Report Prolonged cytopenia following CD19 CAR T cell therapy is linked with bone marrow infiltration of clonally expanded IFNg-expressing CD8 T cells

Autologous anti-CD19 chimeric antigen receptor T cell (CAR T) therapy is highly effective in relapsed/refractory large B cell lymphoma (rrLBCL) but is associated with toxicities that delay recovery. While the biological mechanisms of cytokine release syndrome and neurotoxicity have been investigated, the pathophysiology is poorly understood for prolonged cytopenia, defined as grade = 3 cytopenia lasting beyond 30 days after CAR T infusion. We performed single-cell RNA sequencing of bone marrow samples from healthy donors and rrLBCL patients with or without prolonged cytopenia and identified significantly increased frequencies of clonally expanded CX3CR1(hi )cytotoxic T cells, expressing high interferon (IFN)-g and cytokine signaling gene sets, associated with prolonged cytopenia. In line with this, we found that hematopoietic stem cells from these patients expressed IFN-g response signatures. IFN-g deregulates hematopoietic stem cell self renewal and differentiation and can be targeted with thrombopoietin agonists or IFN-g-neutralizing antibodies, highlighting a potential mechanism-based approach for the treatment of CAR T-associated prolonged cytopenia.

Automated summary

Autologous anti-CD19 CAR T therapy shows high effectiveness in rrLBCL, but its toxicities result in delayed recovery. The pathophysiology of prolonged cytopenia after CAR T infusion is poorly understood. Single-cell RNA sequencing reveals that clonally expanded CX3CR1(hi) cytotoxic T cells with high IFN-g and cytokine signaling are associated with prolonged cytopenia, suggesting a potential mechanism-based approach for its treatment.