FDA Grants Fast Track Status to Azercabtagene Zapreleucel in CLL/SLL and MZL

The FDA has granted fast track designation to azercabtagene zapreleucel (azer-cel; PBCAR0191), an investigational allogeneic CD19-directed chimeric antigen receptor (CAR) T-cell therapy, for 2 B-cell malignancy indications: relapsed or refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and R/R marginal zone lymphoma (MZL). The announcement follows interim phase 1b trial data demonstrating a 100% overall response rate (ORR) in patients with CAR T-naive CLL/SLL and an 83% ORR in MZL, including 4 complete responses (CRs) among 6 evaluable patients.¹

The FDA's tast Track program is designed to facilitate development and expedite review of therapies that address serious or life-threatening conditions with unmet medical need. Among its advantages are more frequent FDA interactions during drug development, eligibility for rolling review of regulatory submissions, and potential qualification for accelerated approval and priority review upon meeting applicable criteria.

Disease Burden and Unmet Need

CLL/SLL is the most common adult leukemia in Western countries. The Surveillance, Epidemiology, and End Results (SEER) database estimates an age-adjusted incidence of 4.6 per 100,000 persons per year in the US, with approximately 20,700 new CLL cases diagnosed nationally in 2024 and an estimated 215,107 Americans currently living with the disease.² The median age at diagnosis is 70 years, and although targeted therapies have substantially improved outcomes, many patients experience disease progression despite multiple lines of treatment.

MZL is an indolent, incurable B-cell lymphoma representing approximately 7% of all mature non-Hodgkin lymphomas (NHLs). Incidence rates have been increasing since 2001, and despite the availability of anti-CD20 chemoimmunotherapy as standard frontline therapy, patients who relapse have limited treatment options.³ A significant unmet need persists particularly for patients who are refractory to Bruton tyrosine kinase (BTK) inhibitors or anti-CD20-based regimens.

Phase 1b Trial Data

The fast track Designation is supported by results from an ongoing phase 1b basket trial (NCT03666000), an open-label, multicenter, dose-escalation and dose-expansion study evaluating the safety and clinical activity of azercabtagene zapreleucel in patients with R/R NHL and R/R B-cell acute lymphoblastic leukemia.¹

In the CLL/SLL cohort, all patients who were CAR T-naive and had received a median of 3 or more prior lines of therapy achieved a partial response, yielding a 100% ORR. Updated data for the MZL cohort show an 83% ORR based on 5 of 6 evaluable patients responding, including 4 CRs, in patients who had received a median of 2 or more prior lines of therapy.

More comprehensive interim results from the trial's dose expansion cohort, presented at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting (abstract 7012), included 19 patients across multiple B-cell malignancy subtypes: diffuse large B-cell lymphoma (DLBCL; n = 5), MZL (n = 5), CLL (n = 4), primary central nervous system lymphoma (PCNSL; n = 3), follicular lymphoma (n=1), and Waldenström macroglobulinemia (n = 1).⁴ Following 3 days of lymphodepletion with fludarabine and cyclophosphamide, patients received an infusion of 500×10⁶ azer-cel cells with low-dose interleukin-2 (IL-2).

Across the full cohort, the ORR was 81% with a CR rate of 31%. Patients with MZL, CLL, follicular lymphoma, and Waldenström macroglobulinemia achieved a 100% objective response, while response rates were 60% in DLBCL and 50% in PCNSL. Pharmacokinetic analyses in 16 patients demonstrated robust CAR T-cell expansion, with an average peak expansion of 1.7×10⁵ copies/µg genomic DNA at a median of 5.9 days—earlier than the 10- to 14-day peak typically observed with autologous CAR T products, and quantitatively comparable to expansion levels reported for approved autologous agents including axicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene maraleucel.

Safety data from the ASCO presentation noted that cytokine release syndrome (CRS) occurred in 79% of patients (n = 15/19), with all events classified as grade 1 to 2. Immune effector cell-associated neurotoxicity syndrome (ICANS) was observed in 37% of patients (7/19), including 3 grade 1 to 2 events, 3 grade 3 events, and 1 grade 4 event. These rates warrant continued monitoring as enrollment expands, and the ICANS incidence, while consistent with CAR T-class effects, will require further characterization in larger cohorts.

Allogeneic Platform: Clinical Rationale

Azer-cel is engineered using premanufactured, donor-derived T cells, circumventing the 3- to 6-week manufacturing timeline associated with conventional autologous CAR T therapies, which require patient-specific cell collection and expansion. Because the product is manufactured in advance and in batches, it can in principle be made available within days of a clinical decision.

For patients with R/R CLL/SLL or MZL who have exhausted standard options, this rapid availability has clinical relevance. Patients with heavily pretreated, rapidly progressive disease may not survive the wait time required for autologous manufacturing, or may present with T-cell dysfunction that compromises autologous product quality. An off-the-shelf approach addresses both constraints.

A protocol amendment has expanded the cilnical trial to include patients with mantle cell lymphoma and a new combination arm investigating azer-cel with BTK inhibitors in patients refractory to BTK inhibitor therapy. Preclinical and translational evidence suggests BTK inhibitor exposure may shift T cells toward a Th1 phenotype, expand the central memory compartment, and attenuate CAR T-cell exhaustion, potentially enhancing response durability.

Regulatory Significance

This is the second fast track designation azer-cel has received; the FDA previously granted the designation for R/R DLBCL.⁵ Fast track status in both CLL/SLL and MZL increases the depth and frequency of FDA engagement as the sponsor advances regulatory discussions, and may support a streamlined path toward registrational trials and eventual approval in these indications.

"FDA fast track designation for both CLL/SLL and MZL reflects the meaningful clinical activity we are seeing with azer-cel across multiple B-cell malignancies," said Leslie Chong, managing director and CEO of Imugene, in a news release. "For patients who have exhausted standard treatment options in these indications, we believe azer-cel represents a genuinely promising approach, and this designation will support closer engagement with the FDA as we advance the program."

Limitations and Context

The current efficacy data derive from small, single-arm, phase 1b cohorts. Although the response rates are noteworthy, particularly in heavily pretreated patients, definitive conclusions about efficacy await confirmation in larger, controlled trials. Duration of response data remain limited, and long-term outcomes including overall survival have not been reported. The ICANS rate, while not unusual for CD19-directed CAR T therapies, will require monitoring in expanded cohorts. Additionally, because the trial was designed as a basket study, cross-cohort comparisons must be interpreted with caution given differences in baseline disease characteristics, prior therapies, and cohort sizes.

REFERENCES

1. Imugene's Azer-cel Granted FDA Fast Track Designation for CLL/SLL and MZL. News relase. Imugene. June 9, 2026. Accessed June 10, 2026.

2. Hallek M. Chronic Lymphocytic Leukemia: 2025 Update on the Epidemiology, Pathogenesis, Diagnosis, and Therapy. Am J Hematol. 2025 Mar;100(3):450-480. doi: 10.1002/ajh.27546. Epub 2025 Jan 28. PMID: 39871707; PMCID: PMC11803567.

3. Cheah CY, Zucca E, Rossi D, Habermann TM. Marginal zone lymphoma: present status and future perspectives. Haematologica. 2022 Jan 1;107(1):35-43. doi: 10.3324/haematol.2021.278755. PMID: 34985232; PMCID: PMC8719063.

4. Blunt D, et al. Azercabtagene zapreleucel (azer-cel) in relapsed or refractory CLL and non-Hodgkin lymphoma. Presented at: 2026 American Society of Clinical Oncology Annual Meeting; May 29, 2026. Abstract 7012.

5. Azer-cel granted FDA fast track designation in blood cancer DLBCL. News release. Imugene. March 19, 2025. Accessed June 10, 2026. https://tinyurl.com/2f9efr4k