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Medical Policy Adjunct Medications to Support Hematopoietic Stem Cell Transplantation and its Complications Table of Contents • Policy: Commercial • Coding Information
• Information Pertaining to All Policies
• Policy: Medicare • Description
• References
• Authorization Information • Policy History
• Endnotes Policy Number: 028 BCBSA Reference Number: 8.01.68 (For Plan internal use only) NCD/LCD: N/A Related Policies
Hematopoietic Cell Transplantation for Non-Hodgkin Lymphomas, #143 Hematopoietic Cell Transplantation for Acute Myeloid Leukemia, #150 Hematopoietic Cell Transplantation for Hodgkin Lymphoma, #270 Hematopoietic Cell Transplantation for Chronic Myeloid Leukemia, #155
Adjunct Medications to Support Hematopoietic Stem Cell Transplantation and its Complications Prior Authorization Request Form, #067 Policy1 Commercial Members: Managed Care (HMO and POS), PPO, and Indemnity
Medicare HMO BlueSM and Medicare PPO BlueSM Members

Omisirge (omidubicel-onlv): Criteria for initial approval for one-time infusion one treatment course per lifetime

Omidubicel-onlv (Omisirge®) is a nicotinamide modified allogeneic hematopoietic progenitor cell therapy derived from cord blood may be considered MEDICALLY NECESSARY when the following criteria are met: • Individual is 12 years of age and older AND • Individual has a diagnosis of hematologic malignancies who are planned for umbilical cord blood transplantation following myeloablative conditioning to reduce:
o time to neutrophil recovery AND
o the incidence of infection. • Individual is candidate for myeloablative allogeneic hematopoietic stem cell transplantation (HSCT) AND • Individual does not have ANY of the following: o Availability of human leukocyte antigen-identical or human leukocyte antigen-matched donor or human leukocyte antigen-haploidentical donor o History of receiving prior allogenic hematopoietic stem cell transplant

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o Other malignancy or significant immunodeficiency disorder o Active, uncontrolled HCV or HBV infection AND • The medication is being prescribed by or in consultation with hematologist/oncologist.

Omidubicel-onlv (Omisirge®) is considered INVESTIGATIONAL for individuals who do not meet the above policy criteria.

Omidubicel-onlv (Omisirge®) is considered INVESTIGATIONAL for all other indications.

Continuation of Therapy: This is not a covered service. Approval is limited to one treatment course per lifetime.

Quantity Limits: Treatment is limited to one treatment course per lifetime.

Dosage and Administration: For dosage and administration instructions, see prescribing information. Gamida Cell Inc. 2023

Ryoncil (remestemcel-L-rknd): Criteria for initial approval

Ryoncil (remestemcel-L-rknd) is an allogeneic bone marrow-derived mesenchymal stromal cell (MSC) therapy may be considered MEDICALLY NECESSARY when the following criteria are met:

• Diagnosis of steroid-refractory acute graft versus host disease (SR-aGvHD), AND • Age ≥ 2 months, AND • Patient’s acute graft versus host disease (aGvHD) progressed within 3 days or did not improve within 7 consecutive days of treatment with methylprednisolone 2 mg/kg/day or other corticosteroid equivalent

Dosage and Administration: Refer to Ryoncil Prescribing Information.

Continuation of Therapy: Additional doses may be considered based on Ryoncil Prescribing Label that outlines recommended treatment based on Day 28 Response:

Response Recommendation Complete Response No further treatment with RYONCIL Partial or Mixed Response Repeat administration of RYONCIL once a week for additional 4 weeks (4 infusions total) No Response Consider alternative treatments Recurrence of GvHD after complete response Repeat administration of RYONCIL twice a week for an additional 4 consecutive weeks (8 infusions total) Partial response defined as organ improvement of at least one stage without worsening in any other organ, whereas mixed response was defined as improvement of at least one evaluable organ with worsening in another organ as per International Blood and Marrow Transplantation Registry Severity Index Criteria grading system.

Prior Authorization Information
Inpatient • For services described in this policy, precertification/preauthorization IS REQUIRED for all products if the procedure is performed inpatient.
Outpatient • For services described in this policy, see below for products where prior authorization might be required if the procedure is performed outpatient.

Outpatient

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Commercial Managed Care (HMO and POS) Prior authorization is required. Commercial PPO and Indemnity Prior authorization is required. Medicare HMO BlueSM Prior authorization is required. Medicare PPO BlueSM Prior authorization is required.

Requesting Prior Authorization Using Authorization Manager Providers will need to use Authorization Manager to submit initial authorization requests for services. Authorization Manager, available 24/7, is the quickest way to review authorization requirements, request authorizations, submit clinical documentation, check existing case status, and view/print the decision letter. For commercial members, the requests must meet medical policy guidelines.

To ensure the request is processed accurately and quickly: • Enter the facility’s NPI or provider ID for where services are being performed. • Enter the appropriate surgeon’s NPI or provider ID as the servicing provider, not the billing group.

Authorization Manager Resources • Refer to our Authorization Manager page for tips, guides, and video demonstrations.

Complete Prior Authorization Request Form for Gene Therapies using Authorization Manager for:
• Omidubicel (Omisirge), (#067)

For out of network providers: Requests should still be faxed to 888-973-0726.

CPT Codes / HCPCS Codes / ICD Codes
Inclusion or exclusion of a code does not constitute or imply member coverage or provider reimbursement. Please refer to the member’s contract benefits in effect at the time of service to determine coverage or non-coverage as it applies to an individual member.

Providers should report all services using the most up-to-date industry-standard procedure, revenue, and diagnosis codes, including modifiers where applicable.

According to the policy statement above, the following CPT codes are considered medically necessary for the conditions listed for Commercial Members: Managed Care (HMO and POS), PPO, Indemnity, Medicare HMO Blue and Medicare PPO Blue: HCPCS Codes HCPCS codes:

Code Description J3402 Injection, remestemcel-l-rknd, per therapeutic dose J3590 Unclassified biologics C9399 Unclassified drugs or biologicals Description Hematologic Malignancies Hematologic malignancies are a heterogeneous group of diseases characterized by distinct biological subtypes, marked by cellular, immunophenotypic, and genetic profile variations. Therapeutic approaches may involve hematopoietic cell transplantation, and in cases where a suitable matched donor is unavailable, umbilical cord blood may serve as a source of hematopoietic stem and progenitor cells for transplantation. Ex vivo expansion strategies using nicotinamide have been investigated to expedite hematopoietic recovery and enhance cell volume without inducing differentiation or cellular stress commonly associated with culturing hematopoietic progenitor cells outside their natural environment. Omidubicel is a modified allogeneic hematopoietic progenitor cell therapy derived from cord blood utilizing a proprietary nicotinamide enrichment technology.

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Treatment for Hematologic Malignancies: Hematopoietic Stem Cell Transplantation Hematopoietic cell transplantation (HCT) is a procedure in which hematopoietic stem cells are intravenously infused to restore bone marrow and immune function in cancer patients who receive bone marrow-toxic doses of cytotoxic drugs with or without whole-body radiotherapy. Hematopoietic stem cells may be obtained from the transplant recipient (autologous HCT) or a donor (allogeneic HCT [allo-HCT]). These cells can be harvested from bone marrow, peripheral blood, or the umbilical cord blood shortly after delivery of neonates.

Immunologic compatibility between infused hematopoietic stem cells and the recipient is not an issue in autologous HCT. In allogeneic stem cell transplantation, immunologic compatibility between donor and patient is a critical factor for achieving a successful outcome. Compatibility is established by typing human leukocyte antigens (HLA) using cellular, serologic, or molecular techniques. HLA refers to the gene complex expressed at the HLA-A, -B, and -DR (antigen-D related) loci on each arm of chromosome 6. An acceptable donor will match the patient at all or most of the HLA loci.

Umbilical Cord Blood Grafts Umbilical cord blood (UCB) transplant utilizes blood remaining in the umbilical cord and placenta following the birth of a child. This provides a source of hematopoietic stem and progenitor cells (HSPCs) for allogenic HCT for individuals who lack an HLA-matched related or unrelated donor. In recent years the demand for UCB transplantation has increased due to: a lack of suitable HLA-matched unrelated donors, this is especially true in individuals who are not of Northern European descent, attrition of donors, timing constraints with identifying and typing a candidate as well as harvesting, and the increased incidence of GVHD when HLA-mismatched donor cells are used. Advantages of using UCB grafts include rapid cell procurement, lower incidence of chronic GVHD, and less stringent HLA-matching requirements. UCB transplantation is typically reserved for patients without an HLA-matched donor and should be performed in centers with expertise in this procedure. Patients without an HLA-matched donor may also be candidates for HCT from a haploidentical, or half HLA-matched, related donor.

Ex Vivo Expansion with Omidubicel UCB transplantation is limited by the cell doses that can be achieved in recipients with high body weight and is also associated with delayed engraftment, higher risk for graft failure, higher rates of infectious complications, and higher costs for procurement. Omidubicel is a blood-based stem cell therapy derived from a single allogenic UCB unit. The therapy uses a proprietary expansion technology based on nicotinamide, proposed to enable donor cells to grow while maintaining their functionality, increase homing to the recipient's bone marrow, and retention of engraftment capacity. Omidubicel is designed to accelerate the rate of neutrophil recovery and lower the risk of infection in patients with hematologic malignancies planning allogenic hematopoietic stem cell transplant (HSCT) but lacking a matched sibling or unrelated donor source.

Summary of Evidence: Omisirge For individuals who have hematologic malignancies and are eligible to undergo omidubicel-modified umbilical cord blood transplant, the evidence includes results from a phase 3 randomized trial (Horwitz et al 2021. #NCT02730299). This multicenter, randomized study included 125 patients assigned to the omidubicel treatment group (N=62) vs standard UCBT treatment group (N=63). The effectiveness of omidubicel compared with standard umbilical cord blood transplantation was evaluated. Results from this study show that Omidubicel has proven to be better than standard umbilical cord blood transplantation in several respects and suggests that it could be considered as the new standard of care. The results showed the median time to neutrophil engraftment was 12 days versus 22 days with the standard UCBT.
Also, neutrophil engraftment was 96% vs 89% with just UCBT. Those treated with Omidubicel experienced faster platelet recovery and had a lower incidence of grade 2 to 3 bacterial or invasive fungal infection, and individuals spent less time in the hospital than the control group, (39 days vs 52 days for the control group). The use of Omidubicel led to quicker hematopoietic recovery and it reduced early transplant related complications.

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In a secondary analysis from the Pivotal Phase 3 Clinical Trial, the authors concluded that based on their assessment, faster hematopoietic recovery in omidubicel-onlv patients is associated with significantly shorter hospital stay and reduced healthcare resource use compared with UCB (Navneet S et al 2023).

Acute graft versus host disease Acute Graft-versus-host Disease (aGvHD) is a complication that may occur after a donor stem cell transplant. In aGVHD, the cells received from the hematopoietic stem cell transplant (HCT) attack areas of the body such as the skin, liver, and gastrointestinal tract. After diagnosis, each organ receives a stage (Stages 1-4) that is factored together to assign a grade to the disease, and treatment is determined by the patient’s staging.

Treatments for stage 1 aGvHD include observation or continuing or restarting an immunosuppressant with topical steroids. In stages 2-4, treatments include continuing or restarting an immunosuppressant, systemic steroids with or without topical steroids, assignment to Clinical trials, or sirolimus.

If aGVHD doesn’t respond to treatment, it is considered steroid-refractory disease, which occurs in about half of patients with acute Graft-versus-host-disease. According to the NCCN guidelines, suggested system agents for steroid-refractory Acute GvHD include, but are not limited to:

FDA Approved, Category 1 Agents: • Ruxolitinib Alternative Agents:
• Alemtuzumab,
• Alpha-1 antitrypsin,
• ATG,
• Basiliximab,
• Calcineurin inhibitors (E.g. tacrolimus, cyclosporine),
• Etanercept, • Extracorporeal photopheresis (ECP), • Infliximab • mTOR inhibitors (E.g. sirolimus) • Mycophenolate mofetil • Pentostatin • Tocilizumab • Urinary-derived human chorionic gonadotropin/ epidermal growth factor (uhCG/EGF), • Vedolizumab NOTE: Although Ryoncil was FDA approved for the treatment of steroid-refractory acute graft-versus-host- disease, NCCN has not yet incorporated it into their guidelines yet.

Summary of Evidence: Ryoncil The efficacy of Ryoncil for steroid-refractory Acute Graft-versus-host Disease was evaluated in Clinical Trial NCT02336230, also known as MSB-GVHD-001. This was a multicenter, prospective, single-arm study that treated 54 pediatric patients with SR-GvHD Grade B-D. Patients were treated with Ryoncil 2 x 106 MSCs/kg 2x a week for 4 weeks, for a total of eight infusions. Patients with partial or mixed response at Day 28 received additional infusions of RYONCIL 2 x 106 MSCs/kg once a week for an additional 4 weeks. Patients with complete response at Day 28 who experienced recurrence of aGvHD received infusions of RYONCIL 2 x 106 MSCs/kg twice a week for an additional 4 weeks. The primary end point was measured as Overall Response Rate (ORR), defined as complete or partial response) at day 28 was 70% with duration of 54 median days (FDA approval). Note: median duration of response in follow up safety study, MSB-GVHD002, showed 146 days.

Policy History Date Action

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10/2025 Clarified coding information 9/15/2025 Updated policy, including Description and References sections, to include Ryoncil from July 2025 P&T. Adjusted policy name to “Adjunct Medications to Support Hematopoietic Stem Cell Transplantation and its Complications”. Incorporated the Summary section into the Description section. 4/2024 Policy revised to include medically necessary and investigational indications. Prior authorization is required. Effective 4/1/2024. 1/2024 New medical policy describing investigational indications. Omidubicel is considered investigational for individuals with hematologic malignancies planning myeloablative allogenic umbilical cord transplantation. Effective 1/1/2024. Information Pertaining to All Blue Cross Blue Shield Medical Policies Click on any of the following terms to access the relevant information: Medical Policy Terms of Use Managed Care Guidelines Indemnity/PPO Guidelines Clinical Exception Process Medical Technology Assessment Guidelines References

1. Anand S, Thomas S, Hyslop T, et al. Transplantation of Ex Vivo Expanded Umbilical Cord Blood (NiCord) Decreases Early Infection and Hospitalization. Biol Blood Marrow Transplant. Jul 2017; 23(7): 1151-1157. PMID 28392378
2. Horwitz ME, Chao NJ, Rizzieri DA, et al. Umbilical cord blood expansion with nicotinamide provides long-term multilineage engraftment. J Clin Invest. Jul 2014; 124(7): 3121-8. PMID 24911148
3. Horwitz ME, Stiff PJ, Cutler C, et al. Omidubicel vs standard myeloablative umbilical cord blood transplantation: results of a phase 3 randomized study. Blood. Oct 21 2021; 138(16): 1429-1440. PMID 34157093
4. Horwitz ME, Wease S, Blackwell B, et al. Phase I/II Study of Stem-Cell Transplantation Using a Single Cord Blood Unit Expanded Ex Vivo with Nicotinamide. J Clin Oncol. Feb 10 2019; 37(5): 367-
5. PMID 30523748
6. Kurtzberg, J, Abdel-Azim H, Carpenter P, et al. A Phase 3, Single-Arm, Prospective Study of Remestemcel-L, Ex Vivo Culture-Expanded Adult Human Mesenchymal Stromal Cells for the Treatment of Pediatric Patients Who Failed to Respond to Steroid Treatment for Acute Graft-versus- Host Disease. Identification No. NCT02336230. Retrieved from https://clinicaltrials.gov/study/NCT02336230?term=NCT02336230&rank=1. Accessed July 29, 2025.
7. Kanate AS, Majhail NS, Savani BN, et al. Indications for Hematopoietic Cell Transplantation and Immune Effector Cell Therapy: Guidelines from the American Society for Transplantation and Cellular Therapy. Biol Blood Marrow Transplant. Jul 2020; 26(7): 1247-1256. PMID 32165328
8. Lin C, Sajeev G, Stiff PJ, et al. Health-Related Quality of Life Following Allogeneic Hematopoietic Cell Transplantation with Omidubicel versus Umbilical Cord Blood. Transplant Cell Ther. Jan 2023; 29(1): 52.e1-52.e9. PMID 36179986
9. National Comprehensive Cancer Network (NCCN). NCCN clinical practice guidelines in oncology: Acute Lymphoblastic Leukemia. Version 1.2023. https://www.nccn.org/professionals/physician_gls/pdf/all.pdf. Accessed June 23, 2023.
10. National Comprehensive Cancer Network (NCCN). NCCN clinical practice guidelines in oncology: Acute Myeloid Leukemia. Version 3.2023. https://www.nccn.org/professionals/physician_gls/pdf/aml.pdf. Accessed June 24, 2023.
11. National Comprehensive Cancer Network (NCCN). NCCN clinical practice guidelines in oncology: B- Cell Lymphomas. Version 4.2023. https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf. Accessed June 25, 2023.
12. National Comprehensive Cancer Network (NCCN). NCCN clinical practice guidelines in oncology: Chronic Myeloid Leukemia. Version 2.2023. https://www.nccn.org/professionals/physician_gls/pdf/cml.pdf. Accessed June 26, 2023.

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12. National Comprehensive Cancer Network (NCCN). NCCN clinical practice guidelines in oncology: Hematopoietic Cell Transplantation (HCT). Version 1.2023. https://www.nccn.org/professionals/physician_gls/pdf/hct.pdf. Accessed June 27, 2023.
13. National Comprehensive Cancer Network (NCCN). NCCN clinical practice guidelines in oncology: Hodgkin Lymphoma. Version 2.2023. https://www.nccn.org/professionals/physician_gls/pdf/hodgkins.pdf. Accessed June 28, 2023.
14. National Comprehensive Cancer Network (NCCN). NCCN clinical practice guidelines in oncology: Myelodysplastic Syndromes. Version 1.2023. https://www.nccn.org/professionals/physician_gls/pdf/mds.pdf. Accessed June 29, 2023.
15. National Comprehensive Cancer Network. (2025). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): [Hematopoietic Cell Transplantation]. Retrieved from [https://www.nccn.org/professionals/physician_gls/pdf/hct.pdf]. Accessed July 29, 2025.
16. National Comprehensive Cancer Network. (2025). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): [Graft-Versus-Host Disease]. Retrieved from [https://www.nccn.org/patients/guidelines/content/PDF/GVDH-patient-guideline.pdf]. Accessed July 29, 2025.
17. Navneet S Majhail et al. Hospitalization and Healthcare Resource Utilization of Omidubicel-Onlv versus Umbilical Cord Blood Transplantation for Hematologic Malignancies: Secondary Analysis from a Pivotal Phase 3 Clinical Trial. Transplant Cell Ther . 2023 Dec;29(12):749.e1-749.e5.
18. Omisrge [package insert]. Jerusalem, Israel: Gamida Cell Inc.; April 2023.
19. Ryoncil [package insert]. New York, NY: Mesoblast, Inc.; December 2024.
20. Saiyin T, Kirkham AM, Bailey AJM, et al. Clinical Outcomes of Umbilical Cord Blood Transplantation Using Ex Vivo Expansion: A Systematic Review and Meta-Analysis of Controlled Studies. Transplant Cell Ther. Feb 2023; 29(2): 129.e1-129.e9. PMID 36396108

21. Shearer WT, Lubin BH, Cairo MS, et al. Cord Blood Banking for Potential Future Transplantation. Pediatrics. Nov 2017; 140(5). PMID 29084832

    Endnotes

    1 Based on expert opinion