*Purpose: We report the first case of Dara interference of routine pre-transplant (Tx) crossmatch (XM) repeatedly causing aberrant false positives which inadvertently delayed Tx for a renal waitlist patient. Daratumumab (Dara) is an IgG1κ human monoclonal antibody (mAb) used to treat MM by depleting CD38+ cells, in which, plasma B cells express high levels. We show that a simple cell treatment can effectively mitigate Dara interference preserving the utility of pre-Tx XM in Dara-treated patients. Lastly, we provide preliminary immunophenotyping evidence that CD38 expression is dependent on tissue source, suggesting Dara is a potential treatment strategy to target long-lived plasma cells.

*Methods: XM were performed on pronased donor lymphocytes using a BD FACSLyric flow cytometer with staining of CD45 for leukocytes, CD3 for T cells, CD19 for B cells, G46-2.6 for HLA class I and Tu39 for HLA class II expression. Cell surface CD38 expression was characterized using HB7 anti-human CD38 mAb and analyzed in median channel (MC) values.

*Results: Patient is a 67-yo white female with ESRD secondary to MM who continuously receives Dara infusions. Her sensitization included an autologous hematopoietic cell Tx, transfusions and pregnancies. While solid phase testing confirmed the absence of HLA antibody upon listing, 26/27 deceased donor XM were unexpectedly positive (T+B+, n=21; T-B+, n=5). The strengths of the false positive XM were wide-ranging (up to 250% different), which could be attributed to the highly variable CD38 expression level on donor lymphocytes that differed by as much as 80% on T cells and 83% on B cells. Overall, T cells were found to have 7% lower CD38 expression than B cells, and T cells derived from spleen or PBL tended to have, respectively, 18% and 16% lower CD38 expression than those of lymph nodes (p<0.001). Finally, we found that lymphocyte treatment with mild 0.05M DTT (10 mins at 37°C) was able to cleave off most of the cell surface CD38 and effectively abrogated the Dara-induced false positive XM without affecting XM sensitivity, specificity, or HLA expression.

*Conclusions: The patient was eventually transplanted across a strong positive T and B cell XM and doing well >6 mo post-Tx with no HLA antibodies detected to date. To our knowledge, this is the first case documenting Dara interference in routine XM. We also demonstrated that CD38 expression is tissue dependent, varies on the type of lymphocyte, and stage of differentiation of the lymphocyte. Importantly, cell treatment with DTT can effectively mitigate the interference from Dara and preserve the utility of XM.

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