Axicabtagene Ciloleucel Improves Multiple Clinical Endpoints in Relapsed Follicular Lymphoma

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For the treatment of relapsed or refractory follicular lymphoma, updated data from the ZUMA-5 trial, as compared with the findings of the external control cohort of SCHOLAR-5, showed substantial improvement in all key clinical endpoints with axicabtagene ciloleucel, ZUMA-5 investigators reported in a late-breaking abstract at the European Hematology Association (EHA) 2021 Virtual Congress.1

ZUMA-5 is an ongoing, single-arm, open-label, multicenter trial evaluating 146 patients with relapsed or refractory indolent non-Hodgkin lymphoma, including follicular lymphoma. These patients had received at least two prior lines of systemic therapy, including the combination of an anti-CD20 monoclonal antibody and an alkylating agent.

SCHOLAR-5 is an international, retrospective external control cohort of patients with relapsed or refractory follicular lymphoma. Data are sourced from seven institutions across five countries from patients who started third-line or later treatment, creating a cohort with highly heterogeneous therapies. Findings from the DELTA trial of idelalisib are included in the data set.2

Axicabtagene ciloleucel is the first and only chimeric antigen receptor (CAR) T-cell therapy approved in patients with relapsed or refractory indolent follicular lymphoma. Based on findings from the phase II ZUMA-5 trial, in March 2021, the U.S. Food and Drug Administration approved axicabtagene ciloleucel for the treatment of adults with relapsed or refractory follicular lymphoma after two or more lines of systemic therapy.

“These data certainly support that axicabtagene ciloleucel represents a significant improvement in treatment options for patients with relapsed or refractory follicular lymphoma.”
— John G. Gribben, DSc, FRCP, FRCPath, FMedSci

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In the 18-month analysis, performed at a median follow-up of almost 2 years, median progression-free and overall survival were not reached in ZUMA-5. Compared with other treatments in -SCHOLAR-5, axicabtagene -ciloleucel reduced the risk of disease progression by 70% (P < .001) and the risk of death by 58% (P = .0125), according to senior investigator John G. Gribben, DSc, FRCP, FRCPath, FMedSci, Professor of Medical Oncology at Cancer Research UK Barts Centre, London. Dr. Gribben is also associated with the Christie NHS Foundation Trust and the University of Manchester. The study’s first author is Paola Ghione, MD, of Roswell Park Comprehensive Cancer Center, Buffalo, New York.

Comparing Two Populations

The analysis used propensity score methodology to compare clinical outcomes from ZUMA-5 with the international SCHOLAR-5 trial. The external control cohort from SCHOLAR-5 was generated to provide comparative evidence in patients meeting the ZUMA-5 eligibility criteria and examined outcomes of patients who had received multiple lines of treatment with a variety of agents. The researchers analyzed 86 patients from ZUMA-5 and 85 patients from SCHOLAR-5. Patients had grade 1 or 2 relapsed or refractory follicular lymphoma and had failed to respond to two or more previous lines of treatment.

Paola Ghione, MD

Paola Ghione, MD

Axicabtagene ciloleucel was superior in terms of objective response rate, time to next treatment, progression-free survival, and overall survival, not only in the overall population but also in patients who had received at least three prior lines of treatment. The statistically significant improvements over other therapies, even after multiple rounds of prior therapies, highlight “the deep and durable treatment” effect of axicabtagene ciloleucel, Dr. -Gribben said. “The substantial overall survival benefit (hazard ratio [HR] = 0.42; P = .01) suggests that axicabtagene ciloleucel addresses an important unmet medical need for patients with relapsed or refractory follicular lymphoma.”

The previously reported primary analysis of the ZUMA-5 trial showed that axicabtagene ciloleucel, which targets CD19, generated a 94% response rate and a 12-month overall survival rate of 92.9%.3 Dr. Gribben presented an updated analysis conducted at a median follow-up of 23.3 months.

According to Dr. Gribben, an examination of SCHOLAR-5 has shown that “it is clear the treatment of follicular lymphoma is very heterogeneous in real-world clinical practice. Experimental options were commonly used in late-line treatment.”

ZUMA-5 eligibility criteria were applied to the SCHOLAR-5 cohort, with patients excluded or censored upon transformation. Single-agent anti-CD20 antibody was not counted as a line of therapy for eligibility, similar to ZUMA-5’s eligibility requirements. The eligible line of therapy had to be initiated after July 2014, and any of them could be the index line; one was randomly selected to be used per patient.

“This was a cross-study comparison of a retrospective study vs a prospective clinical trial, and, under normal circumstances, this could be prone to bias,” Dr. Gribben explained. “Therefore, we used propensity score methods to create balance between ZUMA-5 and SCHOLAR-5 for a broad set of prognostic covariates.”

After propensity score weighting, baseline characteristics were similar between the groups in terms of median age (approximately 63), mean lines of prior treatment (about 3.5), percentage refractory to the last line of treatment (approximately 75%), percentage with stem cell transplant (about 26%), median time since last treatment (approximately 8 months), and median time since diagnosis (76 months).

Outcomes Better With Axicabtagene Ciloleucel

The ZUMA-5 cohort, treated with axicabtagene ciloleucel, had higher response rates, longer time to next treatment, longer progression-free survival, and longer overall survival compared with the SCHOLAR-5 cohort, who were treated with a variety of other options:

  • Objective response rate: 94.2% vs 49.9% (odds ratio [OR] = 16.24; P < .0001)
  • Complete response rate: 79.1% vs 29.9% (OR = 8.86; P < .0001)
  • Median progression-free survival: not reached vs 12.7 months (HR = 0.30; P < .001)
  • Median overall survival: not reached vs 59.8 months (HR = 0.42; P = .0125)
  • Median time to next treatment: not reached vs 14.4 months (HR = 0.42; P < .001).

All these improvements with axicabtagene ciloleucel held true for the overall component and for the cohort of patients with three or more prior therapies. In fact, for overall survival, in the patients with more refractory disease, axicabtagene ciloleucel exerted an even greater benefit (HR = 0.31) than for the overall cohort (HR = 0.42), Dr. Gribben reported.

Dr. Gribben pointed out these differences are even more impressive when one considers that assessments of endpoints are much more stringent in clinical trials than in real-world practice. Thus, the benefits in SCHOLAR-5 may have been somewhat underestimated, and the differences may be greater. The findings were maintained across five prespecified sensitivity analyses, he added.


  • In ZUMA-5, treatment of patients with relapsed or refractory follicular lymphoma was substantially improved with the CAR T-cell therapy axicabtagene ciloleucel over standard treatments.
  • An 18-month analysis compared outcomes from ZUMA-5 with those of SCHOLAR-5, a data set that includes patients treated with a variety of agents.
  • Compared with other treatments in SCHOLAR-5, treatment with axicabtagene ciloleucel reduced the risk of disease progression by 70% (P < .001) and the risk of death by 58% (P = .0125).

“These data certainly support that axicabtagene ciloleucel represents a significant improvement in treatment options for patients with relapsed or refractory follicular lymphoma,” Dr. Gribben concluded.

In the ZUMA-5 safety analysis set (n = 146), grade ≥ 3 cytokine-release syndrome and neurologic toxicities occurred in 8% and 21% of patients, respectively.

‘An Important Advance’

“In an indolent disease like follicular lymphoma, longer-term data that demonstrate durable responses are critical. After a patient with follicular lymphoma relapses, the duration of response shortens with each new therapy,” said co-investigator Caron A. Jacobson, MD, MMSc. Dr. Jacobson is Medical Director of the Immune Effector Cell Therapy Program at Dana-Farber Cancer Institute and Assistant Professor of Medicine at Harvard Medical School, Boston.

“In an indolent disease like follicular lymphoma, longer-term data that demonstrate durable responses are critical.”
— Caron A. Jacobson, MD, MMSc

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“The continued durable benefit demonstrated by axicabtagene ciloleucel at nearly 2 years is exciting, and the substantial survival benefit over current therapies that we’re seeing in the SCHOLAR-5 analysis is encouraging. These follow-up data reinforce axicabtagene ciloleucel as an important advance for a group of patients who have historically had few options.” 

DISCLOSURE: Dr. Gribben has received honoraria from AbbVie, Acerta Pharma/AstraZeneca, Celgene, Gilead Sciences, Janssen, Roche/Genentech, and TG Therapeutics; has served as a consultant or advisor to AbbVie, Acerta Pharma/AstraZeneca, Celgene, Janssen, and MorphoSys; and has received research funding from Acerta Pharma/AstraZeneca, Celgene, and Janssen. Dr. Ghione reported no conflicts of interest. Dr. Jacobson has received honoraria from Precision Biosciences, Celgene/Bristol Myers Squibb, Novartis, Nkarta, Lonza, and Kite; has served on the speakers bureau for AXIS and Clinical Care Options; and has received research funding from Pfizer.


1. Ghione P, Patel A, Bobillo, S, et al: A comparison of clinical outcomes from ZUMA-5 (axicabtagene ciloleucel) and the international SCHOLAR-5 external control cohort in relapsed/refractory follicular lymphoma. EHA 2021 Virtual Congress. Abstract LBA1904. Presented June 12, 2021.

2. Gopal AK, Kahl BS, de Vos S, et al: PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med 370:1008-1018, 2014.

3. Jacobson C, Chavez JC, Sehgal AR, et al: Primary analysis of ZUMA-5: A phase 2 study of axicabtagene ciloleucel in patients with relapsed/refractory indolent non-Hodgkin lymphoma. 2020 ASH Annual Meeting & Exposition. Abstract 700. Presented December 7, 2020.