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 Table of Contents  
Year : 2017  |  Volume : 2  |  Issue : 2  |  Page : 163-165

Daratumumab (Anti-CD38) interference with serological testing: An emerging challenge for blood banks in developing countries

1 Department of Hematology and Transfusion Medicine, BLK Super Specialty Hospital, New Delhi, India
2 Department of Hemato-Oncology and Bone Marrow Transplant, BLK Super Specialty Hospital, New Delhi, India
3 Department of Medical Oncology, BLK Super Specialty Hospital, New Delhi, India

Date of Web Publication11-Sep-2017

Correspondence Address:
Rasika Setia
Department of Hematology and Transfusion Medicine, BLK Super Specialty Hospital, New Delhi
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/GJTM.GJTM_42_17

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Daratumumab (DARA), a monoclonal anti-CD38 antibody, belongs to the new generation of immunotherapy in refractory relapsed multiple myeloma. CD38 is weakly expressed on human erythrocytes. By its intrinsic anti-CD38 activity, DARA also interferes in routine pretransfusion compatibility testing such as antibody screening for red blood cells (RBCs) alloantibodies and compatibility testing. Treating RBCs with dithiothreitol eliminates the DARA interference. We report two cases of serological interference of DARA in pretransfusion testing and how timely information before starting the second patient on DARA prevented the delay in pretransfusion compatibility testing and blood availability.

Keywords: Anti-CD38, antibody screening, compatibility testing, daratumumab, dithiothreitol, red blood cells, serological interference

How to cite this article:
Setia R, Dogra M, Sachdeva P, Handoo A, Choudhary D, Agarwal A. Daratumumab (Anti-CD38) interference with serological testing: An emerging challenge for blood banks in developing countries. Glob J Transfus Med 2017;2:163-5

How to cite this URL:
Setia R, Dogra M, Sachdeva P, Handoo A, Choudhary D, Agarwal A. Daratumumab (Anti-CD38) interference with serological testing: An emerging challenge for blood banks in developing countries. Glob J Transfus Med [serial online] 2017 [cited 2021 Nov 29];2:163-5. Available from: https://www.gjtmonline.com/text.asp?2017/2/2/163/214284

  Introduction Top

Multiple myeloma (MM) is a plasma cell malignancy that accounts for approximately 1% of all cancers.[1] Even in today's era of novel agents, where MM patients are surviving longer, MM remains incurable and outcomes in the relapsed/refractory setting are very poor. This warrants the need for novel agents in the treatment of MM, especially in patients who have become refractory to currently available therapies. In recent years, the introduction of monoclonal antibodies (mAbs) in MM therapy, notably mAbs targeting CD38 and SLAMF7, has been a promising step forward in improving treatment outcomes.[2] Daratumumab (DARA) is a human mAb that targets CD38, a cell-surface protein, which is overexpressed on MM cells and is increasingly being used to treat relapsed/refractory MM.[3] CD38 is also weakly expressed on human erythrocytes. Although DARA does not interfere with routine ABO/RhD typing, the plasma of DARA-treated patients is panreactive in antibody screen, antibody identification, and antiglobulin tests, as a result of binding of DARA to CD38 on reagent erythrocytes.

  Case Report Top

Patient 1

A 71-year-old man diagnosed as MM (IgG kappa) in 2006 was treated with thalidomide and dexamethasone. In 2008, he underwent autologous hematopoietic stem cell transplant and was continued on thalidomide-dexamethasone as maintenance therapy. In 2017, he relapsed and was given bortezomib-cyclophosphamide-dexamethasone. He intermittently required red cell transfusions. Blood grouping was done by column agglutination technology (CAT) using DiaClon ABO/D + Reverse Grouping Cards (BIO-RAD, Switzerland). Antibody screening was done using three cell panels (ID-DiaCell I-II-III Asia panel by BIO-RAD, Switzerland). Patient's antibody screen at this point of time was negative and crossmatch was compatible. On May 1, 2017, his hemoglobin dropped to 6.6 g/dl and a request for one unit of leukoreduced packed cells was raised. A repeat antibody screen was done using three cell panels, which showed pan-reactivity. Direct antiglobulin test was also positive. Antibody identification was put up using 11 cell panels (ID-DiaPanel-P by BIO-RAD, Switzerland) on CAT with LISS/Coombs Cards (ID-Cards by BIO-RAD, Switzerland). The identification panel also showed pan-reactivity and it could not be resolved by adsorption techniques, and all red cells crossmatched were compatible in saline phase but incompatible in Coombs phase on CAT with LISS/Coombs Cards [Figure 1].
Figure 1: Antibody screen and coombs crossmatch (Pre-DTT treatment)

Click here to view

History revealed initiation of DARA therapy a day before sending the blood request. DARA effects mimic as a warm autoantibody and serum/plasma of patient's interfere with serological testing. The enzymatic activity of CD38 is highly sensitive to reducing agents such as dithiothreitol (DTT).[4] The screening cells and K-antigen-negative donor red cells were pretreated with DTT (Sigma-Aldrich).

Dithiothreitol treatment of reagent red blood cells

A detailed method for DTT treatment of red blood cells (RBCs) is described in the AABB Technical Manual.[5] Briefly, 0.2 mol/L DTT was prepared by diluting 1 g of DTT in 32 mL of phosphate-buffered saline (PBS), pH 8.0. K + and E + control RBCs were used to verify that DTT treatment had denatured the K-antigen while preserving the E-antigen. Reagent and control RBCs (100 mL of a 3%–5% suspension) were washed four times with PBS, pH 7.3, before adding 400 mL of 0.2 mol/L DTT to each tube. The RBCs were incubated at 37°C for 30 min with periodic mixing by inversion (three to four times during incubation). The RBCs were washed four times with PBS, pH 7.3, and used for subsequent testing.

Post-DTT treatment, the screen result was negative and the unit was compatible in both saline and Coombs phase [Figure 2]. A total time of 9 h lapsed before the blood unit could be made available for the patient.
Figure 2: Antibody screen and coombs crossmatch (Post-DTT treatment)

Click here to view

Blood transfusion was uneventful, and the patient did not show any evidence of immediate or delayed hemolysis.

Patient 2

Following the first case, the blood request form was modified and inclusion of drug history of DARA treatment made compulsory. Subsequent to this case, a blood request for 2 units of leukoreduced packed RBCs was received for a relapsed MM patient posthematopoietic stem cell transplantation. The blood bank had received prior intimation before initiating DARA therapy. Baseline type and screen of the patient had already been performed. The reagent screening cells (ID-DiaCell I-II-III Asia panel by BIO-RAD, Switzerland) and K-antigen-negative donor red cells were pretreated with DTT following which antibody screen and crossmatch were performed. The antibody screen was negative and crossmatch was compatible in saline phase and Coombs phase. The turnaround time for arranging blood for this case was 2 h 20 min.

Both the units were transfused without any delay, and both transfusions were uneventful.

  Discussion Top

The use of anti-CD38 is a promising treatment for patients with MM recently approved by the US Food and Drug Administration in November 2015.[6] DARA is a mAb that targets CD38, an integral membrane protein expressed on both plasma cells and RBCs. Hence, while the CD38 antibodies destroy the malignant myelomatous plasma cells, they also bind to RBCs causing pan- reactivity during pretransfusion compatibility testing, complicating the safe release of blood products.[4],[7] Anti-CD38 may cause a small decrease in hemoglobin in vivo (~1 g/dL), but severe hemolysis has not been observed among treated patients.[8],[9] Reactions remain positive for 2–6 months after the last DARA infusion.[6],[8] To address this issue, AABB has issued a bulletin on January 15, 2016, on “Mitigating the Anti-CD38 Interference with Serologic Testing.”[10] It recommends protocols to inform the transfusion service when patients start receiving these agents. Before a patient receives DARA treatment:

  • Baseline type and screen
  • Baseline phenotype/genotype recommended.

DTT is known to destroy the Kell blood group and other, less frequently encountered blood group antigens. Therefore, K units should be provided unless the patient is known to be K +.[10]

Another reported approach to prevent DARA binding is neutralization of free DARA in plasma by adding soluble CD38 or an anti-DARA idiotype. Both methods have been reported to be highly effective in preventing DARA binding, and DARA neutralization in solution is simpler to perform. Disadvantages of these neutralization methods, however, are higher costs and a lack of widespread availability of the reagents. DTT treatment of reagent RBCs, till date, is the most simplified and cost-effective method to negate the DARA interference, allowing the safe provision of RBC units to DARA-treated patients.[4] However, DTT is not a readily available reagent in the blood banks in developing countries like India, and lack of awareness of serological interferences caused by DARA can delay in providing compatible blood to the patients. Therefore, blood banks catering to oncology patients should include DTT as one of their routine reagents.

  Conclusion Top

In today's era where at one end, mAb therapy is a revolution in the field of oncology, on the other hand, it poses a challenge in serological testing. Effective communication between oncologists and transfusion services and use of DTT is a simple and effective solution to overcome this challenge.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin 2012;62:10-29.  Back to cited text no. 1
Sanchez L, Wang Y, Siegel DS, Wang ML. Daratumumab: A first-in-class CD38 monoclonal antibody for the treatment of multiple myeloma. J Hematol Oncol 2016;9:51.  Back to cited text no. 2
Lin P, Owens R, Tricot G, Wilson CS. Flow cytometric immunophenotypic analysis of 306 cases of multiple myeloma. Am J Clin Pathol 2004;121:482-8.  Back to cited text no. 3
Chapuy CI, Nicholson RT, Aguad MD, Chapuy B, Laubach JP, Richardson PG, et al. Resolving the daratumumab interference with blood compatibility testing. Transfusion 2015;55(6 Pt 2):1545-54.  Back to cited text no. 4
Roback JD, Grossman BJ, Harris T, Hillyer CD, editors. Technical manual. 17th ed. Bethesda, MD: American Association of Blood Banks; 2011.  Back to cited text no. 5
Darzalex Package Insert. Horsham (PA): Janssen Biotech, Inc.; 2015. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/761036s000lbl.pdf. [Last accessed on 2016 Apr 01].  Back to cited text no. 6
Hannon JL, Clarke G. Transfusion management of patients receiving daratumumab therapy for advanced plasma cell myeloma. Transfusion 2015;55:2770.  Back to cited text no. 7
Oostendorp M, Lammerts van Bueren JJ, Doshi P, Khan I, Ahmadi T, Parren PW, et al. When blood transfusion medicine becomes complicated due to interference by monoclonal antibody therapy. Transfusion 2015;55(6 Pt 2):1555-62.  Back to cited text no. 8
Chari A, Satta T, Tayal A, Jagannath S, Cho HJ, Parekhet S, et al. Outcomes and Management of Red Blood Cell Transfusions in Multiple Myeloma Patients Treated with Daratumumab. Presented at the 57th American Society of Hematology Annual Meeting and Exposition, Orlando, FL; 05-08, December, 2015 (Poster). Available from: http://www.files.shareholder.com/downloads/AMDA-KPIBN/1136677222×0×864880/F472D367-7D89-4212-B9DB-684D886F8DC7/ASH_2015_Blood_Transfusion_poster_Chari_3571.pdf. [Last accessed 2017 Jul 15].  Back to cited text no. 9
Mitigating the Anti-CD38 Interference with Serologic Testing. AABB Association Bulletin #16-02. Bethesda (MD): AABB; 2016. Available from: https://www.aabb.org/programs/publications/bulletins/Documents/ab16-02.pdf. [Last accessed on 2016 May 29].  Back to cited text no. 10


  [Figure 1], [Figure 2]

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