The New England Journal of Medicine February 17, 2022

Axicabtagene Ciloleucel as Second-Line Therapy for Large B-Cell Lymphoma

Frederick L. Locke, David B. Miklos, Caron A. Jacobson, Miguel-Angel Perales, Marie-José Kersten, Olalekan O. Oluwole, Armin Ghobadi, Aaron P. Rapoport, et al.

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Bottom Line

In patients with early relapsed or refractory large B-cell lymphoma, second-line treatment with the CAR T-cell therapy axicabtagene ciloleucel significantly improved event-free survival and response rates compared to standard-of-care salvage chemoimmunotherapy and autologous stem-cell transplantation.

Key Findings

1. At a median follow-up of 24.9 months, median event-free survival (EFS) was 8.3 months in the axi-cel group versus 2.0 months in the standard-care group (hazard ratio for event or death, 0.40; 95% CI, 0.31 to 0.51; P<0.001) [1.2.6].

2. The estimated 24-month EFS rate was 41% with axi-cel compared to 16% with standard care.

3. The objective response rate was notably higher among patients receiving axi-cel (83%) than those receiving standard care (50%).

4. An interim overall survival analysis demonstrated an estimated 2-year survival rate of 61% for axi-cel versus 52% for standard care.

5. Grade 3 or higher adverse events were common in both arms, occurring in 91% of the axi-cel group and 83% of the standard-care group, though no deaths were linked directly to cytokine release syndrome or neurologic events in the axi-cel arm.

Study Design

Design

Phase 3 RCT

Open-Label

Sample

359

Patients

Duration

24.9 mo

Median

Setting

International, multicenter

Population Adult patients with large B-cell lymphoma (LBCL) that was refractory to or had relapsed no more than 12 months after completing first-line chemoimmunotherapy.

Intervention Axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy.

Comparator Standard care: 2 to 3 cycles of investigator-selected, protocol-defined salvage chemoimmunotherapy, followed by high-dose chemotherapy and autologous stem-cell transplantation (ASCT) in responders.

Outcome Event-free survival (EFS) assessed by blinded central review.

Study Limitations

• The trial was open-label, which can introduce bias, although the primary endpoint of event-free survival was rigorously evaluated by a blinded independent central review.

• The trial population was restricted to patients who were refractory to or relapsed within 12 months of first-line therapy, so results may not fully generalize to late-relapsing patients.

• Bridging chemotherapy was not permitted during the CAR T-cell manufacturing period, which may limit generalizability to real-world clinical practice where rapidly progressing patients often require robust bridging.

Clinical Significance

The ZUMA-7 trial catalyzed a paradigm shift in the management of high-risk relapsed/refractory large B-cell lymphoma. By demonstrating the definitive superiority of axicabtagene ciloleucel over the historical approach of salvage chemotherapy and autologous stem-cell transplantation (ASCT), the study established CAR T-cell therapy as the new standard-of-care second-line treatment for patients with early treatment failure.

Historical Context

For nearly three decades, the standard second-line approach for relapsed or refractory large B-cell lymphoma was salvage platinum-based chemotherapy followed by high-dose chemotherapy and ASCT for responding patients. However, outcomes for patients with primary refractory disease or those relapsing within 12 months were notoriously poor, as they rarely responded well enough to salvage chemotherapy to even proceed to transplant. Axicabtagene ciloleucel, a CD19-directed CAR T-cell therapy originally approved for third-line therapy based on the ZUMA-1 trial, was investigated in the ZUMA-7 trial to address the profound unmet need in this high-risk second-line population.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

Axi-cel is a CD19-directed chimeric antigen receptor (CAR) T-cell therapy. What are the key structural components of a CAR, and why is CD19 an ideal target for treating large B-cell lymphoma?

Key Response

A CAR typically consists of an extracellular antigen-recognition domain (usually an scFv from a monoclonal antibody), a transmembrane domain, and an intracellular signaling domain (CD3-zeta) combined with a costimulatory domain (like CD28 in axi-cel). CD19 is ideal because it is uniformly expressed on B-cell lineage lymphomas but absent on pluripotent hematopoietic stem cells and non-hematopoietic tissues, which minimizes severe off-target toxicities while ensuring targeted eradication of the lymphoma.

Resident

Given the integration of axi-cel into the second-line setting for LBCL, what are the two most critical, unique, and potentially life-threatening toxicities associated with CAR T-cell therapy, and what are their primary pharmacologic treatments?

Key Response

The two hallmark toxicities are Cytokine Release Syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS). CRS is primarily managed with tocilizumab (an IL-6 receptor antagonist) and corticosteroids, while ICANS is managed primarily with corticosteroids (e.g., dexamethasone), as tocilizumab does not effectively cross the blood-brain barrier and can sometimes paradoxically worsen neurotoxicity.

Fellow

In the ZUMA-7 trial, axi-cel was compared to standard of care without universally allowing bridging chemotherapy, which contrasts with the BELINDA trial (evaluating tisagenlecleucel) where bridging was common. How might the allowance or prohibition of bridging chemotherapy impact trial outcomes and patient selection in second-line CAR T-cell therapy?

Key Response

Prohibiting bridging chemotherapy, as largely done in ZUMA-7, selects for a patient population whose disease can remain relatively stable during the apheresis and manufacturing period (vein-to-vein time). Conversely, trials allowing bridging (like BELINDA) may include patients with more rapidly proliferating, aggressive disease requiring immediate control, which can negatively skew efficacy results and contribute to differing outcomes across trials evaluating similar modalities.

Attending

ZUMA-7 establishes axi-cel as superior to salvage chemotherapy and ASCT for early relapsed or primary refractory LBCL. How should you counsel a patient who relapses at 18 months after first-line therapy, considering the specific inclusion criteria and historical data for ASCT?

Key Response

ZUMA-7 specifically targeted early relapse (within 12 months) or primary refractory disease, a population known to have notoriously poor outcomes with standard salvage chemo and ASCT. For patients with late relapse (greater than 12 months), standard salvage chemoimmunotherapy followed by ASCT remains the standard of care, as these patients generally have chemo-sensitive disease and can achieve a nearly 50 percent long-term cure rate without the unique logistical and toxicity burdens of CAR T-cell therapy.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The ZUMA-7 trial utilized event-free survival (EFS) as the primary endpoint and allowed substantial crossover from the standard-of-care arm to commercial CAR T-cell therapy off-protocol. How does this high rate of crossover complicate the interpretation of overall survival (OS), and what statistical methodologies can be employed to adjust for this confounding effect?

Key Response

Crossover dilutes the observable overall survival difference between arms because the control group ultimately receives the highly effective experimental intervention, potentially masking OS benefits. To estimate the true OS treatment effect had crossover not occurred, researchers must use complex statistical models such as Rank Preserving Structural Failure Time (RPSFT) models, Inverse Probability of Censoring Weighting (IPCW), or two-stage estimation methods to adjust the survival curves.

Journal Editor

In the standard-of-care arm of ZUMA-7, only about 36 percent of patients actually proceeded to autologous stem-cell transplantation. As a peer reviewer, how does this high attrition rate in the control arm impact the internal validity of the trial, and is it a failure of the control protocol or an accurate reflection of the natural history of this disease?

Key Response

A tough reviewer might initially flag the 36 percent ASCT rate as an underperforming control arm, suggesting it magnifies the experimental arm's benefit. However, the trial strictly enrolled early relapsed or refractory LBCL patients, a phenotype defined by severe chemo-resistance. The low transplantation rate accurately reflects the biological reality that the majority of these patients fail to achieve the required chemo-sensitive complete or partial response to proceed to ASCT, thereby strengthening the validity of the trial and emphasizing the urgent need for CAR-T in this setting.

Guideline Committee

Based on the significant improvement in EFS demonstrated in ZUMA-7, how should NCCN and ESMO guidelines be updated regarding the preferred second-line treatment for patients with LBCL who are refractory to or relapse within 12 months of first-line therapy, and what level of evidence supports this?

Key Response

The ZUMA-7 data, alongside the TRANSFORM trial, provided Level 1/Category 1 evidence prompting both NCCN and ESMO to update their clinical practice guidelines. Axi-cel (and liso-cel) are now established as the preferred, Category 1 second-line therapies over traditional platinum-based salvage chemoimmunotherapy and ASCT, specifically for the subgroup of patients with primary refractory disease or relapse within 12 months of completing first-line therapy.

Clinical Landscape

Noteworthy Related Trials

2017

ZUMA-1 Trial

n = 111 · NEJM

Tested

Axicabtagene ciloleucel (axi-cel)

Population

Refractory large B-cell lymphoma (third-line or later)

Comparator

None (single-arm)

Endpoint

Objective response rate (ORR)

Key result: Axi-cel yielded an 82 percent objective response rate and 54 percent complete response rate in highly refractory patients.

2021

BELINDA Trial

n = 322 · NEJM

Tested

Tisagenlecleucel (tisa-cel)

Population

Relapsed or refractory aggressive B-cell lymphoma

Comparator

Standard of care (salvage chemo + ASCT)

Endpoint

Event-free survival (EFS)

Key result: Tisagenlecleucel did not significantly improve event-free survival compared to standard of care.

2022

TRANSFORM Trial

n = 184 · Lancet

Tested

Lisocabtagene maraleucel (liso-cel)

Population

Primary refractory or early relapsed large B-cell lymphoma

Comparator

Standard of care (salvage chemo + ASCT)

Endpoint

Event-free survival (EFS)

Key result: Liso-cel significantly improved median EFS compared to standard of care (14.8 months vs 5.7 months).

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