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How “Dara” You!

  • Mark T. Friedman
  • Kamille A. West
  • Peyman Bizargity
  • Kyle Annen
  • Jeffrey S. Jhang
Chapter

Abstract

A 73-year-old man with immunoglobulin (Ig)G kappa multiple myeloma is referred for outpatient transfusion due to severe anemia with hemoglobin (Hgb) of 6.6 g/dL. The patient has a history of red blood cell (RBC) transfusion at your hospital 2 years ago at which time the antibody screen was negative. An ethylenediaminetetraacetic acid (EDTA) anticoagulant sample is submitted to the blood bank for type and screen along with a request for two units of irradiated RBCs.

Keywords

Anti-CD38 Anti-CD47 Daratumumab Dithiothreitol/DTT Genotyping Multiple myeloma Trypsin 

Clinical History

A 73-year-old man with immunoglobulin (Ig)G kappa multiple myeloma is referred for outpatient transfusion due to severe anemia with hemoglobin (Hgb) of 6.6 g/dL. The patient has a history of red blood cell (RBC) transfusion at your hospital 2 years ago at which time the antibody screen was negative. An ethylenediaminetetraacetic acid (EDTA) anticoagulant sample is submitted to the blood bank for type and screen along with a request for two units of irradiated RBCs.

ABO/Rh/Antibody Screen

ABO/Rh (gel method)

Patient RBCs (forward typing)

Patient plasma (reverse typing)

Anti-A

Anti-B

Anti-D

A1 cells

B cells

0

0

4+

4+

4+

Antibody screen (AHG/gel method)

SC1

1+

SC2

W+

Reaction scale = 0 (no reaction) to 4 + (strong reaction); W weak

Gel Panel

 

Rh-hr

Kell

Duffy

Kidd

Lewis

MNS

P

Lutheran

Test results

Cell #

Rh-hr

D

C

E

c

e

f

C w

V

K

k

Kp a

Kp b

Js a

Js b

Fy a

Fy b

Jk a

Jk b

Le a

Le b

M

N

S

s

P l

Lu a

Lu b

AHG Gel

1

R 1W R 1

+

+

0

0

+

0

+

0

0

+

0

+

0

+

0

+

+

+

0

+

0

+

+

+

+

0

+

2+

2

R 1 R 1

+

+

0

0

+

0

0

0

+

+

0

+

0

+

+

+

+

0

0

+

+

+

+

+

0

0

+

1+

3

R 2 R 2

+

0

+

+

0

0

0

0

0

+

0

+

0

+

0

+

+

0

0

0

+

0

+

+

+ S

0

+

2+

4

R 0 r

+

0

0

+

+

+

0

+

0

+

0

+

0

+

0

0

0

+

0

0

+

+

+

+

+

0

+

2+

5

r'r

0

+

0

+

+

+

0

0

0

+

0

+

0

+

0

+

0

+

+

0

0

+

0

+

+

0

+

W+

6

r"r

0

0

+

+

+

+

0

0

0

+

0

+

0

+

+

0

0

+

0

+

+

+

+

+

+ W

0

+

1+

7

rr

0

0

0

+

+

+

0

0

+

+

0

+

0

+

0

+

+

+

0

0

+

0

+

+

+ S

0

+

1+

8

rr

0

0

0

+

+

+

0

0

0

+

0

+

0

+

+

+

0

+

+

0

+

+

+

0

+ S

0

+

2+

9

rr

0

0

0

+

+

+

0

0

0

+

+

+

0

+

0

+

+

0

0

+

0

+

0

+

0

0

+

1+

10

rr

0

0

0

+

+

+

0

0

0

+

0

+

0

+

+

0

+

+

0

+

+

+

+

+

+ W

0

+

1+

11

R 1 R 1

+

+

0

0

+

0

0

0

0

+

0

+

0

+

0

+

+

0

0

+

+

0

+

0

+

0

+

1+

Patient cell

                           

0

Reaction scale = 0 (no reaction) to 4+ (strong reaction); S strong, W weak

Additional History

Further history is obtained in regard to the positive findings in the antibody screen and panel. The patient is noted to be on medications including daratumumab, lenalidomide, and dexamethasone for treatment of the multiple myeloma. Based on this history, additional blood bank testing is performed. Meanwhile, the outpatient RBC transfusions are rescheduled for the following day, pending outcome of the additional testing and crossmatch of RBC units.

Gel and Dithiothreitol (DTT) Panel

 

Rh-hr

Kell

Duffy

Kidd

Lewis

MNS

P

Lutheran

Test results

Cell #

Rh-hr

D

C

E

c

e

f

C w

V

K

k

Kp a

Kp b

Js a

Js b

Fy a

Fy b

Jk a

Jk b

Le a

Le b

M

N

S

s

P 1

Lu a

Lu b

AHG Gel

DTT

1

R 1W R 1

+

+

0

0

+

0

+

0

0

+

0

+

0

+

0

+

+

+

0

+

0

+

+

+

+

0

+

1+

0

2

R 1 R 1

+

+

0

0

+

0

0

0

+

+

0

+

0

+

+

+

+

0

0

+

+

+

+

+

0

0

+

1+

0

3

R 2 R 2

+

0

+

+

0

0

0

0

0

+

0

+

0

+

0

+

+

0

0

0

+

0

+

+

+ S

0

+

2+

0

4

R 0 r

+

0

0

+

+

+

0

+

0

+

0

+

0

+

0

0

+

0

0

0

+

+

+

+

+

0

+

2+

0

5

r'r

0

+

0

+

+

+

0

0

0

+

0

+

0

+

0

+

0

+

+

0

0

+

0

+

+

0

+

W+

0

6

r"r

0

0

+

+

+

+

0

0

0

+

0

+

0

+

+

0

0

+

0

+

+

+

+

+

+ W

0

+

1+

0

7

rr

0

0

0

+

+

+

0

0

+

+

0

+

0

+

0

+

+

+

0

0

+

0

+

+

+ S

0

+

W+

0

8

rr

0

0

0

+

+

+

0

0

0

+

0

+

0

+

+

+

0

+

+

0

+

+

+

0

+ S

0

+

2+

0

9

rr

0

0

0

+

+

+

0

0

0

+

+

+

0

+

0

+

+

0

0

+

0

+

0

+

0

0

+

1+

0

10

rr

0

0

0

+

+

+

0

0

0

+

0

+

0

+

+

0

+

0

0

+

+

+

+

+

+ W

0

+

1+

0

11

R 1 R 1

+

+

0

0

+

0

0

0

0

+

0

+

0

+

0

+

+

0

0

+

+

0

+

0

+

0

+

1+

0

Patient cell

                           

0

NT

Reaction scale = 0 (no reaction) to 4+ (strong reaction); S strong, W weak

Further History

Two units of group O, Rh-positive, K-antigen-negative RBCs are crossmatched as below and transfused without any complications.

PEG Crossmatch

PEG crossmatch results

 

AHG

CC

Donor unit #1 (O-positive)

1+

NT

Donor unit #2 (O-positive)

W+

NT

Questions

  1. 1.

    What is the apparent nature of the patient’s antibody findings based on the clinical history and the antibody panels?

     
  2. 2.

    How does the dithiothreitol (DTT) panel help to resolve the nature of the antibody results? What is the significance of the K-antigen-negative phenotype of the crossmatched RBC units in this case? What alternative testing could be done to resolve these antibody findings?

     
  3. 3.

    Why are the two donor RBC units incompatible?

     
  4. 4.

    What additional testing would you advise at this time to make future transfusions of this patient safer against the risk of hemolytic transfusion reactions due to presence of undetected alloantibodies resulting from daratumumab interference?

     

Answers

  1. 1.

    What is the apparent nature of the patient’s antibody findings based on the clinical history and antibody panels? It is apparent that the cause of the antibody reactions is related to daratumumab medication that the patient is taking as part of his treatment for multiple myeloma. Daratumumab is an IgG1 kappa human monoclonal antibody that targets human CD38 cell-surface receptor which is highly expressed on myeloma cells [1]. It is indicated for treatment of previously treated multiple myeloma. However, since RBCs also weakly express CD38 antigen , daratumumab binds to RBCs causing panreactivity in the antibody screen and panel indirect antiglobulin tests (IAT) which may persist for up to 6 months after the last dose of the medication [1, 2]. Although in this case, the autocontrol result is nonreactive, positive autocontrol and IgG direct antiglobulin (DAT) results may also occur [1]. Note that ABO and Rh typing are not affected by daratumumab. Interestingly, and perhaps of concern for immunohematologists, other agents that may interfere with routine blood bank testing are already in development, such as anti-CD47, a humanized monoclonal antibody that may be effective against hematological and solid tumors [3]. Meanwhile, the efficacy of daratumumab is being investigated for use in other conditions such as advanced amyloidosis and pediatric T-cell acute lymphoblastic leukemia [4, 5].

     
  2. 2.

    How does the DTT panel help to resolve the nature of the antibody results? What is the significance of the K-antigen-negative phenotype of the crossmatched RBC units in this case? What alternative testing could be done to resolve these antibody findings? DTT is a reducing agent that breaks disulfide bonds and denatures CD38 on RBCs, preventing daratumumab from binding and interfering with antibody testing. Thus, the DTT panel in this case is nonreactive in all cells, revealing that there are no unexpected alloantibodies identified. One must be cautious, however, when working with DTT since some RBC blood group antigens such as Cartwright (YT), Dombrock (DO), Kell, Landsteiner-Weiner (LW), Lutheran (Lu), and Knops are notably destroyed so that antibodies to these blood group antigens cannot be reliably detected [1]. Therefore, it is prudent to crossmatch K-antigen-negative RBCs if the patient is known to lack K antigen or if the K-antigen phenotype is unknown (recall that the frequency of K antigen is less than 10% so that the majority of people will lack K antigen [refer to Table of RBC Antigen Frequencies in the front section of this workbook]) to prevent potential hemolytic transfusion reactions from occurring in the case that anti-K antibodies are present but not detected because of DTT treatment of the reagent panel cells. Testing with trypsin is an alternative method that disrupts the extracellular domain of CD38, allowing for detection of unexpected RBC alloantibodies [1]. Like DTT, though, trypsin also removes K antigen [6]. However, it should be noted that most hospital blood banks do not use trypsin or DTT for their routine testing, and so, they are unable to perform the workup of patients receiving daratumumab on-site.

     
  3. 3.

    Why are the two donor RBC units incompatible? The two crossmatched O-positive, K-negative RBC units are incompatible because of interference with daratumumab (note that they are only incompatible at the antihuman globulin [AHG] phase of crossmatching but would be compatible by immediate-spin [IS] crossmatch).

     
  4. 4.

    What additional testing would you advise at this time to make future transfusions of this patient safer against the risk of hemolytic transfusion reactions due to presence of undetected alloantibodies resulting from daratumumab interference? Genotyping can be used to obtain a predicted phenotype of RBC antigens so that phenotype-matched blood (i.e., matched for clinically significant antigens, typically C, c, E, e, K, Jka, Jkb, Fya, Fyb, S, and s) can be crossmatched to avoid hemolytic transfusion reactions. Refer to Chap. 30 for more information about RBC antigen genotyping.

     

References

  1. 1.
    Chapuy CI, Nicholson RT, Aquad 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.CrossRefPubMedGoogle Scholar
  2. 2.
    DARZALEX® Prescribing Information. Janssen Biotech, Inc., Horsesham, PA; 2017.Google Scholar
  3. 3.
    Nedelcu E, Hall C, Stoner A, Eichbaum Q, Meena-Leist C. Interference of anti-CD47 therapy with blood bank testing. Transfusion. 2017;57(Suppl S3):148A.Google Scholar
  4. 4.
    Sher T, Fenton B, Akhtar A, Gertz MA. First report of safety and efficacy of daratumumab in two cases of advanced immunoglobulin light chain amyloidosis. Blood. 2016;128:1987–9.CrossRefPubMedGoogle Scholar
  5. 5.
    Bride KL, Vincent TL, Im S-Y, Aplenc R, Barrett DM, Carroll WL, et al. Preclinical efficacy of daratumumab in T-cell acute lymphoblastic leukemia (T-ALL). Blood. 2018;131:995–9.CrossRefPubMedGoogle Scholar
  6. 6.
    Chari A, Arinsburg SA, Jagannath S, Satta T, Treadwell I, Catemero D, et al. Blood transfusion management and transfusion-related outcomes in daratumumab-treated patients with relapsed or refractory multiple myeloma. Clin Lymphoma Myeloma Leuk. 2018;18(1):44–51. http://www.clinical-lymphoma-myeloma-leukemia.com/article/S2152-2650(17)30111-8/fulltext. Accessed 6 Jan 2018CrossRefPubMedGoogle Scholar

Recommended Reading

  1. Chari A, Arinsburg SA, Jagannath S, Satta T, Treadwell I, Catemero D, et al. Blood transfusion management and transfusion-related outcomes in daratumumab-treated patients with relapsed or refractory multiple myeloma. Clin Lymphoma Myeloma Leuk. 2018;18(1):44–51. http://www.clinical-lymphoma-myeloma-leukemia.com/article/S2152-2650(17)30111-8/fulltextCrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Mark T. Friedman
    • 1
  • Kamille A. West
    • 2
  • Peyman Bizargity
    • 3
  • Kyle Annen
    • 4
  • Jeffrey S. Jhang
    • 1
  1. 1.Icahn School of MedicineMount Sinai Health SystemNew YorkUSA
  2. 2.Department of Transfusion MedicineNational Institutes of Health Clinical CenterBethesdaUSA
  3. 3.Department of Molecular & Human GeneticsBaylor College of MedicineHoustonUSA
  4. 4.Department of PathologyChildren’s Hospital ColoradoAuroraUSA

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