Sequential Infusion of Anti-CD19 and Anti-BCMA Chimeric Antigen Receptor T-Cells: A Promising Treatment Strategy for Refractory Immune-Mediated Platelet Transfusion Refractoriness

Background: Immune-mediated platelet transfusion refractoriness (iPTR) represents a challenging, high-cost, and life-threatening problem among patients with hematological malignancies. Refractory iPTR (riPTR), which exhibits resistance to multiple therapeutic plasma exchange, high dose of IgG and rituximab, may result from incomplete elimination of allo-specific B cells and long-lived plasma cells. Therefore, sequential anti-CD19 and anti-B cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cells were used to treat riPTR.

Methods: In this prospective single-arm clinical trial, patients with riPTR received a combination of murine anti-BCMA CAR T-cells and murine anti-CD19 CAR T-cells at a dose of 2×10⁷ cells/kg. The efficacy and safety of this treatment were assessed. This study was registered at clinicaltrials.gov (identifier: NCT04846439).

Results: Twelve patients with riPTR received CAR T-cell treatment with a median follow-up of 33.5 (range, 13.5-34.5) months. Among these 12 patients, the median of the maximum mean fluorescence intensity (MFI) values of anti-human leukocyte antigen (HLA) antibodies decreased by 91.1%, from 15319 (range, 10807-20374) before CAR T-cell infusion to 1369 (range, 997-2923) at 4 months post-infusion (P=0.0001). And four months after CAR T-cell infusion, the median number of anti-HLA class I antibodies with an MFI > 5000 decreased significantly from 18 (range, 3-41) before infusion to 0 (range, 0-0) post-infusion (P=0.0005). Anti-HLA antibodies in all patients turned negative within 5 months after CAR T-cell therapy and have maintained negative for up to 30.5 months to date. After CAR T-cell treatment, the medians of the amount of platelet transfusions within 7 days and the duration of platelet count below 10×10⁹/L were significantly lower (P = 0.0002, P = 0.001). Meanwhile, there was a significant increase in 14-hour corrected count increment (CCI) and no occurrence of 14-hour CCI below 5×10⁹/L in all patients after the administration of CAR T-cells. RiPTR was completely corrected in all patients and never occurred during subsequent chemotherapy or transplantation. All patients who underwent transplantation achieved successful neutrophil and platelet engraftment. No patient developed grade ≥ 3 cytokine release syndrome. All patients experienced transient grade ≥ 3 cytopenia. Only 2 patients (16.7%) experienced infection. All adverse events were reversible and manageable.

Conclusions: CAR T-cell therapy could be well-tolerated and highly effective in overcoming riPTR and eradicating allo-antibodies, making it applicable to antibody-mediated diseases.