Axi-Cel Shows Safety, Clinical Activity in R/R Primary and Secondary CNS Lymphomas

Key Takeaways

  • Axi-cel showed a 94% overall response rate and 67% complete response rate in relapsed/refractory CNS lymphoma patients.
  • Median progression-free survival was 14.3 months, and overall survival was 26.4 months.
Lakshmi Nayak, MD

Lakshmi Nayak, MD

Treatment with axicabtagene ciloleucel (Yescarta; axi-cel) was safe and produced durable responses in heavily pretreated patients with relapsed/refractory primary and secondary central nervous system lymphoma (PCNSL and SCNSL), according to findings from a phase 1 study (NCT04608487) presented during the 2024 ASCO Annual Meeting.1

At a median follow-up of 24 months, axi-cel elicited an overall response rate (ORR) of 94% in the overall patient population (n = 18), including an unconfirmed/confirmed complete response (CR) rate of 67%. The median time to best response was 3 months (range, 1-6), and the median duration of response (DOR) was 13.4 months (range, 1-30). The median progression-free survival (PFS) was 14.3 months (95% CI, 6.3-not reached [NR]), the median overall survival (OS) was 26.4 months (95% CI, 11.2-NR). No treatment-limiting toxicities (TLTs) or grade 4/5 immune effector cell–associated neurotoxicity syndrome (ICANS) events were reported.

“Axi-cel was found to have promising efficacy in a heavily pretreated population, with durable responses and a 1-year PFS [rate] of 55%,” lead study author Lakshmi Nayak, MD, director of the Center for CNS Lymphoma at Dana-Farber Cancer Institute and an associate professor of neurology at Harvard Medical School in Boston, Massachusetts, stated in a presentation of the data. “We determined that axi-cel is safe for treatment of PCNSL and SCNSL with no increased risk of high-grade ICANS or cerebral edema.”

Standard treatment approaches in PCNSL and SCNSL involve induction therapy plus high-dose methotrexate-based chemotherapy, followed by consolidation with high-intensity autologous stem cell transplant (ASCT). Despite favorable initial responses to this regimen, approximately 50% to 60% of patients will experience relapse within the first 2 years, with some patients developing primary refractory disease.

“Optimal salvage therapy for treatment of relapsed and refractory CNS lymphomas is not well established, and we don’t have any standard-of-care guidelines,” Nayak explained during the presentation.

The anti–CD19/CD28-directed autologous CAR T-cell therapy axi-cel is FDA approved as a second-line treatment in primary refractory/early relapsed diffuse large B-cell lymphoma (DLBCL), as well as a third-line treatment in LBCL and follicular lymphoma.2,3 Retrospective data have suggested that axi-cel may have activity in CNSL; however, clinical trials evaluating axi-cel in systemic lymphoma have traditionally excluded patients with CNS disease, and PCNSL remains a specific exclusion to axi-cel’s label.1

This prospective pilot study was conducted to assess the safety and efficacy of axi-cel in CNSL. The current analysis includes longer follow-up data from the complete patient cohort.

The study enrolled patients with CNSLs, including PCNSL and SCNSL, with or without systemic involvement who had experienced relapse after treatment with 1 or more CNS-directed systemic therapies. After undergoing leukapheresis, patients received a conditioning chemotherapy regimen comprising 30 mg/m2 of fludarabine and 300 mg/m2 of cyclophosphamide on day -5 to -3. This was followed by axi-cel infusion and observation from day 0 to at least day 7.

The first 3 patients enrolled onto the study were evaluated for TLTs during the first 28 days, after which 15 more patients were accrued in the event that no TLTs were observed. Paired peripheral blood and cerebrospinal fluid (CSF) was collected at the time of both leukapheresis and conditioning chemotherapy administration, as well as days 0 to 8 of hospitalization, during the first tumor assessment on day 28, and every 3 months thereafter for up to 24 months. These were evaluated for cytokine analysis, flow cytometry, single-cell RNA sequencing, cytometry by time of flight, and minimal residual disease, with the aim of elucidating mechanisms of resistance or ICANS.

The study’s primary end point was safety, specifically the rate of TLTs and grade 3 or higher adverse effects (AEs). Key secondary end points include ORR, CR rate, DOR, PFS, and OS. Serum and CSF levels of axi-cel and cytokines as well as peripheral blood and CSF immune subsets and circulating tumor DNA served as exploratory correlatives.

Of the 24 patients initially screened, 6 did not progress to treatment due to organ function (n = 2), infection (n = 2), progression (n = 1), or patient preference (n = 1). All 18 patients enrolled onto the study underwent leukapheresis, and 5 received palliative targeted radiotherapy immediately preceding screening. No bridging therapy was administered after patient consent was obtained. However, a stable or lower dose of dexamethasone was allowed. This was reduced to 2 mg per day by axi-cel infusion in all patients except 1. Of these, 5 continued receiving steroids from screening until treatment. None of these patients were on steroids at the time of response assessment.

The median age of patients in the study was 62 (range, 33-81) and the majority were male (56%). PCNSL was present in 72% of participants; 22% had SCNSL and 6% had systemic and vitreoretinal lymphoma. Most tumors were parenchymal (94%). The median number of prior treatments was 3 (range, 1-7), and 33% of patients had previously received ASCT. The time from diagnosis to enrollment was 489 days (range, 150-8665), and the time from last treatment to enrollment was 72 days (range, 4-1273).

Additional safety analysis revealed that the incidence of any-grade cytokine release syndrome (CRS) was 89%, and no grade 3 or higher events were reported. The median time to onset was 2 days (range, 1-6) and the median duration was 5.5 days (range, 1-9). Tocilizumab (Actemra) was administered in 78% of patients, with a median of 1 dose received (range, 1-2). Dexamethasone was given to 72% of patients, with a median of 1 dose received (range, 1-7). Any-grade ICANS was observed in 44% of patients, 28% of which were grade 3 events. The median time to onset was 6 days (range, 3-9) and the median duration was 4 days (range, 1-56). No patients required tocilizumab for ICANS, and 29% required dexamethasone, with a median of 2 doses (range, 1-9). Prolonged grade 3 or higher cytopenias occurred in 56% of patients; these resolved by 3 months.

Other AEs of interest included grade 3 Ommaya reservoir infection requiring removal (n = 2), grade 3 electrographic focal status epilepticus (n = 1), grade 2 low-grade renal cell carcinoma (n = 1), and grade 4 low-risk myelodysplastic syndrome at 12 months (n = 1). A total of 7 patients experienced death due to disease progression.

Early findings from ongoing correlative studies showed that CAR T-cell expansion in patients with CNSL was comparable to that seen in those with refractory non-Hodgkin lymphoma from the phase 1/2 ZUMA-1 trial (NCT02348216). Patients with ongoing responses, as well as those experiencing higher-grade ICANS events, had increased CAR T-cell expansion. Moreover, baseline inflammatory cytokines and peak levels of inflammatory interleukin (IL)-6 and myeloid-related MCP1 in serum were associated with high-grade ICANS. Peak levels of IL-15 were also higher in patients with grade 2 or higher ICANS events.

Nayak added that, “Patients with ongoing CRs demonstrated increased levels of the serum pro-inflammatory cytokines interferon gamma, IL-2, and granzyme B.”

Differential gene expression analyses in peripheral blood vs CSF were subsequently conducted at peak expansion. Genes associated with T-cell exhaustion, such as PD-1, TIM-3 and BLIMP-1 were found to be more highly expressed in CSF CAR T cells vs peripheral blood CAR T cells, indicating a higher risk of CAR T-cell inhibition in the CSF.

To elucidate whether this finding correlated with responses, differential gene expression of CSF CD8-directed CAR T cells in patients with ongoing responses was compared with that of patients experiencing early progression. “The analysis of CSF CAR T cells from patients with durable CRs showed an increase in expression of exhaustion-reversing genes such as CD226 and BACH2,” Nayak concluded.

Disclosures: Dr Nayak reports the following disclosures: receiving honoraria from Ono Pharmaceuticals; serving in a consulting or advisory role for BraveBio, Genmab, Kite/Gilead, and Ono Pharmaceuticals; serving on a speakers’ bureau for Ono Pharmaceuticals; receiving institutional research funding from AztraZeneca, Kazia Therapeutics, Merck, and Ono Pharmaceuticals; receiving royalties from Wolters Kluwer/UpToDate, Inc; and having travel expenses paid for by Ono Pharmaceuticals.


  1. Nayak L, Chukwueke UN, Hogan S, et al. A pilot study of axicabtagene ciloleucel (axi-cel) for relapsed/refractory primary and secondary central nervous system lymphoma (PCNSL and SCNSL). J Clin Oncol. 2024;42(suppl 16):2006. doi:10.1200/JCO.2024.42.16_suppl.2006
  2. FDA approves axicabtagene ciloleucel for second-line treatment of large B-cell lymphoma. FDA. April 1, 2022. Accessed June 11, 2024.
  3. US FDA approves Yescarta for relapsed or refractory follicular lymphoma after two or more lines of systemic therapy. News release. Kite. March 5, 2021. Accessed June 11, 2024.
Related Videos
Mazyar Shadman, MD, MPH
Sheldon M. Feldman, MD
Rita Mukhtar, MD
Lajos Pusztai, MD, DPhil
Hope S. Rugo, MD
Craig Eckfeldt, MD, PhD, assistant professor, medicine, faculty, Microbiology, Immunology, and Cancer Biology PhD Graduate Program, Division of Hematology, Oncology, and Transplantation, the University of Minnesota Medical School
Alicia Morgans, MD, MPH, genitourinary medical oncologist, medical director, Survivorship Program, Dana-Farber Cancer Institute; associate professor, medicine, Harvard Medical School
Mark Juckett, MD, professor, medicine, Division of Hematology, Oncology, and Transplantation, the University of Minnesota Medical School
Timothy Hughes, MD, MBBS, FRACP, FRCPA
Hannah Choe, MD, an expert on GVHD