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ORLANDO -- Three-fourths of patients with relapsed/refractory large B-cell lymphomas (LBCLs) responded to treatment with a new anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, according to the largest trial of its kind.

Overall, 73% of 256 patients responded to lisocabtagene maraleucel (liso-cel), including complete responses in half the patients. Responses occurred rapidly and were durable, as more than half were ongoing at 12 months. The cohort had a median progression-free survival (PFS) of 6.8 months and median overall survival (OS) of 21.1 months, although the upper limit of the confidence intervals had yet to be reached.

In contrast to the currently available CAR T-cell therapies, liso-cel was associated with a low rate of grade 3/4 cytokine release syndrome (CRS), Jeremy S. Abramson, MD, reported here at the Transplantation and Cellular Therapy Meetings.

" is the largest clinical study reported to date of CD19-directed CAR T cells in patients with relapsed/refractory aggressive large B-cell lymphomas," said Abramson. " was observed across patient subgroups with unmet medical need, including uncommon large B-cell lymphoma histologic subtypes and those with poor prognostic characteristics.

"The low incidence of severe cytokine release syndrome and neurologic events and their late onset support liso-cel treatment in the outpatient setting," he said.

Another report at the conference demonstrated the safety and feasibility of administering the CAR T-cell therapy to outpatients.

Historically, patients with relapsed/refractory LBCL had few remaining treatment options, which led to objective responses in a . Chemotherapy-refractory disease conferred an , associated with a response rate of 7% and median OS of 6 months with conventional therapy.

The currently available CAR T-cell therapies, tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (axi-cel, Yescarta), have produced high response rates and durable remissions in patients with relapsed/refractory LBCL, Abramson noted. However, both confer a risk of potentially severe CRS and neuropathy. The dose and ratio of CD8+ and CD4+ CAR T cells may influence the incidence and severity of both toxicities.

Treatment with liso-cel involves separate administration of the CD8+ and CD4+ components at equal target doses, Abramson continued. The composition results in consistent administration of CD8+ and CD4+ T-cell doses and is associated with low variability in the CD8+/CD4+ ratio, he added.

Investigators in TRANSCEND NHL 001 enrolled patients for whom at least two prior lines of therapy had failed. Patients with prior stem-cell transplant were eligible, and the protocol had no lower threshold for leukocyte, neutrophil, or platelet counts or hemoglobin.

Following lymphodepletion with fludarabine and cytarabine, patients received one of three doses of liso-cell evaluated in the trial. The dose-finding phase of the trial included 60 patients, the dose-expansion phase included 83, and 126 patients were enrolled in the dose-confirmation phase.

The primary endpoints of the trial were adverse events (AEs) and objective response rate (ORR) as determined by independent review. Secondary endpoints included complete response (CR), duration of response, PFS, OS, and pharmacokinetics. Abramson reported findings after a median follow-up of 12 months.

Data analysis included 269 treated patients, 256 of whom were evaluable for efficacy. Abramson said 89% of the study population had high-risk disease characteristics associated with worse survival. The most common grade 3 or greater AEs were neutropenia (60%), anemia (38%), and thrombocytopenia (27%). CRS occurred in 42% of the patients but grade 3 or greater than 3 CRS occurred in only 2%. Neurologic events occurred in 30% of patients, including grade 3 in 9% and grade 4 in 1%. Both CRS and neurologic events were reversible, he noted.

The treatment led to an ORR of 73% and CR rate of 53%. The median time to first CR was 1 month. Among responding patients, 60.4% of responses were ongoing at 6 months and 54.7% at 12 months. An analysis of ORR and CR across patient and clinical subgroups showed consistent activity. The median PFS was 6.8 months and median OS was 21.1 months. The median values had yet to be reached for patients who had CRs.

Three small studies conducted along with TRANSCEND NHL 001 of administering and following patients in an outpatient setting. The pilot limited enrollment to patients who were ineligible for high-dose chemotherapy and hematopoietic stem cell transplant. Both university and non-university medical centers participated in the pilot, said Carlos Bachier, MD, of the Sarah Cannon Blood Cancer Network in Nashville.

Participating centers had capability for stem-cell transplantation or phase I trials, an outpatient infusion center, affiliated apheresis center, and a multidisciplinary medical team. Eligible centers had one designated hospital for CAR T cell patient care. Patients were required to stay within 1 hour of the treatment site for the first 30 days and have caregiver support for the entire 30 days.

The study included a total of 44 patients: 25 from TRANSCEND NHL 001, 13 from an affiliated outreach program, and six specifically enrolled for the pilot study. Aside from being older (median age of 72 vs 63 for TRANSCEND NHL 001), the six patients in the pilot study did not differ substantially from the overall population.

Patients went home the same day they received the liso-cel infusion, following a period of observation. They returned daily for the first week and then at least twice weekly during the first month after infusion. Patients and caregivers received training to recognize early signs of CRS or neuropathy, which mandated immediate hospitalization.

Bachier said the types and severity of treatment-related AEs in the outpatient group were similar to those of the overall TRANSCEND NHL 001 trial. CRS occurred in 17 of the 44 patients treated in the outpatient setting, including five in the outreach group and none in the pilot. Neurologic events occurred in 13 patients, 11 from TRANSCEND NHL 001 and two from the outreach subgroup. One case each of grade 3 or greater CRS and neuropathy occurred in the TRANSCEND NHL 001 patients.

"The median onset and duration of CRS or neurologic events in outpatients were similar to TRANSCEND NHL 001 inpatients," said Bachier.

Subsequently, 24 patients (55%) in the outpatient study required hospitalization, which had a median duration of 6.5 days. By comparison, inpatients had a median hospital stay of 11 days. None of the six patients in the pilot group required hospitalization.

Treatment with liso-cel led to an ORR of 80% (35 of 44) in the outpatients, including CRs in 55% (24 of 44). All six patients enrolled for the pilot study had objective responses, including four CRs.