Medical Policy

Policy Num:   05.001.050
Policy Name: Omidubicel as Adjunct Treatment for Hematologic Malignancies
Policy ID        [05.001.050]  [Ac / B  M+ / P+]  [8.01.68]

Last Review:   September 23, 2024
Next Review:   September 20, 2025
 

Related Policies:

08.001.048 - Hematopoietic Cell Transplantation for Non-Hodgkin Lymphomas
08.001.050 - Hematopoietic Cell Transplantation for Acute Myeloid Leukemia
08.001.037 - Hematopoietic Cell Transplantation for Hodgkin Lymphoma
08.001.036 - Hematopoietic Cell Transplantation for Chronic Myeloid Leukemia

Omidubicel as Adjunct Treatment for Hematologic Malignancies 

Summary

Description

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.

Summary of Evidence

For individuals with hematologic malignancies who receive omidubicel, the evidence includes 3 cohort studies with historical controls, 1 randomized controlled trial (RCT) with 2 supplementary analyses, and 1 pooled analysis of long-term follow-up datas. Relevant outcomes are overall survival (OS), disease-free survival (DFS), treatment-related morbidity and mortality, adverse events, and quality of life. Omidubicel showed a faster time to neutrophil and platelet engraftment throughout the identified evidence base, and, in some stratified analyses, a lower rate of infection complications when compared to unmanipulated umbilical cord blood (UCB). No differences in OS, DFS, or treatment-related morbidity were observed. A subgroup analysis of the RCT showed an improvement in quality of life (QOL) but had methodological issues related to participation. Another secondary analysis of the same RCT reported a significant reduction in mean hospital length of stay (LOS) for the first 100 days post-transplantation for patients treated with omidubicel compared to standard umbilical cord blood. A pooled, patient-level analysis utilizing data from the RCT and 4 other studies found that rates of OS, DFS, graft versus host disease (GVHD), and relapse were durable through 3 years of follow-up, although this analysis included a minority of patients with sickle cell hemoglobinopathy. Compared to unmanipulated UCB transplantation, omidubicel transplantation for hematologic malignancies resulted in quicker neutrophil and platelet recovery, reduced hospital length of stay, and lower incidence of invasive bacterial and fungal infections with a favorable safety profile through 3 years post-transplantation. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Additional Information

Not applicable.

Objective

The objective of this evidence review is to evaluate the safety and efficacy of omidubicel-modified allogenic hematopoietic progenitor cell therapy derived from umbilical cord blood on the net health outcome in individuals with hematologic malignancies.

Policy Statement

Omidubicel is considered medically necessary in individuals 12 years or older with hematologic malignancies planning myeloablative allogenic umbilical cord transplantation to reduce the time to neutrophil recovery and the incidence of infection.

Omidubicel is considered investigational for all other indications.

Policy Guidelines

Omidubicel

The product label of omidubicel recommends that patients be treated under the supervision of a physician experienced in the treatment of hematologic malignancies at centers with expertise in hematopoietic stem cell transplantation.

The product label contains several boxed warnings:

• Infusion reactions: Fatal infusion reactions may occur. Individuals should be monitored during infusion and discontinue for severe reactions. The use of omidubicel is contraindicated for individuals with a known allergy to dimethyl sulfoxide, Dextran 40, gentamicin, human serum albumin, or bovine material.

• Graft versus host disease (GVHD): Fatal GVHD may occur. The administration of immunosuppressive therapies may decrease the risk of GVHD.

• Engraftment syndrome: Fatal engraftment syndrome may occur. Engraftment syndrome should be treated promptly with corticosteroids.

• Graft failure: Fatal graft failure may occur. Patients should be monitored for hematopoietic recovery using laboratory evidence.

Dosing Limits

One infusion per lifetime.

Coding

See the Codes table for details.

Benefit Application

BlueCard/National Account Issues

State or federal mandates (eg, Federal Employee Program) may dictate that certain U.S. Food and Drug Administration approved devices, drugs, or biologics may not be considered investigational, and thus these devices may be assessed only by their medical necessity.

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered.  Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.

Background

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.

Regulatory Status

According to the U.S. Food and Drug Administration (FDA), cord blood stored for potential use by a patient unrelated to the donor meets the definitions of “drug” and “biological products.” As such, products must be licensed under a biologics license application or an investigational new drug application before use. Facilities that prepare cord blood units only for autologous and/or first- or second-degree relatives are required to register and list their products, adhere to Good Tissue Practices issued by the FDA, and use applicable processes for donor suitability determination.

The FDA approved Omisirge® (omidubicel-onlv) on April 17, 2023 for patients age 12 or older with hematologic malignancies who are planned for umbilical cord transplantation following a myeloablative conditioning regimen.

Rationale

This evidence review was created in August 2023 with a search of the PubMed database. The most recent literature update was performed through June 23, 2024.

Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. Randomized controlled trials are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

Population Reference No. 1

Omidubicel for Hematologic Malignancies

Clinical Context and Therapy Purpose

The purpose of omidubicel in individuals with hematologic malignancies is to provide a treatment option that is an alternative to or an improvement on standard allogenic umbilical cord blood (UCB) transplantation in individuals who lack a matched sibling or matched unrelated donor source.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals 12 years of age or older with hematologic malignancies planning to undergo UCB transplantation following myeloablative conditioning.

Interventions

The therapy being considered is omidubicel.

Comparators

Comparators of interest include standard of care UCB transplantation.

Outcomes

The general outcomes of interest are overall survival (OS), disease-specific survival (DSS), change in disease status, morbid events, treatment-related mortality, treatment-related morbidity, and quality of life.

Follow-up over years is of interest for relevant outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Consistent with a 'best available evidence approach,' within each category of study design, studies with larger sample sizes and longer durations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Systematic Reviews

Lin et al (2023) published a pre-planned, pooled analysis of long-term follow-up data from 5 multicenter clinical trials evaluating allogeneic hematopoietic cell transplantation with omidubicel in patients with hematologic malignancies (3 trials, n=97) and sickle cell hemoglobinopathy (2 trials, n=8) (Table 1).^1, Patients had a median age of 42 years, were 48% female and 39% non-white or Hispanic. Most transplantations consisted of single cord units (88%) and had an HLA matching of 4/6 (72%) (Table 2). Primary graft failure occurred in 5 (5%) patients and 1 patient died before engraftment. The pooled population had a median follow-up of 22 months (range 0.3 to 122.5 months) with a 3-year estimated overall survival and disease-free survival rate of 62.7% and 56.4%, respectively (Table 3). The 3-year cumulative incidence of chronic GVHD was 36.6%, while the 3-year cumulative incidence of disease relapse in all patients was 22.2%. The most common causes of death were relapse (n=16), infection (n=11), and acute GVHD (n=6). Secondary malignancies occurred in 3 patients (2 lymphoproliferative disorders and 1 donor-derived myelodysplastic syndrome).

Table 1. Comparison of Trials/Studies Included in SR & M-A

Table 2. SR & M-A Characteristics

NR: not reported; RCT: randomized controlled trial; UCB: umbilical cord blood 

Table 3. SR & M-A Results

~indicates estimated from figure. 

CI: confidence interval; GVHD: graft versus host disease; NNT: number needed to treat.

Randomized Controlled Trials

A randomized trial (Study P0501, NCT02730299) by Horwitz et al (2021) investigated omidubicel compared to standard unmanipulated UCB transplantation. Participants included pediatric and adult patients with high-risk hematologic malignancies who were candidates for myeloablative allogenic hematopoietic stem cell transplantation (HSCT) but did not have a readily available matched sibling or unrelated donor (Table 4).^2,6, All participants had a UCB unit, HLA matched at 4 or more loci, and underwent standard myeloablative conditioning. Patients had a median age of 41 years (range 13-65 years) and included the following cancer types: 48% acute myeloid leukemia (AML), 33% acute lymphoblastic leukemia (ALL), 7% myelodysplastic syndrome (MDS), 5% chronic myeloid leukemia (CML), 4% lymphoma, and 3% other rare leukemias. Participants were randomized 1:1 to receive either omidubicel (n=62) or standard UCB transplantation (n=63) and were stratified on the treatment center, disease risk index, age, and the intent to perform a single or double UCB transplantation. The median follow-up time for all participants was 10 months post-transplantation (range 1 to 19 months); 10 individuals randomized to the omidubicel group and 8 randomized to UCB transplant alone did not proceed to transplant and were not part of the 'as treated' analyzed population. A single primary endpoint of time to neutrophil engraftment was defined and had 90% power to detect a difference with the selected sample size. Secondary outcomes included the incidence of platelet engraftment on day 42 post-transplant, days alive out of the hospital in the first 100 days post-transplant, and first grade 2 or 3 bacterial or invasive fungal infections within 100 days post-transplant. Several additional outcomes, including safety, infection rate, non-relapse-related mortality (NRM), OS, disease-free survival (DFS), and acute and chronic GVHD, were also reported (Table 5).

The primary outcome of time to neutrophil engraftment favored participants treated with omidubicel over standard of care. The time to neutrophil recovery and the incidence of platelet engraftment also favored the omidubicel-treated arm. The rate of acute grade 2 to 4 GVHD at 100 days (13% difference; 95% CI, -6% to 30%; p=.18) or chronic GVHD at 1 year (6% difference; 95% CI, -21% to 7%; p=.33) were similar between groups. No significant differences were observed for the rate of relapse at 15 months follow-up (8% difference; p=.32), OS (hazard ratio [HR], 0.57; 95% CI, 0.3 to 1.1; p=.09), DFS (HR, 0.79; 95% CI, 0.45 to 1.38; p=.4), NRM (11% vs. 24%; p=.09), or treatment failure (HR, 0.79; 95% CI, 0.45 to 1.38; p=.4). The incidence of first grade 2 or 3 bacterial or invasive fungal infection (according to Bone Marrow Transplant & Clinical Trials Network infection severity grading) was significantly lower in patients treated with omidubicel compared to standard UCB (p=.03). The authors also found a significant reduction in the incidence of first grade 3 viral infections reported in the omidubicel group (p=.02) as well as some other stratified analyses by infection type and grade. More deaths were reported in the standard UCB group (n=18) compared to the omidubicel group (n=11) with GVHD accounting for 4 deaths in each group. Participants allocated to omidubicel also showed a quicker time to discharge from the hospital than those in the standard of care comparator (27 days vs. 35 days; p=.005). The incidence of treatment-related serious adverse events was similar between omidubicel (40%) and standard UCB (41%) groups. Study limitations include: a short median follow-up period for outcomes such as OS, DFS, NRM, and some adverse effects, not being powered to detect differences in important clinical outcomes, and a lack of blinding for participants and investigators.

A supplementary analysis using the same RCT population as the Horwitz trial investigated the health-related quality of life (QOL) for trial participants and prospectively collected data on 3 instruments: the Functional Assessment of Cancer Therapy-General instrument, the Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) and the EuroQol 5-Dimension 3-Level tests.^7, Participants were asked to complete these QOL measures at 42, 100, 180 and 365 days post-transplantation. This study used the 'as treated' population, so only 108 of the original 125 participants were eligible, and of those 75 participated (37 in the omidubicel group and 38 in the standard UCB group) by completing 1 or more assessments. Notably, an assessment comparing characteristics of those who participated in the QOL study and those that did not found that the excluded patients had a significantly lower (p<.001) incidence of platelet engraftment (54.6% vs. 90.7%) more days in the hospital (66.3 days vs. 43.6 days) and lower 1 year overall survival (42.4% vs. 82.7%). On the FACT-G test, the total FACT-G score was significantly better in the omidubicel versus unmanipulated cord blood transplantation (p=.01) with mean differences ranging from 6 to 6.9 points. This exceeded the minimally important clinical difference (MICD) of 5 at all time points follow-up through 1 year. On the FACT-G subscale of physical well being, a significant difference (p=.02) also favored the omidubicel group but significant or MICD was observed for the domains of social/family and emotional quality of life measures on FACT-G. Similarly, the mean change in scores on the FACT-BMT total score also favored the omidubicel group (p=.01) and exceeded the MCID of 7 at all follow-up assessments (range 7.2 to 10 points). No significant difference between groups was observed on the EQ-5D-3L index (p=.06). Another secondary analysis of the same 'as treated' patient population (n=108) focused on hospitalization and healthcare utilization. The authors found that the average hospital length of stay for primary transplantation was shorter in omidubicel recipients compared to UCB (mean, 27.7 days vs. 39.7 days; p<.001) as was the total hospital length of stay within the first 100 days post-transplantation (mean, 41.2 days vs. 50.8 days; p=.027).^8,

Another secondary analysis of the Horowitz RCT population investigated

Table 4. Summary of Key RCT Characteristics

Table 5. Summary of Key RCT Results

aGVHD: acute graft versus host disease; CI: confidence interval; RCT: randomized controlled trial; UCB: umbilical cord blood

The purpose of the study limitations tables (see Tables 6 and 7) is to display notable limitations identified in each study. This information is synthesized as a summary of the body of evidence following each table and provides the conclusions on the sufficiency of evidence supporting the position statement.

Table 6. Study Relevance Limitations

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
^a Population key: 1. Intended use population unclear; 2. Study population is unclear; 3. Study population not representative of intended use; 4, Enrolled populations do not reflect relevant diversity; 5. Other.
^b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4. Not the intervention of interest (e.g., proposed as an adjunct but not tested as such); 5: Other.
^c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively; 5. Other.
^d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. Incomplete reporting of harms; 4. Not establish and validated measurements; 5. Clinically significant difference not prespecified; 6. Clinically significant difference not supported; 7. Other.
^e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms; 3. Other.

Table 7. Study Design and Conduct Limitations

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
^a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias; 5. Other.
^b Blinding key: 1. Participants or study staff not blinded; 2. Outcome assessors not blinded; 3. Outcome assessed by treating physician; 4. Other.
^c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication; 4. Other.
^d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials); 7. Other.
^e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference; 4. Other.
^f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated; 5. Other.

Nonrandomized Studies

Tables 8 and 9 describe the characteristics and results of nonrandomized studies, respectively.

Horwitz et al (2014) allocated 12 adult patients from 2010 to 2012 with hematologic malignancies undergoing UCB transplantation to receive Omidubicel as part of a phase I trial; however, 2 participants did not receive the allocated intervention.^4, Patients receiving omidubicel (n=10) were compared to a cohort of historical controls from the same institution who received unmanipulated UCB (n=17). Time to neutrophil engraftment favored the omidubicel group over UCB transplant, but no difference was observed for the time to platelet engraftment. The rate of acute graft versus host disease was high but not compared to historical controls. OS and progression-free survival (PFS) were 82% and 73%, respectively, and did not report values for the control arm.

Anand et al (2017) conducted a prospective cohort study comparing patients who were treated with omidubicel (n=18) for hematologic malignancies to patients at the same institution who historically received standard UCB (n=86).^9, This study had an overlapping patient population in the omidubicel arm with the phase I trial by Horwitz et al (2014). Similar to Horwitz et al (2014), the median time to neutrophil engraftment favored the omidubicel group but no significant difference in the rate of engraftment failure (6% vs. 12%, p=.68). A total of 56% of omidubicel and 73% of standard UCB patients had one or more grade 2 or 3 infections (p=.16); the authors stratified this by infection type and found that grade 2 or 3 bacterial infections with significantly less common in the omidubicel group (p=.009) but found no difference in the frequency of grade 2 or 3 viral or fungal infections. The infection density, the mean number of total infections during the first 100 days post-transplantation, showed no significant difference between omidubicel and standard UCB transplant (3.7 vs. 4.9; p=.09).

Horwitz et al (2019) evaluated omidubicel (n=36) compared to a cohort of matched historical controls (n=146) from The Center for International Blood and Marrow Transplant Research (CIBMTR) database in patients with high-risk hematologic malignancies and no matched sibling or unrelated donor matches for allogenic HSCT.^3, The median follow-up of omidubicel recipients was 14 months (range, 5 to 36 months). Neutrophil engraftment was higher in the omidubicel recipients (94%) compared to the historical control group (85%), and showed a significantly higher rate of engraftment (Table 9). Time to platelet engraftment showed a similar trend. The 2-year cumulative incidence of NRM was 24% (95% CI, 11% to 39%) for patients treated with omidubicel and showed a significantly reduced risk of NRM compared to standard UCB (HR, 0.41; 95% CI, 0.19 to 0.88; p=.02). The cumulative rate of relapse at 2 years was 33% (95% CI, 16% to 52%); relapse showed conflicting findings in a multivariate analysis with one showing a significant between-group difference and the other showing no difference depending on which variables were adjusted for in the model. DFS was similar between the omidubicel (DFS, 43%; 95% CI, 24% to 60%) and historical control groups (DFS, 45%; 95% CI, 37% to 53%; p=.77). Omidubicel (OS, 51%; 95% CI, 33% to 67%) and historical control (OS, 48%; 95% CI, 40% to 56%; p=.72) did not differ on rates of 2-year overall survival. No differences were observed in the rate of acute GVHD or the incidence of cGVHD at 2-years post-transplantation between the 2 groups.

Table 8. Summary of Key Nonrandomized Trials OR Observational Comparative Study Characteristics

UCB: umbilical cord blood

Table 9. Summary of Key Nonrandomized Trials OR Observational Comparative Study Results

aGVHD: acute graft versus host disease; CI: confidence interval; Diff: difference; DFS: disease free survival; HR: hazard ratio; OR: odds ratio; OS: overall survival; PFS, progression free survival; RCT: randomized controlled trial; RR: relative risk.

Section Summary: Omidubicel for Hematologic Malignancies

For individuals who have hematologic malignancies and undergo omidubicel-modified UCB transplant, the evidence includes 3 cohort studies with historic controls, one RCT with 2 supplementary analyses, and 1 pooled analysis of long-term follow-up data. The RCT found that compared to patients treated with standard UCB, omidubicel-treated patients had a significantly lower time to neutrophil and platelet engraftment, neutrophil recovery, as well as a significant reduction in the incidence of first grade 2 or 3 invasive fungal or bacterial infections and grade 3 viral infections. Differences in OS, DFS, NRM, treatment failure, the rate of acute or chronic GVHD, and treatment-related adverse events were not observed between groups. Supplementary analys es found that omidubicel-treated participants were likelier to have improved scores on several quality-of-life measures and have lower average hospitalization times within the first 100 days of transplant. The evidence from the non-randomized studies suggests that compared to standard UCB, omidubicel showed a faster time to neutrophil engraftment and in one study a lower rate of grade 2 or 3 bacterial infections compared to historic controls; but no differences in the rates of engraftment failure, acute or chronic GVHD, OS, or DFS. A pooled, patient-level analysis utilizing data predominantly from the RCT and 4 other studies found that rates of OS, DFS, GVHD, and relapse were durable through 3 years of follow-up, although this analysis included a minority of patients with sickle cell hemoglobinopathy.

For individuals with hematologic malignancies who receive omidubicel, the evidence includes 3 cohort studies with historical controls, 1 randomized controlled trial (RCT) with 2 supplementary analyses, and 1 pooled analysis of long-term follow-up datas. Relevant outcomes are overall survival (OS), disease-free survival (DFS), treatment-related morbidity and mortality, adverse events, and quality of life. Omidubicel showed a faster time to neutrophil and platelet engraftment throughout the identified evidence base, and, in some stratified analyses, a lower rate of infection complications when compared to unmanipulated umbilical cord blood (UCB). No differences in OS, DFS, or treatment-related morbidity were observed. A subgroup analysis of the RCT showed an improvement in quality of life (QOL) but had methodological issues related to participation. Another secondary analysis of the same RCT reported a significant reduction in mean hospital length of stay (LOS) for the first 100 days post-transplantation for patients treated with omidubicel compared to standard umbilical cord blood. A pooled, patient-level analysis utilizing data from the RCT and 4 other studies found that rates of OS, DFS, graft versus host disease (GVHD), and relapse were durable through 3 years of follow-up, although this analysis included a minority of patients with sickle cell hemoglobinopathy. Compared to unmanipulated UCB transplantation, omidubicel transplantation for hematologic malignancies resulted in quicker neutrophil and platelet recovery, reduced hospital length of stay, and lower incidence of invasive bacterial and fungal infections with a favorable safety profile through 3 years post-transplantation. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

SUPPLEMENTAL INFORMATION

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements

Guidelines or position statements will be considered for inclusion in 'Supplemental Information' if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

American Academy of Pediatrics

The American Academy of Pediatrics issued a position statement in 2017 concerning cord blood banking and selection, but the statement contained no discussion of ex vivo expansion.^10,

National Comprehensive Cancer Network

Current National Comprehensive Cancer Network (NCCN) guidelines on hematopoietic cell transplantation (v1.2024) state that if a myeloablative conditioning regimen is planned for a recipient of umbilical cord blood, omidubicel-onlv has been shown to shorten the time to engraftment and reduce the risk of some infections (Grade 2A).^11, NCCN guidance on acute lymphoblastic leukemia (v1.2024), acute myeloid leukemia (v1.2024), B-cell lymphomas (v2.2024), chronic myeloid leukemia (v2.2024), or myelodysplastic syndromes (v2.2024), Hodgkin lymphoma (v2.2024) do not provide recommendations on the use of omidubicel or ex vivo expansion of cord blood more generally.^{12,13,14,15,16,}

American Society for Transplantation and Cellular Therapy

The American Society for Transplantation and Cellular Therapy published guidelines on the indications for hematopoietic cell transplantation and immune effector cell therapy in 2020; these guidelines did not provide recommendations on the use of omidubicel or ex vivo expansion of cord blood. ^17,

U.S. Preventive Services Task Force Recommendations

Not applicable.

Medicare National Coverage

There is no national coverage determination. In the absence of a national coverage determination, coverage decisions are left to the discretion of local Medicare carriers.

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this review are listed in Table 10.

Table 10. Summary of Key Trials

NCT: national clinical trial.
^a Denotes industry-sponsored or cosponsored trial.

References

1. Lin C, Schwarzbach A, Sanz J, et al. Multicenter Long-Term Follow-Up of Allogeneic Hematopoietic Cell Transplantation with Omidubicel: A Pooled Analysis of Five Prospective Clinical Trials. Transplant Cell Ther. May 2023; 29(5): 338.e1-338.e6. PMID 36775201
2. 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
3. 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): 367-374. PMID 30523748
4. 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
5. Parikh S, Brochstein JA, Galamidi E, et al. Allogeneic stem cell transplantation with omidubicel in sickle cell disease. Blood Adv. Feb 09 2021; 5(3): 843-852. PMID 33560399
6. Food and Drug Administration (FDA). Omisirge (Omidubicel) BLA Clinical Review Memorandum. April 14, 2023. https://www.fda.gov/media/168098/download. Accessed July 1, 2024.
7. 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
8. Majhail NS, Miller B, Dean R, 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. Dec 2023; 29(12): 749.e1-749.e5. PMID 37703995
9. 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
10. Shearer WT, Lubin BH, Cairo MS, et al. Cord Blood Banking for Potential Future Transplantation. Pediatrics. Nov 2017; 140(5). PMID 29084832
11. National Comprehensive Cancer Network (NCCN). NCCN clinical practice guidelines in oncology: Hematopoietic Cell Transplantation (HCT). Version 1.2024. https://www.nccn.org/professionals/physician_gls/pdf/hct.pdf. Accessed June 27, 2024.
12. National Comprehensive Cancer Network (NCCN). NCCN clinical practice guidelines in oncology: Acute Lymphoblastic Leukemia. Version 1.2024. https://www.nccn.org/professionals/physician_gls/pdf/all.pdf. Accessed June 23, 2024.
13. National Comprehensive Cancer Network (NCCN). NCCN clinical practice guidelines in oncology: Acute Myeloid Leukemia. Version 1.2024. https://www.nccn.org/professionals/physician_gls/pdf/aml.pdf. Accessed June 24, 2024.
14. National Comprehensive Cancer Network (NCCN). NCCN clinical practice guidelines in oncology: B-Cell Lymphomas. Version 2.2024. https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf. Accessed June 25, 2024.
15. National Comprehensive Cancer Network (NCCN). NCCN clinical practice guidelines in oncology: Chronic Myeloid Leukemia. Version 2.2024. https://www.nccn.org/professionals/physician_gls/pdf/cml.pdf. Accessed June 26, 2024.
16. National Comprehensive Cancer Network (NCCN). NCCN clinical practice guidelines in oncology: Myelodysplastic Syndromes. Version 2.2024. https://www.nccn.org/professionals/physician_gls/pdf/mds.pdf. Accessed June 29, 2024.
17. 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

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