BELINDA

Published

Bishop MR, et al. "Second-Line Tisagenlecleucel or Standard Care in Aggressive B-Cell Lymphoma". The New England Journal of Medicine. 2022. 368(7):629-639.
PubMed • Full text • PDF • ClinicalTrials.gov

Clinical Question

In patients with aggressive B-cell lymphoma after failure of front-line chemotherapy, is tisagenlecleucel (tisa-cel; Kymriah) with optional bridging therapy better than salvage chemotherapy and autologous hematopoietic stem-cell transplantation (ASCT) at improving progression-free survival?

Bottom Line

Among patients with primary refractory or early relapsed large B-cell lymphoma, the anti-CD19 CART therapy tisagenlecleucel (tisa-cel; Kymriah) does not improve PFS compared to standard-care salvage chemotherapy and ASCT.

Major Points

Aggressive B-cell lymphoma carries a poor prognosis after failure of front-line chemotherapy. Standard therapy for fit patients entails intensive salvage chemotherapy and ASCT, which is curative in only a subset of patients, and novel approaches are needed. In the phase 2 JULIET trial, tisa-cel yielded a 52% response rate, and PFS at 24 months was 33%, prompting a head-to-head comparison with ASCT.

BELINDA was a phase 3, international, randomized trial in a similar patient population. Approximately 320 patients with aggressive B-cell lymphoma whose disease was refractory to first-line therapy or relapsed within 12 months were randomized to tisa-cel with or without bridging therapy, or to standard treatment with salvage chemotherapy followed by high-dose chemotherapy and autologous hematopoietic stem cell transplant (ASCT). Most (83%) in the CART group received bridging therapy, and nearly all (97%) in the ASCT group received two cycles of salvage chemotherapy prior to ASCT. Median event-free survival, the primary endpoint of the study, was 3 months in both groups (HR 1.07, 95% CI 0.82-1.40). In the CART group, CRS occurred in 61.3% of patients, grade ≥3 CRS occurred in 5.2%. Fatal SAEs occurred in 6.8% and 3.1% in CART and ASCT groups, respectively.

This was a negative study indicating that tisa-cel is not more efficacious than salvage and ASCT in patients with primary refractory or early relapsed disease. The authors speculate that tailoring therapy based on pre-infusion disease burden, which has since been shown to have significant prognostic impact, is an important consideration: in BELINDA, a higher proportion of patients in the CART group had progressive disease at infusion compared to those undergoing ASCT (25.9% vs. 13.8%). However, Zuma-7 and TRANSFORM studied axi-cel and liso-cel in a similar patient population, and both studies were positive in favor of CART over salvage plus ASCT.

Guidelines

NCCN Guidelines: B-Cell Lymphomas, Version 6.2023

• Primary refractory disease or those who relapse <12 months from completion of therapy
  1. Salvage chemotherapy or bridging chemotherapy
  2. For those who achieve CR or near CR, proceed with CART or ASCT

Design

• Multicenter, double-blind, phase III randomized, controlled trial
• N=322 patients with aggressive B-cell lymphoma with primary refractory or early relapsed disease
  • Tisagenlecleucel group (n=162)
  • Standard-care group (n=160)
• Setting: 65 centers in 18 countries
• Enrollment: 2019-2021
• Analysis: Intention-to-treat
• Primary endpoint: Event-free survival (randomization to stable or progressive disease at or after 12 weeks)
• Secondary endpoint: Overall survival (only to be tested if the results for primary endpoints were significant), percentage of patients with a response at week 12, safety, and cellular kinetics.

Population

Inclusion Criteria

• Age 18 years or older
• Histologically confirmed aggressive B-cell lymphoma
• Refractory (no complete response) or relapsed after the receipt of a first-line anti-CD20 antibody and anthracycline-containing regimen within 12 months of the last dose
• Eligible for autologous HSCT according to the investigator's assessment
• Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1

Baseline Characteristics

• Median age (range:- 59.5 years (19-79); 54% were aged more than 65 years
• ECOG performance status of 1: 70.4%
• IPI score of 2 or more: 65.4%
• Disease that was refractory to first-line therapy: 66%
• Relapse within 6 months of first-line therapy: 18.5%
• Relapse 6-12 months after the last dose of first-line therapy: 15.4%

Interventions

• After obtaining consent, all participants underwent lymphocyte collection via leukapheresis as the trial allowed for crossover from standard-care therapy to adoptive cellular therapy.
• Following leukapheresis, patients underwent randomization in 1:1 ratio with stratification.
• The tisagenlecleucel arm consisted of optional bridging therapy, lymphodepletion chemotherapy, followed by a single infusion of 0.6-6x10^8 CAR-positive viable T-cells.
• The standard-care treatment arm consisted of investigators' choice of four prespecified chemotherapy regimens (same as bridging therapy) followed by, in patients showing response, high-dose chemotherapy and autologous HSCT.
• Patients in the standard care arm, if deemed to have an inadequate response on PET-CT on the sixth week could receive a second chemotherapy regimen before HSCT (the aim was to have lowest tumor burden before HSCT).
• Palliative ibrutinib or lenalidomide was used if patients were no longer eligible for HSCT.
• After randomization, patients were followed for response at week 6, week 12, every 3 months for the first year, every 6 months for the second year, and annually for 5 years.
• Efficacy evaluations were done starting at week 12 to allow the time for the full effect of treatment in each group.

Outcomes

Comparisons are tisagenlecleucel vs standard-care therapy.

Primary Outcomes

Median event-free survival

3.0 months in both groups (HR 1.07; 95% CI 0.82-1.40; P=0.61)

Secondary Outcomes

Overall survival

Not tested as there was no significant difference in the primary outcome.

Best overall response at or after week 12

46.3% (38.4-54.3) vs. 42.5% (34.7-50.6)

Grade 3 or higher adverse events

84.0% vs 90.0%

Cellular kinetics

Geometric mean in-vivo peak expansion--2X higher in patients with a response

Tisagenlecleucel transgene could be detected in 53 (out of 54) samples four months after randomization

Longer event-free survival was seen in patients with higher-than-median peak expansion

Subgroup Analysis

Patients with high-grade B-cell lymphoma had shorter event-free and overall survival in both treatment groups compared to those with primary mediastinal B-cell lymphoma or diffuse large B-cell lymphoma

Median event-free survival in non-US countries: 3.3 months vs 3.0 months

Median event-free survival in the US: 2.9 months vs 3.1 months

Adjusted hazard ratio for event or death in non-US countries: 0.82 (95% CI, 0.59-1.15)

Adjusted hazard ratio for event or death in the US: 1.19 (95% CI, 0.64-2.19)

Adverse Events

61.3% in the tisagenlecleucel group had cytokine release syndrome (CRS); 5.2% had CRS of grade 3 or higher

10.3% in the tisagenlecleucel group had neurologic events; 1.9% of the neurologic events were grade ≥3

Anemia, neutropenia, thrombocytopenia, and nausea were the most common adverse events in both groups

32.1% in the tisagenlecleucel and 28.1% in the standard-care group died during the trial

Criticisms

• Multiple differing histologic tumor types were included in the study which could have skewed results.

Funding

Supported by Novartis. Manuscript initially written by an industry-sponsored medical writer.