Medical Policy

This document addresses defined composition cellular immunotherapy (for example, Tregzi^™) for hematological malignancies which has been developed to reduce the risk of graft-versus-host-disease (GVHD). GVHD is a serious condition that may develop as a consequence of hematopoietic stem cell transplantation (HSCT) causing significant morbidity and mortality. In defined composition cellular immunotherapy therapy, purified hematopoietic stem and progenitor cells (HSPCs), purified regulatory T cells (Tregs), and conventional T cells (Tcons) are isolated from the blood of a healthy adult donor and infused into an individual undergoing myeloablative allogeneic HSCT for a hematologic malignancy. The types, amounts, and timing of administration of the three cell populations are designed to reduce risk of GVHD caused by a donor graft.

Note: Please see the following related document for additional information:

• TRANS.00024 Hematopoietic Stem Cell Transplantation for Select Leukemias and Myelodysplastic Syndrome

Note: For a high-level overview of this document, please see “Summary for Members and Families” below.

Medically Necessary:

A one-time treatment with defined composition cellular immunotherapy (for example, Tregzi) is considered medically necessary for individuals who meet all of the following criteria:

1. Diagnosed with one of the following diseases:
   1. Acute myeloid, lymphoid or mixed phenotype leukemia in complete remission or complete remission with incomplete hematologic recovery, with or without the presence of known minimal residual disease; or
   2. Myelodysplastic syndromes that are indicated for allogeneic hematopoietic stem cell transplantation per 2017 International Expert Panel recommendations (see Rationale) or have therapy-related or secondary myelodysplastic syndrome, with less than or equal to 10% blast burden in the bone marrow;
      and
2. Are undergoing their first myeloablative hematopoietic stem cell transplant; and
3. Matched to a related or unrelated donor who is an 8/8 match for HLA-A, HLA -B, HLA -C, and HLA -DRB1; and
4. Have not had any of the following:
   1. Receiving systemic immunosuppressive therapy (except topical corticosteroids or oral systemic corticosteroid doses less than or equal to 10 mg/day prednisone equivalent); or
   2. Any uncontrolled autoimmune disease requiring active immunosuppressive treatment; or
   3. Concurrent malignancies or active disease within 1 year, except non-melanoma skin cancers that have been curatively resected; or
   4. Donor lymphocyte infusion; or
   5. Pharmaceutical in vivo or ex vivo T cell depletion.

Investigational and Not Medically Necessary:

Treatment with defined composition cellular immunotherapy (for example, Tregzi) is considered investigational and not medically necessary when any of the medically necessary criteria above are not met.

This document describes clinical studies and expert recommendations, and explains when a specific type of donor-based immune therapy (for example, Tregzi),  is clinically appropriate for treating blood cancer and bone marrow disorders. The following summary does not replace the medical necessity criteria or other information in this document. The summary may not contain all of the relevant criteria or information. This summary is not medical advice. Please check with your healthcare provider for any advice about your health.

Key Information

Defined composition cellular immunotherapy is a type of medical treatment used to provide a stem cell transplant from a donor. This type of transplant is called allogeneic hematopoietic stem cell transplantation and involves taking certain types of cells from the blood of one person and giving them to another who has a problem with their own blood cells. Defined composition cellular immunotherapy is meant to lower the risk of a serious problem that can happen after a transplant when donor immune cells attack the person’s body instead of helping them. This problem is called graft-versus-host-disease or GVHD. Defined composition cellular immunotherapy uses carefully selected cells from a healthy donor, including stem cells and special immune cells, to help rebuild the immune system while lowering the risk of GVHD. It is given one time during a transplant for certain adults with two types of blood cancer, acute leukemia or myelodysplastic syndrome, who meet strict medical criteria.

What the Studies Show

Defined composition cellular immunotherapy includes three types of blood cells from a matched donor. First, stem cells to help rebuild the blood and immune system. Second, regulatory T cells to help control the immune response and lower the risk of GVHD. Third, conventional T cells to help fight infection and any remaining cancer. These cells are given at very specific times over a few days during the transplant process. The goal is to balance immune system recovery with a lower risk of GVHD.

One clinical trial studied 187 adults who received a stem cell transplant to treat acute leukemia or myelodysplastic syndrome. The study compared the use of defined composition cellular immunotherapy to a standard stem cell transplantation. After about 1 year, 78% of people who received defined composition cellular immunotherapy were alive and had not developed moderate or worse GVHD compared to 38% of people in the standard transplant group. Overall survival was similar between groups. Also, fewer people in the defined composition cellular immunotherapy group died from causes other than cancer coming back. Serious side effects happened in 39% of people who received defined composition cellular immunotherapy, compared to 56% with standard treatment. However, people in this study were only followed for about 1 year. Longer follow-up is needed to better understand the long-term safety and effectiveness of this treatment.

When is Defined Composition Cellular Immunotherapy Clinically Appropriate?

Defined composition cellular immunotherapy may be appropriate in these situations:

• Has acute myeloid leukemia, acute lymphoid leukemia, or mixed phenotype leukemia in complete remission, with or without small amounts of remaining disease; or
• Has myelodysplastic syndrome that meets expert criteria for stem cell transplant or is therapy related, with 10 percent or less immature cells in the bone marrow; and
• Is matched with a related or unrelated donor who is an 8 out of 8 match for key tissue types called HLA-A, HLA-B, HLA-C, and HLA-DRB1; and
• Has not had a prior donor stem cell transplant; and
• Is not receiving high dose immune suppressing medicines, except for low dose oral steroids of 10 mg per day or less or topical steroids; and
• Does not have an uncontrolled autoimmune disease that needs active immune suppressing treatment; and
• Does not have another active cancer within the past year, except certain skin cancers that were fully removed; and
• Is not receiving donor lymphocyte infusion or other planned T cell depletion treatments.

When is this not Clinically Appropriate?

Treatment with defined composition cellular immunotherapy is not clinically appropriate when the criteria above are not met. Better studies are needed to know if defined composition cellular immunotherapy improves long term health in other groups. Using treatments that are not proven to help can lead to needless worry, or to treatment that does not help.

(Return to Description/Scope)

Summary

This document outlines the use of defined composition cellular immunotherapy, specifically Tregzi (also known as Orca-T), as a strategy to reduce graft-versus-host disease (GVHD) in adults undergoing myeloablative allogeneic hematopoietic stem cell transplantation (HSCT) for certain hematologic malignancies. GVHD is a serious and potentially fatal complication of HSCT, occurring when donor immune cells attack recipient tissues. Tregzi is composed of purified hematopoietic stem and progenitor cells (HSPCs), regulatory T cells (Tregs), and conventional T cells (Tcons), administered in a controlled sequence to promote immune reconstitution while minimizing GVHD risk. A one-time treatment is considered medically necessary for adults aged 18-65 with specific leukemias or eligible myelodysplastic syndromes, provided they have an 8/8 HLA-matched donor and no disqualifying conditions such as prior allogeneic transplant, active immunosuppression, uncontrolled autoimmune disease, recent malignancy, or pregnancy. Use outside these criteria is considered investigational and not medically necessary.

Evidence supporting defined composition cellular immunotherapy includes one randomized phase 3 trial (Meyer, 2026) comparing defined composition cellular immunotherapy plus tacrolimus to a conventional peripheral blood stem cell transplant with tacrolimus and methotrexate. Results demonstrated significantly higher survival free from moderate-to-severe chronic GVHD at 1 year (78.0% vs. 38.4%), lower non-relapse mortality (3.4% vs. 13.2%), and fewer serious adverse events and hospital readmissions in the defined composition cellular immunotherapy group compared to the conventional transplant group. While overall survival differences were not statistically significant, the therapy met its primary endpoint and showed improved safety outcomes. Despite limited long-term data and evidence from a single published study, defined composition cellular immunotherapy is supported as medically necessary in appropriately selected individuals due to the high morbidity and mortality associated with GVHD and the limitations of standard immunosuppressive treatments.

Discussion

Allogeneic hematopoietic stem cell transplantation (HSCT) from an HLA-matched donor is a potentially curative therapy for acute leukemias and myelodysplastic syndrome. However, GVHD continues to be a major cause of morbidity and mortality. Standard GVHD prophylaxis following matched related or matched unrelated donor HSCT generally consists of pharmacologic immunosuppression using a calcineurin inhibitor (e.g., tacrolimus or cyclosporine) in combination with methotrexate or mycophenolate mofetil. While these approaches reduce GVHD risk, they require prolonged systemic immunosuppression and are associated with delayed immune reconstitution and increased infection risk.

Defined composition cellular immunotherapy is an alternative transplantation strategy designed to reduce risk of GVHD by optimizing the cellular composition of the donor graft rather than relying primarily on pharmacological immunosuppression. Following myeloablative conditioning, three defined donor-derived cell populations are administered: (1) hematopoietic stem and progenitor cells (HSPCs) to establish blood and immune system reconstitution; (2) purified regulatory T cells (Tregs) cells intended to mitigate GVHD: and (3) conventional T cells (Tcons) infused after a delay to support immune recovery and graft-vs-leukemia activity. HSPCs and Tregs are infused on day +0, with Tcon infusion on day +2 or +3.

Defined composition cellular immunotherapy has been evaluated in one published randomized, multicenter, phase 3 trial (PRECISION-T; NCT05316701), which enrolled 187 adults aged 18 to 65 years undergoing first myeloablative allogeneic HSCT from an 8/8 HLA-matched related or unrelated donor. Eligible diseases included acute myeloid leukemia, acute lymphoblastic leukemia, or mixed phenotype acute leukemia in complete remission (CR) or CR with incomplete hematologic recovery (CRi), as well as myelodysplastic syndromes appropriate for transplantation with ≤ 10% bone marrow blasts. Myelodysplastic syndromes that are indicated for transplant have been established by an international expert panel (de Witte, 2017). Participants were randomized to receive defined composition cellular immunotherapy with single-agent tacrolimus or a conventional peripheral blood stem cell allograft with tacrolimus and methotrexate (Tac/MTX). The primary endpoint was survival free from moderate-to-severe chronic GVHD. Median follow-up was 11.4 months (range 0.2-24.3 months).

Survival free from chronic GVHD was significantly higher in the defined composition cellular immunotherapy compared to Tac/MTX (hazard ratio [HR], 0.26; 95% confidence interval [CI], 0.14 to 0.47, p<0.001). At 1 year, survival free from chronic GVHD was 78.0% in the investigational arm compared with 38.4% in the Tac/MTX arm. Overall survival at 1 year was 93.9% with defined composition cellular immunotherapy compared to 83.1% with Tac/MTX (p=0.12). This difference was not statistically significant (p=0.12). Non-relapse mortality at 1 year was 3.4% compared to 13.2% (p=0.03), respectively. The reduction in the primary endpoint was driven both by fewer cases of chronic GVHD and fewer deaths. Serious treatment-emergent adverse events developed in 38.6% of individuals treated with defined composition cellular immunotherapy compared with 56.4% of individuals in the control arm. Hospital readmissions after initial discharge were also less frequent for defined composition cellular immunotherapy compared to the control group (27.3% vs. 45.7%).

PRECISION-T has several strengths, including randomized allocation, multicenter participation, prespecified statistical analysis, blinded adjudication of chronic GVHD, and balanced baseline characteristics between treatment groups. The primary endpoint was clinically meaningful and directly relevant to post-transplant quality of life and morbidity.

However, important limitations should be considered. Median follow-up of approximately 1 year limits assessment of long-term durability of GVHD control, relapse risk, late toxicities, and overall survival. The study was not powered to detect a difference in overall survival, and no statistically significant improvement in overall survival was demonstrated at 1 year. The comparator regimen (tacrolimus/methotrexate) may not reflect contemporary prophylaxis strategies at many centers, where post-transplant cyclophosphamide-based regimens are increasingly used. No randomized data currently compare defined composition cellular immunotherapy with those approaches. Additionally, the study population was restricted to adults aged 18-65 years receiving myeloablative conditioning with matched donors, which may limit generalizability to older individuals, reduced-intensity regimens, or alternative donor matches. Finally, the trial was industry-funded, and several investigators had financial relationships with the sponsor, which should be considered when interpreting the findings.

In summary, the PRECISION-T trial demonstrated a statistically significant and clinically meaningful reduction in moderate-to-severe chronic GVHD at 1 year with defined composition cellular immunotherapy compared to conventional TAC/MTX prophylaxis. However, overall survival was not significantly different at 1 year, follow-up remains limited, and comparative effectiveness relative to contemporary post-transplant cyclophosphamide-based regimens is unknown. Evidence is derived from a single randomized phase 3 trial in a narrowly defined population. Additional follow-up and comparative studies are needed to clarify long-term outcomes, durability of benefit, and relative effectiveness within evolving standards of GVHD prophylaxis.

Tregzi was approved by the U.S. Food and Drug Administration (FDA) on June 30, 2026 for the treatment of adults with hematological malignancies. Tregzi is indicated for use in matched donor HSCT with myeloablative preparative regimen, for hematopoietic and immunologic reconstitution, and to improve chronic graft-versus-host disease (cGVHD)-free survival. The safety and effectiveness of Tregzi were established through the PRECISION-T trial. Tregzi is provided as a single dose and intended for use by a single individual. A dose consists of HSPCs, Tregs, Tcons, and Tcon diluent provided in 4 separate infusion bags labeled for the specific individual. The product was approved for one-time use only; repeat administration of Tregzi and its use for the treatment of other indications has not been evaluated.

Graft-versus-host-disease (GVHD) occurs when immune cells transplanted from a non-identical donor (graft) into the recipient (host) recognize the host cells as foreign and attack the host tissue (Zeiser, 2017). GVHD is a significant complication following HSCT occurring in 42% of individuals by 3 years post-transplant (Bachier, 2021). GVHD is categorized as acute or chronic based on clinical features and timing. Acute GVHD occurs within the first 100 days post-transplant with symptoms including skin rashes, gastrointestinal involvement (including persistent nausea, vomiting, abdominal cramping, and secretory diarrhea that may be large-volume or bloody), and liver dysfunction. Chronic GVHD can appear after 3 months, resembling autoimmune disease with widespread, long-term inflammation and fibrosis of skin, eyes, mouth, joints, and organs. GVHD accounts for approximately 9% of deaths following allogeneic HSCT in the United States, but organ failure and infection contribute to another 33% of deaths at over 100 days post-transplant (Center for International Blood and Marrow Transplant Research [CIBMTR], 2024).

Standard treatment for GVHD involves multi-agent immune suppression, including treatment with glucocorticoids (steroids), calcineurin inhibitors, and tyrosine kinase inhibitors. However, these pharmacological agents used to treat GVHD are associated with their own complications such as infections, organ damage, and metabolic issues. These treatments are not effective in many cases, especially with chronic GVHD. Consequently, these therapy-related toxicities limit the application of allogeneic HSCT to high-risk hematological malignancies and bone marrow failure disorders.

At a mechanistic level, donor T cells play a central role in both the therapeutic and pathologic effects of allogeneic HSCT. Through recognition of recipient major and minor histocompatibility antigens, donor T cells mediate graft-versus-leukemia effects that contribute to disease control (Zeiser, 2017). However, this same alloreactivity can result in tissue injury within GVHD target organs. Standard HSCT grafts contain a heterogeneous mixture of immune cell populations, and the balance between protective graft-versus-leukemia activity and harmful graft-versus-host responses is not precisely controlled. Strategies that selectively modulate donor T-cell activation, differentiation, or effector function while preserving immune reconstitution and anti-leukemic activity represent a major focus of contemporary transplant innovation.

Allogeneic: Tissue or cells taken from different individuals from the same species.

Graft-versus-host-disease (GVHD): A life-threatening complication of hematopoietic stem cell transplants in which the donated cells cause an immune reaction against the recipient’s body.

Hematopoietic stem cell transplantation (HSCT): A medical procedure that involves replacing damaged or diseased blood-forming cells with healthy stem cells.

Human Leukocyte Antigens (HLA): A group of protein markers found on the surface of most body cells that are critical for the immune system to distinguish self-cells from foreign invaders. HLA typing is used to match donors and recipients for organ or stem cell transplants. Examples are HLA-A, HLA-B, HLA-C, and HLA-DRB1.

Immunotherapy: A type of cancer treatment that boosts or changes the body's own immune system to better detect and destroy cancer cells.

Myeloablative conditioning: An intensive pre-transplant treatment using high-dose chemotherapy and radiation to destroy an individual’s bone marrow and immune system, making space for new, healthy donor stem cells to engraft.

Myelodysplastic syndrome (MDS): Conditions that occur when the blood-forming cells in the bone marrow are damaged.

Primary MDS: Initial MDS diagnosis, usually when a cause is unknown; also known as primary MDS.
Secondary MDS: When a cause for the disease is known. Common causes include earlier treatment for a cancer; also known as treatment related MDS.

Relapse: The return of signs and symptoms of cancer after a period of improvement.

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services may be Medically Necessary when criteria are met:
For the following procedure codes or when the code describes a procedure indicated in the Position Statement section as medically necessary.

When services are Investigational and Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met.

Peer Reviewed Publications:

1. Bachier CR, Aggarwal SK, Hennegan K, et al. Epidemiology and treatment of chronic graft-versus-host disease post-allogeneic hematopoietic cell transplantation: a US claims analysis. Transplant Cell Ther. 2021; 27(6):504.e1-504.e6.
2. Meyer EH, Salhotra A, Gandhi AP, et al.  Orca-T versus allogeneic hematopoietic stem cell transplantation (PRECISION-T): a multicenter, randomized phase 3 trial. Blood. 2026; 147(11):1168-1177.
3. Zeiser R, Blazar BR. Acute graft-versus-host disease biology, prevention and therapy. N Engl J Med. 2017; 377(22):2167-2179.

Government Agency, Medical Society, and Other Authoritative Publications:

1. Center for International Blood and Marrow Transplant Research. Summary slides and reports. Available at: https://cibmtr.org/CIBMTR/Resources/Summary-Slides-Reports. Accessed on July 1, 2026.
2. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). Available at: https://clinicaltrials.gov/ct2/home. Accessed on July 1, 2026.
3. De Witte T, Bowen D, Robin M, et al. Allogeneic hematopoietic stem cell transplantation for MDS and CMML: recommendations from an international expert panel. Blood. 2017; 129(13):1753-1762.
4. Döhner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017; 129(4):424-447.
5. U.S. Food and Drug Administration. TREGZI™ highlights of prescribing information. Revised 06/2026. Available at: https://orcabio.com/wp-content/uploads/2026/07/TREGZI-USPI-June-2026.pdf. Accessed on July 1, 2026.

1. Leukemia & Lymphoma Society. Graft-versus-host-disease (GVHD). Available at: https://www.lls.org/treatment/types-treatment/stem-cell-transplantation/graft-versus-host-disease. Accessed July 1, 2026.
2. U.S. National Library of Medicine. Graft-versus-host disease. Last reviewed June 17, 2024. Available at: https://medlineplus.gov/ency/article/001309.htm. Accessed July 1, 2026.

Allogeneic immunotherapy
Orca-T
Tregzi

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