The landscape of lymphoma treatment has witnessed a significant transformation with the advent of CAR T-cell therapy. Early studies have reported impressive overall response rates ranging from 50% to 80%, along with complete response rates ranging from 40% to 54% for patients with diffuse large B-cell lymphoma (DLBCL). These outcomes represent a substantial improvement compared to historical data, where complete response rates were predictably approximately 7%, with a 2-year survival of 16%.

What sets CAR T-cell therapy apart is its potential for long-term remission. Over years of follow-up, as many as 40% of patients who receive CAR T-cell therapy remain long-term relapse-free survivors. While not every patient responds initially, most who achieve a complete response experience enduring remission. A key question that arises is the optimal timing for employing CAR T-cell therapy. Traditionally, patients were considered for CAR T-cell therapy in the third line after receiving salvage chemotherapy and autologous stem cell transplant. However, prospective randomized trials, including the ZUMA-7 (NCT03391466), BELINDA (NCT03570892), and TRANSFORM (NCT03575351) trials, have challenged this paradigm. Two out of these 3 trials demonstrated statistically significant improvements in event-free survival. The most recent ZUMA-7 trial even showed an overall survival advantage.

This compelling evidence has raised questions about whether CAR T-cell therapy should be employed earlier, potentially in the first line, bypassing autologous stem cell transplant. The focus has shifted to patients who predictably have a lower likelihood of complete remission with primary therapy and a higher risk of subsequent relapse. Specifically, patients with high International Prognostic Index (IPI) at diagnosis and those with double or triple-hit lymphomas are the target of these new studies. The ZUMA-12 trial (NCT03761056), focused on high IPI and double or triple-hit lymphomas, employed a strategy where patients received an R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine)-like regimen. After 2 cycles, they underwent an interim PET scan, and if the scan remained positive, they proceeded to CAR T-cell therapy. The results showed impressive complete remissions and durability, paving the way for the ZUMA-23 trial (NCT05605899).

The ZUMA-23 trial is a prospective multicenter study that explores upfront CAR T-cell therapy in high-risk DLBCL. Although these trials are in their early stages, the preliminary ZUMA-12 data has fueled optimism that CAR T-cell therapy might indeed become a game changer in the frontline treatment of high-risk lymphoma. As these studies progress, they hold the potential to redefine the standard of care for patients with lymphoma, providing these patients with an earlier and more effective therapeutic option. The results of these trials will play a pivotal role in shaping the future of lymphoma treatment, offering hope to patients who need innovative solutions.