CLL post-ibrutinib: CAR T-cell therapy shown to result in durable molecular remissions

Use of anti-CD19 Chimeric Antigen Receptor (CAR) T-cell therapy in CLL previously treated with ibrutinib has recently been shown to induce ‘durable molecular remissions’ in a phase I/II open-label study. The study, published in the Journal of Clinical Oncology by Cameron J. Turtle, from the Fred Hutchinson Cancer Research Center, Seattle, Washington, and colleagues evaluated twenty-four patients who received the CAR T-cell therapy. Ibrutinib-resistant CLL is associated with poor prognosis and represents an unmet clinical need.

Twenty-four CLL patients were treated with the CAR-T at three different doses, 2 x 10⁵, 2 x 10⁶, and 2 x 10⁷ cells/kg in a 3+3 design, following a high-dose lymphodepleting regimen consisting of either cyclophosphamide, fludarabine, or both. All patients presented with high-risk disease, including 16 patients with complex karyotype and 14 patients with del17p. Of nineteen patients screened, nine had mutations in BTK or PLCG2, which are known markers of ibrutinib resistance.

Highlights:

• Anti-CD19 CAR-T construct used included the 4-1BB signaling domain, and a target 1:1 ratio of CD4⁺ and CD8⁺ CD19-specific CAR T-cells were reinfused into patients
• Maximum tolerated dose = 2 x 10⁶/kg
• 2 x 10⁷/kg was concluded to be excessively toxic following high grade AEs in one patient

Efficacy:

• ORR by iwCLL criteria 4-weeks post-CAR T-cell infusion = 71%, lymph node response = 70%
• Nineteen pts restaged at 4-weeks post-infusion: ORR = 74%, CR = 21%, PR = 53%
• Four-weeks post-CAR T-cell therapy, 15/17 evaluable patients who had marrow disease no longer had detectable marrow disease by flow cytometry
  • Twelve of these patients at baseline had detectable malignant IGH sequences, 4-weeks after CAR-T infusion 58% of these no longer had detectable malignant IGH sequences
  • With median 6.6-months follow-up, lack of detectable malignant IGH sequences was found to be associated with a 100% PFS and OS rates
• Six patients received a second dose of CAR T-cells following persistent or relapsed disease, of these two achieved a CR
• CAR T-cells were detectable in all evaluable patients over 6-months after receiving the CAR-T infusion

Safety:

• CRS = 83% pts, 20/24 pts (Grade 4 = 1 pt, Grade 5 = 1 pt)
  • Corticosteroids and tocilizumab required for use in 6 pts
• Neurotoxicity = 33% pts, 8/24 pts (Grade 3 = 5 pts, Grade 5 = 1 pt)
  • One patient died from neurotoxicity, but this was reversible in all other patients
• Median hospitalization duration was 9-days (0–49 days)
• Interferon-gamma and IL-10 levels were higher in patients 48-hours after infusion who later went on to develop Grade 2 or higher neurotoxicity (P = 0.034 and P = 0.045, respectively)
• A higher percentage of leukemic B-cells in the marrow before CAR-T infusion was associated with development of CRS and neurotoxicity after infusion (P = 0.35)
• Higher maximum CAR T-cell number after infusion was associated with CRS Grade 1–3 and neurotoxicity Grade 1–3

The authors concluded that this study showed anti-CD19 CAR T-cell therapy to be highly effective with manageable toxicity in CLL patients previously treated with ibrutinib. The authors also state that this therapy can result in sustained molecular remissions, but more studies are needed, especially in patients with high-risk CLL or a high-risk of developing ibrutinib resistance in order to improve the poor-prognosis of this patient population.

Abstract:

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