Treatment with concurrent ibrutinib (Imbruvica) improves expansion of chimeric antigen receptor (CAR) T-cells and could subsequently improve response in patients with chronic lymphocytic leukemia (CLL), according to a study presented during the 2017 ASH Annual Meeting.
Lead study author Mark Blaine Geyer, MD, Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, said that ibrutinib may modulate antitumor T-cell immune responses, adding that studies have shown an enhanced ex vivo expansion of autologous T cells collected from patients treated with ibrutinib.
Geyer et al’s data were from patients with CLL who were treated with ibrutinib at the time of autologous T-cell collection and/or around the time of CAR T-cell infusion enrolled in a phase I clinical trial of CD19-targeted CAR-T cells for adults with relapsed/ refractory CLL or B-cell non-Hodgkin lymphoma.
Eleven patients with CLL underwent leukapheresis followed by T-cell expansion and transduction. Patients were then evaluated for disease status and their peripheral blood and marrow samples were collected, followed by conditioning chemotherapy (2 to 7 days prior to the CAR T-cell infusion). Following the CAR T-cell infusion, peripheral blood samples were collected for postinfusion monitoring, including for cytokine response. “For the control group, we identified all evaluable ibrutinib-naïve patients with CLL treated on this study,” said Geyer.
Among the individuals Geyer et al examined, 5 patients with relapsed/refractory CLL (median age, 58 years at CAR T-cell infusion) underwent therapy with ibrutinib at leukapheresis and/or immediately prior to or through conditioning chemotherapy (2 patients received cyclophosphamide and 3 received fludarabine) and CAR T-cell infusion; 6 additional evaluable patients with relapsed/refractory CLL remained ibrutinib-naïve through the conditioning regimen (4 received cyclophosphamide and 2 received bendamustine) and CAR T-cell infusion.
“We observed a nonsignificant trend toward greater median cumulative fold T-cell expansion ex vivo in the 5 patients on ibrutinib versus the 6 not on ibrutinib at leukapheresis,” Geyer said, “with similar median manufacturing times of 13.5 versus 15 days [respectively].” According to data that Geyer shared, end-of-process T cells in patients treated with ibrutinib included a greater fraction of CD8+CAR+ T cells, with a CD62L+CD127+ phenotype, and decreased fraction of CD62L-negative T cells.
An objective response was achieved by 5 of the 11 patients enrolled in the trial who were treated with conditioning chemotherapy and CAR-T cells. The objective response rate (ORR) was 80% (4/5) among ibrutinib-treated patients, including 1 complete response (CR) without minimal residual disease (MRD), 1 MRD+ CR, and 2 partial responses (P
= .08 for ORR between ibrutinib-treated vs ibrutinib-naïve patients). “Two patients remain in MRD-negative CR at 16 and 50 months, and they saw peak expansion between 7 and 14 days after CAR T-cell infusion,” Geyer said. He added that 4 of the 6 ibrutinib-naïve patients died, while all 5 of the patients treated with ibrutinib are alive.
Geyer also noted that while prior ibrutinib therapy improves autologous T-cell expansion ex vivo and influences CAR T-cell phenotypes, it can potentially amplify toxicities associated with CAR T-cell treatment, including CRS.
All 11 patients developed fevers, which began on the first day of infusion in 4 of the 5 ibrutinib-treated patients and in 2 of the 6 ibrutinib naïve patients. Two of the 5 patients in the ibrutinib group developed severe cytokine release syndrome (CRS) and required vasopressors for hypotension in addition to tocilizumab. No patients in the ibrutinib-naïve group developed severe CRS.
Ibrutinib-treated patients additionally exhibited greater median peak levels of multiple immunoregulatory cytokines associated with cytokine release syndrome, including IL-6, IL-10, IL-2, IL-5, IFNγ, FLT3L, fractalkine, and GM-CSF, Geyer told the audience.
This article was repurposed from AJMC.com
Geyer MB, Park JH, Riviere I, et al. Implications of concurrent ibrutinib therapy on CAR T-cell manufacturing and phenotype and on clinical outcomes following CD19-targeted CAR T-cell administration in adults with relapsed/refractory CLL. Presented at: 58th American Society of Hematology Annual Meeting & Exposition; December 3, 2016; San Diego, CA. Abstract 58.