Lisocabtagene Maraleucel as Second-Line Treatment for Relapsed or Refractory Large B-Cell Lymphoma: TRANSFORM Trial
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%.
KEY POINTS
- Lisocabtagene maraleucel significantly improved event-free survival vs salvage immunochemotherapy followed by autologous HSCT.
- Median event-free survival was 10.1 vs 2.3 months; median progression-free survival was 14.8 vs 5.7 months.
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.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
