CD19 CAR T-Cell Therapy Active in Ibrutinib-Refractory CLL

Cameron J. Turtle, PhD, Clinical Research Division, Fred Hutchinson Cancer Research Center,

Cameron J. Turtle, PhD

Treatment with CD19 chimeric antigen receptor (CAR)-modified T-cell therapy induced a high response rate in patients with high-risk, ibrutinib-refractory chronic lymphocytic leukemia (CLL), according to results recently published in the Journal of Clinical Oncology.

Twenty-four patients with relapsed/refractory CLL were included in the analysis for the phase I/II study and received lymphodepleting chemotherapy and anti-CD19 CAR-T cell-infusion at 1 of 3 dose levels—2 X 10⁵, 2 X 10⁶, or 2 X 10⁷ CAR-T cells/kg). At 4 weeks postinfusion, the overall response rate (ORR) was 71% (17 of 24), according to International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria.

“CD19 CAR-T cells are highly effective with manageable toxicity in patients with high-risk CLL, including those who are ibrutinib refractory,” first study author Cameron J. Turtle, PhD, Clinical Research Division, Fred Hutchinson Cancer Research Center, and coinvestgators wrote. “This approach can achieve sustained molecular remissions and improve the poor prognosis of ibrutinib- refractory CLL. Future studies in patients who are likely to become refractory to ibrutinib on the basis of high-risk cytogenetics or early detection of mutations before relapse that confer ibrutinib resistance are warranted.”

One patient developed fatal neurotoxicity and did not undergo response assessment. Among the 23 restaged patients, the ORR at 4 weeks after CAR-T cell infusion was 70%. One additional patient achieved a late response.

At a median of 6.6 months’ follow-up, the absence of the malignant IGH clone in marrow of patients with CLL who achieved a response was associated with 100% progression-free survival (PFS) and overall survival (OS) after CAR-T cell immunotherapy. The PFS was similar in patients with lymph node partial repsponse or complete response by IWCLL criteria.

Patients in the study had received a median of 5 previous therapies (range, 3-9), and the median age was 61 years (range, 40-73). All patients had high-risk disease and 96% had high-risk cytogenetics. The median percentage of marrow abnormal B cells before lymphodepletion chemotherapy was 61.6% (range, 0%-96%). Twenty-three patients had nodal disease, and 2 had active CNS disease.

Nineteen patients experienced disease progression while receiving ibrutinib (Imbruvica), 3 were ibrutinib-intolerant, and two did not experience progression while receiving ibrutinib. Six patients were refractory to venetoclax (Venclexta), and 23 had a complex karyotype and/or 17p deletion.

Twenty patients (83%) developed cytokine release syndrome (CRS), and eight (33%) developed neurotoxicity, which was reversible in all but 1 patient with a fatal outcome.

Twenty of 24 patients received cyclophosphamide, fludarabine lymphodepletion, and CD19 CAR-T cells at or below the maximum-tolerated dose (≤2 X 10⁶ CAR-T cells/kg). The ORR was 74% 4 weeks after infusion in the 19 patients who were restaged.

Among the 16 ibrutinib-refractory patients included in this subgroup who were treated with cyclophosphamide, fludarabine lymphodepletion, and ≤2 X 10⁶ CAR-T cells/kg, the ORR was 69% (95% CI, 41%-89%). Four patients had complete response.

Among patients diagnosed with marrow disease, 88% had no disease by flow cytometry after CAR-T cell infusion. Twelve of these patients underwent deep IGH sequencing, and 7 (58%) had no malignant IGH sequences detected in marrow.

All patients discontinued ibrutinib before lymphodepletion, including 2 who had not experienced disease progression while receiving ibrutinib because the safety of concurrent CAR-T cells and ibrutinib had not been established.

Six patients with persistent or relapsed disease after the first cycle of lymphodepletion and CAR-T cell infusion underwent a second cycle. One patient had a second cycle at the same dose, 5 were treated with a 10-fold higher dose. Four of the 6 patients developed CRS, 2 were grade ≥3, and 1 developed reversible grade 3 neurologic toxicity after the second CAR-T cell infusion. Two patients had complete responses, and investigators noted that residual CLL was not detected by bone marrow flow cytometry and IGH sequencing.

Overall, 20 patients experienced CRS. There were 18 cases of grade 1/2 CRS, 1 incidence of grade 4, and 1 incidence of grade 5. Six patients (25%) had clinical symptoms severe enough to require tocilizumab and corticosteroid treatment.

There were 2 incidents of grade 1/2 neurotoxicity and 5 incidents of grade 3. One patient had grade 5 neurotoxicity. All patients with neurotoxicity also had CRS. Two patients required intensive care unit management, one of whom developed fatal neurotoxicity after infusion of 2 X 10⁶ CAR-T cells/kg. Neurotoxicity was reversible in all other patients.

Turtle CJ, Hay KA, Hanafi L, et al. Durable molecular remissions in chronic lymphocytic leukemia treated with CD19-specific chimeric antigen receptor—modified T cells after failure of ibrutinib [published online July 17, 2017]. J Clin Oncol. doi: 10.1200/JCO.2017. 72.8519.