T-Cell Large Granular Lymphocyte Population Involving Chimeric Antigen Receptor-Modified T (CAR T) Cells in Patients with Cytopenia after CD19-Targeted CAR T-Cell Therapy: Case Series

Background CD19-targeted chimeric antigen receptor T-cell (CAR-T) therapy has transformed the treatment of relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Prolonged or recurrent cytopenias (PC) are a well-recognized and poorly understood complication which can occur weeks to months (M) after CAR-T cell infusion. We report 3 cases of T-cell large granular lymphocyte (T-LGL) clonal expansion involving the CAR-T population in patients (pts) with PC. Cases Day (D) 0 refers to D of CAR-T infusion. Cytokine release syndrome (CRS) and neurotoxicity (NT) were graded using ASTCT criteria. Cytopenias were graded using CTCAE v5.0.Case 1. A 52-year-old (y/o) female (F) with R/R primary mediastinal B-cell lymphoma with central nervous system (CNS) involvement was treated with out-of-specification tisagenlecleucel. Course was complicated by grade (G) 1 CRS and progressive disease. She had persistent G1-2 anemia and thrombocytopenia after D28 and developed prolonged norovirus gastritis 30.8 M after infusion, followed by recurrence of G3 neutropenia. Flow cytometry (FC) of bone marrow (BM) and peripheral blood (PB) identified an expanded T-LGL population representing 26.7 and 28.6% of white blood cells (WBCs), respectively. Evaluation of T-cell receptor (TCR) Vβ isoforms suggested oligoclonality. STAT3 mutation was not detected (ND). Repeat BM 43.6 and 52 m after CAR-T infusion showed persistent T-LGL population comprising 9.1 and 7.1% of WBCs by FC, respectively.Case 2. A 62 y/o F with R/R diffuse LBCL (DLBCL), NOS and chronic hepatitis B was treated with axicabtagene ciloleucel. Course was complicated by G1 CRS, achieving complete response (CR). She had persistent G1-3 anemia and thrombocytopenia and G2-4 neutropenia after D28. PB FC on 18.6 m after infusion showed an expanded T-LGL population representing 16% of WBCs. A BM 23.7 m after infusion confirmed a T-LGL population comprising 30% of T cells. Clonal TCR (TRG) gene rearrangement was detected by PCR. STAT3 mutation was ND. A PB FC demonstrated that 43.9% of the cells with the T-LGL phenotype expressed the CAR transgene.Case 3. A 50 y/o F, with R/R DLBCL, NOS with CNS involvement and history of cold agglutinin disease was treated with lisocabtagene maraleucel. Course was complicated by G2 CRS and G2 NT, achieving CR. She developed G4 persistent neutropenia after D28. BM FC on D27 identified a T-LGL population representing ∼42% of the WBCs. TCR Vβ isoforms suggested a dominant isoform. TRG gene rearrangement by PCR detected an oligoclonal T-cell population. STAT3 and STAT5B mutations were ND. PB FC demonstrated 65.0% of the T-LGL phenotype cells expressed the CAR transgene. Conclusions Here we report 3 cases of T-LGL clonal expansion diagnosed after CAR-T therapy in patients with PC. In two of the patients, a subset of the clonal population expressed the CAR transgene. This case series highlights T-LGL as a potential cause of PC after CAR-T therapy.