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 Table of Contents  
CASE REPORT
Year : 2021  |  Volume : 6  |  Issue : 1  |  Page : 103-105

Daratumumab interference with immunohematology testing in a nonmultiple myeloma neutropenic patient, in need of granulocyte transfusion


Department of Transfusion Medicine, Advanced Centre for Treatment Research and Education in Cancer, Tata Memorial Centre, Homi Bhabha National Institute, Navi Mumbai, Maharashtra, India

Date of Submission04-Jun-2020
Date of Decision10-Aug-2020
Date of Acceptance17-Aug-2020
Date of Web Publication29-May-2021

Correspondence Address:
Dr. Abhaykumar Malind Gupta
Department of Transfusion Medicine, Advanced Centre for Treatment Research and Education in Cancer, Tata Memorial Centre, Homi Bhabha National Institute, Navi Mumbai, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/GJTM.GJTM_50_20

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  Abstract 


Daratumumab (DARA) may interfere with immunohematology tests by binding to endogenous CD38 present on the surface of the red blood cells. DARA was Food and Drug Administration approved for refractory multiple myeloma patients, but now its application is being explored in other oncology patients also. The disease condition of the patient does not change the process of resolution of incompatible cross-matches, and blood transfusion services (BTS) must be vigilant about the drug but not the diagnosis. Effective communication between BTS and oncology departments is crucial in the timely resolution of DARA interferences. All BTS must have standard operating procedures in place for such discrepancies.

Keywords: Anti-CD38, compatibility testing, daratumumab, dithiothreitol, serology interference


How to cite this article:
Gupta AM, Ojha S, Tirlotkar A, Sathyan V. Daratumumab interference with immunohematology testing in a nonmultiple myeloma neutropenic patient, in need of granulocyte transfusion. Glob J Transfus Med 2021;6:103-5

How to cite this URL:
Gupta AM, Ojha S, Tirlotkar A, Sathyan V. Daratumumab interference with immunohematology testing in a nonmultiple myeloma neutropenic patient, in need of granulocyte transfusion. Glob J Transfus Med [serial online] 2021 [cited 2021 Jun 25];6:103-5. Available from: https://www.gjtmonline.com/text.asp?2021/6/1/103/317174




  Introduction Top


Daratumumab (DARA) is an IgG1 κ human monoclonal antibody that specifically targets human CD38 and is routinely used as the first-line therapy in refractory multiple myeloma (MM), which has overexpression of CD38.[1] DARA may interfere with the indirect antiglobulin test (IAT) by binding to endogenous CD38 present on the surface of the red blood cells (RBCs).[2],[3] Dithiothreitol (DTT) is a reducing agent that cleaves disulfide bonds present on the CD38 receptors. As a result, it can denature the CD38 antigen and prevent DARA from binding and resolve the positive IAT.[4]

DARA was Food and Drug Administration approved for refractory MM patients, but now its application is being explored in the other oncology patients also. Preclinical studies have shown that CD38 is a relevant target in acute lymphoblastic leukemia (ALL).[5]


  Case Report Top


The patient was a 19-year-old male, stem cell-transplant recipient with a diagnosis of ALL. DARA was given for the disease remission, but the same was not communicated to the blood transfusion services (BTS). Blood samples were received by BTS for routine cross-matches and granulocyte donor cross-matches as the patient had persistent neutropenia (Absolute Neutrophil Count <0.5 × 109/L) and was a candidate for the granulocyte transfusion.

Gel cards (Bio-Rad Laboratories, Berkeley, California, USA) were used for the cross-matches and antibody screening and the following results were reported.

  1. The patient's blood grouping was B RhD positive without any grouping discrepancy
  2. All the cross-matched units were compatible at the immediate spin phase but incompatible (2 + to 3+) at the antihuman globulin phase
  3. The antibody screen was pan-reactive (2 + to 3+) with a negative autocontrol
  4. The direct antiglobulin test was positive (the patient had a history of multiple previous transfusions).


For the resolution of the incompatible cross-matches:

  1. Cross-matches were repeated in the conventional test tube method and gel card
  2. A fresh blood sample was requested for repeat cross-matching
  3. Detailed patient history along with drug history was enquired
  4. History and clinical evaluation revealed that the patient had received DARA on the compassionate basis for disease remission, with the dose of 16 mg/kg every week, planned for 4 weeks, and blood samples were received in the BTS within a week of DARA treatment initiation.


For the resolution of this, DTT treatment of RBCs was done as per the 19th edition of the AABB Technical Manual:[6]

  1. Preparation of 0.2 M DTT and washed red cells: A 0.2 M DTT was prepared by dissolving 1 g of DTT powder in 32 mL of phosphate-buffered saline (PBS) at pH 8.0. Donor packed red blood cell (PRBC) units, regent red cells, and control (E + and K+) red cells were washed thrice with PBS (pH 7.3)
  2. Incubation: Four volumes of the 0.2 M DTT solution with one volume of washed, packed red cells of donor PRBC units, reagent red cells, and controls were incubated at 37°C for 30–45 min with mixing every 5 min
  3. Removal of excess DTT: The mixture was washed four times with PBS
  4. Quality control: Controls were tested for E and K antigens. After DTT treatment, K antigen vanished, but the E antigen was still present
  5. Cross-match: A suspension of 2%–5% RBCs in PBS for the test tube method and 0.8% RBCs for gel card was prepared for cross-matching. Four PRBC units and four granulocyte donor samples were tested and found compatible with DTT treatment. The cross-matches and antibody panel results before and after DTT treatment on the gel card are shown in [Figure 1] and [Figure 2], respectively
  6. Transfusion of the PRBCs: Slow PRBCs transfusion under strict medical supervision without any premedication
  7. Patient outcome: One unit PRBC was transfused without any complications to the patient. Four granulocyte donors were cross-match compatible, but patient's infection improved with antimicrobials, and the patient treatment plan changed; he did not require granulocyte transfusions.
Figure 1: Gel card showing the cross-matches and the antibody panel, before dithiothreitol treatment of red cells

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Figure 2: Gel card showing the cross-matches and the antibody panel, after dithiothreitol treatment of red cells

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  Discussion Top


Routinely, BTS staff is very vigilant about MM patients as they are aware that MM patients may receive DARA and it may cause serological interference with BTS testing. With new advances, DARA may be used for other diseases also and BTS staff should be aware of this fact. The disease condition of the patient does not change the process of resolution of incompatible cross-matches in MM and non-MM patients. This experience shows that DARA may be used for multiple diseases in the future, and the BTS should be vigilant about the drug (DARA) but not the diagnosis of MM. The blood component requisition form should have the mandatory patient drug history, and in that, DARA must be highlighted. The incompatibility may persist for up to 6 months after stopping the drug.[2]

Logistic issues for granulocytapheresis in daratumumab patients

The donor selection process for granulocytes is a lengthy procedure, and if cross-match is incompatible due to DARA, then its resolution with DTT would increase the BTS processing time. Hence, in these scenarios, donors should be called earlier so that all the necessary tests could be performed in time and the donor would be ready for mobilization.

Various methods for daratumumab interference resolution

The efficacy of the DTT method has been validated by International Biomedical Excellence for Safer Transfusion Consortium Study conducted at 25 centers worldwide.[7] Various methods of overcoming DARA in BTS may be used, but DTT is the most widely used and it is simple, valid, and reliable. Other methods include trypsin, papain, RBC phenotype and genotype, anti-idiotype antibody, soluble CD38 antigen, F(ab) 2 fragments, and cord blood RBCs.[7],[8]

Importance of K antigen-negative blood

As DTT breaks all the sulfhydryl bonds and denatures Kell, K antigen-negative (K−) patients should always receive the K- PRBCs.[4] The incidence of K antigen in the Indian population is nearly 5% and finding K- PRBCs is straightforward.[9] Apart from Kell, less immunogenic antigens including those in the Lutheran, Yt, JMH, LW, Cromer, Indian, Dombrock, and Knops systems are also destroyed by DTT treatment, and antibodies against these antigens may also be monitored.[4]

AABB recommendations

The AABB recommends that RBC phenotyping and genotyping, blood typing, and antibody screening should be performed before the initiation of DARA treatment, to prevent delayed transfusions. After DARA treatment has started, the AABB recommends that blood typing be performed, that DTT-treated cells to be used for antibody screening and identification, that Kell antigen-negative blood to be given if the Kell antigen status of the patient is unknown, that electronic and immediate spin cross-matching be performed if the patient has no underlying antibodies, and that phenotype- or genotype-matched blood be given.[10]

Implications for the future

Many other anti-CD38 monoclonal antibodies such as isatuximab and MOR202 may also be used in the future, and these drugs may also cause interference with immunohematology testing as false-positive IATs are class-specific for CD38-targeting monoclonal antibodies and are not limited to DARA.[3]


  Conclusions Top


As DARA may be used for many disease conditions, the BTS should be vigilant with the drug history but not the diagnosis of MM. Effective communication between the BTS and oncology department is very important in the timely resolution of DARA interferences. All BTS should have the standard operating procedures in place for the resolution of DARA discrepancies.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Lokhorst HM, Plesner T, Laubach JP, Nahi H, Gimsing P, Hansson M, et al. Targeting CD38 with daratumumab monotherapy in multiple myeloma. N Engl J Med 2015;373:1207-19.  Back to cited text no. 1
    
2.
Chapuy CI, Nicholson RT, Aguad MD, Chapuy B, Laubach JP, Richardson PG, et al. Resolving the daratumumab interference with blood compatibility testing. Transfusion 2015;55:1545-54.  Back to cited text no. 2
    
3.
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;55:1555-62.  Back to cited text no. 3
    
4.
Bub CB. Dithiothreitol treatment of red blood cells. Immunohematology 2017;33:170-2.  Back to cited text no. 4
    
5.
Bride KL, Vincent TL, Im SY, Aplenc R, Barrett DM, Carroll WL, et al. Preclinical efficacy of daratumumab in T-cell acute lymphoblastic leukemia. Blood 2018;131:995-9.  Back to cited text no. 5
    
6.
Fung MK, Grossman BJ, Hillyer CD, Westoff CM. Treating Red Cells Using DTT or AET, Methods Section 3-18, AABB Technical Manual. 19th ed. Bethesda (MD): AABB; 2017.  Back to cited text no. 6
    
7.
Chapuy CI, Aguad MD, Nicholson RT, AuBuchon JP, Cohn CS, Delaney M, et al. International validation of a dithiothreitol (DTT)-based method to resolve the daratumumab interference with blood compatibility testing. Transfusion 2016;56:2964-72.  Back to cited text no. 7
    
8.
Lancman G, Arinsburg S, Jhang J, Cho HJ, Jagannath S, Madduri D, et al. Blood transfusion management for patients treated with anti-CD38 monoclonal antibodies. Front Immunol 2018;9:2616.  Back to cited text no. 8
    
9.
Setya D, Tiwari AK, Arora D, Mitra S, Mehta SP, Aggarwal G. The frequent and the unusual red cell phenotypes in Indian blood donors: A quest for rare donors. Transfus Apher Sci 2020;59:102765.  Back to cited text no. 9
    
10.
Mitigating the Anti-CD38 Interference with Serologic Testing. AABB Web site. Available from: http://www.aabb.org/programs/publications/bulletins/Documents/ab16-02.pdf. Published January 15, 2016. [Last accessed on 2020 Jun 04].  Back to cited text no. 10
    


    Figures

  [Figure 1], [Figure 2]



 

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