FDA Issues New CRL for Tabelecleucel in Epstein Barr Virus–Positive PTLD

The FDA has issued a complete response letter (CRL) for tabelecleucel (tab-cel; Ebvallo) as a treatment for patients 2 years and older with Epstein-Barr virus (EBV)–positive posttransplant lymphoproliferative disease (PTLD) who received 1 or more prior lines of treatment, including a CD20-directed agent, according to a press release from the developer Atara Biotherapeutics.¹

In July 2024, the FDA originally accepted and granted priority review to a biologics license application (BLA) for tab-cel in this EBV-positive PTLD population.² The BLA was supported by data from the phase 3 ALLELE trial (NCT03394365), in which investigators evaluated the agent among patients with EBV-positive PTLD who underwent prior solid organ transplantation or hematopoietic cell transplantation (HCT).

The FDA later issued a complete response letter (CRL) for tab-cel in January 2025.³ The CRL primarily related to observations of a third-party manufacturing facility for the agent. At the time, the agency highlighted no deficiencies associated with the manufacturing, efficacy, or safety of tab-cel in the BLA; no additional clinical trials were requested. Later that month, the FDA placed a clinical hold on the investigational new drug application for tab-cel due to the manufacturing compliance issues described in the CRL.⁴

In May 2025, the FDA lifted its clinical hold on tab-cel after reviewing supplemental data on the finished drug product.⁵ Additionally, the agency accepted and granted priority review to a resubmitted BLA for tab-cel in July 2025.⁶

Regarding the latest CRL, the FDA noted that developers had satisfactorily resolved the Good Manufacturing Practices issues associated with the previous letter. Additionally, the agency identified no safety issues. However, the new CRL noted that findings from the ALLELE trial were no longer sufficient to support the accelerated approval of tab-cel, as the agency stated that the study design, conduct, and analysis confounded the trial’s interpretability.

“We are surprised and disappointed by this FDA decision for [patients with EBV-positive] PTLD who have a significant unmet need, highlighted by tabelecleucel’s orphan drug designation and by the granting of breakthrough status at the time we submitted the ALLELE primary data. The issues highlighted in the CRL were issues that Atara and the FDA had aligned on in previous reviews or communications. We had aligned with the agency to accept an accelerated approval and to perform a post-marketing confirmatory study to support full approval. We proceeded with the BLA submission on this basis and continued all remediation efforts after the resubmission in 2025, in full reliance on the confirmation provided by the FDA,” Cokey Nguyen, president and chief executive officer at Atara, stated in the press release.¹ “We strongly believe that tabelecleucel can bring substantial benefit to [patients with PTLD], and look forward to addressing the concerns of the FDA clinical review team newly in place alongside our partners.”

Investigators previously shared findings from the ALLELE trial at the 51st Annual European Society for Blood and Marrow Transplantation Meeting.⁷ Data revealed that the overall response rate (ORR) among all patients (n = 75) was 50.7% (95% CI, 38.9%-62.4), which included complete responses (CRs) in 28.0% and partial responses (PRs) in 22.7%. Among 26 patients with prior HCT, the ORR was 50.0%, the CR rate was 30.8%, and the PR rate was 19.2%; the respective rates for 49 patients with prior solid organ transplantation were 51.0%, 24.5%, and 26.5%.

At 12 months, the overall survival (OS) rate was 55.7% among all patients, 78.7% in those with a response, and 28.2% in those without a response. Additionally, the median OS was 18.4 months (95% CI, 5.7-not evaluable [NE]), NE (95% CI, 18.6 months-NE), and 3.7 months (95% CI, 1.8-11.0) in each respective group.

“Tabelecleucel represents a transformative treatment for patients with relapsed/refractory EBV-positive PTLD. [This agent] had a promising ORR and OS in this difficult-to-treat patient population,” Sridhar Chaganti, MD, PhD, MRCP, FRCPath, of the Centre for Clinical Haematology at the University Hospitals Birmingham NHS Foundation Trust, stated with coauthors in a presentation of the ALLELE trial findings.⁷

In the international, open-label, multicenter phase 3 ALLELE trial, patients were assigned to receive tab-cel at 2.0 x 10⁶ cells/kg intravenously on days 1, 8, and 15 of each approximately 5-week cycle. Clinical and radiographic assessments took place on approximately day 28 of treatment.

The trial’s primary end point was ORR. Secondary end points included time to response, time to best response, OS, progression-free survival, and the rates of allograft loss or rejection episodes among patients with prior solid organ transplantation.

Patients of any age with locally assessed, biologically proven EBV-positive PTLD and prior solid organ transplant of the kidney, liver, heart, lung, pancreas, or small bowel or prior HCT were eligible for enrollment on the trial.⁸ Other eligibility criteria included having an ECOG performance status of no higher than 3 among patients 16 years and older or a Lansky score of at least 20 for those younger than 16.

Findings presented at the European Society for Blood and Marrow Transplantation Meeting revealed that 62.7% of patients had treatment-emergent serious adverse effects (SAEs), including 8.0% that were related to treatment. There were no instances of tumor flare reactions, infusion-related reactions, cytokine release syndrome, bone marrow rejection, immune effector cell-associated neurotoxicity syndrome, immunogenicity, or transmission of infectious diseases like cytomegalovirus.

Among patients with prior HCT, 11.5% experienced graft-versus-host-disease; 6.1% of patients with prior solid organ transplantation had bone marrow or organ rejection. None of these events were related to treatment with tab-cel.

References

1. Atara Biotherapeutics provides regulatory and business update on EBVALLO™ (tabelecleucel). News release. Atara Biotherapeutics. January 12, 2026. Accessed January 12, 2026. https://tinyurl.com/5h34yxtx
2. Atara Biotherapeutics announces U.S. FDA acceptance and priority review of the biologics license application for tabelecleucel (tab-cel) for the treatment of Epstein-Barr virus positive post-transplant lymphoproliferative disease. News release. Atara Biotherapeutics. July 17, 2024. Accessed January 8, 2026. https://tinyurl.com/yc4dx6yk
3. Atara Biotherapeutics provides regulatory and business update on EBVALLO (tabelecleucel). News release. Atara Biotherapeutics. January 16, 2025. Accessed January 8, 2026. https://tinyurl.com/3p9jrrtj
4. Atara Biotherapeutics provides update on clinical programs related to EBVALLO™ (tabelecleucel) and ATA3219. News release. Atara Biotherapeutics. January 21, 2025. Accessed January 8, 2026. https://tinyurl.com/ywmbn5md
5. Atara Biotherapeutics provides regulatory updates on EBVALLO (tabelecleucel). News release. Atara Biotherapeutics. May 5, 2025. Accessed January 8, 2026. https://tinyurl.com/3cekvud5
6. Pierre Fabre Pharmaceuticals Inc. announces FDA acceptance and priority review of the biologics license application (BLA) for tabelecleucel for the treatment of Epstein-Barr virus positive post-transplant lymphoproliferative disease (EBV+ PTLD). News release. Pierre Fabre Pharmaceuticals. July 25, 2025. Accessed January 8, 2026. https://tinyurl.com/5hfdh7cn
7. Dierick D, Ghobadi A, Baiocchi R, et al. Updated results: multicenter open-label ph 3 study of tabelecleucel for SOT or HCT recipients with EBV+ PTLD after failure of rituximab or rituximab + chemotherapy. Abstract presented at: 51st Annual Meeting of the European Society for Blood Marrow Transplantation; March 30-April 2, 2025; Florence, Italy. Abstract OS17-03.
8. A phase 3 study of tabelecleucel for participants with Epstein-Barr Virus-associated post-transplant lymphoproliferative disease after failure with rituximab or rituximab and chemotherapy (ALLELE). ClinicalTrials.gov. Updated January 7, 2026. Accessed January 8, 2025. https://tinyurl.com/2cyap8h5