Liso-Cel Induces High Rate of Durable Responses in LBCL

Wayne Kuznar
Published: Sunday, Dec 08, 2019

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.

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