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 Table of Contents  
CASE REPORT
Year : 2019  |  Volume : 4  |  Issue : 2  |  Page : 240-242

Interference of daratumumab with compatibility testing in blood bank


Department of Transfusion Medicine, Sakra World Hospital, Bengaluru, Karnataka, India

Date of Submission13-Feb-2019
Date of Acceptance04-Apr-2019
Date of Web Publication17-Oct-2019

Correspondence Address:
Dr. Siva Deepthi
Department of Transfusion Medicine, Sakra World Hospital, Bengaluru, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/GJTM.GJTM_10_19

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  Abstract 


Plasma cell myeloma accounts for 1% of malignant tumors and 10%–15% of hematopoietic neoplasms. Daratumumab (DARA), a novel targeted immunotherapy drug, was approved by the Food and Drug Administration to treat relapsed/refractory multiple myeloma. DARA, which is a CD38-targeted immunomodulatory drug, also cross-reacts with red cells and sensitizes them, causing difficulties and delay in the blood bank. To avoid delay in view of patient care, proper communication with blood bank professionals is required. We present a case of relapsed/refractory multiple myeloma in a 45-year-old male who required transfusions due to anemia and severe thrombocytopenia.

Keywords: CD38, daratumumab, dithiothreitol, refractory relapsed plasma cell myeloma


How to cite this article:
Premkumar R, Deepthi S. Interference of daratumumab with compatibility testing in blood bank. Glob J Transfus Med 2019;4:240-2

How to cite this URL:
Premkumar R, Deepthi S. Interference of daratumumab with compatibility testing in blood bank. Glob J Transfus Med [serial online] 2019 [cited 2019 Nov 12];4:240-2. Available from: http://www.gjtmonline.com/text.asp?2019/4/2/240/269380




  Introduction Top


Transfusion medicine has evolved in recent years, but the principle of red cell serology is still simple and same, namely the antigen–antibody interaction.

Plasma cell myeloma accounts for 1% of malignant tumors and 10%–15% of hematopoietic neoplasms.[1] Daratumumab (DARA), a new novel targeted immunotherapy drug, was approved by the Food and Drug Administration (FDA) to treat relapsed/refractory multiple myeloma. DARA works by targeting the CD38 portion of malignant plasma cells; however, this drug cross-reacts and binds to endogenous CD38 on red blood cells (RBCs) and attaches to red cell reagents used for antibody screening in blood banks causing serological interference like pan positivity in antibody screening, positive DAT, and incompatibility during crossmatch.[2],[3],[4] However, it does not interfere with ABO grouping and Rh typing.

Here, we describe the interference of DARA in the red cell compatibility testing of a patient with refractory multiple myeloma.


  Case Report Top


A 45-year-old male diagnosed with multiple myeloma on treatment came for follow-up and showed plasma cells and thrombocytopenia on the peripheral smear. Bone marrow aspiration and biopsy were done to see the relapse. Results showed 56% plasma cells, and an impression of refractory/relapsed plasma cell myeloma was given. Hemoglobin was 6.6 g/dl, platelet count was 8000, and total count was 4 × 10 3/microliter respectively. The patient was admitted. Blood sample and request for two units of packed red blood 23 Cells were sent to blood bank. His blood group was B Rh D positive, as before. Antibody screening using LISS/Coombs gel card using a commercial three cell panel, DiaCell 1-11-111 (Bio-Rad), was showing pan reactivity with negative auto control. All the ten group-specific RBC units were incompatible in the anti-Human Globulin (AHG) phase using LISS/Coombs gel card by Bio-Rad.

Retrospective examination of clinical records showed that he had received two split doses of DARA (1400 mg divided into two doses of 700 mg each given on 2 consecutive days).

RBC antibody identification using extended 11-cell panel also showed pan reactivity.

The following points indicated interference with the drug DARA:

  1. Patient blood grouping and typing could be done with no difficulty
  2. The donor units were compatible in immediate spin crossmatch
  3. Clinical history revealed two doses of DARA being received by the patient.


Even though dithiothreitol (DTT)-based pretransfusion testing can be used to negate the drug interference, we suspected that DARA interfered in compatibility testing with the test findings and clinical history. The patient was transfused with two units of B-positive red cell unit, and no transfusion reaction was observed.


  Discussion Top


Multiple myeloma is a diverse clonal plasma cell malignancy that results from complex interactions between malignant progenitor cells (mature B lymphocytes), bone marrow stromal cells, and the bone marrow microenvironment.[5] Primary refractory disease means that the patient has failed to achieve any response to initial multiple myeloma treatments, often a combination regimen of two or three novel agents.[3],[6]

DARA, a new novel targeted immunotherapy therapy drug, was approved by the FDA in March 2015. It is the first-class anti-CD38 monoclonal antibody,[7],[8] which produces antibodies toward CD38 on the proliferating plasma cells. In addition to being expressed by leukocytes, CD38 is also seen on erythrocytes, platelets, and immature cells of the bone marrow, and CD38 is also expressed by neuronal cells and glial cells of the central nervous system, peripheral nerves, bronchial epithelium, osteoclasts, pancreatic islet cells, and skeletal and cardiac muscle cells.[9] Several trials were done to avoid serious damage to occur to the patients because of unwanted reactions with normal tissues. As CD38 expression is high in refractory myeloma cells, DARA was taken as treatment of choice.

Pan reactivity with reagent red cells and false-positive indirect ant globulin test (IAT) results in patients receiving DARA, which can last up to 5–6 months, is a huge concern in transfusion medicine. However, the drug does not affect the patients' ABO blood grouping and immediate spin crossmatch. It binds to endogenous CD38 on RBCs. Such sensitized RBCs agglutinate in the Coombs phase resulting in pan reactivityin vitro(antibody screening/identification and crossmatching).[10]

It has been shown that dithiothreitol (DTT) treatment of RBC screening cells negated the interference by DARA. Several studies including one from India by Setia R et al., have described ways of overcoming Daratumumab resistance.[11]

The limitations of our study was that it did not involve DTT treatment and perhaps more research is needed to standardize DTT cross match in such patients.

The researchers discovered that DTT treatment of RBC screening cells negated the interference by DARA. DTT is a reducing agent and acts by denaturing CD38 by cleaving the disulfide bonds; however, caution is necessary as some RBC antigens such as the Kell antigen can be destroyed by DTT. This problem can be solved by giving packed red cells which react negatively to the Kell antigen. A strong alternative in denaturing CD38 is 1% trypsin because it does not destroy the Kell antigen.

Delayed transfusions due to complications caused by DARA can pose a serious threat to patient safety. This threat can be avoided by informing the transfusion service whenever any patient is scheduled to begin taking anti-CD38. A baseline type and screen and if possible a baseline phenotype or genotype is advised for such patients.[12]


  Conclusion Top


DARA is emerging as a good targeted immunotherapy drug in patients with primary refractory multiple myeloma but has certain limitations. Due to the presence of CD38 receptors on other cells in the body, cross-reactions occur and interfere with compatibility testing, leading to misinterpretations and delay in issuing blood for transfusion which affect patients' care.

Appropriate guidance from AABB, drug manufacturer supplemented with proper communication between health-care professionals, and the transfusion medicine department will ensure minimal adverse impact when dealing with DARA.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Swerdlow SH, Campo E, Harris NL, Jaffee ES, Pileri SA, Stein H, et al. WHO classification of tumors of Haematopoietic and lymphoid tissues. In: Mckenna RW, Kyle RA, Kuehl WM, Harris NL, Coupland RW, Fend F, editors. Plasma cell neoplasms. Lyon, France: IARC; 2017. p. 241-51.  Back to cited text no. 1
    
2.
Plesner T, Krejcik J. Daratumumab for treatment of multiple myeloma. Front Immunol 2018;9:1228.  Back to cited text no. 2
    
3.
Murfy MF, Dumont LJ, Greinacher A. Interference of new drugs with compatibility testing for transfusion medicine. N Engl J Med 2016;375:295-6.  Back to cited text no. 3
    
4.
Chari A, Arinsburg S, Jagannath S, Satta T, Treadwell I, Catamero D, et al. Blood transfusion management and transfusion related outcomes I Daratumumab – treated patients with relapsed or refractory multiple myeloma. Clin Lymphoma Myeloma Leukemia 2018;18:44-51.  Back to cited text no. 4
    
5.
Sieqel DS. Relapse/Refractory multiple myeloma: Defining refractory disease and identifying strategies to overcome resistance. Semin hematol 2012:49:10-15.  Back to cited text no. 5
    
6.
Sonneveld P, Brojil A. Treatment of relapsed and refractory multiple myeloma. Haematologica 2016:101:396-406.  Back to cited text no. 6
    
7.
Tewart AK, Rajkumar SV, Dimopoulus MA, Mazzi T, Spicka I, Oriol A, et al. Carfilzomib, lenalidomide and dexamethasone for relapsed multiple myeloma. N Engl J Med 2015;372:142-52.  Back to cited text no. 7
    
8.
Dizon MF. The challenges of Daratumumab in Transfusion Medicine. Lab Med 2017:48:6-9.  Back to cited text no. 8
    
9.
Subramaniyan R, Satheshkumar R, Pereira KR. Role of daratumumab in transfusion medicine: A must know entity. Rev Bras Hematol Hemoter 2017;39:375-8.  Back to cited text no. 9
    
10.
DeWeers M, Tai YT, Van deer Veer MS, Bakker JM, Vink T, Jocobs DC, et al. Daratumumab, a noval CD 38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors. J immunol 2011;186:1840-4.  Back to cited text no. 10
    
11.
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.  Back to cited text no. 11
  [Full text]  
12.
Chapuy CI, Nicholson RT, Aguad MD, Chapuy B, Laubach JP, Richardson PG. Resolving the daratumumab interference with blood compatibility testing. Transfusion 2015;55:154-5.  Back to cited text no. 12
    




 

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