CD38 antibodies interfere with blood group compatibility testing. (A) CD38 antibodies bind to CD38 molecules present on reagent or donor red blood cells (RBCs), and thereby interfere with blood bank compatibility tests, such as antibody screening and crossmatching (both IATs). (B) Several strategies can be used to negate daratumumab interference with blood group compatibility testing to ensure that patients receive a timely transfusion. This includes a chemical method (dithiothreitol [DTT]) to denature CD38 so that daratumumab binding is reversed. Because the Kell blood group system is also sensitive to DTT treatment, K⁻ units should be supplied after ruling out or identifying alloantibodies using DTT-treated RBCs. Approximately 9% of the population is reactive to the Kell blood group system, therefore, >90% of blood units will be Kell⁻ and suitable for transfusion. Alternatively, binding of CD38 antibodies to RBCs can be prevented by using neutralizing agents such as anti-idiotype antibody or recombinant soluble CD38. Furthermore, extensive human erythrocyte antigen phenotyping or genotyping can be performed prior to starting CD38 antibody therapy. Genotyping is not impacted by CD38 antibodies and may therefore be performed at any time, also during CD38 antibody therapy. When patients require blood transfusions, blood products can be identified based on the results of phenotyping and genotyping. Importantly, once treatment with a CD38 antibody is discontinued, pan-agglutination may persist. The duration of this effect varies from patient to patient, but for daratumumab this effect may persist for up to 6 months. Mitigation methods should be used until pan-agglutination is no longer observed.