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CD38 Antibody Interference
How I Manage Laboratory Assay Interference With Anti-CD38 Antibodies in Myeloma

Released: October 17, 2016

Expiration: October 16, 2017

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Case Study
A 68-year-old male with a history of relapsed/refractory multiple myeloma is currently receiving treatment with single-agent daratumumab. He presented at the clinic with shortness of breath and increasing fatigue. A complete blood count revealed a hemoglobin level of 6.8 g/dL. He was scheduled for a transfusion later that day, but his blood screening tests were positive for minor antibodies. The blood bank has been unable to find a match, and now 3 days have gone by without the patient being transfused.

Understanding and Managing Assay Interference
Monoclonal antibodies have demonstrated promising safety and efficacy in myeloma, and both daratumumab and elotuzumab were approved for use in relapsed/refractory myeloma by the FDA in late 2015. Daratumumab, a human IgG1 monoclonal antibody, binds to CD38, which is a protein that is ubiquitously expressed on myeloma cells and to a lesser extent, on red blood cells (RBCs). In the relapsed/refractory setting, patients with myeloma frequently have anemia and often require blood transfusions. Indirect Coombs tests are performed to detect minor antibodies in recipient/donor blood matches before a RBC transfusion. Early clinical data revealed unexpected, false-positive indirect Coombs tests in 100% of daratumumab-treated patients. Daratumumab interferes with the test by binding to endogenous CD38 on RBCs, resulting in pan-agglutination.

Blood banks have a variety of protocols to mitigate daratumumab interference in blood testing, allowing for the identification and provision of safe blood products for daratumumab-treated patients. There are several strategies to resolve this interference:

  • Anti-idiotype antibodies to neutralize daratumumab
  • Soluble extracellular domain of CD38
  • Dithiothreitol treatment of reagent RBCs which denatures CD38, preventing daratumumab (and other anti-CD38 agents) from binding

Informing blood banks that they are receiving a sample from a daratumumab-treated patient is critical to prevent delayed release of blood products. Although procedures may vary among institutions, compatibility typing is often performed before daratumumab treatment begins and the results recorded on a patient’s ID card and chart and then referenced for routine transfusions. For emergency transfusions, non–cross-matched, ABO/RhD-compatible RBCs can be given.

Patients with myeloma should be encouraged to carry their ID card for at least 6 months after their last infusion and should be reassured that transfusions can still be performed safely. To date, no treatment-related transfusion reactions have occurred in daratumumab-treated patients. In the ongoing phase II SIRIUS study in patients with heavily pretreated relapsed or double-refractory myeloma, 42 (40%) patients receiving daratumumab 16 mg/kg as a monotherapy required transfusions during the study, including 40 (38%) patients receiving packed RBCs (126 transfusions) and 14 (13%) receiving platelets (67 transfusions).

It is important to note that assay interference has been observed in studies of daratumumab both as a monotherapy and in combination with proteasome inhibitors or immunomodulatory drugs and has been seen in patients with relapsed/refractory, newly diagnosed, and smoldering myeloma.

Case Study Conclusion
This patient case took place during early clinical trials with daratumumab, prior to knowledge of the potential for RBC interference with anti-CD38 monoclonal antibodies. Although transfusion was delayed for 3 days out of concern from the infusion staff about giving what appeared to be non–cross-matched blood, the patient eventually received 2 units of blood without incidence and had several additional transfusions without complications. He achieved > 90% reduction in his M-protein levels and was able to remain on treatment with daratumumab.

How have you managed the risk of false positives with CD38 antibodies in assessing your patients with myeloma? Share your thoughts in the comment box below!

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How do you manage the risk of false-positive results when testing your daratumumab-treated patients who need transfusions?
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