CAR T-cell Therapy: A Major Shift in the Treatment Landscape for Early-Relapse Aggressive B-Cell Lymphomas

2022 saw a major shift in the management of early-relapse large B-cell lymphoma (LBCL) with two multicenter, randomized phase III trials demonstrating superior efficacy of autologous CD19-directed chimeric antigen reception T-cell (CAR-T) therapy, compared with platinum-based salvage chemotherapy in second-line fit patients experiencing relapse within 12 months of frontline therapy.^1,2  This result is a significant departure from conventional chemotherapy followed by high-dose therapy and autologous stem cell transplantation (HDT/ASCT) for high-risk patients established nearly three decades ago by the PARMA Study.³ 

Although more than 60 percent of patients with advanced disease can anticipate cure with rituximab and anthracycline-based frontline therapy, outcomes can be poor for those with primary refractory disease or those that relapse within 12 months.^4-6  CAR-T therapy has transformed the treatment landscape for patients with chemorefractory LBCL. Three pivotal phase II studies in the third-line or later LBCL resulted in the approval of axicabtagene ciloleucel (axi-cel), tisagenlecleucel (tisa-cel) and lisocabtagene maraleucel (liso-cel) based on durable remissions in approximately 40 percent of heavily pretreated, poor-risk patients.^7-9  Given these impressive results, many had great equipoise to explore the efficacy of CAR-Ts in earlier lines of therapy.

The greatest unmet need was for LBCL patients with refractory disease or early relapse following frontline therapy that would otherwise be considered for standard of care (SOC) platinum-based salvage chemotherapy, followed by HDT/ASCT in the setting of chemosensitive disease.

ZUMA-7 was an international (77 sites), randomized phase III trial comparing axi-cel with SOC in the second line for patients with early-relapse (≤12 months) or refractory LBCL.¹  After screening, patients were randomized to axi-cel or investigator choice platinum-based chemotherapy. Patients achieving a complete response on the SOC arm then went on to HDT/ASCT. No bridging therapy other than corticosteroids was allowed for patients randomized to CAR-T therapy, nor was crossover permitted. A total of 180 patients were randomized to axi-cel and 170 to SOC. Axi-cel therapy led to a significant improvement in event-free survival. No deaths related to cytokine-release syndrome or neurologic events occurred. As a result of ZUMA-7, axi-cel should be considered as the preferred second-line approach for refractory or early-relapse LBCL in which intensive therapy is appropriate.

Two other randomized studies were performed in similar patients: TRANSFORM (liso-cel) and BELINDA (tisa-cel).^2,10  Though there were differences in the study schemas, axi-cel and liso-cel demonstrated significant improvement in response rates and event-free survival estimates compared to SOC, leading to two FDA-approved CAR-T therapies in early-relapse second-line LBCL. The results of BELINDA, however, were less favorable; tisa-cel was not superior to SOC. While these results could suggest inferiority of tisa-cel in the second-line setting, it is important to note considerable differences in BELINDA that could have contributed to the differences in outcomes. First, 83 percent of patients on the treatment arm received bridging therapy, with 47.5 percent receiving at least two or more cycles, which prompts the question: is this truly second-line therapy?¹⁰  Additionally, the median time from leukapheresis to tisa-cel infusion was 52 days compared to 29 days in ZUMA-7. It is unclear what the impact of these findings are, however, if CAR T-cell therapy is considered in second-line LBCL for early-relapse patients, the timing of CAR-T therapy is critical, and every effort is made to minimize unnecessary delays.

Despite the exciting results of ZUMA-7, CAR-T therapy is associated with unique toxicities including cytokine-release syndrome and immune effector cell–associated neurotoxicity syndrome that require referral to a specialized center and present unique challenges when considering therapy, especially in frail patients. These logistical challenges present notable barriers for patients with limited resources, patients from some minority backgrounds, those living in rural communities, and underinsured patients who may have difficulty accessing care at select institutions, further exacerbating health disparities among these populations.^11-15 

ZUMA-7 makes a compelling argument that axi-cel is an effective second-line treatment for patients with refractory or early-relapse LBCL. It could lead to one of the biggest paradigm shifts in the treatment of LBCL in decades. Several challenges require attention for broader adoption of cellular therapy, including unique toxicities, cost of therapy, manufacturing, and product quality. Given the promising efficacy observed, we need to address barriers and minimize delays to improve equity and to avoid further exacerbating previously observed disparities in outcomes in lymphoma.