based on patient and donor phenotype or genotype—might be another way to avoid daratumumab interference, Dr. Kaufman says. “It’s kind of the third approach, after neutralization and denaturation.” It doesn’t involve dealing with the serology at all, he notes. Some Canadian sites have employed this method, and there may be future interest; however, he believes the most common method to deal with interference right now is through use of DTT-treated red cells. “Extended matching is certainly viable and has its own advantages and disadvantages. It is expensive, but it is another way to handle the problem.”

Dr. Westhoff sees extended matching as a promising prevention alternative as monoclonal antibody treatment becomes more common. “To me, this will really drive the field toward prevention of antibody production. Some people become immunized and make antibodies to red cell antigens. But because everybody doesn’t, we don’t address prevention because of the additional expense.”

The only matching done currently is for ABO and RhD, “and we’ve been doing that since the 1940s,” Dr. Westhoff says. “There are 395 other blood group antigens. Not that we would need to match all of them for transfusions, but there are about 12 that are clinically significant, and some are very common.”

She thinks these facts make a higher degree of matching between patient and donor, as is done with organ transplants, more practical as a long-term solution when compatibility can’t be determined by routine methods. “It’s better patient care to actually prevent antibody formation. We have to find a way to afford that in our system,” she says.

But Dr. Westhoff believes that will happen because it will eventually be more cost-effective and economical in the future. “All these heroics we are trying to do to demonstrate the absence of blood group antibodies including DTT chemical modification are just not operationally very efficient when we will eventually be able to do better matching genomically by DNA, and with computerization.” Because most patients needing transfusion are not in a clinical crisis, she adds, at most donor centers patients can wait 24 hours to get a matched unit rather than a unit off the shelf.

An extended blood group antigen profile, in her view, should be performed on every patient as part of the blood bank record. “That does two things. It allows the clinician or the blood bank to have the choice to do a higher extended match and ask for a donor unit that is an extended match. Second, it allows the blood bank to determine which antibodies the patient is at risk to make, and that’s very important information to have. If you have the antigen, you’re not going to make an antibody to the antigen.”

In the near term, notification to the blood center that a patient is taking daratumumab is “spectacularly important” as a means of addressing the interference problem, Dr. Kaufman says. About half the time, his blood center knows of the drug order and half the time it doesn’t know.
“There are something like seven ways to deal with the interference, once you know about it. But you can waste a lot of time and do a lot of work without getting anywhere, if you don’t know a patient is on the drug,” Dr. Kaufman says.

How can blood centers make notification routine? One measure Dr. Kaufman’s blood center is testing is to have an automated alert through the EMR system—in Brigham and Women’s case, Epic—to the blood bank if a patient goes on daratumumab. “If a physician orders daratumumab, then we would automatically get a message directly or through the pharmacy to let us know that.” But he doesn’t believe EMRs are up to this task yet. “I think it’s the kind of thing that if you ask for it, you can have it built at your own institution, but I don’t think the EMR vendors are really incorporating it in their systems.”

Updating laboratory requisition forms to include a query about drugs a patient is taking is another measure that some blood centers are trying. At New York Blood Center, this change has already been implemented, Dr. Westhoff says. “We’ve seen more than 400 patients on daratumumab here in the last few months. Most of our hospitals are very aware now, so we don’t often get surprised. And we’ve learned to recognize it in the lab now too.”

Other blood centers are doing the old-fashioned legwork of making calls to oncology offices to check. Dr. Kaufman notes, at least at academic centers, that if a blood bank technologist sees the diagnosis and finds the antibody screen is positive, “they’re often thinking of the daratumumab interference right away at this point.” However, he adds, as daratumumab begins to be used for other diseases, “that’s where we can run into trouble.”

For now, despite the increasing efforts of the manufacturer, researchers, and blood centers to educate providers about the daratumumab interference problem, “What it comes down to is that the pathologists out in the world had better have a conversation with providers,” Dr. Delaney says. “If a patient is on daratumumab, the provider needs to tell the blood bank.”
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Anne Paxton is a writer and attorney in Seattle.