CD19-Specific CAR T-Cell Therapy Effective in Ibrutinib-Refractory CLL

Anti-CD19 chimeric antigen receptor (CAR)-modified T-cell therapy was highly effective in patients with high-risk chronic lymphocytic leukemia (CLL) who had previously failed treatment with ibrutinib, according to the results of a study published in the Journal of Clinical Oncology.

“We observed a high rate of elimination of CLL from marrow and lymph node response after CAR T-cell therapy,” wrote Cameron J. Turtle, PhD, of Fred Hutchinson Cancer Research Center in Seattle, and colleagues. “Approximately half of the patients who were evaluated by IGH sequencing to detect residual tumor in marrow lacked detectable malignant IGH copies.”

The Bruton tyrosine kinase inhibitor ibrutinib was an important advance in the treatment of CLL; however, although the overall response rate with ibrutinib is high, complete response rate is low and overall survival is short for patients who progress while on the therapy. CD19-specific CAR T-cell therapy has shown impressive responses in patients with refractory B-cell acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma. Therefore, in this small study, Turtle and colleagues tested the therapy in patients with high-risk ibrutinib-refractory CLL.

The study included 24 patients who underwent lymphodepleting chemotherapy and CAR T-cell therapy at one of three dose levels (2 × 10⁵, 2 × 10⁶, or 2 × 10⁷ CAR T cells/kg).

At 4 weeks after CAR T-cell infusion, the overall response rate was 71%, with 17 of the 24 patients responding. Twenty patients received cyclophosphamide and fludarabine lymphodepletion and CD19 CAR T cells at or below the maximum tolerated dose of 2 × 10⁶ CAR T cells/kg. In the 19 patients whose disease was restaged, the overall response rate at 4 weeks was 74%, with 4 of the 19 patients achieving a complete response (21%).

The researchers performed deep IGH sequencing in 12 of these patients, and more than one-half (58%) had no malignant IGH sequences detected in marrow. The absence of malignant IGH clone in the marrow was associated with 100% progression-free survival (PFS) and overall survival rates after CAR T-cell therapy.

“Achieving a malignant IGH-negative status after CAR T cells in our study correlated better with superior PFS than complete response by International Workshop on Chronic Lymphocytic Leukemia CT criteria, which requires that all lymph nodes be < 15 mm,” the researchers wrote. “These data indicate that early restaging by tumor size criteria alone, 4 weeks after CAR T-cell administration, may not be the optimal determinant of prognosis, as suggested after immune checkpoint blockade in other malignancies.”

Eighty-three percent of patients experienced cytokine release syndrome (CRS); 33% developed neurotoxicity, which was reversible in all but one patient with a fatal outcome.

“Our previous report in which CD19 CAR T cells were administered to patients with ALL found that tumor burden is associated with robust CAR T-cell expansion, CRS, and neurotoxicity, and similar associations were observed in this study in patients with CLL,” the researchers wrote. “Thus, modifying CAR T-cell dose in relation to tumor burden may further improve outcomes in CLL.”