In light of the modified protocol, 3 patients who enrolled on stage 2B received cyclophosphamide followed by a split dose of CAR T cells at 0.40 × 107 to 1.0 × 107 CAR-T cells/kg. For stage 3, 9 patients received investigator’s choice of lymphodepleting chemotherapy followed by a split dose of CAR-T, for which the total dose administered was 3 × 107 CAR-T cells/kg. Patients enrolled in the trial during stage 3 were permitted to continue treatment with ibrutinib at the time of leukapheresis and CAR-T cell infusion.
Overall, 6 of the 16 CLL patients (38%) achieved an objective response, but among patients who received lymphodepleting chemotherapy, the response rate was 50% (6 of 12 patients). The response rate increased to 80% (4 of 5 patients) when only patients who received concurrent ibrutinib in addition to lymphodepleting chemotherapy were considered. In all, 3 complete responses were seen—and all of these complete responses occurred in patients whom had yet to relapse at a median follow-up of 40.6 months (range, 1.8-79.8 months) and all of whom received lymphodepleting chemotherapy; 2 patients who achieved a complete response received concurrent ibrutinib.
“We know that lymphodepleting chemotherapy is important for the activity of CAR-T cells,” Carlos Ramos, MD, Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas, told Cancer Therapy Advisor. Although he was not involved in the trial, Dr Ramos said that the initial lack of lymphodepleting chemotherapy may explain why the response rates were low and pointed out that the lymphodepleting chemotherapy regimens used were not uniform. Among the 12 evaluable patients who received lymphodepleting chemotherapy, 7 received cyclophosphamide alone, 2 receive bendamustine alone, and 3 received cyclophosphamide plus fludarabine.
Dr Siddiqi said it was “reassuring” to see that the CAR-T cells weren’t “super toxic” in this patient population. Most evaluable patients had grade 2 or lower cytokine release syndrome; 1 had grade 3 cytokine release syndrome. Six patients had any grade neurological toxicity; 1 instance of neurotoxicity was grade 3.
In an exploratory analysis of ibrutinib-exposed versus ibrutinib-naive patients, study researchers found that those who received ibrutinib had better ex vivo T-cell expansion at the time of leukapheresis (P =.040) and at the end of production of the CAR-T cell product (P =.056), as well as different populations of central memory and effector memory T cells in the reinfused product. Patients who received ibrutinib also had significantly increased levels of interleukin 6 and interleukin 10 and increased levels of interferon γ that neared statistical significance; these are all markers for not only cytokine release syndrome, but also efficacy. Altogether, these associations suggest ibrutinib may alter the phenotype of the final CAR-T cell product.