Anti-CD19 CAR T-Cell Therapy Results in Sustained Molecular Remissions in Patients With Ibrutinib-Refractory CLL

Patients with chronic lymphocytic leukemia (CLL) with complex cytogenetics who relapse after treatment with ibrutinib have few treatment options and a short expected survival. According to results from a phase I/II feasibility and safety study published in the Journal of Clinical Oncology, treatment with anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, combined with lymphodepletion chemotherapy, could be effective in these patients.

The 24 patients included in the study (median age = 61 years; range = 40-73 years) achieved an overall response rate (ORR) of 71 percent (n=17) four weeks after CAR T-cell infusion, and “a high rate of elimination of CLL from marrow and lymph node response after CAR T-cell therapy,” lead author Cameron J. Turtle, PhD, of the Clinical Research Division at the Fred Hutchinson Cancer Research Center in Seattle, Washington, and co-authors reported.

The study included patients with CLL who had relapsed disease following treatment with an anti-CD20 antibody and fludarabine or bendamustine. They also received prior ibrutinib for a median duration of 13 months (range = 0.75-39 months). Nineteen patients experienced disease progression while receiving ibrutinib, and three were considered ibrutinib intolerant. The median number of previous therapies was five (range = 3-9 therapies).

All patients had high-risk disease, and 96 percent had high-risk cytogenetics. Nine of the 19 patients whose disease progressed after ibrutinib were found to have mutations associated with ibrutinib resistance, including BTK (n=7) and PLCG2 (n=2). Ibrutinib was discontinued prior to lymphodepletion with cyclophosphamide and fludarabine.

The study used a 3+3 design to determine the maximum tolerated dose (MTD) of CAR T cells: 2×105 cells/kg (n=4), 2×106 cells/kg (n=19), or 2×107 cells/kg (n=1).

The most common safety events in this patient population were cytokine release syndrome (CRS) and neurotoxicity – side effects commonly associated with CAR T-cell therapies. Twenty patients (83%) experienced CRS, mostly grade 1/2 (n=18), and eight patients (33%) reported neurotoxicity, mostly grade 3 (n=5). All patients who had neurotoxicity also experienced CRS. Two patients were admitted to the intensive care unit, and one patient died from neurotoxicity after receiving the 2×106 cells/kg dose. Neurotoxicity was reversible in all other patients.

The median duration of all-cause hospitalization was nine days (range = 0-49 days). The investigators selected 2×106 cells/kg as the maximum dose for subsequent patients with CLL, given the grade 4 CRS and grade 3 neurotoxicity at higher dose levels in this study and previous reports of excessive toxicity with the 2×107 cells/kg dose in patients with acute lymphocytic leukemia and non-Hodgkin lymphoma.

The percentage of leukemic B cells in the bone marrow prior to therapy was higher in patients who developed CRS and neurotoxicity, compared with those who did not (CRS grade 0 vs. grade 1-5; median = 1.8% vs. 65.5%; p=0.35; neurotoxicity grade 0 vs. grade 1-5; median = 36.7% vs. 77.5%; p=0.13). Peak CD4+ and CD8+ CAR T-cell counts after infusion were higher in patients with grade 1 to 3 CRS or grade 1 to 3 neurotoxicity, compared with those who did not experience those adverse events, but they were not higher in those with grade 4 to 5 toxicity, “potentially a result of high-dose corticosteroids administered to treat serious toxicity,” the authors noted.

For the 23 surviving patients who were restaged by tumor size, the ORR (defined by the International Workshop on Chronic Lymphocytic Leukemia [IWCLL] criteria and including partial remissions [PRs] and complete remissions [CRs]) at four weeks was 70 percent (n=16), with one additional patient achieving a late response.

Twenty patients received cyclophosphamide plus fludarabine lymphodepletion and a single CAR T-cell infusion at or below the MTD (2×106 cells/kg). In 19 restaged patients, the ORR was 74 percent (95% CI 49-91), including four CRs (21%) and 10 PRs (53%). Responses were similar among the 16 ibrutinib-refractory patients included in this subgroup, with an ORR of 69 percent (n=11; 95% CI 41-89), including four CRs (25%).

“A lymph node response (defined as CR or PR) was associated with longer progression-free survival (PFS) and overall survival (OS), compared with those who experienced treatment failure (defined as stable or progressive disease),” the authors reported, adding that “patients who achieved PR did not have inferior PFS or OS, compared with those who achieved CR.”

Twenty-one patients underwent bone marrow evaluation four weeks after infusion, and 17 patients (81%) had no marrow disease detected by high-resolution flow cytometry. “Approximately half of the patients (58%) who were evaluated by immunoglobulin heavy chain (IGH) sequencing to detect residual tumor in [the] marrow lacked detectable malignant IGH copies,” the authors found.

Marrow clearance was associated with a non-significant improved PFS: Median PFS for detectable versus not detectable malignant IGH copies was 8.5 months and not reached, respectively (p=0.063). Median OS was not reached in either group.

In addition to demonstrating the feasibility of anti-CD19 CAR T-cell therapy for this high-risk population, “these data indicate that early restaging by tumor size criteria alone, four weeks after CAR T-cell administration, may not be the optimal determinant of prognosis, as suggested after immune checkpoint blockade in other malignancies,” the authors noted. “Additional studies will be required to determine whether strategies such as IGH sequencing, [positron emission tomography] imaging, or delayed restaging after CAR T-cell immunotherapy of CLL can identify patients who might benefit from additional CAR T-cell infusions to improve outcomes.”

The study is limited by its single-center design and small patient population. Two patients received less than the target CAR T-cell dose, which may have limited the findings. In addition, the low incidence of complete elimination of bulky nodal disease suggests that the malignant lymph node environment may impair CAR T-cell infiltration or function.

The authors report no financial conflicts.


Reference

Turtle CJ, Hay KA, Hanafi LA, 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. 2017;35:3010-20.

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