Liso-Cel Induces High Rate of Durable Responses in LBCL

Jeremy Abramson, MD, associate professor of medicine, Harvard Medical School, Boston, and director of the Jon and JoAnn Hagler Center for Lymphoma at Massachusetts General Hospital Cancer Center

Jeremy Abramson, MD

CD19-directed CAR T-cell therapy induced a high rate of rapid and durable complete responses (CRs) in patients with aggressive relapsed/refractory large B-cell lymphoma (LBCL).

In the multicenter phase I TRANSCEND study, treatment with lisocabtagene maraleucel (liso-cel) resulted in an objective response rate (ORR) of 73% and a CR rate of 53%, with the time to first CR or partial response occurring at a median of 1 month.¹

The median duration of response has not been reached at a median follow-up of 12 months. Some 60.4% and 54.7% of patients remained in response at 6 and 12 months, respectively, reported Jeremy Abramson, MD, at the 2019 ASH Annual Meeting.

Median progression-free survival (PFS) was 6.8 months (95% CI, 3.3-14.1) “with 44% of patients remaining progression free,” said Abramson. Median OS was 21.1 months (95% CI, 13.3-NR), with 58% of patients alive at 1 year, including 86% of complete responders. The incidences of severe cytokine release syndrome and neurologic events were low. Grade-3 or -4 cytokine release syndrome each occurred in only 1% of patients, and only 10% had grade-3 or -4 neurologic events, said Abramson, associate professor of medicine, Harvard Medical School, Boston, and director of the Jon and JoAnn Hagler Center for Lymphoma at Massachusetts General Hospital Cancer Center.

“The low incidence of severe cytokine release syndrome and neurologic events, and their late time of onset, support use of liso-cel in a broad range of patients and in the outpatient setting,” he said.

“Historically, patients with relapsed/refractory aggressive LBCL who have progressed after second-line therapy have no curative options available, with fewer than half of patients achieving response to subsequent standard treatments,” said Abramson.^2,3 “Outcomes are even worse in patients with chemotherapy-refractory disease, where CR rates to conventional treatments are only 7%, with an overall survival of approximately 6 months.”⁴

Liso-cel is an investigational anti-CD19, defined composition, 4-1BB CAR T cell product administered separately at equal target doses of CD4+ and CD8+ CAR T cells.

In TRANSCEND, 344 patients with LBCL who had received ≥2 prior lines of therapy underwent leukapheresis, and 269 patients received liso-cel at 1 of 3 dose levels (50 × 10⁶ [n=51]; 100 × 10⁶ [n=177]; and 150 × 10⁶ [n=41]). Patients with high-risk characteristics who have been excluded from previous clinical trials were eligible, including patients with secondary central nervous system involvement and those with moderate medical comorbidities, including patients with creatinine clearance as low as 30 mL/min or left ventricular ejection fraction as low as 40%. There was no lower limit of absolute lymphocyte count for eligibility.

Patients were allowed to receive bridging therapy after leukapheresis at the discretion of the treating investigator if urgent disease control was required. CAR T cell infusion was preceded by 3 days of lymphodepleting therapy with fludarabine and cyclophosphamide.

Twenty-five patients received nonconforming product that did not meet all specifications for liso-cel and were not included in the primary analysis set. In 2 instances, the CAR T product could not be manufactured.

Thirteen patients who received CAR T cell infusion were excluded from the efficacy analysis because they either did not have positron emission tomography (PET)-positive LBCL before liso-cel administration (n = 4), no PET scan after bridging therapy (n = 6), and other reasons (n = 3). The efficacy set therefore consisted of 256 patients.

Patients were heavily pretreated, with a median of 3 prior lines of therapy including 35% of patients who underwent prior autologous or allogeneic hematopoietic stem cell transplant, and 67% of patients with chemotherapy-refractory disease. Forty-four percent never achieved a CR with prior therapy. Bridging therapy was administered to 59% of patients. Because similar safety and analogous safety was found across all 3 dose levels, all treated patients were pooled for the analysis.

Some 89% of patients had high-risk features known to portend a shortened OS, including high-grade BCL, an ECOG performance status of 2, primary refractory disease, refractory to second line of therapy or later, no prior autologous stem cell transplant, and never achieving a CR with prior therapy.

Responses were similar across all patient subgroups, including numerous LBCL histologies and patients with high-risk features. “Patients with the highest tumor burden and those receiving bridging therapy did have lower rates of CR but notably could still respond to liso-cel treatment,” said Abramson. Efficacy results of the 25 patients who received nonconforming product were similar to those of the overall study population.

By histology, PFS was similar to the overall diffuse LBCL population in patients with double-hit lymphoma or transformed lymphoma from nonfollicular histologies.

The median PFS and OS for patients who achieved a CR was not reached with 65.1% of patients progression free and 85.5% of patients alive at 12 months, respectively.

“Patients who received bridging therapy had a slightly inferior PFS compared to those who did not, and not surprisingly, patients had an inferior PFS if they had medical comorbidities compared to those who did not, but notably, both of these high-risk subsets could achieve durable PFS,” he said.

“Evaluation of treatment-emergent adverse events [TEAEs] shows an overall favorable safety profile,” said Abramson. Neutropenia was the most commonly reported AE (63%; grade ≥3, 60%). Other grade ≥3 TEAEs included neutropenia anemia (38%) and thrombocytopenia (27%). “All other AEs occurred in fewer than half of patients, and were predominantly low grade,” he said. Ongoing grade≥3 cytopenias at day 29 was observed in 37% of patients. The incidence of severe infections was 12%. Infusion-related reactions and tumor lysis syndrome occurred at a rate of 1% each. The rate of hypogammaglobulinemia was 14%. Intravenous immunoglobulin was administered to 21% over the entire study follow-up.

The incidence of treatment-emergent death was 3%, “and no deaths were related to cytokine release syndrome or neurologic toxicities,” he said. “It is notable that the majority of patients on study experienced neither cytokine release syndrome nor neurologic toxicities.”

The incidence of any grade cytokine release syndrome was 42% (113 of 269), which occurred at a median onset of 5 days. As mentioned previously, grade ≥3 cytokine release syndrome occurred in 2% of patients. Neurologic events occurred in 30% of patients, with grade ≥3 occurring in 10%, at a median onset of 9 days. Intensive care unit admission was required in 7% of patients; only 3% of patients required vasopressors for cytokine release syndrome.

In assessing the use of rescue medications, 19% and 21% of patients received tocilizumab and corticosteroids, respectively. “Importantly, nearly all cases of cytokine release syndrome and neurotoxicity were entirely reversible,” he said.

References

1. Abramson JS, Palomba ML, Gordon LI, et al. Pivotal safety and efficacy results from Transcend NHL 001, a multicenter phase 1 study of lisocabtagene maraleucel (liso-cel) in relapsed/refractory (R/R) large B cell lymphomas. Presented at: American Society of Hematology Annual Meeting; December 7-10, 2019; Orlando, FL. Abstract 241.
2. Van Den Neste E, Schmitz N, Mounier N, et al. Outcome of patients with relapsed diffuse large B-cell lymphoma who fail second-line salvage regimens in the International CORAL study. Bone Marrow Transplant. 2016;51(1):51-57. doi: 10.1038/bmt.2015.213.
3. González-Barca E, Boumendil A, Blaise D, et al. Outcome in patients with diffuse large B-cell lymphoma who relapse after autologous stem cell transplantation and receive active therapy. A retrospective analysis of the Lymphoma Working Party of the European Society for Blood and Marrow Transplantation (EBMT). Bone Marrow Transplant. 2019. doi: 10.1038/s41409-019-0650-x. [Epub ahead of print]
4. Crump M, Neelapu SS, Faroq U, et al. Outcomes in refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study. Blood. 2017;130(16):1800-1808. doi: 10.1182/blood-2017-03-769620.

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