SALT LAKE CITY (FRONTLINE MEDICAL NEWS) – A CD19-directed 4-1BB chimeric antigen receptor (CAR) T cell product showed efficacy and a low rate of cytokine release syndrome and neurotoxicity in patients with aggressive lymphomas and poor prognoses, raising the possibility of outpatient administration and fewer hospitalization days in this high-risk group.

A total of 86 patients who received inpatient infusions of lisocabtagene maraleucel (liso-cel, also known as JCAR017) had a mean 15.6 days of hospitalization, compared with 9.3 days for 8 outpatient recipients, said Jeremy Abramson, MD , speaking at a top abstracts session of the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.

“We feel that the timing of these toxicities, as well as the lower overall incidence, favor exploration of this as an outpatient administration product,” he said. “Liso-cel toxicities have been manageable, with almost all of the toxicities being reversible.”

As of October 2017, eight patients had received liso-cel infusion as outpatients with at least 28 days of postinfusion data, Dr. Abramson said.

Although all but one required hospital admission, at a median of 5 days postinfusion (range, 4-22 days), there had been no intensive care unit admissions, and no outpatient recipients had experienced severe cytokine release syndrome (CRS) or neurotoxicity. All admitted patients presented with fever.

Among the study population, “Cytokine release syndrome was only seen in 35% of our entire dataset,” with neurologic toxicity seen in 19% of participants, Dr. Abramson said. “The majority of subjects had no CRS and no toxicity,” he said. Severe CRS occurred in 1% of the study population, and severe neurotoxicity in 12%. There were no deaths related to either complication.

Dr. Abramson reported these results from the TRANSCEND NHL 001 trial , a seamless design phase 1 pivotal trial of liso-cel enrolling patients with relapsed and refractory aggressive B cell non-Hodgkin lymphoma (NHL). Liso-cel delivers CD19-directed CD4 and CD8 CAR T cells in a 1:1 ratio, said Dr. Abramson, director of the lymphoma program at the Massachusetts General Hospital Cancer Center, Boston.

A total of 91 patients were randomized to one of the three dose-finding cohorts of the multicenter trial of liso-cel. One cohort received 5 x 107 cells in a single dose; a second cohort received the same number of cells but in two doses administered 14 days apart; the third cohort received a single dose of 1 x 108 cells.

The seamless trial design then moved to dose expansion, using the two single doses established in the dose-finding phase of the study. Ultimately, Dr. Abramson said, the third and pivotal diffuse large B-cell lymphoma (DLBCL) cohort received the higher single dose, since a dose-response relationship was seen in the earlier cohorts. No increase in cytokine release syndrome or neurotoxicity has been seen with the higher dose in patients evaluated to date.

Patients (median age, 61 years) were eligible to participate in the trial if they had relapsed or refractory DLBCL, primary mediastinal B-cell lymphoma, grade 3B follicular lymphoma, or mantle cell lymphoma. Patients with a failed prior allogeneic stem cell transplant or secondary central nervous system involvement were eligible, but all patients had to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.

As the trial moved to the core pivotal phase, eligibility requirements shifted slightly to include patients with ECOG status 0 or 1, and lymphoma diagnoses narrowed to include only DLBCL not otherwise specified (NOS), transformed follicular lymphoma, and high-grade B-cell lymphoma with double- and triple-hit cytogenetics. The core group was nearing completion of accrual at the time of the presentation, which presented preliminary results from this phase of the trial.

Among the 88 evaluable patients in the initial population with DLBCL receiving any of three dose levels, the best overall response rate (ORR) was 74% (95% confidence interval, 63%-83%); 52% of these patients achieved complete response (CR; 95% CI, 41%-63%).

For patients receiving the higher dose of liso-cel, the ORR was 81% (95% CI, 62%-94%), with a 63% CR rate (95% CI, 42%-81%), bearing out the dose-response rate that had been seen earlier in the trial, Dr. Abramson said.

The median duration of response in all TRANSCEND patients was 9.2 months; the median duration of remission has not been reached, he said. “We see evidence of durable response at 3 months in all our high-risk subsets, and that includes double- and triple-hit lymphomas, double-expresser lymphomas, patients who’ve never achieved prior complete remission, and patients with refractory disease.”

“The overall results are similarly encouraging,” Dr. Abramson said, with 86% of all patients alive at 6 months. Among the complete responders, 94% are alive at the 6-month mark. “The median duration of complete responders has not been reached in this cohort,” he said.

These results are notable, Dr. Abramson said, since about 90% of study participants have at least one disease risk factor that would predict median overall survival of 3-6 months.

During the period after leukapheresis while the CAR T cells were in production, patients could have ongoing treatment, but received PET scans to confirm disease before continuing enrollment in the trial and receiving liso-cel. The time from apheresis to product release for the pivotal cohort is now under 21 days, he said.

The study was supported by Juno Therapeutics, which plans to market liso-cel. Dr. Abramson reported ties with Celgene, Gilead, Seattle Genetics, Novartis, and Genentech.

SOURCE: Abramson J et al. Abstract 5 .


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