The therapeutic landscape for chronic lymphocytic leukaemia (CLL) changed with the approval of the targeted agents ibrutinib and venetoclax; however, patients with progressive CLL after treatment with these agents have poor outcomes. Now, Cameron Turtle and collaborators have demonstrated promising antitumour activity of CD19-specific chimeric antigen receptor (CAR) T cells in patients with progressive CLL after ibrutinib.
The 24 patients involved in this phase I/II study had high-risk disease that was refractory, or had relapsed after treatment with a regimen containing fludarabine and rituximab and, subsequently, ibrutinib. All patients received CD4+ and CD8+ CD19-specific CAR T cells following lymphodepletion using fludarabine and/or cyclophosphamide. Of 19 patients who underwent disease restaging after receiving fludarabine and cyclophosphamide (the preferred lymphodepletion regimen) and CAR T cells, 14 had a lymph-node response, four had a complete response and ten had a partial response, according to IWCLL criteria.
Bone-marrow disease was detected before treatment in 20 of the 24 patients; 4 weeks after CAR-T-cell infusion, flow cytometry revealed an absence of bone-marrow disease in 17 of 21 patients evaluated. Bone-marrow clearance was confirmed by the absence of malignant IGH sequences in seven patients, for whom the median progression-free survival duration was not reached, whereas for seven patients with IGH-positive disease it was 8.5 months.
A total of 20 of 24 patients developed cytokine-release syndrome, which was of grade 1–2 in 18 patients, grade 4 in one patient, and grade 5 in another. Eight patients had neurotoxicity, two of grade 1–2, five of grade 3, and one of grade 5.
The antitumour activity of CD19-specific CAR T cells in patients with ibrutinib-resistant CLL need to be confirmed in studies with large cohorts because the toxicities associated with this treatment required careful management.
References
Turtle, C. J. et al. Durable molecular remissions in chronic lymphocytic leukemia treated with CD19-specific chimeric antigen receptor-modified T cells after failure of ibrutinib. J. Clin. Oncol. http://dx.doi.org/10.1200/JCO.2017.72.8519 (2017)
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Younes, A. et al. The landscape of new drugs in lymphoma. Nat. Rev. Clin. Oncol. 14, 335–346 (2017)
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Romero, D. After ibrutinib, CAR T cells induce responses. Nat Rev Clin Oncol 14, 588 (2017). https://doi.org/10.1038/nrclinonc.2017.124
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DOI: https://doi.org/10.1038/nrclinonc.2017.124
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