Second-line tisagenlecleucel renders no EFS benefit in aggressive B-cell lymphoma

The anti-CD19 chimeric antigen receptor (CAR) T-cell treatment tisagenlecleucel did not improve event-free survival (EFS) compared with standard care in patients refractory or who had progressed following first-line therapy for aggressive B-cell non-Hodgkin’s lymphoma, results of the phase III BELINDA trial showed.

Participants in this international study (18 countries) were 322 adults (68.9 percent age <65 years) with aggressive B-cell lymphoma that was refractory or had progressed within 12 months after the last dose of first-line treatment (anti-CD20 antibody and anthracycline regimen) and who had ECOG performance status 0–1. They were randomized 1:1 to receive standard care (salvage chemotherapy and autologous haematopoietic stem-cell transplantation [HSCT*]) or tisagenlecleucel (single infusion of 0.6 to 6.0×10⁸ CAR-positive viable T cells) with optional bridging therapy** (~83 percent).

There were more patients with high-grade lymphomas in the tisagenlecleucel than standard care group at baseline (24.1 percent vs 16.9 percent), and more patients in the former than latter group with International Prognostic Index score ≥2 (65.4 percent vs 57.5 percent). Patients were randomized a median <1.5 months following progression on first-line therapy. Nineteen percent of patients relapsed <6 months after first-line therapy, while 66.5 percent were refractory to first-line therapy. About 33 percent of patients in the standard care group received autologous HSCT (median 3 months post-randomization). Patients in the tisagenlecleucel group received treatment a median 52 days post-leukapheresis.

Lymphoma progression at week 6 occurred in more patients in the tisagenlecleucel than standard care group (25.9 percent vs 13.8 percent).

EFS at or after 12 weeks did not significantly differ between patients assigned to tisagenlecleucel or standard care (median 3 months for both; unadjusted hazard ratio, 1.07, 95 percent confidence interval, 0.82–1.40; p=0.61). [ASH 2021, abstract LBA-6; N Engl J Med 2021;doi:10.1056/NEJMoa2116596]

“We were surprised that EFS was identical in both study arms,” said study author Professor Michael Bishop from The David and Etta Jonas Center for Cellular Therapy, University of Chicago, Chicago, Illinois, US.

Overall survival was immature at data cut-off (median 10 months after randomization), with an unadjusted HR for death of 1.24.

EFS and OS in both groups were shorter in patients with high-grade B-cell lymphoma compared with primary mediastinal B-cell lymphoma or diffuse large B-cell lymphoma.

Responses at or after week 12 were observed in 46.3 and 42.5 percent of patients in the tisagenlecleucel and standard care groups, respectively, with 28 percent in both groups having a complete response.

Adverse events (AEs) occurred in 98.8 percent of each group, with 84 and 90 percent of tisagenlecleucel and standard care recipients, respectively, experiencing grade ≥3 AEs, and 74.7 and 85.6 percent, respectively, experiencing treatment-related grade ≥3 AEs.

Among tisagenlecleucel recipients, 61.3 percent experienced cytokine release syndrome (CRS), with 5.2 percent experiencing grade ≥3 CRS. CRS occurred a median 4 days post-infusion and resolved within a median 5 days. Sixteen patients (10.3 percent) experienced neurologic events, three of grade ≥3, with a median time to onset and resolution of 5 and 9 days, respectively.

The most common AEs in both groups, aside from CRS with tisagenlecleucel, were anaemia, neutropenia, thrombocytopenia, and nausea.

Deaths from AEs were documented in 10 and 13 patients in the tisagenlecleucel and standard care groups, respectively, two in each group from SARS-CoV-2–related complications. Twenty-six and 20 percent of patients in the tisagenlecleucel and standard care groups, respectively, died due to disease progression.

Eighty-one patients (50.6 percent) on standard care crossed over to receive tisagenlecleucel, at a median 4.3 months post-randomization.

More research warranted

“Management of aggressive lymphoma that does not respond to or that progresses shortly after first-line therapy remains a substantial clinical challenge,” said the co-authors.

“As this field progresses, we’re learning that there may be more variables to consider as we seek to optimize CAR-T therapies,” noted Bishop. “It gives us tremendous insights into the biology of these very aggressive diseases and points to an opportunity to more closely examine many factors,” he said.

“[F]urther research [is warranted] on the underlying effect of disease burden, cell dose, T-cell function in patients with lymphoma, and expansion on disease response. Our data [also] suggest the importance of disease control with more effective bridging therapy before CAR T-cell infusion and a shorter time to infusion may be needed for this population of patients with disease refractory to chemotherapy,” the authors concluded.