Daratumumab and Blood Bank Testing
Daratumumab (Darzalex) is a therapeutic monoclonal antibody directed against CD38, a protein highly expressed on plasma cells. Unfortunately for the blood bank, CD38 is also expressed at low levels on normal red blood cells.
As a result, daratumumab in the patient's plasma can bind to CD38 on reagent red cells and produce panreactivity in indirect antiglobulin testing (IAT). This can affect antibody screens, antibody identification panels, and AHG crossmatches and may mask an underlying clinically significant alloantibody. Reactions are often weak, although stronger reactions can occur depending on the testing platform.
Daratumumab generally does not interfere with routine ABO or RhD typing, since these tests do not depend on the indirect antiglobulin phase. Immediate-spin crossmatches are likewise unaffected by the anti-CD38 interference.
Interference can persist for up to six months after the final dose of daratumumab.
DTT Testing
One of the best-established methods for eliminating daratumumab interference is treatment of reagent red blood cells with dithiothreitol (DTT).
DTT reduces disulfide bonds within the CD38 protein, disrupting its structure and preventing daratumumab from binding effectively to CD38 on the reagent cells. When the patient's plasma is subsequently tested against DTT-treated screening or panel cells, the anti-CD38 panreactivity is generally eliminated, allowing underlying alloantibodies to be investigated. This approach has been extensively validated for pretransfusion testing.
DTT is not completely selective for CD38, however. Most importantly, conventional DTT treatment also destroys Kell blood group antigens. For this reason, patients tested using DTT-treated cells are generally provided K-negative RBCs unless they are known to be K-positive. Other DTT-sensitive antigens, including some in the Lutheran, Yt, Dombrock and other blood group systems, may also become undetectable.
Current AABB guidance also recognizes several alternatives to conventional DTT testing, including soluble CD38 reagents, daratumumab-specific anti-idiotype reagents, CD38-masking Fab fragments, and other validated methods.
What About ABO Isoagglutinin Titers?
Routine ABO typing is generally unaffected by daratumumab, but ABO isoagglutinin titration can present a different problem.
IgG anti-A or anti-B titers are often read at the AHG phase. These procedures may use A1 or B reagent red cells as indicator cells. Because those reagent RBCs also express CD38, daratumumab present in the patient's plasma can bind to them.
Once anti-human globulin is added, the test system may therefore detect not only IgG anti-A or anti-B bound to the reagent cells, but also daratumumab bound to CD38.
The result can be persistent reactivity through multiple dilutions and a falsely elevated apparent IgG isoagglutinin titer.
This distinction is important in settings where ABO titers are used for clinical decision-making, such as ABO-incompatible solid-organ or hematopoietic stem-cell transplantation.
Using DTT-Treated Cells for ABO Titers
When anti-CD38 interference is suspected, treatment of the A1 or B indicator red cells with DTT can remove CD38-mediated reactivity before the titration is performed.
If the apparent high titer is largely caused by daratumumab, reactivity may fall dramatically after the indicator cells are treated. Published reports have demonstrated strikingly high apparent ABO IgG titers in patients receiving anti-CD38 therapy that decreased substantially when the interference was removed.
Because antibody-titer methodology is notoriously dependent on technique, however, laboratories should use a locally validated procedure rather than simply substituting DTT-treated cells into an established titer method without validation.
Daratumumab Changes More Than the Antibody Screen
Daratumumab is a good example of why medication history matters in immunohematology. A seemingly straightforward panreactive antibody screen may actually represent a therapeutic monoclonal antibody rather than a conventional RBC alloantibody.
And although routine ABO/RhD typing is usually unaffected, tests that use reagent RBCs at the antiglobulin phase—including certain ABO isoagglutinin titers—may still be vulnerable to anti-CD38 interference.
Communication between the clinical team and transfusion service remains one of the most important parts of managing these patients. Current AABB recommendations call for the transfusion service to be notified before anti-CD38 therapy begins and recommend obtaining a baseline type and screen. Phenotyping or genotyping may also be considered depending on local practice.
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