Safety and Efficacy of CD19-CAR T-Cells in Richter’s Transformation Following Targeted Therapy for CLL

Richter’s transformation (RT) is a rare complication of chronic lymphocytic leukemia (CLL) in which an aggressive large-cell lymphoma develops in the setting of CLL/small lymphocytic lymphoma, usually into clonally related diffuse large B-cell lymphoma (DLBCL). Chimeric antigen receptor (CAR)-modified T-cells directed to CD19+ B-cell malignancies have demonstrated promising results in the treatment of relapsed DLBCL,¹ but less is known about its effectiveness in CLL relapse after targeted therapy and RT. Researchers evaluated treatment with CD19-CAR T-cells in patients with RT.

Between July 2019 and May 2020, 9 patients were enrolled as part of a single-center phase 2 study of CAR T-cell therapy in B-cell malignancies. Enrolled patients had CLL and disease transformation after chemoimmunotherapy. Following lymphodepletion with Cytoxan (cyclophosphamide) and Fludara (fludarabine), patients received an infusion of locally produced CD19-CAR T-cells.²

Enrolled patients had a median age of 57 years at the time of CLL diagnosis. Disease transformation developed after a median of 8 years from CLL diagnosis. A majority (88%) of patients had 17p deletion or TP53 mutation. Patients were treated with CD19-CAR T-cells at a median age of 64 years. Among enrolled patients, 75% had advanced-stage DLBCL, 44% had extranodal disease, and 44% had bulky disease.

Patients had received a median of 4 CLL therapies before receiving CAR T-cells. All patients had been treated with targeted therapies, 67% received dual targeted therapies, and 78% received chemoimmunotherapy. Patients had spent a median of 8 months on Venclexta (venetoclax) and 28 months on Imbruvica (ibrutinib). Four patients proceeded directly to CAR T-cell treatment after RT diagnosis while 5 patients received further salvage therapies before proceeding.

All patients had progressive disease before treatment with CAR T-cells. After infusion of CAR T-cells, 7 patients had cytokine release syndrome, of which 3 were grade 3/4, requiring tocilizumab. Central nervous system toxicity occurred in 4 patients, of which 3 were grade 3/4. Neutropenia developed in 75% of patients and resolved in all but 1 patient who succumbed to disease progression. Infections occurred in 2 patients, specifically, Campylobacter and H1N1 influenza. No fatalities occurred due to CAR T-cell toxicity. Two fatalities occurred due to disease progression.

Complete remission was achieved in 6 patients (67%). The remaining 3 patients were refractory to CAR T-cell therapy. Two fatalities occurred within 8 weeks of treatment due to disease progression. One patient who was refractory to CAR T-cell therapy responded to chemotherapy. Of patients initially responding to CAR T-cell therapy, 2 patients had disease progression at 6-month follow-up. Of these, one responded to chemotherapy and another proceeded to B-cell prolymphocytic leukemia and underwent a second allogeneic stem-cell transplantation. One patient who had achieved complete remission proceeded to allogeneic stem-cell transplantation and died due to severe graft-versus-host disease.

Therapy with CD19-CAR T-cells in patients with CLL and disease transformation demonstrates a high complete remission rate with promising clinical response. In these patients, CD19-CAR T-cell therapy was found to be safe. The investigators conclude that the rate of long-term remission after CD19-CAR T-cell therapy for RT should be further evaluated in a larger patient population.

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References

1. Al-Mansour M, Al-Foheidi M, Ibrahim E. Efficacy and safety of second-generation CAR T-cell therapy in diffuse large B-cell lymphoma: A meta-analysis. Mol Clin Oncol. 2020;13(4):33.
2. Benjamini O, Shimoni A, Besser M, et al. Safety and Efficacy of CD19-CAR T Cells in Richter’s Transformation after Targeted Therapy for Chronic Lymphocytic Leukemia. American Society of Hematology 62nd Annual Meeting and Exposition. Abstract 545.