Placental and Umbilical Cord Blood as a Source of Stem Cells - CAM 70150

Description: 
This evidence review addresses the collection, storage, and transplantation of placental and umbilical cord blood ("cord blood") as a source of stem cells for allogeneic and autologous stem cell transplantation. Potential indications for the use of cord blood are not addressed herein; they are discussed in the disease-specific evidence reviews.  

For individuals who have an appropriate indication for allogeneic stem cell transplant who receive cord blood as a source of stem cells, the evidence includes a number of observational studies, a meta-analysis of observational studies, and a randomized controlled trial (RCT) comparing outcomes after single- or double-cord blood units. Relevant outcomes are overall survival, disease-specific survival, resource utilization, and treatment-related mortality. The meta-analysis of observational studies found similar survival outcomes and lower graft-versus-host disease after cord blood transplantation than bone marrow transplantation. In the RCT, survival rates were similar after single- and double-unit cord blood transplantation. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have an unspecified potential future need for stem cell transplant who receive prophylactic collection and storage of cord blood, the evidence includes no published studies. Relevant outcomes are overall survival, disease-specific survival, resource utilization, and treatment-related mortality. No evidence was identified on the safety or effectiveness of autologous cord blood transplantation from prophylactically stored cord blood for the treatment of malignant neoplasms. The evidence is insufficient to determine the effects of the technology on health outcomes.

Background
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]). They can be harvested from bone marrow, peripheral blood, or umbilical cord blood shortly after delivery of neonates. Cord blood transplantation is discussed in detail in evidence review 7.01.50.

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 of 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 six. An acceptable donor will match the patient at all or most of the HLA loci.

Conditioning for Hematopoietic Cell Transplantation
Conventional Conditioning
The conventional (“classical”) practice of allo-HCT involves administration of cytotoxic agents (e.g., cyclophosphamide, busulfan) with or without total body irradiation at doses sufficient to cause bone marrow ablation in the recipient. The beneficial treatment effect of this procedure is due to a combination of the initial eradication of malignant cells and subsequent graft-versus-malignancy effect mediated by non-self-immunologic effector cells. While the slower graft-versus-malignancy effect is considered the potentially curative component, it may be overwhelmed by existing disease in the absence of pretransplant conditioning. Intense conditioning regimens are limited to patients who are sufficiently medically fit to tolerate substantial adverse effects. These include opportunistic infections secondary to loss of endogenous bone marrow function and organ damage or failure caused by cytotoxic drugs. Subsequent to graft infusion in allo-HCT, immunosuppressant drugs are required to minimize graft rejection and graft-versus-host disease, which increases susceptibility to opportunistic infections.

The success of autologous HCT is predicated on the potential of cytotoxic chemotherapy, with or without radiotherapy, to eradicate cancerous cells from the blood and bone marrow. This permits subsequent engraftment and repopulation of the bone marrow with presumably normal hematopoietic stem cells obtained from the patient before undergoing bone marrow ablation. Therefore, autologous HCT is typically performed as consolidation therapy when the patient’s disease is in complete remission. Patients who undergo autologous HCT are also susceptible to chemotherapy-related toxicities and opportunistic infections before engraftment, but not graft-versus-host disease.

Reduced-Intensity Conditioning Allogeneic Hematopoietic Cell Transplantation
RIC refers to the pretransplant use of lower doses of cytotoxic drugs or less intense regimens of radiotherapy than are used in traditional full-dose myeloablative conditioning treatments. Although the definition of RIC is variable, with numerous versions employed, all regimens seek to balance the competing effects of relapse due to residual disease and non-relapse mortality. The goal of RIC is to reduce disease burden and to minimize associated treatment-related morbidity and non-relapse mortality in the period during which the beneficial graft-versus-malignancy effect of allogeneic transplantation develops. RIC regimens range from nearly total myeloablative to minimally myeloablative with lymphoablation, with intensity tailored to specific diseases and patient condition. Patients who undergo RIC with allo-HCT initially demonstrate donor cell engraftment and bone marrow mixed chimerism. Most will subsequently convert to full-donor chimerism. In this review, the term reduced-intensity conditioning will refer to all conditioning regimens intended to be nonmyeloablative.

Regulatory Issues
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.4

Policy:
Transplantation of cord blood stem cells from related or unrelated donors may be considered MEDICALLY NECESSARY in patients with an appropriate indication for allogeneic stem-cell transplant.

Transplantation of cord blood stem cells from related or unrelated donors is considered investigational and/or unproven and therefore NOT MEDICALLY NECESSARY  in all other situations.

Collection and storage of cord blood from a neonate may be considered MEDICALLY NECESSARY when an allogeneic transplant is imminent (for use within 90 days or less) in an identified recipient with a diagnosis that is consistent with the possible need for allogeneic transplant.

Prophylactic collection and storage of cord blood from a neonate is considered NOT MEDICALLY NECESSARY when proposed for some unspecified future use as an autologous stem-cell transplant in the original donor, or for some unspecified future use as an allogeneic stem-cell transplant in a related or unrelated donor.

Policy Guidelines
Refer to the evidence reviews for specific conditions and diseases that have patient selection criteria for which allogeneic stem cell transplantation may be considered medically necessary.

Please see the Codes table for details.

Benefit Application
Through the National Marrow Donor Program’s Related Donor Cord Blood Program, eligible families within the U.S. can collect and store their neonate’s cord blood unit free of charge. When the stored unit is transplanted, a fee is charged. A family is considered eligible if:

  • the sibling of the neonate has been diagnosed with a disease treatable by a related cord blood transplant;
  • the neonate does not have the same disease as the affected biological sibling (determined after birth);
  • the affected sibling and the neonate have the same biological parents;

or if:

  • an affected biological parent is enrolled in a clinical or research trial that would accept a haploidentical, related, allogeneic cord blood unit as a treatment option.

Rationale 
This evidence review was created in November 1996 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through Nov. 20, 2020.

Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the 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 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 technology, 2 domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent 1 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 (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs 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.

Cord Blood as Source of Stem Cells for Stem Cell Transplant
A variety of malignant diseases and nonmalignant bone marrow disorders are treated with myeloablative therapy followed by infusion of the allogeneic stem and progenitor cells collected from immunologically compatible donors, either family members or an unrelated donor identified through a bone marrow donor bank. In some cases, a suitable donor is not found.

Blood harvested from the umbilical cord and placenta shortly after delivery of neonates contains stem and progenitor cells capable of restoring hematopoietic function after myeloablation. This cord blood has been used as an alternative source of allogeneic stem cells. Cord blood is readily available and is thought to be antigenically “naive,” thus potentially minimizing the incidence of graft-versus-host disease (GVHD) and permitting the broader use of unrelated cord blood transplants. Unrelated donors are typically typed at low resolution for human leukocyte antigen (HLA)-A and -B and at high resolution only for HLA DR; HLA matching at 4 of 6 loci is considered acceptable. Under this matching protocol, an acceptable donor can be identified for almost any patient.

Several cord blood banks have been created in the U.S. and Europe. In addition to obtaining cord blood for specific related or unrelated patients, some cord blood banks collect and store neonate cord blood for some unspecified future use in the unlikely event that the child develops a condition that would require autologous transplantation. Also, some neonate cord blood is collected and stored for use by a sibling in whom an allogeneic transplant is anticipated due to a history of leukemia or other condition requiring an allogeneic transplant. 

Standards and accreditation for cord blood banks are important for assisting transplant programs in knowing whether individual banks have quality control measures in place to address issues such as monitoring cell loss, change in potency, and prevention of product mix-up.Two major organizations have created accreditation standards for cord blood banks in the U.S.: the American Association of Blood Banks and the International NetCord Foundation/Foundation for the Accreditation of Cellular Therapy. Both the American Association of Blood Banks and the International NetCord Foundation/Foundation for the Accreditation of Cellular Therapy have developed and implemented a program of voluntary inspection and accreditation for cord blood banking. The American Association of Blood Banks and the International NetCord Foundation/Foundation for the Accreditation of Cellular Therapy publish standards for cord blood banks that define the collection, testing, processing, storage, and release of cord blood products.3 

Clinical Context and Therapy Purpose
The purpose of using placental and umbilical cord blood as a source of stem cells is to provide an alternative to or an improvement on existing donor sources in patients with an appropriate indication for allogeneic stem cell transplant.

The question addressed in this evidence review is: Does the use of placental and umbilical cord blood as a source of stem cells for individuals with an indication for allogeneic stem cell transplantation result in an improvement in net health outcomes?

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

Populations
The relevant population of interest is individuals with an appropriate indication for allogeneic stem cell transplant.

Interventions
The therapy being considered is placental or umbilical cord blood as a source of stem cells for allogeneic stem cell transplantation.

Patients with an appropriate indication for allogeneic stem cell transplant are managed by a transplant specialist in an inpatient clinical setting.

Comparators
Comparators of interest include stem cells from other donor sources.

Outcomes
The general outcomes of interest are overall survival (OS), disease-specific survival, resource utilization, and treatment-related mortality.

The timing of follow-up is initially the first post-transplant year for successful engraftment and monitoring relevant outcomes. Follow-up is life-long for successful transplantation. 

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 effects, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
  • Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Related Allogeneic Cord Blood Transplant
The first cord blood transplant involved a child with Fanconi anemia; results were reported in 1989.4 Subsequently, other cord transplants have been performed in matched siblings. The results of these transplants have demonstrated that cord blood contains sufficient numbers of hematopoietic stem and progenitor cells to reconstitute pediatric patients. Lower incidences of acute and chronic GVHD have been observed when cord blood, compared with bone marrow, was used as the source of donor cells.5 This led to the idea that cord blood could be banked and used as a source of unrelated donor cells, possibly without full HLA matching.6 

Unrelated Allogeneic Cord Blood Transplant
The first prospective evaluation of unrelated cord blood transplant was the Cord Blood Transplantation study, published in 2005. The Cord Blood Transplantation study was designed to examine the safety of unrelated cord blood transplantation in infants, children, and adults. Two-year event-free survival was 55% in children with high-risk malignancies7 and 78% in children with nonmalignant conditions.8, Across all groups, the cumulative incidence of engraftment by day 42 was 80%. Engraftment and survival were adversely affected by lower cell doses, pretransplant cytomegalovirus seropositivity in the recipient, non-European ancestry, and higher HLA mismatching. This slower engraftment led to longer hospitalizations and greater utilization of medical resources.9 In the Cord Blood Transplantation study, outcomes in adults were inferior to the outcomes achieved in children. 

Zhang et al. (2012) published a meta-analysis of studies comparing unrelated donor cord blood transplantation with unrelated donor bone marrow transplantation in patients who had acute leukemia.10 Reviewers identified 7 studies (N = 3389 patients). Pooled event rates of engraftment failure (n = 5 studies) were 18% (127/694 patients) in the cord blood transplant group and 6% (57/951 patients) in bone marrow transplant groups. The rate of engraftment graft failure was significantly higher in cord blood transplant recipients (p < 0.001). However, rates of acute GVHD were significantly lower in the cord blood transplant group. Pooled event rates of GVHD (n = 7 studies) were 34% (397/1179 patients) in the cord blood group and 44% (953/2189 patients) in the bone marrow group (p < 0.001). Relapse rates, reported in all studies, did not differ significantly between groups. Several survival outcomes, including OS, leukemia-free survival, and nonrelapse mortality, favored the bone marrow transplant group. 

Also, numerous retrospective and registry studies have generally found that unrelated cord blood transplantation is effective in both children and adults with hematologic malignancies and children with a variety of nonmalignant conditions.11,12,13  For example, a study by Liu et al. (2014) compared outcomes after unrelated donor cord blood transplantation with matched-sibling donor peripheral blood transplantation.13  The study included patients ages 16 years or older who had hematologic malignancies. Seventy patients received unrelated cord blood, and 115 patients received HLA-identical peripheral blood stem cells, alone or in combination with bone marrow. Primary engraftment rates were similar in the 2 groups (97% in the cord blood group, 100% in the peripheral blood stem cell group). Rates for most outcomes, including grades III and IV acute GVHD and 3 -year disease-free survival, were also similar between groups. However, the rate of chronic GVHD was lower in the unrelated donor cord blood group. Specifically, limited or extensive chronic GVHD occurred in 12 (21%) of 58 evaluable patients in the cord blood group and in 46 (42%) of 109 evaluable patients in the peripheral blood stem cell group (p = 0.005). 

Fuchs et al. (2020) reported on outcomes of 2 parallel phase 2 trials comparing unrelated umbilical cord blood transplantation versus haploidentical bone marrow transplantation in 368 patients aged 18 to 70 years old.14 The 2-year progression-free survival (the primary endpoint) was 35% (95% confidence interval [CI], 28% to 42%) after cord blood transplants and 41% (95% CI, 34% to 48%) after haploidentical bone marrow transplants (p = 0.41). The 2-year non-relapse mortality was 18% (95% CI, 13% to 24%) with cord blood transplant versus 11% (95% CI, 6% to 16%) with haploidentical transplants (p = 0.04), resulting in a 2-year OS of 46% (95% CI, 38% to 53%) with cord blood transplant versus 57% (95% CI, 49% to 64%) with haploidentical bone marrow transplants (p = 0.04). 

Haplo-Cord Blood Transplantation
Haplo-cord transplants involve a combination of donated cord blood stem cells and half-matched (haploidentical) cells from a related donor.

Mo et al. (2016) reported on outcomes after umbilical cord blood and haploidentical hematopoietic cell transplantation (HCT) in 129 children younger than 14 years old.15 The 2-year probability of OS was 82% (95% CI, 72.2% to 91.8%) in the haploidentical HCT group and 69.9% (95% CI, 58.0% to 81.2%) in the cord blood group. The difference in OS rates between groups was not statistically significant (p = 0.07). The 2-year incidence of relapse was also similar in both groups: 16% (95% CI, 6.1% to 26.1%) in the haploidentical HCT group and 24.1% (95% CI, 12.5% to 37.5%) in the cord blood group (p = 0.17). 

Hsu et al. (2018) reported on patients with lymphoma or chronic lymphoblastic leukemia who underwent haplo-cord allogeneic stem cell transplantation.16 Forty-two patients treated between 2007 and 2016 were included in the analysis. After a median survivor follow-up of 42 months, the median 3-year GVHD relapse-free survival, progression-free survival, and OS were 53% (95% CI: 36% to 68%), 62% (95% CI: 44% to 75%), and 65% (95% CI: 48% to 78%), respectively. The cumulative incidence of relapse was 12% at 100 days and 19.5% at 1 year.16 

Poonsombudlert et al. (2019) performed a meta-analysis of 7 studies (N = 3,434) comparing haploidentical transplant utilizing post transplant cyclophosphamide versus umbilical cord transplant in patients without a matched relative.17 Compared with umbilical cord transplant, haploidentical transplant utilizing cyclophosphamide was associated with a decreased risk of acute GVHD (odds ratio [OR], 0.78; 95% CI, 0.67 to 0.92) and relapse (OR, 0.74; 95% CI, 0.57 to 0.97) and an improved rate of chronic GVHD (OR, 1.41; 95% CI, 1.02 to 1.95) and OS (OR, 1.77; 95% CI, 1.1 to 2.87). 

Li et al. (2020) performed a meta-analysis of 7 studies in adult and pediatric patients with hematological malignancies (N = 2,422) undergoing umbilical cord blood transplantation or haploidentical transplantation.18 The results revealed a similar incidence of chronic GVHD and disease-free survival at 2 years between the 2 types of transplant in children. In adults, grade II to IV acute GVHD occurred at a higher rate with umbilical cord blood transplantation versus haploidentical transplantation (relative risk [RR], 1.17; 95% CI, 1.02 to 1.34; p = 0.02). Rates of grade III to IV acute GVHD, chronic GVHD, relapse, nonrelapse mortality, and disease-free survival at 2 years were similar between the 2 transplant types in adults. 

Wu et al. (2020) performed a meta-analysis of 12 studies (N = 2,793) comparing haploidentical HCT versus umbilical cord blood transplantation for hematologic malignancies.19 Compared with umbilical cord blood transplantation, HCT improved OS (OR, 0.74; 95% CI, 0.68 to 0.80), progression-free survival (OR, 0.77; 95% CI, 0.72 to 0.83), non-relapse mortality (OR, 0.72, 95% CI, 0.64 to 0.80), and acute GVHD (OR, 0.87; 95% CI, 0.77 to 0.98) but also increased the risk for chronic GVHD (OR, 1.40; 95% CI, 1.22 to 1.62). 

Double Unit Cord Blood Transplantation
Transplantation of 2 umbilical cord blood units (or double-unit transplants) has been evaluated as a strategy to overcome cell dose limitations with 1 cord blood unit in older and heavier patients. Initial experience at a university showed that using 2 units of cord blood for a single transplant in adults improved rates of engraftment and OS.20 Although cell doses are higher with double-unit transplants, studies published to date have found that survival rates are similar to transplants using single-cord blood units, and there is some suggestion of higher rates of GVHD ( Tables 1 and 2).21 

Table 1. Summary of Key Trial Characteristics

  Interventions
Author (Year) Countries Sites Dates Participants Active Comparator

Wagner et al. (2014)21   

  1  

Patients (age range, 1 to 21 y) who had high-risk acute leukemia, chronic myeloid leukemia, or myelodysplastic syndrome for whom there were 2 HLA-matched cord blood units available

2 units 1 unit

HLA: human leukocyte antigen.

Table 2. Summary of Key Trial Results 

Study (Year) 1-Year OS 1-Year DFS Acute GVHD Chronic GVHD

Wagner et al. (2014)21

       

Single unit (95% CI), %

73 (63 to 80)

70 (60 to 77)

13 (7 to 20)

30 (22 to 39)

Double unit (95% CI), %

65 (56 to 74)

64 (54 to 72)

23 (15 to 31)

32 (23 to 40)

p

0.17

0.011

0.02

0.51

CI: confidence interval; DFS: disease-free survival; GVHD: graft-versus-host disease; OS: overall survival.

Results of observational studies are similar to those of the Wagner et al. (2014) RCT ( Tables 3 and 4). In a study by Scaradavou et al. (2013), there was a significantly higher risk of acute GVHD (grade II to IV) in recipients of double-cord blood units treated during the first several years of observation.22 In the later period (2004 to 2009), rates of acute GVHD (grade II to IV) did not differ significantly between single- and double-units of cord blood. An analysis by Baron et al. (2017) found no significant differences between single- and double-cord blood transplantation for relapse or nonrelapse mortality, with a trend (p = 0.08) toward a higher incidence of GVHD with double units.23 

Table 3. Summary of Key Observational Study Characteristics

        Treatment  

Author (Year)

Study Type

Dates

Participants

Arm 1

Arm 2

Follow-Up

Scaradavou et al. (2013)22  

Comparative cohort

2002 to 2004
2004 to 2009

 

Single unit

Double unit 

 

Baron et al. (2017)23

Registry  2004 to 2014  Adults with first CBT for AML or ALL

Single unit

Double unit 

2y 

ALL: acute lymphocytic leukemia; AML: acute myeloid leukemia; CBT: cord blood transplantation.

Table 4. Summary of Key Observational Study Results

       

Acute GVHD (95% CI)

Study (Year)

N

Relapse Mortality

Nonrelapse Mortality

2002 to 2004

2004 to 2009

Scaradavou et al. (2013)22 

         

Single unit

106

       

Double unit

303        

HR (95% CI)

     

6.14 (2.54 to 14.87)

1.69 (0.68 to 4.18)

p

     

< 0.001

0.30

Baron et al. (2017)23

     

2004 to 2014

 

Single unit

172    

28%

 

Double unit

362    

36%

 

HR (95% CI)

 

0.9 (0.6 to 1.3)

0.8 (0.5 to 1.2)

   

p

 

0.5

0.3

0.08

 

CI: confidence interval; GVHD: graft-versus-host disease; HR: hazard ratio

Section Summary: Cord Blood as Source of Stem Cells for Stem Cell Transplant
A number of observational studies and meta-analyses of observational studies have compared outcomes after cord blood transplantation with stem cells from a different source. One meta-analysis found similar survival outcomes and lower GVHD after cord blood transplantation than bone marrow transplantation, but a recent RCT showed improved survival outcomes with haploidentical bone marrow transplantation over umbilical cord blood transplantation. Also, an RCT has compared single- and double-unit cord blood transplantation and found similar outcomes.

Prophylactic Collection and Storage of Cord Blood
Clinical Context and Therapy Purpose
The purpose of prophylactic collection and storage of placental or umbilical cord blood stem cells is to provide an alternative donor source for individuals without or with an unspecified potential future need for stem cell transplant.

The question addressed in this evidence review is: Does the prophylactic collection and storage of placental and umbilical cord blood stem cells to provide an alternative donor source for individuals without or with an unspecified potential future need for stem cell transplantation improve net health outcomes?

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

Populations
The relevant population of interest is individuals without or with an unspecified potential future need for stem cell transplant.

Interventions
The test being considered is prophylactic collection and storage of placental or umbilical cord blood stem cells.

The collection and preservation of placental or umbilical cord for future use is carried out at the time of labor and delivery and is carried out by commercial service providers.

Comparators
Comparators of interest include usual care without prophylactic storage of cord blood.

Outcomes
The general outcomes of interest are OS, disease-specific survival, resource utilization, and treatment-related mortality.

The future use of stored stem cells is unknown and, thus, the follow-up time period to transplant is indeterminate.

Review of Evidence
No studies have compared outcomes after prophylactic collection and storage of cord blood from a neonate for individuals who have an unspecified future need for transplant to standard care without cord blood collection and storage.

Also, although blood banks are collecting and storing neonate cord blood for potential future use, data on the use of cord blood for autologous stem cell transplantation are limited. A 2017 position paper from the American Academy of Pediatrics noted that there is little evidence of the safety or effectiveness of autologous cord blood transplantation for the treatment of malignant neoplasms.24 Also, a 2009 survey of pediatric hematologists noted few transplants had been performed using cord blood stored in the absence of a known indication.25 

Section Summary: Prophylactic Collection and Storage of Cord Blood
There is a lack of published evidence comparing outcomes after prophylactic collection and storage of cord blood from a neonate for individuals who have an unspecified future need for transplant with standard care without cord blood collection and storage.

Summary of Evidence
For individuals who have an appropriate indication for allogeneic stem cell transplant who receive cord blood as a source of stem cells, the evidence includes a number of observational studies, a meta-analysis of observational studies, and randomized controlled trials (RCTs). Relevant outcomes are overall survival (OS), disease-specific survival, resource utilization, and treatment-related mortality. A meta-analysis of observational studies found similar survival outcomes and lower graft-versushost disease after cord blood transplantation than bone marrow transplantation, but a recent RCT showed improved survival outcomes with haploidentical bone marrow transplantation over umbilical cord blood transplantation. In another RCT, survival rates were similar after single- and double-unit cord blood transplantation. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have an unspecified potential future need for stem cell transplant who receive prophylactic collection and storage of cord blood, the evidence includes no published studies. Relevant outcomes are OS, disease-specific survival, resource utilization, and treatment-related mortality. No evidence was identified on the safety or effectiveness of autologous cord blood transplantation from prophylactically stored cord blood for the treatment of malignant neoplasms. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Practice Guidelines and Position Statements
American Academy of Pediatrics
In 2017, a position statement on cord blood banking for potential future transplantation was published by the American Academy of Pediatrics.24 The Academy recommended cord blood banking for public use, with a more limited role for private cord blood banking for families with a known fatal illness that could be rescued by cord blood transplant. 

American College of Obstetricians and Gynecologists
In 2015, with an update in 2019, the American College of Obstetricians and Gynecologists published an opinion on umbilical cord blood (UCB) banking.26 The statement discussed counseling patients on options for UCB banking, as well as the benefits and limitations of this practice. The relevant recommendations included the following: 

  • "(UCB) collected from a neonate cannot be used to treat a genetic disease or malignancy in that same individual.” 
  • The routine collection and storage of (UCB) with a private cord blood bank is not supported by the available evidence. 
  • “Private (UCB) banking may be considered when there is knowledge of a family member with a medical condition (malignant or genetic) who could potentially benefit from cord blood transplantation.” 
  • “Public (UCB) banking is the recommended method of obtaining (UBC) for use in transplantation, immune therapies, or other medically validated indications.” 
  • “Umbilical cord blood collection should not compromise obstetric or neonatal care or alter routine practice for the timing of umbilical cord clamping.” 
  • “The current indications for cord blood transplant are limited to select genetic, hematologic, and malignant disorders.” 
  • “If a patient requests information about (UCB) banking, balanced and accurate information regarding the advantages and disadvantages of public and private [UCB] banking should be provided.” 

American Society for Blood and Marrow Transplantation
In 2008, on behalf of the American Society for Blood and Marrow Transplantation, Ballen et al. published recommendations related to the banking of UCB27:

  • Public banking of cord blood is “encouraged.” 
  • Storing cord blood for autologous (i.e., personal) use “is not recommended.” 
  • “Family member banking (collecting and storing cord blood for a family member) is recommended when there is a sibling with a disease that may be successfully treated with an allogeneic transplant. Family member banking on behalf of a parent with a disease that may be successfully treated with an allogeneic transplant is only recommended when there are shared HLA (human leukocyte)-antigens between the parents.” 

American Society of Transplantation and Cellular Therapy
In 2020, the American Society of Transplantation and Cellular Therapy released an evidence-based review on hematopoietic cell transplantation for treating newly diagnosed adult acute myeloid leukemia.28 The summary stated that a haploidenticalrelated donor is preferred over UCB in the absence of a fully HLA-matched donor, but UCB unit transplantation is an option for centers with this expertise. 

U.S. Preventive Services Task Force Recommendations
Not applicable

Ongoing and Unpublished Clinical Trials
Some currently ongoing and unpublished trials that might influence this review are listed in Table 5.

Table 5. Summary of Key Trials

NCT No.

Trial Name

Planned Enrollment

Completion Date

Ongoing

     

NCT01728545

The Collection and Storage of Umbilical Cord Blood for Transplantation

250,000

Apr 2099

NCT00012545

Collection and Storage of Umbilical Cord Stem Cells for Treatment of Sickle Cell Disease

99,999,999

NR

NCT: national clinical trial; NR: not reported.

References:  

  1. Food and Drug Administration (FDA). Cord Blood Banking: Information for Consumers. 2012 July 23; http://www.fda.gov/biologicsbloodvaccines/resourcesforyou/consumers/ucm236044.htm. Accessed November 20, 2020.
  2. Wall DA. Regulatory issues in cord blood banking and transplantation. Best Pract Res Clin Haematol. Jun 2010; 23(2): 171-7. PMID 20837328
  3. NetCord-FACT. International standards for cord blood collection banking and release of information accreditation manual. Sixth Edition Draft. 2015 September; http://www.factwebsite.org/uploadedFiles/Standards/NetCord%20FACT%206th%20Ed%20Manual%20Draft.09.01.15.pdf. Accessed November 20, 2020.
  4. Gluckman E, Broxmeyer HA, Auerbach AD, et al. Hematopoietic reconstitution in a patient with Fanconi's anemia by means of umbilical-cord blood from an HLA-identical sibling. N Engl J Med. Oct 26 1989; 321(17): 1174-8. PMID 2571931
  5. Wagner JE, Rosenthal J, Sweetman R, et al. Successful transplantation of HLA-matched and HLA-mismatched umbilical cord blood from unrelated donors: analysis of engraftment and acute graft-versus-host disease. Blood. Aug 01 1996; 88(3): 795-802. PMID 8704232
  6. Broxmeyer HE, Douglas GW, Hangoc G, et al. Human umbilical cord blood as a potential source of transplantable hematopoietic stem/progenitor cells. Proc Natl Acad Sci U S A. May 1989; 86(10): 3828-32. PMID 2566997
  7. Kurtzberg J, Cairo MS, Fraser JK, et al. Results of the cord blood transplantation (COBLT) study unrelated donor banking program. Transfusion. Jun 2005; 45(6): 842-55. PMID 15934981
  8. Martin PL, Carter SL, Kernan NA, et al. Results of the cord blood transplantation study (COBLT): outcomes of unrelated donor umbilical cord blood transplantation in pediatric patients with lysosomal and peroxisomal storage diseases. Biol Blood Marrow Transplant. Feb 2006; 12(2): 184-94. PMID 16443516
  9. Kurtzberg J. Update on umbilical cord blood transplantation. Curr Opin Pediatr. Feb 2009; 21(1): 22-9. PMID 19253461
  10. Zhang H, Chen J, Que W. A meta-analysis of unrelated donor umbilical cord blood transplantation versus unrelated donor bone marrow transplantation in acute leukemia patients. Biol Blood Marrow Transplant. Aug 2012; 18(8): 1164-73. PMID 22289799
  11. Rocha V, Cornish J, Sievers EL, et al. Comparison of outcomes of unrelated bone marrow and umbilical cord blood transplants in children with acute leukemia. Blood. May 15 2001; 97(10): 2962-71. PMID 11342418
  12. Kato K, Choi I, Wake A, et al. Treatment of patients with adult T cell leukemia/lymphoma with cord blood transplantation: a Japanese nationwide retrospective survey. Biol Blood Marrow Transplant. Dec 2014; 20(12): 1968-74. PMID 25172635
  13. Liu HL, Sun ZM, Geng LQ, et al. Similar survival, but better quality of life after myeloablative transplantation using unrelated cord blood vs matched sibling donors in adults with hematologic malignancies. Bone Marrow Transplant. Aug 2014; 49(8): 1063-9. PMID 24842525
  14. Fuchs EJ, O'Donnell PV, Eapen M, et al. Double unrelated umbilical cord blood versus HLA-haploidentical bone marrow transplantation (BMT CTN 1101). Blood. Aug 31 2020. PMID 32870242
  15. Mo XD, Tang BL, Zhang XH, et al. Comparison of outcomes after umbilical cord blood and unmanipulated haploidentical hematopoietic stem cell transplantation in children with high-risk acute lymphoblastic leukemia. Int J Cancer. Nov 01 2016; 139(9): 2106-15. PMID 27356906
  16. Hsu J, Artz A, Mayer SA, et al. Combined Haploidentical and Umbilical Cord Blood Allogeneic Stem Cell Transplantation for High-Risk Lymphoma and Chronic Lymphoblastic Leukemia. Biol Blood Marrow Transplant. Feb 2018; 24(2): 359-365. PMID 29128555
  17. Poonsombudlert K, Kewcharoen J, Prueksapraopong C, et al. Post transplant cyclophosphamide based haplo-identical transplant versus umbilical cord blood transplant; a meta-analysis. Jpn J Clin Oncol. Oct 01 2019; 49(10): 924-931. PMID 31265729
  18. Li D, Li X, Liao L, et al. Unrelated cord blood transplantation versus haploidentical transplantation in adult and pediatric patients with hematological malignancies-A meta-analysis and systematic review. Am J Blood Res. 2020; 10(1): 1-10. PMID 32206440
  19. Wu R, Ma L. Haploidentical Hematopoietic Stem Cell Transplantation Versus Umbilical Cord Blood Transplantation in Hematologic Malignancies: A Systematic Review and Meta-Analysis. Cell Transplant. Jan-Dec 2020; 29: 963689720964771. PMID 33040595
  20. Barker JN, Weisdorf DJ, DeFor TE, et al. Transplantation of 2 partially HLA-matched umbilical cord blood units to enhance engraftment in adults with hematologic malignancy. Blood. Feb 01 2005; 105(3): 1343-7. PMID 15466923
  21. Wagner JE, Eapen M, Carter S, et al. One-unit versus two-unit cord-blood transplantation for hematologic cancers. N Engl J Med. Oct 30 2014; 371(18): 1685-94. PMID 25354103
  22. Scaradavou A, Brunstein CG, Eapen M, et al. Double unit grafts successfully extend the application of umbilical cord blood transplantation in adults with acute leukemia. Blood. Jan 31 2013; 121(5): 752-8. PMID 23223509
  23. Baron F, Ruggeri A, Beohou E, et al. Single- or double-unit UCBT following RIC in adults with AL: a report from Eurocord, the ALWP and the CTIWP of the EBMT. J Hematol Oncol. Jun 21 2017; 10(1): 128. PMID 28637512
  24. Shearer WT, Lubin BH, Cairo MS, et al. Cord Blood Banking for Potential Future Transplantation. Pediatrics. Nov 2017; 140(5). PMID 29084832
  25. Thornley I, Eapen M, Sung L, et al. Private cord blood banking: experiences and views of pediatric hematopoietic cell transplantation physicians. Pediatrics. Mar 2009; 123(3): 1011-7. PMID 19255033
  26. ACOG Committee Opinion No. 771: Umbilical Cord Blood Banking. Obstet Gynecol. Mar 2019; 133(3): e249-e253. PMID 30801478
  27. Ballen KK, Barker JN, Stewart SK, et al. Collection and preservation of cord blood for personal use. Biol Blood Marrow Transplant. Mar 2008; 14(3): 356-63. PMID 18275904
  28. Dholaria B, Savani BN, Hamilton BK, et al. Hematopoietic Cell Transplantation in the Treatment of Newly Diagnosed Adult Acute Myeloid Leukemia: An Evidence-Based Review from the American Society of Transplantation and Cellular Therapy. Biol Blood Marrow Transplant. Sep 20 2020. PMID 32966881 

Coding Section

Codes

Number

Description

CPT

 

No specific code

HCPCS

S2140

Cord blood harvesting for transplantation, allogeneic

 

S2142

Cord blood derived stem-cell transplantation, allogeneic

 

S2150

Bone marrow or blood-derived stem cells (peripheral or umbilical), allogeneic or autologous, harvesting, transplantation, and related complications; including: pheresis and cell preparation/storage; marrow ablative therapy; drugs; supplies; hospitalization with outpatient follow-up; medical/surgical, diagnostic, emergency, and rehabilitative services; and the number of days of pre- and post-transplant care in the global definition

ICD-10-CM

 

[See the diagnosis codes listed in the various policies relevant to allogeneic stem cell transplantation in the Therapy section of the MPRM (eg, 8.01.15, 8.01.21, 8.01.22)]

ICD-10-PCS

30243X0, 30243X1

Percutaneous transfusion, central vein, stem cells, cord blood, autologous or nonautologous, code list

Type of Service

Transplant

 

Place of Service

Inpatient

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

"Current Procedural Terminology © American Medical Association. All Rights Reserved" 

History From 2013 Forward     

11/01/2021 

Annual review, no change to policy intent. Updating rationale and references. 

11/01/2020 

Annual review, no change to policy intent. Updating background, guidelines, coding, rationale and references. 

11/03/2019 

Annual review, no change to policy intent. Updating rationale and references 

12/04/2018 

Annual review, no change to policy intent. Updating rationale and references. 

11/01/2017 

Annual review, no change to policy intent. Updating description, rationale and references.

11/01/2016 

Annual review, no change to policy intent. Updating background, description, rationale and references. Adding guidelines. 

11/4/2015 

Annual review, no change to policy intent. Updated background, description, rationale and references. 

11/11/2014 

Annual review, no change to policy intent. Updated description, background, regulatory status, rationale and references. Added coding.

11/11/2013

Updated Desription, Regulatory Issues, Rationale and References.

11/19/2013 Adding verbiage specific to 90 days or less for imminent use of cord blood.
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