FDA Issues CRL for Tabelecleucel in EBV+ Post-Transplant Lymphoproliferative Disease

The FDA has issued a CRL for the biologics license application (BLA) seeking the approval of tabelecleucel (Ebvallo) for the treatment of Epstein-Barr virus (EBV)–positive post-transplant lymphoproliferative disease after progression on standard-of-care therapy.¹

The decision follows the FDA’s acceptance of a resubmitted BLA in July 2025.

The BLA submission was supported by clinical data from the phase 3 ALLELE trial (NCT03394365), which evaluated tabelecleucel in patients with relapsed or refractory EBV-positive post-transplant lymphoproliferative disease following hematopoietic stem cell transplant (HSCT) or solid organ transplant.

The agent is also being assessed in a phase 2 multicohort label-expansion study (NCT04554914) across patients with multiple EBV-associated diseases.

What was the reason for the CRL for tabelecleucel in EBV-positive post-transplant lymphoproliferative disease?

In July 2024, the FDA granted priority review to tabelecleucel for this indication.² The BLA supporting the priority review was subsequently issued a CRL by the FDA in January 2025.³ This initial CRL cited issues solely related to findings from an inspection at a third-party manufacturer.

According to the present news release, although the FDA acknowledged that the manufacturer-related issue had been resolved and did not raise any safety concerns, the agency indicated that it no longer considers the previously accepted single-arm ALLELE study sufficient to support accelerated approval and requested a new study.¹ The company noted that this is an unexpected shift that contrasts with more than 5 years of ongoing dialogue with the agency.

How was the ALLELE study designed?

The open-label, multicenter ALLELE study is enrolling patients with EBV-associated post-transplant lymphoproliferative disease following progression on rituximab (Rituxan) or a commercially available biosimilar with or without chemotherapy in the setting of either solid organ transplant or HSCT.⁴ Eligible patients must have confirmed availability of partially human leukocyte antigen (HLA)–matched tabelecleucel.

All patients have to demonstrate measurable, FDG-avid disease with a Deauville score of at least 3 per Lugano Classification per PET-CT or MRI when clinically appropriate. Central nervous system (CNS) involvement is permitted if imaging confirms measurable disease and CNS-directed therapy has been completed.

Patients are assigned to 1 of the following cohorts: solid organ transplant recipients who had progressed on rituximab alone, solid organ transplant recipients who had progressed on both rituximab and chemotherapy, or HSCT recipients who had progressed on rituximab alone. All enrolled patients receive intravenous tabelecleucel at a dose of 2 × 10⁶ cells/kg on days 1, 8, and 15 of each 35-day cycle. Treatment continues until maximal response, unacceptable toxicity, initiation of non-protocol therapy, or lack of response after up to 2 HLA restrictions in the solid organ transplant cohorts or 4 restrictions in the HSCT cohort.

The trial’s primary end point is ORR. Secondary end points include duration of response (DOR), overall survival (OS), time to response, time to best response, and rates of allograft loss or rejection episodes.

What findings did the ALLELE trial establish with tabelecleucel?

Updated results presented at the 2024 ASH Annual Meeting showed that patients with relapsed/refractory EBV-positive post-transplant lymphoproliferative disease treated with tabelecleucel (n = 75) achieved an ORR of 50.7%.⁵ The ORR was 51.0% in patients who underwent a solid organ transplant (n = 49) and 50.0% in those who received a hematopoietic stem cell transplant (HSCT; n = 26). Patients in the overall cohort achieved a median DOR of 23 months and a median OS of 18.4 months.

Regarding safety, serious treatment-emergent adverse effects (TEAEs) occurred at a rate of 65.4% in HSCT recipients treated with tabelecleucel and 61.2% in patients who received a solid organ transplant. The respective rates of fatal TEAEs were 19.2% and 18.4%. No fatal TEAEs were treatment related, and no instances of cytokine release syndrome, tumor flare or infusion reactions, immune effector cell–associated neurotoxicity syndrome, or transmission of infectious diseases were reported. No graft-vs-host disease or organ rejection related to tabelecleucel were reported.

References

1. Pierre Fabre Pharmaceuticals statement regarding receipt of complete response letter for tabelecleucel biologics license application from the U.S. Food and Drug Administration. News Release. Pierre Fabre Pharmaceuticals. January 12, 2026. Accessed January 12, 2026. https://www.pierrefabrepharmaceuticals.com/sites/default/files/press/20260112_PS_FDA%20CRL%20on%20EBVALLO%20BLA.pdf
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, Inc. July 24, 2024. Accessed January 12, 2025. https://investors.atarabio.com/news-events/press-releases/detail/376/atara-biotherapeutics-announces-u-s-fda-acceptance-and
3. Atara Biotherapeutics provides regulatory and business update on Ebvallo (tabelecleucel). News release. Atara Biotherapeutics. January 16, 2025. Accessed January 12, 2026. https://investors.atarabio.com/news-events/press-releases/detail/367/atara-biotherapeutics-provides-regulatory-and-business
4. Tabelecleucel for solid organ or allogeneic hematopoietic cell transplant participants with Epstein-Barr virus-associated post-transplant lymphoproliferative disease (EBV+ PTLD) after failure of rituximab or rituximab and chemotherapy (ALLELE). ClinicalTrials.gov. Updated January 7, 2026. Accessed January 12, 2026. https://clinicaltrials.gov/study/NCT03394365
5. Updated results of phase 3 ALLELE study presented at 66th American Society of Hematology Annual Meeting confirm efficacy, safety and durability of novel allogeneic cell therapy tabelecleucel in relapsed or refractory Epstein-Barr virus positive post-transplant lymphoproliferative disease (EBV+ PTLD). News release. Pierre Fabre Pharmaceuticals. December 7, 2024. Accessed January 12, 2026. https://www.prnewswire.com/news-releases/updated-results-of-phase-3-allele-study-presented-at-66th-american-society-of-hematology-annual-meeting-confirm-efficacy-safety-and-durability-of-novel-allogeneic-cell-therapy-tabelecleucel-in-relapsed-or-refractory-epstein-barr--302325211.html