Cameron Turtle, MBBS, PhD Photo by Robert Hood, Fred Hutchinson Cancer

A chimeric antigen receptor (CAR) T-cell therapy is “highly effective” in high-risk patients with chronic lymphocytic leukemia (CLL), according to researchers.

The CD19 CAR T-cell therapy, JCAR014, produced an overall response rate of 71% and a complete response (CR) rate of 17% in a phase 1/2 trial of patients with relapsed/refractory CLL.

Eighty-three percent of patients experienced cytokine release syndrome (CRS), and 33% developed neurotoxicity. One patient died of CRS/neurotoxicity.

Researchers reported these results in The Journal of Clinical Oncology.

The study was supported by Juno Therapeutics, Life Science Discovery Fund, the Bezos Family, the University of British Columbia Clinical Investigator Program, and grants from the National Cancer Institute and National Institute of Diabetes and Digestive and Kidney Diseases.

The trial included 24 patients with relapsed or refractory CLL. The patients’ median age was 61 (range, 40-73), and they had received a median of 5 prior therapies (range, 3-9). Nineteen patients had progressed while on ibrutinib, and 3 could not tolerate the drug.

“It was not known whether CAR T cells could be used to treat these high-risk CLL patients,” said study author Cameron Turtle, MBBS, PhD, of Fred Hutchinson Cancer Research Center in Seattle, Washington.

“Our study shows that CD19 CAR T cells are a highly promising treatment for CLL patients who have failed ibrutinib.”

Treatment and safety

All 24 patients received lymphodepletion prior to JCAR014. Lymphodepleting regimens consisted of cyclophosphamide, fludarabine, or both.

Patients received JCAR014 at 1 of 3 dose levels—2 x 10⁵, 2 x 10⁶, or 2 x 10⁷ CAR T cells/kg.

Twenty patients (83%) developed CRS—18 with grade 1/2, 1 with grade 4, and 1 with grade 5 CRS.

Eight patients (33%) developed neurotoxicity, all of whom also had CRS. Five patients had grade 3 neurotoxicity, and 1 had grade 5 (same patient with grade 5 CRS).

Initial response

The overall response rate, according to IWCLL criteria, was 71%. Seventeen patients responded, 4 with CRs and 13 with partial responses (PRs).

One of the patients who achieved a CR had received a second dose of JCAR014, without lymphodepletion, 14 days after the first dose.

One of the patients with a PR initially had stable disease (SD) at the 4-week assessment but was in PR 8 weeks later.

Twenty-one patients had a bone marrow evaluation 4 weeks after treatment with JCAR014. Seventeen of these patients (81%) had no residual disease according to high-resolution flow cytometry.

The researchers also performed IGH sequencing of bone marrow in 12 patients with no residual disease by flow cytometry. Seven of these patients (58%) had no detectable malignant IGH sequences 4 weeks after receiving JCAR014.

Second dose

Six patients who had persistent disease or who relapsed after receiving JCAR014 received a second cycle of lymphodepletion and JCAR014 at the same dose (n=1) or a 10-fold higher dose (n=5).

Four of these patients developed CRS (2 grade 3 or higher), and 1 developed reversible neurotoxicity (grade 3).

Two patients achieved a CR and had no residual disease by flow cytometry or IGH sequencing.

Survival

Responders had significantly superior progression-free survival (PFS) and overall survival (OS) compared to non-responders.

The median PFS was 9.8 months in patients who achieved a CR, was not reached in those with a PR, and was 1.1 months in patients with progressive disease (PD) or SD (P=0.0068 for CR/PR vs SD/PD).

The median OS was not reached in patients who achieved a CR or a PR, but it was 11.2 months in patients with SD or PD (P=0.0011 for CR/PR vs SD/PD).

The researchers also found that IGH sequencing revealed patients with durable PFS.

The median PFS was not reached in patients with no malignant IGH sequences, but it was 8.5 months in IGH-positive patients (P=0.253). The median OS was not reached in either group (P=0.25).

CAR T-cell therapy ‘highly effective’ in high-risk CLL