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CD19 CAR T-cell immunotherapy plus ibrutinib results in durable responses in R/R CLL

Jul 26, 2019

For patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL), who have already failed ibrutinib therapy, CD19-targeted chimeric antigen receptor-engineered T-cells (CAR T) could enable durable response to therapy.

In a pilot phase I/II study ( NCT01865617) conducted by Jordan Gauthier, Fred Hutchinson Cancer Research Center, Seattle, US, and colleagues, the safety and efficacy of ibrutinib plus CD19 CAR T infusion was evaluated in patients with R/R CLL, who had previously failed ibrutinib therapy. The primary goal of this trial was to investigate a potential synergistic association between ibrutinib and CAR T therapy, with the hope of improving outcomes for patients with R/R CLL. Results showed that ibrutinib may improve CAR T cell anti-tumor efficacy and could also reduce the risk of cytokine release syndrome (CRS).

Study design

During the study, 19 patients with R/R CLL were enrolled. The median number of prior therapies was 5 (range, 1–10), with 17 patients (89%) having high-risk cytogenetics (17p deletion and/or complex karyotype and/or 11q abnormalities). All enrolled patients had previously failed ibrutinib treatment.

Ibrutinib (420mg, daily) was administered to patients, along with a defined composition of 2x10 5or 2x10 6/kg CD4 +and CD8 +CD19 CAR T cells after lymphodepletion chemotherapy. Ibrutinib was scheduled from <2 weeks before leukapheresis, and up to >3 months after CAR T infusion.

Key findings

  • Fourteen (74%) patients developed CRS (CRS; Grade 1, n=6, 32%; Grade 2, n=8, 42%)
  • Grade >3 CRS was not observed
  • Five patients developed neurotoxicity (Grade 3, n=5, 26%)
  • One patient died due to presumed ibrutinib-mediated cardiac arrhythmia during Grade 2 CRS
  • Eighteen patients were evaluable for response at restaging 4 weeks after CAR T infusion
  • Patients responding to treatment (International workshop on CLL [iwCLL] criteria): 15 (83%):
    • Complete response with incomplete blood count (CRi): n=4, 22%
    • Partial response (PR): n=11, 61%
  • Ten out of 14 patients (71%) with nodal disease by computed tomography (CT), achieved CR or PR by iwCLL CT criteria
  • Bone marrow disease was eliminated in 13 (72%) patients
  • Eleven (61%) patients were minimal residual disease (MRD) negative by immunoglobin heavy chain (IGH) sequencing
  • One-year overall survival (OS) and progression-free survival (PFS) rates in responders (n=15) were 80% (95% CI, 57–100) and 49% (95% CI, 23–100), respectively
  • Patients who achieved MRD negative bone marrow response by IGH sequencing (n=11) achieved 100% (95% CI, 12–100) and 62% (95% CI, 32–100), one-year OS and PFS rates respectively
    • Nine out of 11 (82%) MRD negative patients were free of disease at last follow-up (median follow-up, 9.5 months)

Conclusion

As results of the study showed that CD19 CAR T-cell therapy combined with ibrutinib led to high rates of durable responses without >grade 3 CRS, the research team concluded that that this combination would be a reasonable choice in patients with R/R CLL. In a previous study, Marie Kersten, from the Academic Medical Center, Amsterdam, NL, found that CAR T therapy lead to durable remissions in patients with DLBCL, and was a feasible treatment option. Below, Renier Brentjens speaks about the latest advances in CAR T-cell therapy.

Expert Opinion

  1. GauthierJ. et al., Durable responses after CD19‐targeted CAR‐T cell immunotherapy with concurrent ibrutinib for CLL after prior ibrutinib failure. Hematol Oncol . 2019 Jun. 37(S2):168-70. DOI: 10.1002/hon.126_2629