Description
A number of inherited and acquired conditions have the potential for severe and/or progressive disease. For some conditions, allogeneic hematopoietic cell transplantation (allo-HCT) has been used to alter the natural history of the disease or potentially offer a cure.

For individuals who have a hemoglobinopathy, bone marrow failure syndrome, primary immunodeficiency, inherited metabolic syndrome disease (specifically those other than Hunter, Sanfilippo, or Morquio syndromes), or a genetic disorder affecting skeletal tissue who receive allo-HCT, the evidence includes mostly case series, case reports, and registry data. Relevant outcomes are overall survival, disease-specific survival, symptoms, quality of life, and treatment-related morbidity. The evidence has shown that, for most of these disorders, there is a demonstrable improvement in overall survival and other disease-specific outcomes. Allo-HCT is likely to improve health outcomes in select patients with certain inherited and acquired diseases. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have an inherited metabolic syndrome disease (specifically those including Hunter, Sanfilippo, and Morquio syndromes) who receive allo-HCT, the evidence includes case reports. Relevant outcomes are overall survival, disease-specific survival, symptoms, quality of life, and treatment-related morbidity. Use of allo-HCT to treat patients with Hunter, Sanfilippo, or Morquio syndromes does not result in improvements in neurologic, neuropsychologic, and neurophysiologic function. The evidence is insufficient to determine the effects of the technology on health outcomes.

Background     
Genetic Diseases and Acquired Anemias
Hemoglobinopathies
Thalassemias result from variants in the globin genes, resulting in reduced or absent hemoglobin production, thereby reducing oxygen delivery. The supportive treatment of b-thalassemia major requires life-long red blood cell transfusions that lead to progressive iron overload and the potential for organ damage and impaired cardiac, hepatic, and endocrine function. Sickle cell disease is caused by a single amino acid substitution in the beta chain of hemoglobin and, unlike thalassemia major, has a variable course of clinical severity.¹ Sickle cell disease typically manifests clinically with anemia, severe painful crises, acute chest syndrome, stroke, chronic pulmonary and renal dysfunction, growth retardation, neurologic deficits, and premature death. The mean age of death for patients with sickle cell disease has been demonstrated as 42 years for men and 48 for women.

Treatment
The only definitive cure for thalassemia is to correct the genetic defect with allogeneic hematopoietic cell transplantation (allo-HCT).

Three major therapeutic options are available for sickle cell disease: chronic blood transfusions, hydroxyurea, and allo-HCT, the latter being the only possibility for cure.¹

Bone Marrow Failure Syndromes
Aplastic anemia in children is rare; most often, it is idiopathic and, less commonly, due to a hereditary disorder. Inherited syndromes include Fanconi anemia, a rare, autosomal recessive disease characterized by genomic instability, with congenital abnormalities, chromosome breakage, cancer susceptibility, and progressive bone marrow failure leading to pancytopenia and severe aplastic anemia. Frequently, this disease terminates in myelodysplastic syndrome or acute myeloid leukemia. Most patients with Fanconi anemia succumb to the complications of severe aplastic anemia, leukemia, or solid tumors, with a median survival of 30 years of age.²

Dyskeratosis congenita is characterized by marked telomere dysregulation with clinical features of reticulated skin hyperpigmentation, nail dystrophy, and oral leukoplakia.³ Early mortality is associated with bone marrow failure, infections, pulmonary complications, or malignancy.

Variants affecting ribosome assembly and function are associated with Shwachman-Diamond syndrome and Diamond-Blackfan syndrome.³ Shwachman-Diamond has clinical features that include pancreatic exocrine insufficiency, skeletal abnormalities, and cytopenias, with some patients developing aplastic anemia. As with other bone marrow failure syndromes, patients are at increased risk of myelodysplastic syndrome and malignant transformation, especially acute myeloid leukemia. Diamond-Blackfan anemia is characterized by absent or decreased erythroid precursors in the bone marrow, with 30% of patients also having a variety of physical anomalies.³

Treatment
In Fanconi anemia, HCT is currently the only treatment that definitively restores normal hematopoiesis. Excellent results have been observed with the use of human leukocyte antigen (HLA)-matched sibling allo-HCT, with cure of the marrow failure and amelioration of the risk of leukemia.

Primary Immunodeficiencies
The primary immunodeficiencies are a genetically heterogeneous group of diseases that affect distinct components of the immune system. More than 120 gene defects have been described, causing more than 150 disease phenotypes.⁴ The most severe defects (collectively known as severe combined immunodeficiency) cause an absence or dysfunction of T lymphocytes and sometimes B lymphocytes and natural killer cells.⁴

Treatment
Without treatment, patients with severe combined immunodeficiency usually die by 12 to 18 months of age. With supportive care, including prophylactic medication, the lifespan of these patients can be prolonged, but long-term outlook is still poor, with many dying from infectious or inflammatory complications or malignancy by early adulthood.⁴ Bone marrow transplantation is the only definitive cure, and the treatment of choice for severe combined immunodeficiency and other primary immunodeficiencies, including Wiskott-Aldrich syndrome and congenital defects of neutrophil function.⁵

Inherited Metabolic Diseases
Lysosomal storage disorders consist of many different rare diseases caused by a single gene defect, and most are inherited as an autosomal recessive trait.⁶ Lysosomal storage disorders are caused by specific enzyme deficiencies that result in defective lysosomal acid hydrolysis of endogenous macromolecules that subsequently accumulate as a toxic substance. Peroxisomal storage disorders arise due to a defect in a membrane transporter protein that leads to defects in the metabolism of long-chain fatty acids. Lysosomal storage disorders and peroxisomal storage disorders affect multiple organ systems, including the central and peripheral nervous systems. These disorders are progressive and often fatal in childhood due to both the accumulation of toxic substrate and a deficiency of the product of the enzyme reaction.⁶ Hurler syndrome usually leads to premature death by 5 years of age.

Treatment
Exogenous enzyme replacement therapy is available for a limited number of the inherited metabolic diseases; however, these drugs do not cross the blood-brain barrier, which results in the ineffective treatment of the central nervous system. Stem cell transplantation provides a constant source of enzyme replacement from the engrafted donor cells, which are not impeded by the blood-brain barrier.⁶ The donor-derived cells can migrate and engraft in many organ systems, giving rise to different types of cells (e.g., microglial cells in the brain and Kupffer cells in the liver).⁶

Allo-HCT has been primarily used to treat the inherited metabolic diseases that belong to the lysosomal and peroxisomal storage disorders, as listed in Table 1.⁶ The first stem cell transplant for an inherited metabolic disease was performed in 1980 in a patient with Hurler syndrome. Since that time, more than 1,000 transplants have been performed worldwide.⁶

Table 1. Lysosomal and Peroxisomal Storage Disorders

Category	Diagnosis	Other Names
Mucopolysaccharidosis	Mucopolysaccharidosis I H or H/S Mucopolysaccharidosis II Mucopolysaccharidosis III A-D Mucopolysaccharidosis IV A-B Mucopolysaccharidosis VI Mucopolysaccharidosis VII	Hurler syndrome or Hurler-Scheie syndrome Hunter syndrome Sanfilippo syndrome A-D Morquio syndrome A-B Maroteaux-Lamy syndrome Sly syndrome
Sphingolipidosis	Fabry disease Farber disease Gaucher disease types 1 and 3 GM1 gangliosidosis Niemann-Pick disease A and B Tay-Sachs disease Sandhoff disease Globoid cell leukodystrophy Metachromatic leukodystrophy	Lipogranulomatosis           Krabbe disease MLD
Glycoproteinosis	Aspartylglucosaminuria Fucosidosis Alpha-mannosidosis Beta-mannosidosis Mucolipidosis III and IV	Sialidosis
Other lipidoses	Niemann-Pick disease C Wolman disease Ceroid lipofuscinosis type III	Batten disease
Glycogen storage	Glycogen storage disease type II	Pompe disease
Multiple enzyme deficiency	Galactosialidosis Mucolipidosis type II	I-cell disease
Lysosomal transport defects	Cystinosis Sialic acid storage disease Salla disease
Peroxisomal storage disorders	Adrenoleukodystrophy Adrenomyeloneuropathy	ALD AMN

Genetic Disorders Affecting Skeletal Tissue
Osteopetrosis is a condition caused by defects in osteoclast development and/or function. The osteoclast (the cell that functions in the breakdown and resorption of bone tissue) is known to be part of the hematopoietic family and shares a common progenitor with the macrophage in the bone marrow.⁷ Osteopetrosis is a heterogeneous group of heritable disorders, resulting in several different types of variable severity. The most severely affected patients are those with infantile malignant osteopetrosis (Albers-Schonberg disease or marble bone disease). Patients with infantile malignant osteopetrosis suffer from dense bone, including a heavy head with frontal bossing, exophthalmos, blindness by approximately 6 months of age, and severe hematologic malfunction with bone marrow failure.⁷ Seventy percent of these patients die before the age of 6 years, often of recurrent infections.⁷

Treatment
HCT is the only curative therapy for this fatal disease.

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 (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 ofHLA 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.

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 GVH 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 non-myeloablative.

Regulatory Status
The U.S. Food and Drug Administration regulates human cells and tissues intended for implantation, transplantation or infusion through the Center for Biologics Evaluation and Research, under the Code of Federal Regulation title 21, parts 1270 and 1271.⁸ Hematopoietic stem cells are included in these regulations. 

Policy:
Allogeneic hematopoietic stem cell transplantation is considered MEDICALLY NECESSARY for selected patients with the following disorders:

Hemoglobinopathies

• Sickle cell anemia for children or young adults with either a history of prior stroke or at increased risk of stroke or end-organ damage
• Homozygous beta-thalassemia (i.e., thalassemia major)

Bone Marrow Failure Syndromes

• Aplastic anemia including hereditary (including Fanconi anemia, dyskeratosis congenita, Shwachman-Diamond, Diamond-Blackfan) or acquired (e.g., secondary to drug or toxin exposure) forms

Primary Immunodeficiencies

• Absent or defective T-cell function (e.g., severe combined immunodeficiency, Wiskott-Aldrich syndrome, X-linked lymphoproliferative syndrome)
• Absent or defective natural killer function (e.g., Chediak-Higashi syndrome)
• Absent or defective neutrophil function (e.g., Kostmann syndrome, chronic granulomatous disease, leukocyte adhesion defect)

(See Policy Guideline # 1.)

Inherited Metabolic Disease

• Lysosomal and peroxisomal storage disorders except Hunter, Sanfilippo and Morquio syndromes

(See Policy Guideline # 2.)

Genetic Disorders Affecting Skeletal Tissue

• Infantile malignant osteopetrosis (Albers-Schonberg disease or marble bone disease)

Policy Guidelines
1. The following lists the immunodeficiencies that have been successfully treated by allogeneic hematopoietic stem-cell transplantation (HSCT) (4):

Lymphocyte Immunodeficiencies

• Adenosine deaminase deficiency
• Artemis deficiency
• Calcium channel deficiency
• CD 40 ligand deficiency
• Cernunnos/X-linked lymphoproliferative disease deficiency
• CHARGE syndrome with immune deficiency
• Common gamma chain deficiency
• Deficiencies in CD 45, CD3, CD8
• DiGeorge syndrome
• DNA ligase IV
• Interleukin-7 receptor alpha deficiency
• Janus-associated kinase three (JAK3) deficiency
• Major histocompatibility class II deficiency
• Omenn syndrome
• Purine nucleoside phosphorylase deficiency
• Recombinase-activating gene (RAG) 1/2 deficiency
• Reticular dysgenesis
• Winged helix deficiency
• Wiskott-Aldrich syndrome
• X-linked lymphoproliferative disease
• Zeta-chain-associated protein-70 (ZAP-70) deficiency

Phagocytic Deficiencies

• Chediak-Higashi syndrome
• Chronic granulomatous disease
• Hemophagocytic lymphohistiocytosis
• Griscelli syndrome, type 2
• Interferon-gamma receptor deficiencies
• Leukocyte adhesion deficiency
• Severe congenital neutropenias
• Shwachman-Diamond syndrome

Other Immunodeficiencies

• Autoimmune lymphoproliferative syndrome
• Cartilage hair hypoplasia
• CD25 deficiency
• Hyper IgD and IgE syndromes
• ICF syndrome
• IPEX syndrome
• NEMO deficiency
• NF-κB inhibitor, alpha (IκB-alpha) deficiency
• Nijmegen breakage syndrome

2. In the inherited metabolic disorders, allogeneic HSCT has been proven effective in some cases of Hurler, Maroteaux-Lamy and Sly syndromes, childhood onset cerebral X-linked adrenoleukodystrophy, globoid-cell leukodystrophy, metachromatic leukodystrophy, alpha-mannosidosis and aspartylglucosaminuria. Allogeneic HSCT is possibly effective for fucosidosis, Gaucher types one and 3, Farber lipogranulomatosis, galactosialidosis, GM₁, gangliosidosis, mucolipidosis II (I-cell disease), multiple sulfatase deficiency, Niemann-Pick, neuronal ceroid lipofuscinosis, sialidosis and Wolman disease. Allogeneic HSCT has not been effective in Hunter, Sanfilippo or Morquio syndromes. (8)

The experience with reduced-intensity conditioning (RIC) and allogeneic HSCT for the diseases listed in this policy has been limited to small numbers of patients and has yielded mixed results, depending upon the disease category. In general, the results have been most promising in the bone marrow failure syndromes and primary immunodeficiencies. In the hemoglobinopathies, success has been hampered by difficulties with high rates of graft rejection, and in adult patients, severe graft versus host disease (GVHD). Several Phase II/III trials are ongoing examining the role of this type of transplant for these diseases, as outlined in the clinical trial section under each disease type.

Benefit Application
BlueCard/National Account Issues
State or federal mandates (e.g., FEP) 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 on the basis of their medical necessity.

Rationale  
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 (QOL) and ability to function — including benefits and harms. Every clinical condition has specific outcomes that are important to patients and managing the courseof 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 one or more intended clinical uses 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.

Clinical Context and Test Purpose
The purpose of allogeneic hematopoietic cell transplantation (allo-HCT) is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with a hemoglobinopathy.

The question addressed in this evidence review is: Does the use of allo-HCT improve the net health outcome in individuals with a hemoglobinopathy?

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

Populations
The relevant population of interest is individuals with a hemoglobinopathy.

Interventions
The therapy being considered is allo-HCT.

Patients with a hemoglobinopathy are actively managed by hematologists and primary care providers in an outpatient clinical setting. Patients with a hemoglobinopathy undergoing HCT are actively managed in the inpatient clinical setting.

Comparators
Comparators of interest include standard of care.

Outcomes
The general outcomes of interest are overall survival (OS), disease-specific survival (DSS), symptoms, QOL, and treatment-related morbidity (TRM).

Follow-up at 3- and 12- years is of interest for allo-HCT to monitor 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.
• Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Hemoglobinopathies
Systematic Reviews
Review articles summarize the experience to date with HCT and the hemoglobinopathies.^8,9,10,11

β-Thalassemia
Systematic Reviews
More than 3,000 patients worldwide have been treated for β-thalassemia with allo-HCT.¹⁰ The OS rates have ranged from 65% to 98% at 5 years, up to 87% at 15 years, up to 89% at 20 years, and thalassemia-free survival has been reported to be as high as 86% at 6 years.¹² The Pesaro risk stratification system classifies patients with thalassemia who plan to undergo allo-HCT into risk groups 1 through 3 based on the presence of hepatomegaly, portal fibrosis, or adequacy of chelation (class 1 having no risk factors, class 2 with 2 risk factors, and class 3 with all 3 risk factors).¹³ The outcome of allo-HCT in more than 800 patients with thalassemia according to risk stratification has shown OS and event-free survival (EFS) rates of 95% and 90% for Pesaro class 1, 87% and 84% for class 2, and 79% and 58% for class 3.

Noncomparative Studies
A 2015 study of 489 patients with nonmalignant hematologic disorders who underwent allo-HCT between 1997 and 2012 included 152 patients with β-thalassemia.¹⁴ Mean age at transplantation was 5.7 years (range, 1.1 – 23 years). At the time of transplantation, 26 (17%) patients had Pesaro class 1, 103 (68%) had class 2, and 23 (15%) had class 3; 132 patients received peripheral blood stem cells and 20 received bone marrow grafts. Mean times to neutrophil and platelet engraftment were 21.4 days (range, 8 – 69 days) and 32.8 days (range, 7 – 134 days), respectively. The incidence of graft rejection was significantly lower in patients who received peripheral blood stem cells than in those who received bone marrow grafts (9% vs. 25%; p = 0.036). Acute graft-versus-host-disease (GVHD) grade II, III, and IV occurred in 15% of β-thalassemia patients, and chronic GVHD occurred in 12%. The incidence of transplant-related mortality for this group was 18%. After a median follow-up period of 12 years, the OS rate for these patients was 82.4%. The disease-free survival (DFS) rate for the whole group of β-thalassemia patients was 72.4% (74% in the peripheral blood cell transplantation group vs. 64% in the bone marrow cell transplantation group; p = 0.381), which might be attributed to the higher incidence of graft rejection in bone marrow groups.

Bernardo et al. (2012) reported on the results of 60 thalassemia patients (median age, 7 years; range, 1 – 37 years) who underwent allo-HCT after a reduced-intensity conditioning (RIC) regimen based on treosulfan.¹⁵ Before the transplant, 27 children were assigned to class 1 of the Pesaro risk stratification system, 17 to class 2, and 4 to class 3; 12 patients were adults. Twenty patients were transplanted from a human leukocyte antigen (HLA)-identical sibling and 40 from an unrelated donor. The cumulative incidence of graft failure and transplantation-related mortality were 9% and 7%, respectively. Eight patients experienced grade II, III, or IV acute GVHD, the cumulative incidence being 14%. Among 56 patients at risk, 1 developed limited chronic GVHD. With a median follow-up of 36 months (range, 4 – 72 months), the 5-year probability of survival and thalassemia-free survival were 93% and 84%, respectively. Neither the class of risk nor the donor used influenced outcomes.

In a 2014 report on RIC HCT, 98 patients with class 3 thalassemia were transplanted with related or unrelated donor stemcells.¹⁶ Seventy-six of patients less than 10 years of age received a conventional myeloablative conditioning regimen (cyclophosphamide, busulfan, with or without fludarabine). The remaining 22 patients were 10 years of age or older with hepatomegaly and, in several instances, additional comorbidity problems, who underwent HCT with a novel RIC regimen (fludarabine and busulfan). Rates of EFS (86% vs. 90%, respectively), and OS (95% vs. 90%, respectively) did not differ significantly between groups. However, a higher incidence of serious treatment-related complications was observed in the group that received myeloablative conditioning. Furthermore, graft failures occurred in 6 patients in the myeloablatedgroup (8%), although none occurred in the RIC group.

Sickle Cell Disease
Systematic Reviews
A Cochrane systematic review published in 2013,¹⁷ and updated in 2016¹⁸, and 2020¹⁹, identified no completed RCTs that assessed risk or benefit of any method of HCT in patients with sickle cell disease.

Noncomparative Studies
Approximately 500 to 600 patients with sickle cell disease have undergone allo-HCT, and most of the experience with allo-HCT and sickle cell disease comes from 3 major clinical series^.1,10 The largest series to date consists of 87 symptomatic patients, most of whom received donor allografts from siblings who are HLA-identical.20, The results from that series and the 2 others^21,22 were similar, with rates of OS ranging from 92% to 94% and EFS from 82% to 86%, with a median follow-up ranging from 0.9 to 17.9 years.¹

Experience with reduced-intensity preparative regimens (RIC and allo-HCT for the hemoglobinopathies) is limited to asmall number of patients. Challenges have included high rates of graft rejection (10% – 30%)⁸ and, in adult patients, severe GVHD, which has been observed with the use of RIC regimens.⁹

Hsieh et al. (2014) reported on results from 30 patients aged 16 to 65 years with severe sickle cell phenotype who were enrolled in a RIC allo-HCT study, consisting of alemtuzumab (1 mg/kg in divided doses), total body irradiation (300centigray), sirolimus, and infusion of unmanipulated filgrastim-mobilized peripheral blood stem cells from HLA-matchedsiblings.²³ The primary endpoint was treatment success at 1 year after the transplant, defined as full-donor-typehemoglobin for patients with sickle cell disease and transfusion independence for patients with thalassemia. Secondary endpoints included the level of donor leukocyte chimerism; incidence of acute and chronic GVHD; and sickle cell-thalassemia DFS, immunologic recovery, and changes in organ function. Twenty-nine patients survived a median of 3.4years (range, 1 – 8.6 years), with no nonrelapse mortality. One patient died from intracranial bleeding after relapse. Normalized hemoglobin and resolution of hemolysis among engrafted patients were accompanied by stabilization in brain imaging, a reduction of echocardiographic estimates of pulmonary pressure, and allowed for phlebotomy to reduce hepatic iron. A total of 38 serious adverse events were reported: pain and related management, infections, abdominal events, and sirolimus-related toxic effects.

Section Summary: Hemoglobinopathies
The use of allo-HCT to treat patients with β-thalassemia or sickle cell disease has been shown to improve OS, EFS, or DFS.

Clinical Context and Test Purpose
The purpose of allo-HCT is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with a bone marrow failure syndrome.

The question addressed in this evidence review is: Does the use of allo-HCT improve the net health outcome in individuals with a bone marrow failure syndrome?

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

Populations
The relevant population of interest is individuals with bone marrow failure syndrome.

Interventions
The therapy being considered is allo-HCT.

Patients with bone marrow failure syndrome are actively managed by hematologists and primary care providers in an outpatient clinical setting. Patients with bone marrow failure syndrome undergoing HCT are actively managed in the inpatient clinical setting.

Comparators
Comparators of interest include standard of care.

Outcomes
The general outcomes of interest are OS, DSS, symptoms, QOL, and TRM.

Follow-up at 1.1- and 8-years is of interest for allo-HCT to monitor 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.
• Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Bone Marrow Failure Syndromes
Systematic Reviews
Review articles summarize the experience to date on the use of HCT to treat bone marrow failure syndromes.^8,24,25,26

Fanconi Anemia
Noncomparative Studies
Yabe et al. (2020) analyzed nationwide records of 163 patients with Fanconi anemia who received an allo-HCT in Japan between 1987 and 2015.²⁷ The 5-year OS rate was 81%. The 10-year and 15-year OS rates were 77% and 72%. Of the 163 patients, 154 had a stable engraftment. Among evaluable patients (n = 154), 17% and 5.8% developed grade II-IV andgrade III – IV GVHD, respectively.

In a 2008 summary of patients with Fanconi anemia who received allo-HCT from matched related donors over 6 years (N = 103 patients), OS rates ranged from 83% to 88%, with transplant-related mortality ranging from 8% to 18.5% and average chronic GVHD of 12%.²⁸

The outcomes in patients with Fanconi anemia and an unrelated donor allo-HCT have not been as promising. The European Group for Blood and Marrow Transplantation has analyzed the outcomes using alternative donors in 67 patients with Fanconi anemia. Median 2-year survival was 28%.³ Causes of death included infection, hemorrhage, acute and chronic GVHD, and liver veno-occlusive disease.³ The Center for International Blood and Marrow Transplant Research analyzed 98 patients transplanted with unrelated donor marrow between 1990 and 2003. Three-year OS rates were 13% and 52%, respectively, in patients who received non-fludarabine- or fludarabine-based regimens.³

Zanis-Neto et al. (2005) reported on the results of 30 patients with Fanconi anemia treated with RIC regimens, consisting of low-dose cyclophosphamide.²⁹ Seven patients were treated with cyclophosphamide at 80 mg/kg and 23 with 60mg/kg. Grade II or III acute GVHD rates were 57% and 14% for patients who received the higher and lower doses, respectively (p = 0.001). Four of the 7 patients who received the higher dose were alive at a median of 47 months (range,44 – 58 months), and 22 of 23 given the lower dose were alive at a median of 16 months (range, 3 – 52 months). The authors concluded that a lower dose of cyclophosphamide conditioning resulted in lower rates of GVHD and was acceptable for engraftment.

In a retrospective study of 98 unrelated donor transplantations for Fanconi anemia reported to the Center for International Blood and Marrow Transplant Research, Wagner et al. (2007) reported that fludarabine-based (reduced-intensity) regimens were associated with improved engraftment, decreased treatment-related mortality, and improved 3 – year OS rates (52% vs. 13%, respectively; p < 0.001) compared with non-fludarabine-based regimens.³⁰

Dyskeratosis Congenita
Noncomparative Studies
Results with allo-HCT in dyskeratosis congenita have been disappointing because of severe late effects, including diffuse vasculitis and lung fibrosis.³ Currently, nonmyeloablative conditioning regimens with fludarabine are being explored;however, very few results have been published.³

Outcomes after allo-HCT were reported in 2013 for 34 patients with dyskeratosis congenita who underwent transplantation between 1981 and 2009.³¹ Median age at transplantation was 13 years (range, 2 – 35 years).Approximately 50% of transplantations were from related donors. The day-28 probability of neutrophil recovery was 73%, and the day-100 platelet recovery was 72%. The day-100 probability of grade II, III, or IV acute GVHD and the 3-year probability of chronic GVHD were 24% and 37%, respectively. The 10-year probability of survival was 30% and 14 patients were still alive at last follow-up. Ten deaths occurred within 4 months from transplantation because of graft failure (n = 6) or other transplantation-related complications; 9 of these patients had undergone transplantation from mismatched related or unrelated donors. Another 10 deaths occurred after 4 months; 6 of which occurred more than 5 years after transplantation, and 4 deaths were attributed to pulmonary failure. Transplantation regimen intensity and transplantations from mismatched related or unrelated donors were associated with early mortality. Transplantation of grafts from HLA-matched siblings with cyclophosphamide-containing nonradiation regimens was associated with early low toxicity. Late mortality was attributed mainly to pulmonary complications and likely related to the underlying disease.

Shwachman-Diamond Syndrome
Noncomparative Studies
Experience with allo-HCT in Shwachman-Diamond syndrome is limited because very few patients have undergone allogeneic transplants for this disease.³ Cesaro et al. (2005) reported on 26 patients with Shwachman-Diamond syndrome from the European Group for Blood and Marrow Transplantation registry, who received HCT for treatment of severe aplastic anemia (n = 16); myelodysplastic syndrome-acute myeloid leukemia (n = 9); or another diagnosis (n = 1).32,Various preparative regimens were used; most included busulfan (54%) or total body irradiation (23%) followed by an HLA-matched sibling (n = 6), mismatched related (n = 1), or unrelated graft (n = 19). Graft failure occurred in 5 (19%)patients, and the incidence of grade III to IV acute and chronic GVHD were 24% and 29%, respectively. With a median follow-up of 1.1 years, the OS rate was 65%. Deaths were primarily caused by infections with or without GVHD (n = 5) or major organ toxicities (n = 3). The analysis suggested that the presence of myelodysplastic syndrome-acute myeloidleukemia or use of total body irradiation-based conditioning regimens were factors associated with a poorer outcome.

Myers et al. (2020) evaluated outcomes in 52 patients with Shwachman-Diamond syndrome who received a HCT between 2000 and 2017 for bone marrow failure (n = 39) or myelodysplastic syndrome-acute myeloid leukemia (n = 13).³³ For patients with bone marrow failure, preparative regimens were myeloablative in 13 patients and reduced intensity in 26 patients. The 5-year OS in this subgroup was 72%. For patients with myelodysplastic syndrome-acute myeloid leukemia,preparative regimens were myeloablative in 8 patients and reduced intensity in 5. At the time of the study report, only 2 of 13 (15%) were alive. Most deaths in this subgroup (8/11) occurred within 8 months after transplantation.

Cesaro et al. (2020) reported on outcomes in 74 patients with Shwachman-Diamond syndrome who received a HCT between 1988 and 2016 for bone marrow failure (n = 61), myelodysplastic syndrome (n = 7), or acute myeloid leukemia (n = 6) in an updated report from the European Group for Blood and Marrow Transplantation registry.³⁴ The preparative regimens were myeloablative and reduced intensity in 54% and 46% of the cases, respectively. After a median follow-up of 7.3 years, the 5-year OS was 63.3%. The 5-year OS was significantly higher in patients who received HCT due to bone marrow failure (70.7%) versus in patients who received HCT due to myelodysplastic syndrome/acute myeloid leukemia (28.8%; p = 0.005).The rate of graft failure was 15% and grades I-IV GVHD were reported in 55% of patients.

Diamond-Blackfan Syndrome
Noncomparative Studies
In Diamond-Blackfan syndrome, allo-HCT is an option in corticosteroid-resistant disease.³ In a report from the Diamond­ Blackfan Anemia Registry (2008), 20 of 354 registered patients underwent allo-HCT, and the 5-year survival rate was 87.5% when recipients received HLA-identical sibling grafts but was poor in recipients of alternative donors.³ Another team of investigators (2005) examined outcomes reported to the International Bone Marrow Transplant Registry between 1984 and 2000 for 61 patients with Diamond-Blackfan syndrome who underwent HCT.^3,5 Sixty-seven percent of patients were transplanted with an HLA-identical sibling donor. Probability of OS after transplantation for patients transplanted from an HLA-identical sibling donor (vs. an alternative donor) was 78% versus 45% (p = 0.01) at 1 year and 76% versus 39% (p = 0.01) at 3 years, respectively.

Randomized Controlled Trials
A randomized phase 3 trial (2012) compared 2 conditioning regimens in patients (n = 79) with high-risk aplastic anemia who underwent allo-HCT.³⁷ Patients in the cyclophosphamide plus anti-thymocyte globulin (ATG) arm (n = 39) received cyclophosphamide at 200 mg/kg; those in the cyclophosphamide-fludarabine-ATG arm (n = 40) received cyclophosphamide at 100 mg/kg and fludarabine at 150 mg/m2. No difference in engraftment rates was reported between arms. Infections with an identified causative organism and sinusoidal obstruction syndrome, hematuria, febrile episodes, and death from any cause tended to be more frequent among those receiving cyclophosphamide-ATG but did not differ significantly between treatment arms. For example, at 4 years, OS rates did not differ significantly between the cyclophosphamide-ATG (78%) and the cyclophosphamide-fludarabine-ATG arms (86%; p = 0.41). Although this study was underpowered to detect real differences between the conditioning regimens, the results suggested that a RIC regimen with cyclophosphamide-fludarabine-ATG appears to be as safe as a more conventional myeloablative regimen using cyclophosphamide plus ATG in allo-HCT.

Section Summary: Bone Marrow Failure Syndromes
Use of allo-HCT to treat patients with Fanconi anemia, dyskeratosis congenital, Shwachman-Diamond syndrome, Diamond-Blackfan syndrome, and aplastic anemia have been shown to improve OS or DFS.

Review articles summarize experience the use of HCT to treat primary immunodeficiencies.^39.40 Additional individual studies are reported next.

Hassan et al. (2012) reported on a multicenter retrospective study, which analyzed HCT outcomes in 106 patients with adenosine deaminase deficient-SCIO who received a total of 119 transplants.⁴⁵ HCT using matched sibling and family donors had significantly better OS (86% and 81%, respectively) compared with HCT using matched unrelated (66%; p < 0.05) and haploidentical donors (43%; p < 0.001). Superior OS was also seen in patients who received unconditioned transplants compared with myeloablative procedures (81% vs. 54%; p < 0.003), although in unconditioned haploidentical donor HCT, nonengraftment was a major problem. Long-term immune recovery showed that, regardless of transplant type, overall T-cell counts were similar, although a faster rate of T-cell recovery was observed following matched sibling and family donor HCT. Humoral immunity and donor B-cell engraftment was achieved in nearly all evaluable surviving patients and was seen even after unconditioned HCT.

Section Summary: Primary Immunodeficienciesspan >
Use of allo-HCT to treat select patients with primary immunodeficiencies results in improvements in OS or DFS.

Follow-up at 7- to 17-years is of interest for allo-HCT to monitor relevant outcomes.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

Morquio Syndrome
Allo-HCT has not been effective in Morquio syndromes.⁵⁰

Matched sibling donor (allogeneic) HGT is the treatment of choice for severe aplastic anemia; however, for patients aged 35 to 50 years, patients need to be assessed for comorbidities before being considered for HGT.

For adults, unrelated donor HGT should be considered if patients fail to respond to a single course of immunosuppressive therapy.

NCT No.                     I Trial Name		Planned Enrollment	Completion Date
Ongoing
NCT02766465	A Study to Compare Bone Marrow Transplantation to Standard Care in Adolescents and Young Adults With Severe Sickle Cell Disease	200	Mar 2023
NCT02356653	Expanded Access Protocol Using CD3+/CD19+ Depleted Unrelated Donor or Partially Matched Related Donor Peripheral Stem Cells	100	Jan 2021
NCT02986698	A Single-Center, Non-Randomized Study of the Safety and Efficacy of In Utero Hematopoietic Stem Cell Transplantation for the Treatment of Fetuses With Alpha Thalassemia Major	10	Feb 2024
Unpublished
NCT00176826	In-vivo T-cell Depletion and Hematopoietic Stem Cell Transplantation for Life-Threatening Immune Deficiencies and Histiocytic Disorders	22	Aug 2015 (Terminated)

NCT: national clinical trial.

References  

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Coding Section

Codes	Number	Description
CPT	38204	Management of recipient hematopoietic cell donor search and cell acquisition
	38205	Blood-derived hematopoietic progenitor cell harvesting for transplantation, per collection, allogeneic
	38208	Transplant preparation of hematopoietic progenitor cells; thawing of previously frozen harvest, without washing
	38209	Thawing of previously frozen harvest, with washing
	38210	Specific cell depletion within harvest, T-cell depletion
	38212	Red blood cell removal
	38213	Platelet depletion
	38214	Plasma (volume) depletion
	38215	Cell concentration in plasma, mononuclear, or buffy coat layer
	38220	Bone marrow; aspiration only
	38221	Bone marrow; biopsy, needle or trocar
	38230	Bone marrow harvesting for transplantation; allogeneic
	38240	Bone marrow or blood-derived peripheral stem-cell transplantation; allogeneic
	38242	Allogeneic donor lymphocyte infusions
	86812-86822	Histocompatibility studies code range
ICD-9 Procedure	41.02	Allogeneic bone marrow transplant with purging
	41.03	Allogeneic bone marrow transplant without purging
	41.05	Allogeneic hematopoietic stem-cell transplant without purging
	41.08	Allogeneic hematopoietic stem-cell transplant with purging
	41.91	Aspiration of bone marrow from donor for transplant
	99.79	Other therapeutic apheresis (includes harvest of stem cells)
ICD-9 Diagnosis	272.7	Lipidoses (includes mucolipidosis)
	277.5	Mucopolysaccharidosis
	279.12	Wiskott-Aldrich syndrome
	279.2	Combined immunity deficiency
	282.41-282.49	Thalassemia code range
	282.60-282.69	Sickle-cell disease code range
	284.01-284.9	Aplastic anemia code range
	288.01	Congenital neutropenia (includes Kostmann’s syndrome)
	756.52	Osteopetrosis
HCPCS	G0265	Cryopreservation, freezing and storage of cells for therapeutic use, each cell line
	G0266	Thawing and expansion of frozen cells for therapeutic use, each cell line
	G0267	Bone marrow or peripheral stem-cell harvest, modification or treatment to eliminate cell type(s) (e.g., T cells, metastatic carcinoma)
	Q0083-Q0085	Chemotherapy administration code range
	J9000-J9999	Chemotherapy drug code range
	S2140	Cord blood harvesting for transplantation, allogeneic
	S2142	Cord blood-derived stem-cell transplantation, allogeneic
	S2150	Bone marrow or blood-derived peripheral stem-cell harvesting and transplantation, allogeneic or autologous, including pheresis, high-dose chemotherapy, and the number of days of post-transplant care in the global definition (including drugs; hospitalization; medical, surgical, diagnostic and emergency services)
ICD-10-CM (effective 10/01/15)	D56.1	Beta thalassemia
	D57.00-D57.819	Sickle-cell disorders code range
	D61.01-D61.89	Other aplastic anemias and other bone marrow failure syndromes code range (includes Fanconi anemia)
	D70.0	Congenital agranulocytosis (includes Kostmann’s disease)
	D71	Functional disorders of polymorphonuclear neutrophils (includes chronic granulomatous disease)
	D81.0-D81.9	Combined immunodeficiencies code range
	D82.0-D82.9	Immunodeficiency associated with other major defects code range (includes Wiskott-Aldrich and X-linked lymphoproliferative syndromes)
	E70.330	Chediak-Higashi syndrome
	E71.50-E71.548	Peroxisomal disorders code range (includes childhood cerebral X-linked adrenoleukodystrophy)
	E75.25	Metachromatic leukodystrophy
	E76.01	Hurler’s syndrome
	E76.29	Other mucopolysaccharidoses (includes Maroteaux-Lamy syndrome)
	E77.01	Defects in glycoprotein degradation (includes aspartylglucosaminuria, mannosidosis and fucosidosis)
	Q78.2	Osteopetrosis (includes Albers-Schonberg syndrome)
ICD-10-PCS (effective 10/01/15)		ICD-10-PCS codes are only used for inpatient services.
	30243G1, 30243X1, 30243Y1	Percutaneous transfusion, central vein, bone marrow or stem cells, nonautologous, code list
	07DQ0ZZ, 07DQ3ZZ, 07DR0ZZ, 07DR3ZZ, 07DS0ZZ, 07DS3ZZ	Surgical, lymphatic and hemic systems, extraction, bone marrow, code list
Type of Service	Therapy
Place of Service	Inpatient/Outpatient

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 2014 Forward     

07/03/2023	Annual review, no change to policy intent.
07/06/2022	Annual review, no change to policy intent.
07/06/2021	Annual review, no change to policy intent. Updating rationale and references.
07/28/2020	Annual review, no change to policy intent. Updating background.
07/01/2019	Annual review, no change to policy intent. Updating rationale and references.
07/27/2018	Annual review, no change to policy intent. Updating background, description, rationale and references.
07/03/2017	Annual review, no change to policy intent.
07/25/2016	Annual review, no change to policy intent. Updating background, description, rationale and references. Adding benefit application and regulatory status.
07/29/2015	Annual review, no change to policy intent. Updated background, description, rationale and references. Added coding.
07/08/2014	Annual review. Updated rationale and references. No change to policy intent.