As reported in The New England Journal of Medicine by Bishop et al, the phase III BELINDA trial showed no improvement in event-free survival with second-line tisagenlecleucel vs standard of care including salvage chemotherapy and autologous hematopoietic stem cell transplantation (HSCT) in patients with aggressive B-cell lymphoma.

As stated by the investigators, “Patient outcomes are poor for aggressive B-cell non-Hodgkin lymphomas not responding to or progressing within 12 months after first-line therapy. Tisagenlecleucel … is approved for diffuse large B-cell lymphoma after at least two treatment lines.”

Study Details

In the trial, 322 patients with disease refractory to or progressing within 12 months after first-line therapy from sites in 18 countries were randomly assigned between May 2019 and January 2021 to receive tisagenlecleucel with optional bridging therapy (n = 162) or salvage chemotherapy and autologous HSCT (standard-care group, n = 160). In the tisagenlecleucel group, optional bridging therapy consisted of investigator’s choice among four prespecified platinum-containing regimens, lymphodepletion chemotherapy, and a single infusion of tisagenlecleucel at 0.6 to 6.0 × 10⁸ chimeric antigen receptor–positive viable T cells. The standard-care group received investigator’s choice among the same four chemotherapy regimen options for bridging therapy followed by high-dose chemotherapy and HSCT in responders.

The primary endpoint was event-free survival, defined as the time from random assignment to stable or progressive disease at or after week 12 assessment or death. Crossover to receive tisagenlecleucel was permitted if a defined event occurred at or after the week 12 assessment.

Event-Free Survival

The tisagenlecleucel group had higher proportions of patients with high-grade lymphomas (24.1% vs 16.9%) and patients with International Prognostic Index score ≥ 2 (65.4% vs 57.5%).

Overall, 95.7% of patients in the tisagenlecleucel group received tisagenlecleucel and 32.5% of the standard-care group received HSCT. In the tisagenlecleucel group, 16.7% of patients did not receiving bridging therapy, 35.8% received one cycle, and 47.5% received two or more cycles or regimens. In the standard-care group, 96.9% received two or more chemotherapy cycles, including 53.8% who received two or more regimens. Median time from leukapheresis to tisagenlecleucel infusion was 52 days.

Lymphoma progression at week 6 was observed in 25.9% of the tisagenlecleucel group vs 13.8% of the standard-care group. Median event-free survival was 3.0 months (95% confidence interval [CI] = 2.9–4.2 months) vs 3.0 months (95% CI = 3.0–3.5 months) in the standard-care group (unadjusted hazard ratio [HR] = 1.07, 95% CI = 0.82–1.40, P = .61; HR adjusted for age, sex, race, Eastern Cooperative Group performance status, histologic subgroup, disease stage, and disease subtype = 0.95, 95% CI = 0.72–1.25).

The investigators noted that more non–U.S.-based patients (n = 114) vs U.S.-based patients (n = 48) received two or more cycles or regimens of bridging therapy (59% vs 21%) and that less progressive disease prior to tisagenlecleucel infusion was observed in non–U.S.-based patients than in U.S. patients despite a longer time to infusion (57 vs 41 days).

A total of 81 patients crossed over from the standard-care group to receive tisagenlecleucel.

Data on overall survival were immature at data cutoff. The unadjusted hazard ratio for death was 1.24 (95% CI = 0.83–1.85); the adjusted hazard ratio was 0.99 (95% CI = 0.64–1.52). Complete or partial response was observed in 46.3% (complete response in 28.4%) vs 42.5% (complete response in 27.5%) of patients.

Adverse Events

Grade ≥ 3 adverse events occurred in 84.0% of patients in the tisagenlecleucel group vs 90.0% of the standard-care group. Cytokine-release syndrome of any grade occurred in 61.3% of patients receiving tisagenlecleucel (grade ≥ 3 in 5.2%). Any-grade neurologic toxicity occurred in 10.3% (grade ≥ 3 in 1.9%). Apart from cytokine-release syndrome in the tisagenlecleucel group, the most common adverse events in both groups were anemia, neutropenia, thrombocytopenia, and nausea. Adverse events led to death in 10 patients in the tisagenlecleucel group and 13 in the standard-care group.

The investigators concluded, “Tisagenlecleucel was not superior to standard salvage therapy in this trial. Additional studies are needed to assess which patients may obtain the most benefit from each approach.”

Disclosure: The study was funded by Novartis. For full disclosures of the study authors, visit nejm.org.