STOCKHOLM — The advent of monoclonal antibody (mAb) therapies is a significant milestone in the treatment of hematologic malignancies. It has also introduced new challenges, however, such as interference with transfusion testing. Experts in immunohematology, laboratory professionals, and clinicians discussed the topic during an educational session at the European Hematology Association (EHA) 2026 Congress. 

More than 10 years have passed since the FDA approved the anti-CD38 mAb daratumumab in 2015 as monotherapy for heavily pretreated patients with relapsed or refractory multiple myeloma. Yet the challenge of overcoming mAbs’ interference with pretransfusion compatibility testing remains a topic of discussion. These interactions significantly complicate the work of transfusion laboratory personnel and clinicians and may adversely affect patient care.

“Although the manufacturer soon identified the problem, it was not initially considered clinically relevant. This perception likely contributed to the lack of an earlier solution,” Miquel Lozano, MD, PhD, hemotherapy section head at the Hospital Clinic de Barcelona, Barcelona, Spain, told Medscape News Europe. Lozano, who chaired the session, explained that the company had already developed an anti-idiotype antibody against daratumumab but ultimately decided not to commercialize it. “Today, we are still awaiting the availability of a similar molecule being developed by another manufacturer,” he added, noting that questions remain about its cost and market accessibility.

At the Root of Interference 

Stijn Van Landeghem, of the blood bank laboratory of the Flemish Red Cross at Ghent University Hospital, Brussels University Hospital, and University Hospitals Leuven, Belgium, opened the session by discussing the importance of the interaction between mAb-based therapies and transfusion testing. He began by defining immunohematology as a discipline at the crossroads of immunology, hematology, and transfusion medicine. It is the foundation of transfusion medicine and blood banking, he said. “Transfusion is one of the most common in-hospital procedures and one of the riskiest,” he noted, identifying the indirect antiglobulin test and cross-matching as among the most important tests performed in a blood bank laboratory. 

In patients treated with an anti-CD38 mAb, the test may yield a positive result because of drug-related interference that occurs because CD38 is expressed not only on multiple myeloma and plasma cells but also on red blood cells, albeit at lower levels. From a laboratory point of view, the drug behaves like a pan-reactive antibody and, although the interference is predictable, it persists for as long as 6 months after the last dose of anti-CD38. Moreover, it is independent of the test platform and masks real alloantibodies, often generating misreadings of the results. 

Mitigation Strategies 

The number of affected test results is expected to increase as the indications for anti-CD38 monoclonal antibodies increase and new molecules enter pharmaceutical companies’ pipelines. The strategies developed over the past decade to mitigate interference can be classified into the following four major groups: preventing the mAb from binding to the reagent cells, removing or neutralizing the mAb in patients’ plasma, modifying the reagents, and implementing alternative transfusion strategies without modifying the test. 

Karen de Vooght, PhD, a clinical chemistry resident at University Medical Center Utrecht, Utrecht, Netherlands, commented that each of these approaches has advantages and disadvantages. She discussed the pros and cons of the various strategies in detail, emphasizing that no single method is ideal. The most appropriate choice depends on the antibodies being evaluated, the available reagents and expertise, and the regulatory requirements of each laboratory, she said. 

Dithiothreitol (DTT) treatment and anti-idiotype antibodies were among the mitigation strategies described. DTT can be used to treat the reagent red cells and cleave CD38. Shortly after the first reports of the interference with transfusion testing, DTT was presented as the main solution to the problem. An important advantage of this method is that it is not manufacturer-specific and can work with anti-CD38 antibodies other than daratumumab (eg, isatuximab). The main limitation lies in DTT’s ability to denature other red blood cell antigens, most notably those of the Kell antigen system. Consequently, anti-K antibodies can become undetectable and potentially be missed. 

Among strategies aimed at removing mAbs from the patient’s plasma, anti-idiotype antibodies play a central role, as they can bind specifically to the therapeutic mAb, forming immune complexes that no longer bind to red blood cell antigens. “Results from trials are highly encouraging, so we are now awaiting commercial availability and CE certification,” de Vooght said. “Anticipation beats reaction,” she emphasized. “A baseline workup before the first dose is the single most valuable step, turning a difficult sample into a manageable one.” 

From Bench to Bedside 

By discussing three clinical cases, Ena Ranković, MD, PhD, hematologist at the University Hospital Centre Zagreb, Zagreb, Croatia, brought the audience’s attention to the clinic. She stressed that anti-CD38 antibodies are used across all lines of treatment for multiple myeloma, and the associated interferences are no longer rare. These interferences have become part of routine clinical practice, and the clinical community must be prepared for new interferences to emerge, for example with anti-CD47 therapies, she said. “The hematologist’s decision is what protects the patient.” In particularly challenging situations, responsibility cannot lie with the blood bank alone, she added. 

In this context, the challenge is no longer recognizing the disease but recognizing when the therapy imitates it, Ranković added.

Given that every case is influenced by several variables, conducting baseline serology before starting a mAb-based treatment is the most important step, Ranković continued. She also provided attendees with a practical guide that included recommendations extending beyond purely medical and technical strategies, such as determining the patient’s extended genotype or phenotype at baseline, to encompass communication and organizational aspects as well. “Early communication between hematology and transfusion medicine prevents most complications,” she said. 

The mitigation strategies described during the session are now in place, but samples often arrive without information about the use of mAbs, Lozano told Medscape News Europe. “Effective communication, together with good connectivity and the proper use of electronic tools, is a key factor in the management of these complications,” he concluded.

Ranković and Van Landeghem reported no relevant financial relationships. De Vooght and Lozano did not disclose their financial relationships. 

Cristina Ferrario is a molecular biologist and former researcher in molecular oncology at three institutes in Milan. She has a master’s degree in communication and health from the University of Milan and a master’s degree in cancer genetics from the University of Pavia. She has worked as a science journalist for more than 20 years.