Durable Molecular Remissions in Chronic Lymphocytic Leukemia Treated With CD19-Specific Chimeric Antigen Receptor–Modified T Cells After Failure of Ibrutinib

Authors

Cameron J. Turtle

Cameron J. Turtle, Kevin A. Hay, Laïla-Aïcha Hanafi, Shelly Heimfeld, Stanley R. Riddell, and David G. Maloney, Fred Hutchinson Cancer Research Center; Cameron J. Turtle, Sindhu Cherian, Xueyan Chen, Brent Wood, Stanley R. Riddell, and David G. Maloney, University of Washington; Daniel Li, Juno Therapeutics, Seattle, WA; and Arletta Lozanski and John C. Byrd, The Ohio State University, Columbus, OH.

Cameron J. Turtle, Kevin A. Hay, Laïla-Aïcha Hanafi, Daniel Li, Sindhu Cherian, Xueyan Chen, Brent Wood, Arletta Lozanski, John C. Byrd, Shelly Heimfeld, Stanley R. Riddell, David G. Maloney

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Purpose

We evaluated the safety and feasibility of anti-CD19 chimeric antigen receptor–modified T (CAR-T) cell therapy in patients with chronic lymphocytic leukemia (CLL) who had previously received ibrutinib.

Twenty-four patients with CLL received lymphodepleting chemotherapy and anti-CD19 CAR-T cells at one of three dose levels (2 × 10⁵, 2 × 10⁶, or 2 × 10⁷ CAR-T cells/kg). Nineteen patients experienced disease progression while receiving ibrutinib, three were ibrutinib intolerant, and two did not experience progression while receiving ibrutinib. Six patients were venetoclax refractory, and 23 had a complex karyotype and/or 17p deletion.

Four weeks after CAR-T cell infusion, the overall response rate (complete response [CR] and/or partial response [PR]) by International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria was 71% (17 of 24). Twenty patients (83%) developed cytokine release syndrome, and eight (33%) developed neurotoxicity, which was reversible in all but one patient with a fatal outcome. Twenty of 24 patients received cyclophosphamide and fludarabine lymphodepletion and CD19 CAR-T cells at or below the maximum tolerated dose (≤ 2 × 10⁶ CAR-T cells/kg). In 19 of these patients who were restaged, the overall response rate by IWCLL imaging criteria 4 weeks after infusion was 74% (CR, 4/19, 21%; PR, 10/19, 53%), and 15/17 patients (88%) with marrow disease before CAR-T cells had no disease by flow cytometry after CAR-T cells. Twelve of these patients underwent deep IGH sequencing, and seven (58%) had no malignant IGH sequences detected in marrow. Absence of the malignant IGH clone in marrow of patients with CLL who responded by IWCLL criteria was associated with 100% progression-free survival and overall survival (median 6.6 months follow-up) after CAR-T cell immunotherapy. The progression-free survival was similar in patients with lymph node PR or CR by IWCLL criteria.

CD19 CAR-T cells are highly effective in high-risk patients with CLL after they experience treatment failure with ibrutinib therapy.