Daratumumab
Daratumumab (Darzalex, Janssen Biotech, Horsham, PA) is a human IgG1k monoclonal antibody that was approved by the Food and Drug Administration in November 2015 for the treatment of patients with multiple myeloma who have failed treatment with proteasome inhibitors, immunomodulators and alkylating agents. Daratumumab binds with high affinity to CD38, which is a transmembrane glycoprotein that is highly expressed on the surface of multiple myeloma cells. It is believed to induce rapid tumor cell death through multiple mechanisms including apoptosis, complement-dependent cytotoxicity, antibody-dependent cellular phagocytosis and antibody-dependent cellular cytotoxicity.
The cost per infusion is approximately $5,850 for a typical 176-pound (80 kilogram) patient. A course of treatment is estimated to cost $23,400 per month for the first two months, $11,700 per month for the next four months, and $5,850 per month for each month thereafter.
Daratumumab also binds to red blood cells and platelets because they weakly express CD38. It does not appear to cause hemolysis or thrombocytopenia. Plasma samples from patients treated with daratumumab consistently have a positive indirect antiglobulin test and less often, a positive direct antiglobulin test. This occurs because daratumumab binds to CD38 on reagent red blood cells causing panreactivity in vitro. Affected tests include antibody screen, antibody identification panels, and antihuman globulin crossmatches. Daratumumab does not interfere with ABO and Rh typing or with immediate spin crossmatches.
Coating of reagent red blood cells with anti-CD38 antibody interferes with the ability to detect alloantibodies in patient sera. Daratumumab may persist in plasma for up to 6 months after the last infusion. Daratumumab cannot be removed by adsorption because CD38 is too weakly expressed on red blood cells.
Patient's plasma is usually weakly to 1+ reactive with all panel red blood cells. DAT is positive for IgG only. The degree of reactivity can vary over time. Agglutination due to anti-CD38 may occur with all suspension media including saline, low ionic strength saline (LISS) and polyethylene glycol. Reactions are seen with all methods including tube, gel and solid phase.
In an article published in the June 2015 issue of Transfusion, five of five (100%) of treated patients had a positive antibody screen and three of five (60%) had a positive direct antiglobulin test.
If the transfusion service is unaware that a patient has received daratumumab therapy, these serologic reactions could cause delays in issuing red blood cells and result in failure to identify a clinically significant alloantibody. To avoid these problems, the hematology/oncology service needs to notify the transfusion service whenever a patient is scheduled to receive this drug. Before the first dose, a baseline type and screen and red blood cell phenotype or genotype should be performed.
After the first dose, antibody screen and identification should be performed using DTT treated reagent red blood cells. The extracellular domain of CD38 contains six disulfide bonds that are necessary to maintain its structural conformation. Treatment of reagent red blood cells with dithiothreitol (DTT) denatures CD38 and prevents daratumumab binding. DTT treatment of reagent red blood cells prior to addition of patient serum eliminates daratumumab interference and allows detection of alloantibodies with the exception of alloantibodies to Kell system antigens. Because DTT treatment destroys Kell system antigens, Kell negative units should be provided unless the patient is known to be K positive. Other antigens such as k, Yta, Doa and Dob are denatured by DTT. Therefore antibodies against these antigens are also not detected when DTT treated reagent cells are used. However, these antibodies occur very infrequently.
Another transfusion strategy is to perform extended genotyping on patients treated with daratumumab and provide matched units for common blood group antigens to patients with daratumumab interference. This approach eliminates the need for DTT treatment of reagent red blood cells.
If an emergency transfusion is necessary, uncrossmatched ABO and RhD compatible red blood cells may be given.
References
Chapuy CL, et al. Resolving the daratumumab interference with blood compatibility testing. Transfusion 2015;55:1545-54.
Hannon JL and Clarke G. Transfusion management of patients receiving daratumumab therapy for advanced plasma cell myeloma. Transfusion 2015;55:2770.
Schmidt AE. et al. An alternative method to dithiothreitol treatment for antibody screening in patients receiving daratumumab. Transfusion 2015;55:2292-93.
AABB Association Bulletin #16-02, January 15, 2016.
