Lisocabtagene maraleucel could be ‘CAR T-cell treatment of choice’ for lymphoma subset
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Nearly three-quarters of patients who received lisocabtagene maraleucel for relapsed or refractory large B-cell lymphoma achieved objective response, according to results of the TRANSCEND NHL 001 trial published in The Lancet.
Participants in the multicenter, seamless design study also showed relatively low levels of treatment-related adverse events, including cytokine release syndrome (CRS) and neurotoxicity.
Lisocabtagene maraleucel (Bristol Myers Squibb), also known as liso-cel, is an autologous CAR T-cell therapy that targets the CD19 antigen expressed on the surface of cancer cells.
The investigational compound contains a CAR construct composed of CD8 and CD4 CAR T cells. It includes an anti-CD19 single-chain variable fragment that targets the specific antigen domain, a transmembrane domain, a 4-1BB costimulatory domain and a CD3-zeta T-cell activation domain.
The CAR construct of liso-cel is different than that of both FDA-approved CAR T-cell therapies for large B-cell lymphoma — axicabtagene ciloleucel (Yescarta, Kite Pharma/Gilead) and tisagenlecleucel (Kymriah, Novartis) — which target the same CD19 antigen.
“A major difference is that to produce liso-cel, the patient’s CD4 and CD8 T cells are separately transduced and expanded and then administered back to the patient in equal target doses, which produces a consistent product for each patient,” study author Jeremy S. Abramson, MD, MMSc, associate professor of medicine at Harvard Medical School and director of the lymphoma center at Massachusetts General Hospital, told Healio. “In contrast, axicabtagene ciloleucel and tisagenlecleucel are manufactured on bulk T cells, which results in interpatient variability in CD8 and CD4 CAR T-cell components.”
Patients with aggressive B-cell lymphoma who are refractory to treatment with chemotherapy typically have a very poor prognosis, Abramson said.
“Anti-CD19 CAR T cells have emerged as potentially curative therapies, but [they] carry significant risks, including CRS and neurologic toxicities,” he told Healio. “This trial of lisocabtagene maraleucel was designed to try to maximize both efficacy and safety in a broader population of patients with high-risk relapsed and refractory aggressive B-cell lymphoma.”
The TRANSCEND NHL 001 trial included 269 patients (median age, 63 years; interquartile range, 54-70; 65% men) treated with liso-cel between Jan. 11, 2016, and July 5, 2019. Nearly all of the patients (97%) received at least two previous lines of therapy and 67% had chemotherapy-refractory disease.
Results showed consistent safety and clinical activity of liso-cel regardless of dose level. Researchers identified a recommended target dose of 100 × 106 CAR T cells (50 × 106 CD8+ and 50 × 106 CD4+ CAR T cells).
The efficacy analysis, which included 256 patients, showed 186 (73%; 95% CI, 66.8-78) achieved an objective response and 136 (53%; 95% CI, 46.8-59.4) achieved complete response.
The safety analysis showed 42% of patients experienced CRS, whereas 30% had symptoms of neurotoxicity. However, only 2% of patients had high-grade (grade 3 or greater) CRS, and 10% of patients had high-grade neurotoxicity.
Nine patients (6%) had a dose-limiting toxicity, and one patient died of diffuse alveolar damage after receiving a liso-cel dose of 50 × 106 CAR T cells.
Other common grade 3 or greater adverse events included neutropenia (60%), anemia (37%) and thrombocytopenia (27%).
The results demonstrate clinically meaningful survival and response rates with liso-cel, Abramson said.
“Patients with chemotherapy-refractory large B-cell lymphomas have a less than 10% chance of complete response to conventional therapies, with an estimated median OS of about 6 months,” he told Healio.
In contrast, Abramson said that 58% of all patients in TRANSCEND NHL 001 were alive at 1 year, including 86% of those who achieved a complete response to therapy.
“I think the favorable balance of efficacy and safety could make liso-cel the CAR T-cell treatment of choice in most patients with relapsed/refractory large B-cell lymphomas,” he said.
For more information:
Jeremy S. Abramson, MD, MMSc, can be reached at Massachusetts General Hospital, 55 Fruit St., Boston, MA 02114; email: jabramson@mgh.harvard.edu.
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