publications 

High Cost Therapy Profile: January 2025

Tabelecleucel Intravenous (IV) 
Oncology 

January 8, 2025

Proposed indications 

Epstein-Barr virus-positive (EBV+) post-transplant lymphoproliferative disease (PTLD)  

United States (U.S.) Food and Drug Administration (FDA) approval timeline

Jan. 15, 2025

  • Breakthrough Therapy 
  • Orphan Drug 
  • Priority Review 

Place in therapy 

Tabelecleucel (tab-cel) is an allogeneic, Epstein-Barr virus (EBV)-specific T-cell immunotherapy that kills EBV infected cells in a targeted manner. 

  • If approved, tab-cel will be monotherapy treatment of EBV+ PTLD in patients ≥ 2 years of age who have received at least one prior therapy (this includes chemotherapy, unless inappropriate, in solid organ transplant [SOT] recipients). 
  • If approved, tab-cel will be the first treatment specifically indicated for EBV+ PTLD. It will likely be used as a second-line treatment following rituximab. 
  • As an allogeneic T-cell therapy, tab-cel offers potential advantages over autologous chimeric antigen receptor (CAR) T-cell therapies. Unlike CAR T-cell therapy, tab-cel is readily available and administered over a few minutes compared to a 30-minute infusion with autologous CAR T.  
  • In addition, tab-cel does not require the patient to undergo apheresis or lymphodepletion and is not associated with cytokine release syndrome (CRS) or neurotoxicity. 
  • Tab-cel may be more accessible as it requires a shorter monitoring time during and after the dose (1 to 2 hours) in a controlled setting equipped to manage adverse reactions compared to one to two weeks of inpatient monitoring with autologous CAR T-cell therapy.  
  • Institute for Clinical and Economic Review (ICER) released a final evidence report on tab-cel for EBV+ PTLD suggesting, with high certainty, that there is a substantial net health benefit compared to usual care. Although evidence is limited, ICER suggests that tab-cel provides important clinical benefit to patients by extending survival with minimal damage. However, longer-term safety data is needed. 

Understanding your data 

Tab-cel is an “off-the-shelf” donor-derived EBV-specific cytotoxic T-cell immunotherapy designed to target and eliminate EBV+ cells. Clinical trial data on tab-cel demonstrated complete remission or sustained partial remission in a significant number of patients resulting in longer survival and higher survival rates. Studies evaluating tab-cel in EBV+ PTLD include the following: 

  • NCT02822495: Expanded access protocol for providing tab-cel to patients with EBV-associated viremia or malignancies for whom there are no appropriate alternative therapies 
  • NCT03394365 ALLELE: Multicenter, open-label, phase 3 study of tab-cel for solid organ or allogeneic HSCT subjects with EBV-associated PTLD after failure of rituximab or rituximab and chemotherapy  
  • NCT04554914 EBVision: An open-label, single-arm, multicohort, phase 2 study to assess the efficacy and safety of tab-cel in subjects with EBV-associated diseases 
  • NCT03769467: An open-label phase 1B/2 study to evaluate the safety and efficacy of tab-cel in combination with pembrolizumab in subjects with platinum-pretreated, recurrent/metastatic EBV-associated nasopharyngeal carcinoma 

Identification of patients would reflect the clinical trials criteria listed in the studies above, as well as diagnosis codes identified from claims data requiring among others: 

Common Measurable Inclusion Criteria: 

  • Diagnosis of PTLD. 
  • Treatment failure of rituximab or biosimilar monotherapy (SOT subgroup A or HSCT cohort) or rituximab for treatment of PTLD. 
  • For HSCT cohort only: 
    • If allogenic HSCT performed as treatment for an acute lymphoid or myeloid malignancy, the underlying primary disease for which the patient underwent transplant must be in morphologic remission. 

Common Measurable Exclusion Criteria:

  • Pregnancy or lactating.
  • Diagnosis of Burkitt lymphoma, classical Hodgkin lymphoma, or any T-cell lymphoma.
  • Ongoing methotrexate or extracorporeal photopheresis. 
  • Ongoing use of a checkpoint inhibitor agent (e.g., ipilimumab, pembrolizumab, nivolumab). 

Appendix

CATEGORY PROCEDURE CODES
PTLD International Classification of Diseases, Tenth Revision (ICD-10): D47.Z1
Rituximab and biosimilars Healthcare Common Procedure Coding System (HCPCS): J9311, J9312, Q5123, Q5115, Q5119
Allogenic HSCT for acute lymphoid or myeloid malignancy in remission HSCT cohort only ICD-10-PCS (Allogeneic HSCT): 30230G2, 30230G3, 30233U2, 30233U3, 30230Y2, 30230Y3, 30233G2, 30233G3, 30243U2, 30243U3, 30233Y2, 30233Y3, 30240G2, 30240G3, 30240Y2, 30240Y3, 30243G2, 30243G3, 30243Y2, 30243Y3 Current Procedural Terminology (CPT): 38240 Medicare Severity Diagnosis Related Groups (MS-DRG) (Bone marrow transplant): 009 ICD-10: C91.01, C92.01, C92.41, C92.51, C92.61, C92.A1, C93.01, C94.01, C94.21
Pregnancy and lactation ICD-10: Z34.00, Z34.8, Z34.90, Z33.1, O09.00, O09.10, O09.291, O09.40, O09.211, O09.30, O09.511, O09.521, O09.611, O09.621, O09.819, O09.821, O09.822, O09.823, O09.829, O36.80x0, O09.891, O09.892, O09.893, O09.899, Z39.0, Z39.1, Z39.2, Z36, Z37, Z37.1, Z37.2, Z37.3, Z37.4, Z37.59, Z37.69, Z37.7, Z37.9, Z64.0, Z32.01, O30.009, O30.019, O30.039, O30.049, O30.099, O30.109, O30.119, O30.129, O30.199, O30.209, O30.219, O30.229, O30.299, O30.809, O30.819, O30.829, O30.899, O20.0, O44.01, O44.02, O44.03, O10.011, O10.012, O10.013, O10.02, O10.911, O10.912, O10.913, O10.92, O10.03, O21.0, O60.12X0, O60.13X0, O60.14X0, O48.0, O31.01X0, O31.02X0, O31.03X0, O98.111, O98.112, O98.113, O98.12, O98.13, O24.32, O24.911, O24.912, O24.913, O24.92, O24.93, O99.331, O99.332, O99.333, O99.334, O99.335, O80, O30.001, O30.002, O30.003, O32.0XX0, O33.0, O34.01, O34.02, O34.03, O34.01, O34.02, O34.03, O35.0XX0, O43.011, O36.0110, O36.0120, O36.0130, O36.0910, O36.0920, O36.0930, O36.1110, O36.1120, O36.1130, O36.1910, O36.1920, O36.1930, O68, O36.5110, O36.5120, O36.5130, O36.5910, O36.5920, O36.5930, O36.61X0, O36.62X0, O36.63X0, O43.101, O43.102, O43.103, O43.811, O43.812, O43.813, O43.91, O43.92, O43.93, O36.8910, O36.8920, O36.8930, O68, O77.0, O36.91X0, O36.92X0, O36.93X0, O40.1XX0, O40.2XX0, O40.3XX0, O41.01X0, O41.02X0, O41.03X0, O61.1, O64.9XX0, O62.0, O63.0, O70.0, O71.02, O71.03, O72.0, O43.211, O43.212, O43.213, O43.221, O43.222, O43.231, O43.232, O43.233, O73, O74.1, O89.09, O75.0, O86.89, O22.01, O22.02, O22.03, O87.4, O86.4, O88.011, O88.012, O88.013, O88.02, O88.03, O99.411, O99.412, O99.413, O99.42, O99.43, O91.011, O91.012, O91.013, O91.02, O92.011, O92.012, O92.013,O92.03, O35.8XX0, O36.8210, O36.8220, O36.8230, O75.89, Z37.0, Z37.2, Z37.3, Z37.59, Z37.69, O86.12, O85, O86.81, O86.89
Burkitt lymphoma ICD-10: C83.70, C83.71, C83.72, C83.73, C83.74, C83.75, C83.76, C83.77, C83.78, C83.79
Classical Hodgkin lymphoma ICD-10: C81.10, C81.11, C81.12, C81.13, C81.14, C81.15, C81.16, C81.17, C81.18, C81.19, C81.20, C81.21, C81.22, C81.23, C81.24, C81.25, C81.26, C81.27, C81.28, C81.29, C81.30, C81.31, C81.32, C81.33, C81.34, C81.35, C81.36, C81.37, C81.38, C81.39, C81.40, C81.41, C81.42, C81.43, C81.44, C81.45, C81.46, C81.47, C81.48, C81.49, C81.70, C81.71, C81.72, C81.73, C81.74, C81.75, C81.76, C81.77, C81.78, C81.79, C81.90, C81.91, C81.92, C81.93, C81.94, C81.95, C81.96, C81.97, C81.98, C81.99
Any T-cell lymphoma ICD-10: C84.40, C84.41, C84.42, C84.43, C84.44, C84.45, C84.46, C84.47, C84.48, C84.49, C84.A0, C84.A1, C84.A2, C84.A3, C84.A4, C84.A5, C84.A6, C84.A7, C84.A8, C84.A9, C86.0, C86.1, C86.2, C86.3, C86.5, C86.6, C91.50, C91.51, C91.52
Methotrexate ICD-10: J8610, J8612, J9255, J9260, J9250, J8611
Extracorporeal photopheresis CPT: 36522 ICD-10-PCS: 6A650ZZ, 6A651ZZ
Immune checkpoint inhibitors Generic product identifier (GPI): 2135822000 (Bavencio), 2135822900 (Imfinzi), 2135528010 (Imjudo), 2135792830 (Jemperli), 2135795300 (Keytruda), 2135792340 (Libtayo), 2135797072 (Loqtorzi), 2135794100 (Opdivo), 2199350250 (Opdualag), 2135821500 (Tecentriq), 2199000205 (Tecentriq), 2135796700 (Tevimbra), 2135523200 (Yervoy), 2135796020 (Zynyz)

Clinical deep dive 

Disease state overview
Post-transplant lymphoproliferative disease (PTLD) is an ultra-rare, acute, life-threatening, hematologic malignancy that can occur after SOT or an allogeneic HSCT. It typically appears in the first year after transplantation in patients with weakened T cell activity due to immunosuppressive therapy. While HSCT recipients have a limited time during which they are at risk for PTLD, SOT recipients carry a long-term risk of developing PTLD since they require lifelong immunosuppression. Epstein-Barr virus (EBV) is implicated in the majority of PTLD cases. The most significant risk factor for developing PTLD is a transplant involving an EBV-seropositive donor and an EBV-seronegative recipient. Pediatric transplant recipients are more susceptible to developing PTLD than adult recipients, as roughly 95% of all adults over 40 years of age have been exposed to EBV. High-dose post-transplant immunosuppression therapy is also associated with the development of PTLD.

Epidemiology 
The reported incidence of PTLD ranges from 1% to 30% for SOT, depending on organ type, and about 3% for HSCT. Over 46,000 SOT procedures were performed in the US, in 2023, with the majority being kidney transplants (25,000), followed by liver transplants (10,660), and then lung transplants (3,000). About 1,900 of those procedures occurred in children. In 2023, about 24,000 HSCT procedures were performed in the US, with approximately 10,000 from a donor source and 14,500 from the patient’s own viable stem cells. In the US, EBV+ PTLD occurs in <1,000 cases per year. 

Treatment 
Treatment for PTLD includes a reduction in immunosuppression therapy for early EBV+ PTLD lesions. If a complete response is not achieved, off-label use of rituximab with or without chemotherapy is initiated and results in a response in about 50% to 60% of patients. Among patients who relapse or are refractory to treatment, options are limited, and survival is poor. Non-pharmacologic treatments include surgery to remove localized lesions, and radiation therapy for localized disease or CNS involvement. Adoptive immunotherapy involving EBV-specific cytotoxic T lymphocytes (EBV-CTLs), or donor lymphocyte infusion is also used but may increase the risk for GVHD, and is therefore, reserved for EBV+ PTLD cases that persists despite initial treatment. 

Drug and clinical trial overview 

The global, open-label, phase 3 ALLELE trial evaluated tab-cel in 43 patients with EBV+ PTLD following HSCT or SOT. Participants had EBV+ PTLD that was refractory to or relapsed after rituximab (after HSCT) or rituximab and chemotherapy (after SOT). The objective response rate (ORR) was 51.2% (50% in HSCT cohort, 52% in SOT cohort). The median duration of response (DOR) was 23 months, and the median overall survival (OS) was 18.4 months. At one year, the OS rate was 84.4% among responders compared to 34.8% among non-responders. In the clinical trial, patients received tab-cel administered IV over five to 10 minutes at a dose of 2 × 106 cells/kg on days one, eight, and 15 in 35-day cycles. Treatment continued until maximal response, unacceptable toxicity, initiation of non-protocol therapy, or failure of tab-cel. The median number of treatment courses received was two cycles in the SOT cohort and three cycles in the HSCT cohort. Tab-cel was generally well tolerated, with no episodes of CRS, immune effector cell-associated neurotoxicity syndrome or transplant rejection related to tab-cel.  

Tab-cel is manufactured from T cells collected from healthy EBV+ donors. The cells are enhanced to recognize EBV and expanded to produce thousands of doses from a single donor. The resulting cells are characterized by EBV-specific cytotoxicity, alloreactivity, and phenotype to establish a tab-cel product inventory. While tab-cel is an off-the-shelf therapy, it requires individualization based on patient disease criteria including human leukocyte antigen (HLA)-matching. The use of EBV-targeted cells, along with partial HLA matching, reduces the risk of off-target binding and host rejection. In addition, tab-cel’s diverse inventory allows for patients who do not initially respond to tab-cel to be switched to another product (donor source) within the tab-cel library. 

Pipeline (late-stage development)

Drug name Manufacturer Route of administration Mechanism of action Proposed / studied indication Status
Acalabrutinib (Calquence) plus rituximab AstraZeneca PO HER3-targeted monoclonal antibody NSCLC and solid tumors with NRG1 gene fusions Phase 2
Polatuzumab Vedotin-piiq (Polivy) plus rituximab Genentech IV CD79b-directed antibody and microtubule inhibitor conjugate PTLD Phase 1/2
Allogeneic latent membrane proteins LMP-Specific T-Cells TBD IV allogeneic LMP1/LMP2-specific cytotoxic T-lymphocytes EBV+ PTLD Phase 2
Tafasitamab-cxix (Monjuvi) plus rituximab Morphosys IV CD19-directed cytolytic antibody PTLD Phase 2

References: 

  1. Allogeneic hematopoietic stem cell transplant market to grow rapidly during the study period (2020–2034) | DelveInsight. October 21, 2024. Available at: https://www.globenewswire.com/news-release/2024/10/21/2966426/0/en/Allogeneic-Hematopoietic-Stem-Cell-Transplant-Market-to-Grow-Rapidly-During-the-Study-Period-2020-2034 DelveInsight.html#:~:text=According%20to%20DelveInsight's%20analysis%2C%20the,acute%20myeloid%20leukemia%20(AML). Accessed December 11, 2024. 

  1. Atara Biotherapeutics submits tabelecleucel (Tab-cel®) biologics license application for treatment of Epstein-Barr Virus positive post-transplant lymphoproliferative disease with U.S. FDA. May 20, 2024. Available at: https://investors.atarabio.com/news-events/press-releases/detail/348/atara-biotherapeutics-submits-tabelecleucel-tab-cel. Accessed December 10, 2024. 

  1. ClinicalTrials.gov. NCT03394365. multicenter, open-label, phase 3 study of tabelecleucel for solid organ or allogeneic hematopoietic cell transplant subjects with Epstein-Barr Virus-associated post-transplant lymphoproliferative disease after failure of rituximab or rituximab and chemotherapy (ALLELE). Available at: https://clinicaltrials.gov/study/NCT03394365?intr=NCT03394365&rank=1. Accessed December 4, 2024. 

  1. ClinicalTrials.gov. NCT02900976: a pilot study of rituximab (RTX) and third party latent membrane protein (LMP)-specific cytotoxic T-lymphocytes (LMP-TC) in pediatric solid organ recipients (SOT) with EBV-positive CD20-positive post-transplant lymphoproliferative disease (PTLD). Available at: https://clinicaltrials.gov/study/NCT02900976?cond=Post-transplant%20Lymphoproliferative%20Disorder&rank=4. Accessed December 4, 2024.  

  1. ClinicalTrials.gov. NCT05786040: phase II study to assess the efficacy of combined tafasitamab and rituximab in front-line treatment of post-transplant lymphoproliferative disorder. Available at: https://clinicaltrials.gov/study/NCT05786040?cond=Post- transplant%20Lymphoproliferative%20Disorder&rank=11. Accessed December 4, 2024.  

  1. ClinicalTrials.gov. NCT04337827: phase II study of rituximab and acalabrutinib in newly diagnosed B cell post transplant lymphoproliferative disorder (PTLD). Available at: https://clinicaltrials.gov/study/NCT04337827?cond=Post-transplant%20Lymphoproliferative%20Disorder&rank=2. Accessed December 4, 2024.  

  1. ClinicalTrials.gov. NCT06040320: a phase I/II study of frontline therapy with polatuzumab vedotin (Pola) plus rituximab (R) in patients with post-transplant lymphoproliferative disorder (PTLD). Available at: https://clinicaltrials.gov/study/NCT06040320?cond=Post-transplant%20Lymphoproliferative%20Disorder&rank=1. Accessed December 4, 2024.  

  1. Colvin MM, Smith CA, Tullius SG, et al. Aging and the immune response to organ transplantation. J Clin Invest. 2017 May 15;127(7):2523–2529. DOI: 10.1172/JCI90601. PMCID: PMC5490761  PMID: 28504651.  

  1. Doherty K. FDA grants Priority Review to tabelecleucel for adult/pediatric EBV+ post-transplant lymphoproliferative disease. July 17, 2024.  Available at: FDA Grants Priority Review to Tabelecleucel for Adult/Pediatric EBV+ Post-Transplant Lymphoproliferative Disease (onclive.com). Accessed December 5, 2024.  

  1. Ghobadi A, Baiocchi R, Beitinjaneh AM, et al. Updated Clinical Results: A Multicenter, Open-Label, Phase 3 Study of Tabelecleucel for Solid Organ or Allogeneic Hematopoietic Cell Transplant Recipients with Epstein-Barr Virus-Driven Post Transplant Lymphoproliferative Disease after Failure of Rituximab or Rituximab Plus Chemotherapy. Blood, 2024. 144 (1): 70. https://doi.org/10.1182/blood-2024-198159. ISSN 0006-4971. 

  1. Grillis D, Siddiqi H, Lu S, et al. Milliman Report. Kidney transplantation admissions in the Medicare fee-for-service population. Available at: https://www.milliman.com/-/media/milliman/pdfs/2024-articles/5-14-24_milliman-kidney-transplant-lds-report.ashx#:~:text=federal%20and%20state%20governments%2C%20and,admissions%20paid%20under%20the%20IPPS. Accessed December 6, 2024.  

  1. Health Resources and Services Administration (HRSA). March 2024. Donation and transplantation statistics. Available at:  https://bloodstemcell.hrsa.gov/data/donation-and-transplantation-statistics#:~:text=A%20total%20of%2022%2C827%20HCTs,who%20had%20an%20unrelated%20donor. Accessed December 6, 2024.  

  1. Institute for Clinical and Economic Review (ICER). ICER publishes evidence report on treatment for Epstein-Barr Virus positive post-transplant lymphoproliferative disease. October 31, 2024. Available at: https://icer.org/news-insights/press-releases/icer-ebv-ptld-2024-evidence-report/. 

  1. Lindsay J, Jad Othman J, Heldman MR, et al. EBV post-transplant lymphoproliferative disorder – update on management and outcomes. Curr Opin Infect Dis. 2021 Dec 1;34(6):635–645. DOI: 10.1097/QCO.0000000000000787. PMCID: PMC8589110  NIHMSID: NIHMS1739280  PMID: 34751183. Garfin PM, Shapiro R, Twist CJ, et al.  Posttransplant lymphoproliferative disease (PTLD). Updated: Feb 08, 2024. Available at: https://emedicine.medscape.com/article/431364-overview. Accessed December 5, 2024.  

  1. Liu L, Liu Q, and Feng S. Management of Epstein–Barr virus-related post-transplant lymphoproliferative disorder after allogeneic hematopoietic stem cell transplantation. Ther Adv Hematol. 2020 Apr 28;11:2040620720910964. DOI: 10.1177/2040620720910964. PMCID: PMC7236397  PMID: 32523657.  

  1. Mahadeo KM, Baiocchi R, Beitinjaneh A, et al. Tabelecleucel for allogeneic haematopoietic stem-cell or solid organ transplant recipients with Epstein–Barr virus-positive post-transplant lymphoproliferative disease after failure of rituximab or rituximab and chemotherapy (ALLELE): a phase 3, multicentre, open-label trial. Lancet Oncol. 2024 Mar; 25(3): 376-387. DOI: 10.1016/S1470-2045(23)00649-6. Epub 2024 Jan 31.PMID: 38309282.  

  1. Organ Procurement and Transportation Network. Continued increase in organ donation drives new records in 2023; New milestones exceeded. January 24, 2024. Available at:  https://optn.transplant.hrsa.gov/news/continued-increase-in-organ-donation-drives-new-records-in-2023-new-milestones-exceeded/. Accessed December 10, 2024. 

  1. Pediatric Donation. Available at: https://donatelife.net/donation/types/pediatric-donation/#:~:text=How%20many%20children%20require%20organ,and%20save%20and%20heal%20lives. Accessed December 6, 2024. 

  1. Prockop S, Doubrovina E, Suser S, et al. Off-the-shelf EBV-specific T cell immunotherapy for rituximab-refractory EBV-associated lymphoma following transplantation. J Clin Invest. 2020 Feb; 130(2):733-747. DOI: 10.1172/JCI121127.PMID: 31689242. 

  1. United Network for Organ Sharing. 2022 organ transplants again set annual records. January 10, 2023.  Available at: https://unos.org/news/2022-organ-transplants-again-set-annual-records/. Accessed December 6, 2024.  


The information provided has been developed based on available information as of January 2, 2025. This therapy is NOT FDA approved, and content may change as more information becomes available. Caution should be used when developing formulary and utilization management strategies. 

By receipt of this report, each recipient agrees that the information contained herein will be kept confidential and that the information will not be photocopied, reproduced, or distributed to or disclosed to others at any time without the prior written consent of Prime Therapeutics. The information contained in this report is intended for educational purposes only and is not intended to define a standard of care or exclusive course of treatment, nor be a substitute for treatment. 

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