Blood bank: On guard against daratumumab interference

Anne Paxton

October 2016—As fans of spycraft know, offensive counterintelligence can include an arsenal of strategies: initiating a diversion, sowing confusion, creating false identities—anything that makes another party believe something that isn’t true.

If the cancer treatment drug daratumumab were capable of deceptive intent, it might be accused of all those ploys when it comes to interfering with blood transfusion crossmatching. The reason: For patients receiving daratumumab, marketed as Darzalex by Janssen Pharmaceuticals, antibody testing for transfusion is subject to erratic false-positives, often leaving transfusion services confused, uncertain, and on hold.

“The blood bank can’t release any blood for these patients, and the transfusion will sometimes be delayed for hours or days while the problem can be figured out,” says Richard Kaufman, MD, medical director for the Brigham and Women’s Hospital transfusion service in Boston.

Daratumumab was approved by the Food and Drug Administration last year for one application: third-line multiple myeloma treatment. But much wider use of the cancer drug is anticipated soon because trials are showing that it is quite effective. Janssen, a subsidiary of Johnson & Johnson, is working on combining daratumumab with the current first-line myeloma drug, bortezomib (Velcade), for treatment of earlier stage myeloma. And preliminary research findings suggest that daratumumab may work against several other cancers as well, such as B-cell leukemia and lymphomas.

“There is more widespread use of this drug coming down the pike,” predicts Connie M. Westhoff, SBB, PhD, director of immunohematology and genomics at New York Blood Center in New York City. Use of daratumumab for multiple myeloma is “only the tip of the iceberg.”

Experts at the nation’s top blood centers are sounding a warning in the face of this trend: Without increased awareness and a plan for determining when transfusion candidates are receiving daratumumab, the risk to patient care created by the drug’s interference with antibody testing is likely to get worse. “Essentially,” says Meghan Delaney, DO, MPH, medical director of the immunohematology and red cell genomics laboratory at Bloodworks Northwest and director of transfusion services at Seattle Children’s Hospital, “every blood bank in the country is going to have to deal with this.”

When crossmatching is attempted on patients who are taking daratumumab, explains Dr. Kaufman, the antibody screen looks for so-called unexpected (non-ABO) antibodies in the patient’s plasma, so the blood bank can ensure that donor red blood cells that are selected for a particular patient will survive normally when transfused to that patient. “The problem with daratumumab is you can’t tell if there are antibodies hiding in the patient’s plasma because all the testing to detect the antibodies comes out positive. Daratumumab can essentially mask the presence of one or more unexpected antibodies.”

This creates a blood bank predicament that is without precedent, according to Dr. Delaney. “There’s no other drug that does what daratumumab does in blood bank testing,” she says. But daratumumab could just be the leading edge of a longer-term problem; other drugs now being tested are similar and could produce the same interference.

Dr. Westhoff agrees. “Monoclonal antibodies used for treatment are becoming much more prevalent, and many of the target antigens are also expressed on red cells, so I see this as a continuing problem, and maybe even becoming a much larger problem,” she says.

The delay caused by daratumumab’s interference with pretransfusion testing and crossmatching is not highly dangerous because the blood is normally not needed urgently. Multiple myeloma patients are mostly being treated as outpatients, not on an emergency basis, Dr. Kaufman says. “Usually they can wait, but sometimes patients come in fairly anemic, and it’s a hassle. It’s certainly a big inconvenience.” However, the delays and consternation the interference causes are unnecessary, Dr. Delaney notes. “If the doctor tells the blood bank that the patient is on daratumumab, then the blood bank could have that information and know to use special testing protocols that get around the problem.”

Multiple myeloma affects a large number of patients; it is one of the more common blood cancers, Dr. Delaney points out. “When the FDA approved daratumumab, it meant that it moved out from the academic centers to wide availability. So community oncologists will now use the drug. It will become much more widespread than just an agent used at big cancer centers.”
problem,” she says.

Daratumumab’s progress to the market as an approved drug has been relatively swift. When Janssen applied for FDA approval, it focused on third-line therapy because it was trying to get a fast approval for the drug, Dr. Delaney explains. Generally, “you first do a study of cases that are multiply resistant to other therapies. And if your drug works, you can get the FDA to approve it for that setting. Meanwhile, right now they are doing multiple other studies to move up in the line, and eventually they want it to become a primary therapy.”
problem,” she says.

It was early in the evolution of daratumumab that Janssen became aware, and clinical trial centers confirmed, that the drug could interfere with blood bank pretransfusion testing. Seattle’s Bloodworks Northwest was one of the centers included in the trials. “We had some patients here in Seattle who were getting the drug when it was still in the trial, and we knew. We were told and then we were working with those samples and giving providers feedback about what we found,” Dr. Delaney recalls.
problem,” she says.

“The big challenge with daratumumab is that this drug is now being given to patients in every hospital everywhere. Yet the only way to know for sure if the patient is on daratumumab or another similar agent is for the provider to inform the blood bank.” That’s not something providers typically do. “They tell the blood bank very little. They prescribe a unit of blood or they order a type and screen, and they don’t tell the blood bank what the patient is on. Nothing magical in that tube lets you know there’s daratumumab there unless they tell you,” Dr. Delaney says.
Janssen has been active in working with blood bank leaders to solve the interference problem, she notes. “Most traditional chemotherapy drugs are chemical agents that are cell killers. They don’t create this kind of interference, whereas the new class of cancer drugs, biologics, are antibodies that are directed at certain targets.”
problem,” she says.

Biologics have been around quite awhile but their toolbox keeps expanding, she points out, and the interference issue has added a new twist to cancer drug development. “Janssen didn’t mean to develop a drug that did this. They just wanted a drug that’s a blockbuster for myeloma. They’ve had to start learning about blood banking, so it’s been a trial by fire. But they’re really engaged in trying to figure out how to let labs handle patients who are on this drug, because they want the drug to be successful.”

When the blood bank tests a sample and finds reactivity with all cells, called panreactivity, the technologists have algorithms for how to deal with that. “But if they don’t know the patient is on daratumumab, they’ll go down the wrong algorithmic branch,” Dr. Delaney points out.

For this reason, the AABB recommends that patients be tested before they begin daratumumab treatment. “This pre-testing, to ensure the patient doesn’t have antibodies to blood group antigens before receiving the drug, sets the stage for the blood bank to be informed. They also can do an extended blood typing, sometimes by genotyping,” she says. When the patient starts the drug and the next sample comes in, “the blood bank technologists look at the record and say, ‘Ah, the patient is on daratumumab.’”

Daratumumab does not interfere with routine blood typing for detection of ABO and Rh antigens. Rather, daratumumab interferes with antibody detection and crossmatching because daratumumab works by targeting CD38, a protein widely expressed on tissues and red blood cells, says Dr. Westhoff.

The presence of the circulating free drug antibody in the patient’s plasma is what causes the confusion during laboratory testing. “In serologic tests, the presence of this drug reacts like an antibody to a high-prevalence antigen. If the blood bank is unaware that the patient has received the drug, time-consuming and complex testing will be undertaken to try to identify the specificity of the antibody present, when in fact the reactivity is not due to a specific antigen that may be lacking on some cells and present on the majority of others. It is directed to CD38, present on all the red cells tested,” Dr. Westhoff explains.

New York Blood Center received its first case with unknown daratumumab interference in June 2014. A large amount of testing was done on the initial case because the reactivity suggested an antibody to a high prevalence antigen. Based on the strength of reactivity, enzyme testing, and the lack of reactivity with cord RBCs, the first suspicion was a Knops antibody. “This was quickly ruled out, and uncommon specificities were investigated using rare RBCs,” Dr. Westhoff says. “Only Lu(a–b–) RBCs of the dominant In(Lu) type did not react, but the very rare recessive type of Lu(a–b–) RBCs did react. The lab was perplexed because we couldn’t believe the specificity could not be identified. It took two additional mystery samples to connect the common diagnosis of multiple myeloma.”

To avoid interference, 0.2M dithiothreitol (DTT) can be used to address the problem serologically. DTT reduces the disulfide bonds in the CD38 molecule on the red blood cells. “The DTT denatures CD38 on the reagent red cells,” Dr. Delaney says.

Bloodworks Northwest performs DTT testing, as do other reference labs, but it’s not routine in most hospital laboratory testing. “So hospitals with patients on daratumumab, when they have interference, will send the tests to us,” says Dr. Delaney. Over time, some hospitals may decide they don’t wish to send out the samples and will bring the DTT protocol into the laboratory if they have the test volume and staff to do it. “But for many blood banks, the DTT chemical treatment is actually a reagent they have to make themselves, it has to be made fresh, and that’s something most hospital blood banks are not interested in doing.”

Another downside of DTT treatment is that, while it reduces the disulfide bond, it also destroys other antigens. “So when you do DTT-treated antibody detection testing, you can’t exclude that the patient has antibodies to the antigens that have been destroyed by the DTT,” Dr. Delaney says, citing Kell antigens as the most common ones to worry about.