As reported in The Lancet by Manali Kamdar, MD, and colleagues, an interim analysis of the phase III TRANSFORM trial has shown significantly improved event-free survival with second-line lisocabtagene maraleucel vs standard-of-care salvage immunochemotherapy followed by autologous hematopoietic stem cell transplantation (HSCT) in patients with relapsed or refractory large B-cell lymphoma.

These results support lisocabtagene maraleucel as a new second-line treatment recommendation in patients with early relapsed or refractory large B-cell lymphoma.

— Manali Kamdar, MD, and colleagues

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Lisocabtagene maraleucel was approved for third- or later-line treatment of relapsed or refractory large B-cell lymphoma in February 2021 on the basis of findings from the TRANSCEND NHL 001 trial.

Study Details

The open-label trial included 184 patients with primary refractory or early (≤ 12 months) relapsed large B-cell lymphoma from sites in the United States, Europe, and Japan. They were randomly assigned between October 2018 and December 2020 to receive lisocabtagene maraleucel in two sequential infusions with a target dose of 100 × 10⁶ chimeric antigen receptor (CAR)+ T cells (n = 92) or standard-of-care treatment (n = 92). Standard of care consisted of investigator’s choice of three cycles of salvage immunochemotherapy with:

• R-DHAP (rituximab at 375 mg/m² on day 1, dexamethasone at 40 mg on days 1–4, two infusions of cytarabine at 2,000 mg/m² on day 2, and cisplatin at 100 mg/m² on day 1)
• R-ICE (rituximab at 375 mg/m² on day 1, ifosfamide at 5,000 mg/m² on day 2, etoposide at 100 mg/m² on days 1–3, and carboplatin at area under the curve = 5 on day 2)
• R-GDP (rituximab at 375 mg/m² on day 1, dexamethasone at 40 mg on days 1–4, gemcitabine at 1,000 mg/m² on days 1 and 8, and cisplatin at 75 mg/m² on day 1).

Standard-of-care responders received high-dose chemotherapy and autologous HSCT. The primary endpoint was event-free survival on independent review committee assessment in the intention-to-treat population.

Event-Free Survival

Among the patients in the lisocabtagene maraleucel group, 89 received the agent and 1 received a nonconforming product. In the standard-of-care group, 91 patients started standard-of-care treatment, 43 received high-dose chemotherapy, and 42 underwent autologous HSCT. The overall response rates were 86% vs 48%, with complete response in 66% vs 39% (P < .0001)

At data cutoff for the interim analysis (in March 2021), median follow-up was 6.2 months (interquartile range = 4.4–11.5 months). Median event-free survival was 10.1 months (95% confidence interval [CI] = 6.1 months–not reached) in the lisocabtagene maraleucel group vs 2.3 months (95% CI = 2.2–4.3 months) in the standard-of-care group (stratified hazard ratio [HR] = 0.35, 95% CI = 0.23–0.53, P < .0001). Rates at 6 and 12 months were 63.3% vs 33.4% and 44.5% vs 23.7%.

Median progression-free survival was 14.8 months (95% CI = 6.6 months–not reached) in the lisocabtagene maraleucel group vs 5.7 months (95% CI = 3.9–9.4 months) in the standard-of-care group (stratified HR = 0.41, 95% CI = 0.25–0.66, P = .0001), with 6- and 12-month rates of 69.4% vs 47.8% and 52.3% vs 33.9%. A total of 46 patients in the standard-of-care group crossed over to receive lisocabtagene maraleucel, primarily during salvage immunochemotherapy; the most common reason for crossover was disease progression, followed by suboptimal response and relapse. Median overall survival was not reached (95% CI = 15.8 months–not reached) in the lisocabtagene maraleucel group vs 16.4 months (95% CI = 11.0 months–not reached) in the standard-of-care group (stratified HR = 0.51, 95% CI = 0.26–1.00, P = .026), with 6- and 12-month rates of 91.8% vs 89.4% and 79.1% vs 64.2%. In analysis adjusting for crossover, the stratified hazard ratio for overall survival was 0.32 (95% CI = 0.16–0.64) using a two-stage estimator model. 

Adverse Events

Grade ≥ 3 adverse events occurred in 92% of patients in the lisocabtagene maraleucel group vs 87% of the standard-of-care group, with the most common in the lisocabtagene maraleucel group being neutropenia (80% vs 51%), anemia (49% vs 49%), thrombocytopenia (49% vs 64%), and prolonged cytopenia (43% vs 3%). In the lisocabtagene maraleucel group, grade 3 cytokine-release syndrome occurred in one patient (1%) and grade 3 neurologic toxicity occurred in four patients (4%), with no grade 4 or 5 events reported. Serious adverse events occurred in 48% of patients in each group; the most common in the lisocabtagene maraleucel group were cytokine-release syndrome (13%), febrile neutropenia (8%), and pyrexia (7%). Adverse events led to death in one patient in the lisocabtagene maraleucel group and five patients in the standard-of-care group; one death in the standard-of-care group, due to sepsis, was considered related to treatment. 

The investigators concluded, “These results support lisocabtagene maraleucel as a new second-line treatment recommendation in patients with early relapsed or refractory large B-cell lymphoma.”

Dr. Kamdar, of the Division of Hematology, Hematologic Malignancies and Stem Cell Transplantation, University of Colorado Cancer Center, Aurora, is the corresponding author for The Lancet article.

Disclosure: The study was funded by Celgene, a Bristol Myers Squibb Company. For full disclosures of the study authors, visit thelancet.com.