Highlight
• Lisocabtagene maraleucel (liso-cel) shows substantial improvements in event-free and progression-free survival over standard of care (SOC) at 3 years in second-line relapsed/refractory large B-cell lymphoma (LBCL).
• Median event-free survival with liso-cel was 29.5 months versus 2.4 months with SOC; progression-free survival was not reached with liso-cel, compared to 6.2 months with SOC.
• Overall survival (OS) benefits with liso-cel become more apparent after adjusting for crossover treatments, supporting its curative potential.
• Safety profile of liso-cel remains consistent with earlier findings without new safety signals over extended follow-up.
Study Background and Disease Burden
Large B-cell lymphoma (LBCL) represents the most common subtype of non-Hodgkin lymphoma, with heterogeneous clinical outcomes. Patients with LBCL who are refractory or relapse early (within 12 months) after first-line therapy have historically faced poor prognoses. The standard second-line approach involves salvage immunochemotherapy followed by autologous stem cell transplantation (ASCT) in eligible patients. However, conventional therapies often fail to induce durable remissions in this high-risk population, highlighting a critical unmet need for more effective second-line treatments.
Chimeric antigen receptor (CAR) T-cell therapies targeting CD19 have revolutionized treatment in relapsed/refractory LBCL after multiple prior lines of therapy, but their role as second-line therapy remained under investigation. Lisocabtagene maraleucel (liso-cel), a defined-composition CAR T-cell product, offers a novel therapeutic option with potential to improve survival outcomes in the second-line setting for patients eligible for ASCT. The randomized, phase III TRANSFORM trial was designed to directly compare liso-cel with SOC in this high-risk population.
Study Design
The TRANSFORM study is a randomized, open-label phase III clinical trial enrolling adults (N=184) with second-line primary refractory or early relapsed (≤12 months from first-line therapy) LBCL who were eligible for ASCT. Participants were randomized 1:1 to receive either liso-cel (administered as 100 × 106 CAR-positive T cells) or SOC, consisting of salvage chemotherapy followed by ASCT.
The primary endpoints evaluated included event-free survival (EFS), progression-free survival (PFS), and overall survival (OS). Secondary endpoints captured safety, duration of response, and quality of life measures. Key features included allowance for patient crossover from SOC to liso-cel upon disease progression, which was accounted for in survival analyses using appropriate statistical methods. Median follow-up for this 3-year update was 33.9 months.
Key Findings
After a median follow-up of nearly 3 years, the results demonstrated marked and durable efficacy advantages for liso-cel compared with SOC.
Event-Free Survival: Median EFS was 29.5 months (95% CI, 9.5 to not reached) for the liso-cel group versus 2.4 months (95% CI, 2.2 to 4.9 months) for the SOC group. The hazard ratio (HR) for EFS was 0.375 (95% CI, 0.259 to 0.542), indicating a 62.5% reduction in risk of progression, relapse, or death with liso-cel.
Progression-Free Survival: Median PFS was not reached (95% CI, 12.6 months to NR) for liso-cel versus 6.2 months (95% CI, 4.3 to 8.6 months) for SOC, with an HR of 0.422 (95% CI, 0.279 to 0.639). The 36-month PFS rate was 51% for liso-cel compared to 26.5% for SOC, illustrating superior disease control.
Overall Survival: Median OS was not reached in either arm at the time of analysis. The unadjusted HR was 0.757 (95% CI, 0.481 to 1.191), with 36-month OS rates of 63% for liso-cel and 52% for SOC. Importantly, 66% of patients in the SOC arm crossed over to receive liso-cel, confounding OS interpretation. After accounting for crossover effects using rank-preserving structural failure time models, the adjusted OS HR favored liso-cel significantly at 0.566 (95% CI, 0.359 to 0.895), suggesting meaningful survival benefit.
Safety: The safety profile of liso-cel was consistent with prior reports, with no new or unexpected adverse events emerging during long-term follow-up. Common adverse events related to CAR T-cell therapy included cytokine release syndrome and neurotoxicity, generally manageable with contemporary supportive care. Compared to SOC, the liso-cel arm demonstrated a favorable tolerability profile overall.
Expert Commentary
The TRANSFORM study’s 3-year data solidify the role of lisocabtagene maraleucel as a transformative second-line therapy for patients with high-risk relapsed/refractory LBCL. The substantial improvements in event-free and progression-free survival, along with robust indications of improved overall survival after adjusting for crossover, mark a significant advance over salvage chemotherapy and ASCT.
From a mechanistic standpoint, liso-cel’s defined cell composition and controlled manufacturing process may contribute to its efficacy and safety advantages. Furthermore, these findings align with emerging evidence supporting earlier use of CAR T-cell therapies in aggressive lymphoma, challenging traditional sequential treatment paradigms.
Notably, the allowance of patient crossover to liso-cel after SOC failure reflects real-world clinical practice but complicates interpretation of OS. The statistical adjustments employed help clarify treatment effects but highlight the difficulty of maintaining equipoise in rapidly evolving treatment landscapes. Nevertheless, the durable remissions observed support the hypothesis of potential curative benefit in this population.
Limitations include the restricted enrollment to patients eligible for ASCT, leaving an evidence gap for transplant-ineligible individuals. Additional studies may further define biomarkers predictive of response and expand access.
Conclusion
The 3-year follow-up results from the randomized phase III TRANSFORM study conclusively demonstrate that lisocabtagene maraleucel offers superior, durable efficacy with a manageable safety profile compared to standard salvage immunochemotherapy followed by ASCT in second-line therapy for relapsed/refractory large B-cell lymphoma. These findings support liso-cel as a new standard second-line treatment with transformative and potentially curative impact on this high-risk patient group.
Future research directions include evaluating liso-cel in broader patient populations, optimizing sequencing strategies, and investigating combination approaches to further improve outcomes. Clinicians should consider integrating CAR T-cell therapy into earlier lines of treatment for eligible patients to maximize long-term survival and quality of life.
References
Kamdar M, Solomon SR, Arnason J, Johnston PB, Glass B, Bachanova V, Ibrahimi S, Mielke S, Mutsaers P, Hernandez-Ilizaliturri F, Izutsu K, Morschhauser F, Lunning M, Chow VA, Montheard S, Santamaria J, Colicino S, Ogasawara K, Stepan L, Liu FF, Abramson JS. Lisocabtagene Maraleucel Versus Standard of Care for Second-Line Relapsed/Refractory Large B-Cell Lymphoma: 3-Year Follow-Up From the Randomized, Phase III TRANSFORM Study. J Clin Oncol. 2025 Aug 20;43(24):2671-2678. doi: 10.1200/JCO-25-00399. Epub 2025 Jul 7. PMID: 40623279; PMCID: PMC12352567.
