Pending Policies - Surgery

Hematopoietic Stem-Cell Transplantation for Genetic Diseases and Acquired Anemias


Effective Date:05-15-2018



Allogeneic hematopoietic stem-cell transplantation (HSCT; allo-HSCT) may be considered medically necessary for selected patients with the following disorders:


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 β-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).

NOTE 1: Refer to the Description for a listing of immunodeficiencies that have been treated successfully with allo-HSCT.

Inherited Metabolic Disease:

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

NOTE 2: Refer to the Description for a discussion of inherited metabolic disorders that have been proven effective when treated with allo-HSCT.

Genetic Disorders Affecting Skeletal Tissue:

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

Allo-HSCT is considered experimental, investigational and/or unproven for any condition or disorder not included above.

Autologous HSCT (auto-HSCT) is considered experimental, investigational and/or unproven for any genetic disease or acquired anemia.

NOTE 3: See Medical Policy SUR703.002 Hematopoietic Stem-Cell Transplantation (HSCT) or Additional Infusion Following Preparative Regimens (General Donor and Recipient Information) for detailed, descriptive information on HSCT related services.


Hematopoietic Stem-Cell Transplantation (HSCT)

HSCT refers to a procedure in which hematopoietic stem-cells are infused to restore bone marrow function in patients who receive bone-marrow-toxic doses of cytotoxic drugs with or without whole body radiation therapy. Hematopoietic stem-cells may be obtained from the transplant recipient (autologous HSCT; auto-HSCT) or from a donor (allogeneic HSCT; allo-HSCT). They can be harvested from bone marrow, peripheral blood, or umbilical cord blood shortly after delivery of neonates. Although cord blood is an allogeneic source, the stem-cells in it are antigenically “naive” and thus, are associated with a lower incidence of rejection or graft-versus-host disease (GVHD).

Immunologic compatibility between infused hematopoietic stem-cells and the recipient is not an issue in auto-HSCT. However, immunologic compatibility between donor and patient is a critical factor for achieving a good outcome of allo-HSCT. Compatibility is established by typing of human leukocyte antigens (HLA) using cellular, serologic, or molecular techniques. HLA refers to the tissue type expressed at the class I and class II loci on chromosome 6. Depending on the disease being treated, an acceptable donor will match the patient at all or most of the HLA loci (with the exception of umbilical cord blood).


A number of inherited and acquired conditions have the potential for severe and/or progressive disease. For some conditions, allo-HSCT has been used to alter the natural history of the disease or potentially offer a cure. This policy addresses primarily marrow-based diseases that are not malignant but nonetheless are considered fatal if not adequately treated (i.e., aplastic anemia or immunodeficiencies) or are associated with severe morbidity in some subsets of patients (i.e., sickle cell disease). The inborn errors of metabolism (mucopolysaccharidoses, mucolipidoses) are characterized by a congenital defect in one of the enzymes critical to intermediate metabolism.

Genetic Diseases and Acquired Anemias


Thalassemias result from variants in the globin genes, resulting in reduced or absent hemoglobin production, thereby reducing oxygen delivery. The supportive treatment of ß-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. The only definitive cure for thalassemia is to correct the genetic defect with allo-HSCT.

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. Three major therapeutic options are available: chronic blood transfusions, hydroxyurea, and allo-HSCT, 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 (FA), 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 a myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Most patients with FA succumb to the complications of severe aplastic anemia, leukemia, or solid tumors, with a median survival of 30 years of age. (2) In FA, HSCT is currently the only treatment that definitively restores normal hematopoiesis. Excellent results have been observed with the use of HLA-matched sibling allo-HSCT, with cure of the marrow failure and amelioration of the risk of leukemia. (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 MDS and malignant transformation, especially AML. 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.

Primary Immunodeficiencies:

The primary immunodeficiencies are a genetically heterogeneous group of diseases that affect distinct components of the immune system. (4) More than 120 gene defects have been described, causing more than 150 disease phenotypes. The most severe defects (collectively known as severe combined immunodeficiency [SCID]) cause an absence or dysfunction of T-lymphocytes and sometimes B-lymphocytes and natural killer cells (NKC). Without treatment, patients with SCID 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. 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)

Other conditions that have been successfully treated with HSCT include the following (4):

1. Lymphocyte immunodeficiencies:

Adenosine deaminase deficiency,

Artemis deficiency,

Calcium channel deficiency,

CD (cluster of differentiation) 40 ligand deficiency,

Cernunnos/X-linked lymphoproliferative disease deficiency,

CHARGE (coloboma, heart defects, atresia choanae (also known as choanal atresia), growth retardation, genital abnormalities, and ear abnormalities) syndrome with immune deficiency,

Common gamma chain deficiency,

Deficiencies in CD 45, CD 3, CD 8,

DiGeorge syndrome,

DNA ligase IV deficiency syndrome,

Interleukin-7 receptor alpha deficiency,

Janus-associated kinase 3 (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.

2. Phagocytic deficiencies:

Chediak-Higashi syndrome,

Chronic granulomatous disease,

Griscelli syndrome, type 2,

Hemophagocytic lymphohistiocytosis,

Interferon-gamma receptor deficiencies,

Leukocyte adhesion deficiency,

Severe congenital neutropenias,

Shwachman-Diamond syndrome.

3. Other immunodeficiencies:

Autoimmune lymphoproliferative syndrome,

Cartilage hair hypoplasia,

CD25 deficiency,

Hyper IgD and IgE syndromes,

ICF (immunodeficiency, centromere instability and facial anomalies syndrome) syndrome,

IPEX (immunodysregulation polyendocrinopathy enteropathy X-linked) syndrome,

NEMO (nuclear factor-kappa-B essential modulator) deficiency,

NF (nuclear factor)-κB inhibitor, alpha (IκB-alpha) deficiency,

Nijmegen breakage syndrome.

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.

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. (6) Stem-cell transplantation provides a constant source of enzyme replacement from the engrafted donor cells, which are not impeded by the blood-brain barrier. 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).

Allo-HSCT 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 1000 transplants have been performed worldwide.

Table 1. Lysosomal and Peroxisomal Storage Disorders



Other Names








Hurler, Scheie, H-S


Sanfilippo A-D

Morquio A-B






Gaucher’s I, II, III

GM1 gangliosidosis

Niemann-Pick disease A and B

Tay-Sachs disease

Sandhoff’s disease

Globoid leukodystrophy

Metachromatic leukodystrophy


Krabbe disease

MLD, Arylsulfatase A deficiency






Mucolipidosis III and IV


Other lipidoses

Niemann-Pick disease C

Wolman disease

Ceroid lipofuscinosis

Type III-Batten disease

Glycogen storage

GSD type II


Multiple enzyme deficiency


Mucolipidosis type II

I-cell disease

Lysosomal transport defects


Sialic acid storage disease

Salla disease


Peroxisomal storage disorders





Table Key:

MPS: Mucopolysaccharidoses;

GM1: Monosialotetrahexosylganglioside;

GSD: Glycogen storage disease;

MLD: Metachromatic leukodystrophy;

ALD: Adrenoleukodystrophy;

AMN: Adrenomyeloneuropathy;

N/A: not available.

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. Seventy percent of these patients die before the age of 6 years, often of recurrent infections. HSCT is the only curative therapy for this fatal disease.

NOTE 4: For additional information regarding autoimmune diseases such as rheumatoid arthritis and multiple sclerosis, please see Medical Policy SUR703.036, “Hematopoietic Stem-cell Transplantation for Autoimmune Disorders.”

Regulatory Status

The U.S. Food and Drug Administration (FDA) 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.


This policy was originally created in 1990, moved to this policy in 2010; and was originally created based on 3 Blue Cross Blue Shield Association (BCBSA) Technology Evaluation Center (TEC) Assessments from 1988 (61), 1992 (62), and 1997 (63), in addition to searches of the MedLine database. The most recent search was conducted through March 26, 2018. The following is a summary of the key literature reviewed.

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

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (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.


Review articles summarize the experience to date with hematopoietic stem-cell transplantation (HSCT) and the hemoglobinopathies. (9-12)


More than 3000 patients worldwide have been treated for β-thalassemia with allogeneic HSCT (allo-HSCT). (11) Overall survival (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. (13) The Pesaro risk stratification system classifies patients with thalassemia who plan to undergo allo-HSCT into risk groups 1 through 3 based on the presence of hepatomegaly, portal fibrosis, or adequacy of chelation (class 1 having no risk factors, 2 with 2 risk factors, and 3 with all 3 risk factors). (14) The outcome of allo-HSCT 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.

A 2015 study of 489 patients with nonmalignant hematologic disorders who underwent allo-HSCT between 1997 and 2012 included 152 patients with β-thalassemia. (15) 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% versus 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 stem-cell transplantation group versus 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-HSCT after a reduced-intensity conditioning (RIC) regimen based on treosulfan. (16) 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 HSCT, 98 patients with class 3 thalassemia were transplanted with related or unrelated donor stem-cells. (17) Seventy-six of patients less than 10 years of age received a conventional myeloablative conditioning (MAC) regimen (cyclophosphamide, busulfan [BU], 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 HSCT with a novel RIC regimen (fludarabine and BU). Rates of EFS (86% versus 90%, respectively), and OS (95% versus 90%, respectively) did not differ significantly between groups. However, a higher incidence of serious treatment-related complications was observed in the group that received MAC. Furthermore, graft failures occurred in 6 patients in the myeloablated group (8%), although none occurred in the RIC group.

Sickle Cell Disease (SCD)

A Cochrane systematic review published in 2013 (18) and updated in 2016, (19) identified no RCTs that assessed a risk or benefit of any method of HSCT in patients with SCD.

Approximately 500 to 600 patients with SCD have undergone allo-HSCT, and most of the experience with allo-HSCT and SCD comes from 3 major clinical series. (1, 11) 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 RIC preparative regimens and allo-HSCT for the hemoglobinopathies is limited to a small number of patients. Challenges have included high rates of graft rejection (10%-30%) (9) and, in adult patients, severe GVHD, which has been observed with the use of RIC regimens. (10)

Hsieh et al. (2014) reported on results from 30 patients aged 16 to 65 years with severe sickle cell phenotype who were enrolled in an RIC allo-HSCT study, consisting of alemtuzumab (1 mg/kg in divided doses), total body irradiation (300 centigray; cGy), sirolimus, and infusion of unmanipulated filgrastim mobilized peripheral blood stem-cells from HLA-matched siblings. (23) The primary end point was treatment success at 1 year after the transplant, defined as a full-donor-type hemoglobin for patients with sickle cell disease and transfusion independence for patients with thalassemia. Secondary end points 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 3.4 years (range, 1-8.6 years), with no non-relapse 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

Use of allo-HSCT to treat patients with β-thalassemia or SCD has been shown to improve OS, EFS, or DFS.

Bone Marrow Failure Syndromes

Review articles summarize the experience to date on the use of HSCT to treat bone marrow failure syndromes. (8, 24-26)

Fanconi Anemia (FA)

In a 2008 summary of patients with FA who received allo-HSCT from matched related donors over 6 years (total 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%. (27)

The outcomes in patients with FA and an unrelated donor allo-HSCT have not been as promising. The European Group for Blood and Marrow Transplantation (EBMT) has analyzed the outcomes using alternative donors in 67 patients with FA. 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 (CIBMTR) 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 FA treated with RIC regimens, consisting of low-dose cyclophosphamide. (28) Seven patients were treated with cyclophosphamide at 80 mg/kg and 23 with 60 mg/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 FA reported to the CIBMTR, 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% versus 13%, respectively; p<0.001) compared with non-fludarabine-based regimens. (29)

Dyskeratosis Congenita

Results with allo-HSCT in dyskeratosis congenita have been disappointing because of severe late effects, including diffuse vasculitis and lung fibrosis. (3) Currently, non-MAC regimens with fludarabine are being explored; however, very few results have been published.

Outcomes after allo-HSCT were reported in 2013 for 34 patients with dyskeratosis congenita who underwent transplantation between 1981 and 2009. (30) 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; six of which occurred more than 5 years after transplantation, and 4 of 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 non-radiation 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

Experience with allo-HSCT 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 EBMT registry, who received HSCT for treatment of severe aplastic anemia (n=16); myelodysplastic syndrome (MDS)-acute myeloid leukemia (n=9); or another diagnosis (n=1). (31) Various preparative regimens were used; most included BU (54%) or total body irradiation (TBI) (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 presence of MDS -- acute myeloid leukemia (AML)or use of TBI-based conditioning regimens were factors associated with a poorer outcome.

Diamond-Blackfan Syndrome

In Diamond-Blackfan syndrome, allo-HSCT 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-HSCT, 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 (IBMTR) between 1984 and 2000 for 61 patients with Diamond-Blackfan syndrome who underwent HSCT. (32) 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 (versus an alternative donor) was 78% versus 45% (p=0.01) at 1 year and 76% versus 39% (p=0.01) at 3 years, respectively.

Aplastic Anemia

A randomized phase 3 trial (2012) compared 2 conditioning regimens in patients (n=79) with high-risk aplastic anemia who underwent allo-HSCT. (33) Patients in the cyclophosphamide plus antithymocyte 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 an RIC regimen with cyclophosphamide-fludarabine-ATG appears to be as safe as a more conventional myeloablative regimen using cyclophosphamide plus ATG in allo-HSCT.

A 2015 study analyzed outcomes reported to the EBMT of children with idiopathic aplastic anemia, according to treatment received. (34) Front-line immunosuppressive therapy (IST) was compared with front-line HSCT from an HLA-matched family donor, to evaluate the outcomes of patients who, after having failed IST, underwent rescue HSCT, and to compare their outcomes using front-line HSCT with those who did not fail IST (IST with no subsequent transplant). Additional outcomes that were evaluated were the cumulative incidence of posttherapy tumors and prognostic factors that might affect the outcome of the disease. Included in the analysis were records from 563 consecutive children (313 boys, 250 girls [age range, 0-12 years]) diagnosed between 2000 and 2009. Geographical origin, if known, was distributed as follows: 383 patients from Europe, 51 from Africa, 51 from the Middle East, 2 from Australia, and 1 from Brazil. The median age at diagnosis was 7.8 years (range, 0.01-11.9 years). A total of 167 children received front-line IST (consisting of ATG plus cyclosporine); of these, 91 (55%) failed IST as front-line treatment and underwent rescue HSCT (HSCT post-IST failure) whereas IST was the only treatment received (IST alone) for 76 patients. The 3-year probability of OS and EFS for the whole population was 90% and 86%, respectively. The 3-year OS rate was 91% after matched family donor front-line HSCT and 87% after first-line IST (p=0.18). The 3-year probability of OS after HSCT post-IST failure was 83%, 91% after matched family donor front-line HSCT, and 97% after IST alone (p=0.017). A subgroup analysis showed no significant difference between IST alone and matched family donor front-line HSCT (p=0.21), but significantly longer OS of both matched family donor front-line HSCT (p=0.02) and IST alone (p=0.047) over HSCT post-IST failure.

A 2015 study (discussed earlier), which examined 489 patients with nonmalignant hematologic disorders who underwent allo-HSCT, including 273 patients with severe aplastic anemia. (15) Of these subjects, 212 were men, and 61 were women, and the mean age at transplantation was 19.7 years (range, 1.5-51 years). Mean times to neutrophil and platelet engraftment were 13.9 days (range, 10-26 days) and 14.1 days (range, 8-83 days), respectively. Graft rejection occurred in 1% of patients. Acute GVHD grade II, III, or IV occurred in 15%, and chronic GVHD occurred in 28% of patients. The incidence of transplant-related mortality was 22%. At 8 years, OS and DFS rates were both 74%. Conditioning regimens differed among the patients, with 181 receiving fludarabine and cyclophosphamide and 92 receiving cyclophosphamide and ATG. No statistically significant differences between conditioning groups were observed regarding mean time to neutrophil engraftment (p=0.136) or incidence of extensive chronic GVHD (p=0.651). Mean time to platelet engraftment was significantly longer in the cyclophosphamide plus ATG group (p=0.016). The incidence of transplant-related mortality in the fludarabine plus cyclophosphamide group was 17%, which was significantly lower than in the cyclophosphamide plus ATG group (33%; p=0.002). After a median follow-up of 8 years, the OS rate was statistically significantly better in the fludarabine plus cyclophosphamide group (80%) than in the cyclophosphamide plus ATG group of patients (64%; p=0.021).

Section Summary: Bone Marrow Failure Syndromes

Use of allo-HSCT to treat patients with Fanconi anemia, dyskeratosis congenital, Shwachman-Diamond syndrome, Diamond-Blackfan syndrome, and aplastic anemia has been shown to improve OS or DFS.

Primary Immunodeficiencies

Review articles summarize experience the use of HSCT to treat primary immunodeficiencies. (35, 36) Additional individual studies are reported next.

Chronic Granulomatous Disease (CGD)

HSCT outcomes were compared with those of conventional treatment in a study of 41 patients in Sweden who were diagnosed with CGD between 1990 and 2012. (37) From 1997 to 2012, 14 patients (age range, 1-35 years) underwent HSCT and received grafts either from an HLA-matched sibling donor or a matched unrelated donor. Thirteen (93%) of the 14 transplanted patients were reported alive and well in 2013. The mean age at transplantation was 10.4 years and the mean survival time was 7.7 years. In contrast, 7 of 13 men or boys with X-linked CGD who were treated conventionally died from complications of CGD at a mean age of 19 years, while the remainder suffered life-threatening infections.

A 2014 prospective study in 16 centers across 10 countries worldwide enrolled CGD patients ages 0 to 40 years to examine the effects of an RIC regimen before HSCT, consisting of high-dose fludarabine, serotherapy, or low-dose alemtuzumab, and low-dose (50% to 72% of myeloablative dose) or targeted BU administration. (38) Unmanipulated bone marrow or peripheral blood stem-cells from HLA-matched related donors or HLA-9/10 or HLA-10/10 matched unrelated donors were infused. The primary end points were OS and EFS, probabilities of OS and EFS at 2 years, the incidence of acute and chronic GVHD, achievement of at least 90% myeloid donor chimerism, and incidence of graft failure after at least 6 months of follow-up. A total of 56 patients (median age 12.7 years) were included; 42 (75%) patients had high-risk features (i.e., intractable infections and auto-inflammation) and 25 (45%) were adolescents and young adults (age range, 14-39 years). Median time to engraftment was 19 days for neutrophils and 21 days for platelets. At a median follow-up of 21 months, the OS rate was 93%, and the EFS rate was 89%. The 2-year probability of OS was 96% (95% confidence interval [CI], 86.46% to 99.09%) and of EFS was 91% (95% CI, 79.78% to 96.17%). Graft failure occurred in 5% of patients. The cumulative incidence of acute GVHD grade III or IV was 4% and of chronic GVHD was 7%. Stable (≥90%) myeloid donor chimerism was documented in 52 (93%) surviving patients.

Severe Combined Immunodeficiency (SCID)

HSCT using HLA-identical sibling donors can correct underlying primary immunodeficiencies, such as SCID, Wiskott-Aldrich syndrome, and other prematurely lethal X-linked immunodeficiencies, in approximately 90% of cases. (39) According to a 2008 European series of 475 patients collected between 1968 and 1999, survival rates for SCID were approximately 80% with a matched sibling donor, 50% with a haploidentical donor, and 70% with a transplant from an unrelated donor.38 Another 2008 report found an OS rate for patients with SCID who have undergone HSCT to be 71%. (4)

Hassan et al. (2012) reported on a multicenter retrospective study, which analyzed HSCT outcomes in 106 patients with adenosine deaminase deficient–SCID who received a total of 119 transplants. (40) HSCT using matched sibling and family donors had significantly better OS (86% and 81%, respectively) compared with HSCT 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% versus 54%; p<0.003), although in unconditioned haploidentical donor HSCT, non-engraftment 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 HSCT. Humoral immunity and donor B-cell engraftment was achieved in nearly all evaluable surviving patients and was seen even after unconditioned HSCT.

Wiskott-Aldrich Syndrome

For Wiskott-Aldrich syndrome, a 2001 analysis of 170 patients transplanted between 1968 and 1996 demonstrated the impact of donor type on outcomes. (41) Fifty-five transplants were from HLA-identical sibling donors, with a 5-year survival probability of 87% (95% CI, 74% to 93%); 48 were from other relatives, with a 5-year survival probability of 52% (95% CI, 37% to 65%); and 67 were from unrelated donors with a 5-year survival probability of 71% (95% CI, 58% to 80%; p<0.001).

Moratto et al. (2011) retrospectively reported on the long-term outcome and donor cell engraftment in 194 patients with Wiskott-Aldrich syndrome treated by HSCT from 1980 to 2009. (42) The OS rate was 84.0% and was even higher (89.1% 5-year survival) for those who had received HSCT since the year 2000, reflecting the recent improvement in outcome after transplantation from mismatched family donors and for patients who received HSCT from an unrelated donor older than 5 years of age. Also, patients who proceeded to transplantation in better clinical condition had a lower rate of post-HSCT complications. Retrospective analysis of lineage-specific donor cell engraftment showed that stable full-donor chimerism was attained by 72.3% of the patients who survived for at least 1 year after HSCT. Mixed chimerism was associated with an increased risk of incomplete reconstitution of lymphocyte counts and post-HSCT autoimmunity, and myeloid donor cell chimerism less than 50% was associated with persistent thrombocytopenia.

X-Linked Lymphoproliferative (XLP) Disease

XLP type 1 (XLP1) is a rare, deadly immune deficiency caused by variants in the SH2D1A gene. Allo-HSCT is often performed because of the morbidity and mortality associated with XLP1. There is limited experience using RIC regimens for these patients. One study (2014) reported on an 8-year single-center experience. (43) Sixteen consecutive patients diagnosed with XLP1 underwent allo-HSCT between 2006 and 2013 after an RIC regimen consisting of alemtuzumab, fludarabine, and melphalan. Fourteen of 16 patients received fully HLA-matched (8/8) unrelated or related bone marrow grafts, whereas 2 patients received mismatched unrelated grafts. All patients had hematopoietic recovery. No cases of hepatic veno-occlusive disease or pulmonary hemorrhage were reported. One (6%) patient developed acute GVHD and later also developed chronic GVHD. Five (31%) patients developed mixed chimerism. One-year survival estimated by Kaplan-Meier analysis was 80%, with long-term survival estimated at 71%. There were no occurrences of lymphoma after HSCT.

Other Immunodeficiencies

For patients with genetic immune or inflammatory disorders, such as hemophagocytic lymphohistiocytosis, the 5-year DFS rates with allo-HSCT ranged from 60% to 70%.

For patients with other immunodeficiencies, reported OS rates are 74%, with even better results (90%) with well-matched donors for defined conditions, such as CGD. (4)

To date, studies have indicated that RIC regimens have an important role in treating patients with primary immunodeficiency. (36) In the absence of prospective or larger registry studies, it is not possible to prove the superiority of RIC in more stable patients with primary immunodeficiency; however, RIC does offer the advantage that long-term sequelae (e.g., infertility, growth retardation) may be avoided or reduced. Currently, RIC HSCT using unrelated donors may offer a survival advantage in patients with T-cell deficiencies, hemophagocytic lymphohistiocytosis, Wiskott-Aldrich syndrome (patients >5 years of age), and CGD with ongoing inflammatory or infective complications. Minimal-intensity conditioning HSCT may be particularly suited to unrelated donor HSCT in young SCID patients with significant comorbidities.

Inherited Metabolic Diseases Including Hunter, Sanfilippo, or Morquio Syndromes

Review articles summarize the experience with HSCT and the inherited metabolic diseases. (44-47)

Hunter Syndrome

Hunter syndrome is composed of 2 distinct clinical entities, a severe and an attenuated form. The attenuated form is characterized by a prolonged lifespan, minimal to no central nervous system (CNS) involvement, and a slow progression. (44) Experience with allo-HSCT in patients with severe Hunter syndrome has shown that it has failed to alter the disease course favorably or significantly. Some have suggested that HSCT would not be justifiable in the attenuated form because the risks outweigh the possible benefits.

Eight patients with Hunter syndrome received an allo-HSCT between the ages of 3 and 16 years. (45) In 6 cases, the donor was an HLA-identical sibling; in 1 case, an HLA-compatible unrelated donor was used, and in another, a mismatched unrelated donor was used. The severity of disease before the transplant was rated by assessing the age at diagnosis, behavior, and IQs at the time of graft and genotype. Five patients were considered to have severe CNS involvement (i.e., diagnosis before the age of 4 years and an IQ <80), 2 were considered to have the attenuated form (i.e., diagnosis at 5 years of age and normal IQ), and 1 as intermediate (i.e., diagnosis after the age of 4 years and IQ between 80 and 90). After follow-up ranging from 7 to 17 years, all were still alive except 1 patient who died of unrelated causes. Successful engraftment was achieved in all patients, and cardiovascular abnormalities stabilized in all patients, hepatosplenomegaly resolved, and joint stiffness improved. Perceptual hearing defects remained stable, and transmission hearing defects improved. The neuropsychological outcome was variable: the 2 patients with the attenuated phenotype reached adulthood with normal IQ, social and scholastic development, and no language impairment. Four patients with the severe form of the syndrome deteriorated after the graft, and their IQ/developmental quotient had declined below 50 at their last evaluation. Of the patients with the severe form, 3 lost the ability to walk in their early teens, 2 lost language at 9 and 11 years of age, respectively, and 2 developed epilepsy. The remaining 2 patients with the severe form required special schooling and had poor social and language skills.

Sanfilippo Syndrome (MPS III)

Experience with allo-HSCT in patients with MPS III has shown no alteration in the course of neuropsychologic deterioration seen in these patients. (44) The literature addressing the use of HSCT in Sanfilippo syndrome consists of 2 older case reports. (46, 47) Vellodi et al. (1992) reported on the outcomes of twin girls diagnosed with MPS III who underwent allo-HSCT and were followed for 9 years. (47) At the time of transplant, both girls were functioning in the low–average range of intellectual development. Over the next 8 years, both girls had a steady decline in cognitive development, and both functioned in the area of significant developmental delay. The authors postulated that the continued deterioration in the twins, despite the demonstration of full chimerism, was a very low level of enzyme throughout the years after transplant. One other patient with MPS III who had received allo-HSCT was 5.3 years old at the time of the transplant and continued to deteriorate posttransplant. (47)

Morquio Syndrome

Allo-HSCT has not been effective in Morquio syndromes. (44)

Section Summary: Inherited Metabolic Diseases Including Hunter, Sanfilippo, or Morquio Syndromes

Use of allo-HSCT to treat patients with Hunter, Sanfilippo, or Morquio syndromes does not result in improvements in neurologic, neuropsychologic, and neurophysiologic function.

Inherited Metabolic Diseases Excluding Hunter, Sanfilippo, or Morquio Syndromes

Review articles summarize the experience using HSCT to treat inherited metabolic diseases. (48, 49)

Lysosomal Storage Disorders

HSCT has been performed in approximately 20 of the estimated 40 known lysosomal storage disorders and peroxisomal storage disorders. (6) Most instances (>80%) have been in patients with Hurler syndrome (mucopolysaccharidosis I [MPS I]) or other MPS syndromes (Hunter syndrome [MPS II], Sanfilippo syndrome types A [MPS IIIA] and B [MPS IIIB], Maroteaux-Lamy syndrome [MPS VI]), adrenoleukodystrophy, metachromatic leukodystrophy, and globoid cell leukodystrophy. (6) Except for Hurler syndrome and globoid cell leukodystrophy, most published data are from single-case reports or small series with short follow-up. (50) The benefit of allo-HSCT appears to be limited to select subsets of patients with few types of lysosomal storage diseases and is not effective in patients who have developed overt neurologic symptoms or in those with aggressive infantile forms. (50)

Hurler syndrome is a lysosomal storage disease that, if left untreated, results in progressive multisystem morbidity including neuro-developmental deterioration, severe orthopedic manifestations, and cardiopulmonary complications leading to death in early childhood. Although enzyme replacement therapy is available, HSCT remains the only treatment that delivers the deficient enzyme to the CNS. (51) Impressive results have been observed with allo-HSCT in Hurler syndrome. The benefits that have been observed include improvements in neurocognitive functioning, joint integrity, motor development, linear growth, corneal clouding, cardiac function, and others. (6) Survival of engrafted Hurler syndrome patients has been radically changed from that of un-transplanted patients, with long-term survival data indicating that lifespan can be extended by many decades. (44) A 2007 analysis of nearly 150 transplanted patients with Hurler syndrome showed an OS rate of more than 80%. (52)

In 2015, an international retrospective analysis reported on long-term results of 217 patients with Hurler syndrome who successfully underwent allo-HSCT between 1985 and 2011. (51) Median follow-up was 9.2 years (range, 3-23 years), median age at diagnosis was 9 months (range, 0-42 months), and median age at transplant was 16 months (range, 2-47 months). Primary study end points were neurodevelopmental outcomes and growth; secondary end points included outcomes involving several different organ systems. Pre-HSCT, 56.9% of patients showed normal neurodevelopment, and 26.6% showed only mildly impaired neurodevelopment. At last follow-up post-HSCT, normal or only mildly impaired neurodevelopment was observed in 26.9% and 28.3% of the patients, respectively, and 44.9% suffered from moderately to severely impaired neurodevelopment. Predictors of better outcomes posttransplant were higher baseline developmental and IQ pre-transplant, younger age at transplant, and a normal α-L-iduronidase enzyme level post-transplant.

Experience with allo-HSCT and an RIC regimen was reported in 2008 for 7 patients with Hurler syndrome. (53) Six of the patients received transplants from unrelated donors, and one received the transplant from a sibling. All patients had initial donor engraftment at 100 days, and there were no reports of severe acute GVHD. Six of the 7 children were alive at a median of 1014 days (range, 726–2222 days) post-transplant.

Mynarek et al. (2012) reported on the results of a retrospective, multicenter analysis of 17 patients with α-mannosidosis who underwent allo-HSCT. (54) Patients were diagnosed with the disease at a median age of 2.5 years (range, 1.1-23 years) and underwent allo-HSCT at a median age of 3.6 years (1.3-23.1 years). After a median follow-up of 5.5 years (range, 2.1-12.6 years), the OS rate was 88%. One patient died 76 days after transplantation from sepsis, GVHD, and pulmonary hemorrhage, and another patient died on day 135 post-transplant due to viral infections and multi-organ failure. Before allo-HSCT, the extent of developmental delay in the 17 patients varied over a wide range. After allo-HSCT, patients made some developmental progress; however, normal development was not achieved. Hearing ability improved in some but not all patients.

Fewer than 40 patients with globoid cell leukodystrophy have undergone allo-HSCT; however, there have been reports of dramatic improvements in neurologic, neuropsychologic, and neurophysiologic function. (44)

Many patients with metachromatic leukodystrophy who have undergone allo-HSCT and had long-term engraftment have had amelioration of the disease signs and symptoms and prolonged survival. (44)

The few patients with Maroteaux-Lamy syndrome (MPS VI) or Sly syndrome (MPS VII) who have received transplants have shown promising results, with clinical improvement post-transplant. (44)

Peroxisomal Disorders

Outcomes with allo-HSCT have varied but promising. In boys and men with X-linked adrenoleukodystrophy, outcomes have depended on disease status at transplant and transplant-related complications, (44) but reports of preservation of neuropsychologic and neurologic function have been presented.

Miller et al. (2011) reported on the results of 60 boys who underwent allo-HSCT for cerebral adrenoleukodystrophy between 2000 and 2009. (55) Median age at transplantation was 8.7 years; conditioning regimens and allograft sources varied. At HSCT, 50% demonstrated a Loes (a rating/scoring of the severity of abnormalities in the brain, from 0 to 34) radiographic severity score of 10 or more, and 62% showed clinical evidence of neurologic dysfunction. A total of 78% (n=47) were alive at a median 3.7 years after allo-HSCT. The 5-year survival estimate for boys with a Loes score less than 10 at HSCT was 89%, whereas that for boys with a Loes score of 10 or more was 60% (p=0.03). The 5-year survival estimate for boys without clinical cerebral disease at HSCT was 91%, whereas that for boys with neurologic dysfunction was 66% (p=0.08). The cumulative incidence of transplantation-related mortality at day 100 was 8%. Post-transplantation progression of neurologic dysfunction depended significantly on the pre-HSCT Loes score and clinical neurologic status.

Section Summary: Inherited Metabolic Diseases Excluding Hunter, Sanfilippo, or Morquio Syndromes

Use of allo-HSCT to treat select subsets of patients without overt neurologic symptoms or without aggressive infantile forms with lysosomal and peroxisomal storage disorders results in improvements in neurologic, neuropsychologic, and neurophysiologic function.

Genetic Disorders Affecting Skeletal Tissue

A 2010 review article has summarized the experience using HSCT to treat osteopetrosis. (56)

Infantile Malignant Osteopetrosis

The success of allo-HSCT in infantile malignant osteopetrosis has depended greatly on the type of donor, with patients receiving grafts from HLA-identical siblings having a 5-year DFS rates of 73% to 79% versus 13% to 45% for those requiring a transplantation from an unrelated or mismatched donor. (7)

A 2003 retrospective analysis of 122 children who received an allo-HSCT for autosomal recessive osteopetrosis between 1980 and 2001 reported 5-year DFS rates of 73% for recipients of a genotype HLA-identical HSCT (n=40); 43% for those of a phenotype HLA-identical or 1 HLA-antigen mismatch graft from a related donor (n=21); 40% for recipients of a graft from a matched unrelated donor (n=20); and 24% for patients who received an HLA-haplotype mismatch graft from a related donor (n=41). (57)

Genetic Diseases and Acquired Anemias Treated with Autologous HSCT (Auto-HSCT)

There were no peer-reviewed clinical studies addressing the treatment of any genetic disease or acquired anemia by auto-HSCT.

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this review are listed in Table 2.

Table 2. Summary of Key Trials

NCT Number

Trial Name

Planned Enrollment

Completion Date



Allogeneic Hematopoietic Stem-cell Transplant for Patients with High Risk Hemoglobinopathy Using a Preparative Regimen to Achieve Stable Mixed Chimerism


Jun 2019



In-vivo T-cell Depletion and Hematopoietic Stem-cell Transplantation for Life-Threatening Immune Deficiencies and Histiocytic Disorders


Jul 2015 (unknown)


Allogeneic Hematopoietic Stem-cell Transplantation for Severe Osteopetrosis


Oct 2016 (unknown)

Table Key:

NCT: National Clinical Trial.

There were no clinical trials found for auto-HSCT for the treatment of genetic disease or acquired anemias.

Clinical Input Received through Physician Specialty Societies and Academic Medical Centers: Genetic Diseases and Acquired Anemias

In 2009, Blue Cross Blue Shield Association requested and received clinical input from various physician specialty societies and academic medical centers. In particular, the reviewers were specifically asked to address the issue of the use of HSCT in the inherited metabolic diseases, except for Hunter, Sanfilippo, and Morquio syndromes; 4 reviewers agreed with the current policy statement, 1 disagreed, and 1 did not address this specific question. Therefore, there was no consensus among the reviewers in the value of patients with these diseases treated with HSCT.

Practice Guidelines and Position Statements

American Society for Blood and Marrow Transplantation (ASBMT)

In 2015 the ASBMT published consensus guidelines on the use of HSCT to treat specific conditions in and out of the clinical trial settings. (58) Specific to this policy Table 3 provides the allogeneic guidelines for specific indications.

Table 3. Recommendations for Use of Allo-HSCT to Treat Genetic Diseases and Acquired Anemias


Allo-HSCT <18 Years

Severe aplastic anemia, new diagnosis


Severe aplastic anemia, relapse/refractory


Fanconi anemia


Dyskeratosis congenita


Blackfan-Diamond anemia


Sickle cell disease




Congenital amegakaryocytic thrombocytopenia


Severe combined immunodeficiency


T-cell immunodeficiency, severe combined immunodeficiency variants


Wiskott-Aldrich syndrome


Hemophagocytic disorders


Lymphoproliferative disorders


Severe congenital neutropenia


Chronic granulomatous disease


Other phagocytic cell disorders


Immunodysregulation polyendocrinopathy enteropathy X-linked syndrome


Juvenile rheumatoid arthritis


Systemic sclerosis


Other autoimmune and immune dysregulation disorders


Mucopolysaccharidoses (MPS-I and MPS-VI)


Other metabolic diseases




Globoid cell leukodystrophy (Krabbe)


Metachromatic leukodystrophy


Cerebral X-linked adrenoleukodystrophy



Allo-HSCT >18 Years

Severe aplastic anemia, new diagnosis


Severe aplastic anemia, relapse/refractory


Fanconi anemia


Dyskeratosis congenita


Sickle cell disease




Hemophagocytic syndromes, refractory


Mast cell diseases


Common variable immunodeficiency


Wiskott-Aldrich syndrome


Chronic granulomatous disease


Multiple sclerosis

Systemic sclerosis


Rheumatoid arthritis


Systemic lupus erythematosus


Crohn’s disease




Table Key:

HSCT: hematopoietic stem-cell transplantation;

C: clinical evidence available;

D: developmental;

N: not generally recommended;

R: standard of care, rare indication;

S: standard of care.

British Committee for Standards (BCS) in Haematology

In 2015, the BCS in Haematology published guidelines on the diagnosis and management of adult aplastic anemia. (59) The following key recommendations on HSCT were included in the guidelines:

Matched sibling donor (allogeneic) HSCT 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 HSCT.

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

Although there have been improvements in outcomes after alternative donor HSCT, these transplants are still experimental, and expert consultation should be sought before considering their use.

European Blood and Marrow Transplantation (EBMT)

In 2014, the EBMT provided consensus-based recommendations on indications for HSCT and transplant management in the hemoglobinopathies. (11)

Pediatric Haemato-Oncology Italian Association

In 2015, the Pediatric Haemato-Oncology Italian Association issued guidelines on the diagnosis and treatment of acquired aplastic anemia in childhood. (60)

Summary of Evidence

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 allogeneic hematopoietic stem-cell transplantation (allo-HSCT), 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-HSCT 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-HSCT, the evidence includes case reports. Relevant outcomes are overall survival, disease-specific survival, symptoms, quality of life, and treatment-related morbidity. Use of allo-HSCT 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.

As of this update, no trials have been published that would alter the current coverage statement for autologous HSCT, which is considered experimental, investigational and/or unproven to treat genetic diseases and acquired anemias.


Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions. Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply. If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.



Disclaimer for coding information on Medical Policies

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.

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage versus. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.


The following codes may be applicable to this Medical policy and may not be all inclusive.

CPT Codes

36511, 38204, 38205, 38206, 38207, 38208, 38209, 38210, 38211, 38212, 38213, 38214, 38215, 38220, 38221, 38222, 38230, 38232, 38240, 38241, 38242, 38243, 81265, 81266, 81267, 81268, 81370, 81371, 81372, 81373, 81374, 81375, 81376, 81377, 81378, 81379, 81380, 81381, 81382, 81383, 86805, 86806, 86807, 86808, 86812, 86813, 86816, 86817, 86821, 86822, 86825, 86826, 86828, 86829, 86830, 86831, 86832, 86833, 86834, 86835, 86849, 86950, 86985, 88240, 88241


S2140, S2142, S2150

ICD-9 Diagnosis Codes

Refer to the ICD-9-CM manual

ICD-9 Procedure Codes

Refer to the ICD-9-CM manual

ICD-10 Diagnosis Codes

Refer to the ICD-10-CM manual

ICD-10 Procedure Codes

Refer to the ICD-10-CM manual

Medicare Coverage:

The information contained in this section is for informational purposes only. HCSC makes no representation as to the accuracy of this information. It is not to be used for claims adjudication for HCSC Plans.

The Centers for Medicare and Medicaid Services (CMS) does not have a national Medicare coverage position. Coverage may be subject to local carrier discretion.

A national coverage position for Medicare may have been developed since this medical policy document was written. See Medicare's National Coverage at <>.


1. Bhatia M, Walters MC. Hematopoietic cell transplantation for thalassemia and sickle cell disease: past, present and future. Bone Marrow Transplant. Jan 2008; 41(2):109-17. PMID 18059330

2. Mehta P. Hematopoietic stem-cell transplantation for inherited bone marrow failure syndromes. In: Mehta P, ed. Pediatric Stem-cell Transplantation. Sudbury, MA: Jones and Bartlett Publishers; 2004:281-316.

3. Gluckman E, Wagner JE. Hematopoietic stem-cell transplantation in childhood inherited bone marrow failure syndrome. Bone Marrow Transplant. Jan 2008; 41(2):127-32. PMID 18084332

4. Gennery AR, Cant AJ. Advances in hematopoietic stem-cell transplantation for primary immunodeficiency. Immunol Allergy Clin North Am. May 2008; 28(2):439-56. PMID 18424341

5. Porta F, Forino C, De Martiis D, et al. Stem-cell transplantation for primary immunodeficiencies. Bone Marrow Transplant. Jun 2008; 41(suppl 2):S83-6. PMID 18545252

6. Prasad VK, Kurtzberg J. Emerging trends in transplantation of inherited metabolic diseases. Bone Marrow Transplant. Jan 2008; 41(2):99-108. PMID 18176609

7. Askmyr MK, Fasth A, Richter J. Towards a better understanding and new therapeutics of osteopetrosis. Br J Haematol. Mar 2008; 140(6):597-609. PMID 18241253

8. FDA – Tissue and Tissue Products (Parts 1270 and 1271) (February 23, 2016). Food and Drug Administration – Center for Biologics Evaluation and Research. Available at <> (accessed on 2016 April 12).

9. MacMillan ML, Walters MC, Gluckman E. Transplant outcomes in bone marrow failure syndromes and hemoglobinopathies. Semin Hematol. Jan 2010; 47(1):37-45. PMID 20109610

10. Smiers F, Krishnamurti L, Lucarelli G. Hematopoietic stem-cell transplantation for hemoglobinopathies: current practice and emerging trends. Pediatr Clin N Am. Feb 2010; 57(1):181-205. PMID 20307718

11. Angelucci E, Matthes-Martin S, Baronciani D, et al. Hematopoietic stem-cell transplantation in thalassemia major and sickle cell disease: indications and management recommendations from an international expert panel. Haematologica. May 2014; 99(5):811-20. PMID 24790059

12. Mathews V, Srivastava A, Chandy M. Allogeneic stem-cell transplantation for thalassemia major. Hematol Oncol Clin North Am. Dec 2014; 28(6):1187-200. PMID 25459187

13. Locatelli F, Kabbara N, Ruggeri A, et al. Outcome of patients with hemoglobinopathies given either cord blood or bone marrow transplantation from an HLA-identical sibling. Blood. Aug 8 2013; 122(6):1072-8. PMID 23692854

14. Mehta P. Hematopoietic stem-cell transplantation for hemoglobinopathies. In: Mehta P, ed. Pediatric Stem-cell Transplantation. Sudbury, MA: Jones and Bartlett Publishers; 2004:259-79.

15. Mahmoud HK, Elhaddad AM, Fahmy OA, et al. Allogeneic hematopoietic stem-cell transplantation for nonmalignant hematological disorders. J Adv Res. May 2015; 6(3):449-58. PMID 26257943

16. Bernardo ME, Piras E, Vacca A et al. Allogeneic hematopoietic stem-cell transplantation in thalassemia major: results of a reduced-toxicity conditioning regimen based on the use of treosulfan. Blood. Jul 12 2012; 120(2):473-6. PMID 22645178

17. Anurathapan U, Pakakasama S, Mekjaruskul P, et al. Outcomes of Thalassemia Patients Undergoing Hematopoietic Stem-cell Transplantation by Using a Standard Myeloablative versus a Novel Reduced Toxicity Conditioning Regimen According to a New Risk Stratification. Biol Blood Marrow Transplant. Jul 23 2014. PMID 25064743

18. Oringanje C, Nemecek E, Oniyangi O. Hematopoietic stem-cell transplantation for people with sickle cell disease. Cochrane Database Syst Rev. May 31 2013; 5:CD007001. PMID 23728664

19. Oringanje C, Nemecek E, Oniyangi O. Hematopoietic stem cell transplantation for people with sickle cell disease. Cochrane Database Syst Rev. May 19 2016; 5:CD007001. PMID 27194464

20. Bernaudin F, Socie G, Kuentz M, et al. Long-term results of related, myeloablative stem-cell transplantation to cure sickle cell disease. Blood. Oct 1 2007; 110(7):2749-56. PMID 17606762

21. Walters MC, Patience M, Leisenring W, et al. Bone marrow transplantation for sickle cell disease. N Engl J Med. Aug 8 1996; 335(6):369-76. PMID 8663884

22. Walters MC, Storb R, Patience M, et al. Impact of bone marrow transplantation for symptomatic sickle cell disease an interim report: an interim report. Multicenter investigation of bone marrow transplantation for sickle cell disease. Blood. Mar 15 2000; 95(6):1918-24. PMID 10706855

23. Hsieh MM, Fitzhugh CD, Weitzel RP, et al. Nonmyeloablative HLA-matched sibling allogeneic hematopoietic stem-cell transplantation for severe sickle cell phenotype. JAMA. Jul 2 2014; 312(1):48-56. PMID 25058217

24. Mehta P, Locatelli F, Stary J et al. Bone marrow transplantation for inherited bone marrow failure syndromes. Pediatr Clin N Am. Feb 2010; 57(1):147-70. PMID 20307716

25. Miano M, Dufour C. The diagnosis and treatment of aplastic anemia: a review. Int J Hematol. Jun 2015; 101(6):527-35. PMID 25837779

26. Bacigalupo A. Bone marrow transplantation for acquired severe aplastic anemia. Hematol Oncol Clin North Am. Dec 2014; 28(6):1145-55. PMID 25459184

27. Dufour C, Svahn J. Fanconi anaemia: new strategies. Bone Marrow Transplant. Jun 2008; 41(suppl 2):S90-5. PMID 18545254

28. Zanis-Neto J, Flowers ME, Medeiros CR, et al. Low-dose cyclophosphamide conditioning for haematopoietic cell transplantation from HLA-matched related donors in patients with Fanconi anaemia. Br J Haematol. Jul 2005; 130(1):99-106. PMID 15982351

29. Wagner JE, Eapen M, MacMillan ML, et al. Unrelated donor bone marrow transplantation for the treatment of Fanconi anemia. Blood. Mar 1 2007; 109(5):2256–62. PMID 17038525

30. Gadalla SM, Sales-Bonfim C, Carreras J, et al. Outcomes of allogeneic hematopoietic cell transplantation in patients with dyskeratosis congenita. Biol Blood Marrow Transplant. Aug 2013; 19(8):1238-43. PMID 23751955

31. Cesaro S, Oneto R, Messina C, et al. Haematopoietic stem-cell transplantation for Shwachman-Diamond disease: a study from the European Group for Blood and Marrow Transplantation. Br J Haematol. Oct 2005; 131(2):231-6. PMID 16197456

32. Roy V, Perez WS, Eapen M, et al. Bone marrow transplantation for Diamond-Blackfan anemia. Biol Blood Marrow Transplant. Aug 2005; 11(8):600-8. PMID 16041310

33. Kim H, Lee JH, Joo YD, et al. A randomized comparison of cyclophosphamide versus. reduced dose cyclophosphamide plus fludarabine for allogeneic hematopoietic cell transplantation in patients with aplastic anemia and hypoplastic myelodysplastic syndrome. Ann Hematol. Sep 2012; 91(9):1459-69. PMID 225263636

34. Dufour C, Pillon M, Socie G, et al. Outcome of aplastic anaemia in children. A study by the severe aplastic anaemia and paediatric disease working parties of the European group blood and bone marrow transplant. Br J Haematol. May 2015; 169(4):565-73. PMID 25683884

35. Smith AR, Gross TG, Baker KS. Transplant outcomes for primary immunodeficiency disease. Semin Hematol. Jan 2010; 47(1):79-85. PMID 20109615

36. Szabolcs P, Cavazzana-Calvo M, Fischer A, et al. Bone marrow transplantation for primary immunodeficiency diseases. Pediatr Clin N Am. Feb 2010; 57(1):207-37. PMID 20307719

37. Ahlin A, Fugelang J, de Boer M, et al. Chronic granulomatous disease-haematopoietic stem-cell transplantation versus conventional treatment. Acta Paediatr. Nov 2013; 102(11):1087-94. PMID 23937637

38. Gungor T, Teira P, Slatter M, et al. Reduced-intensity conditioning and HLA-matched haemopoietic stem-cell transplantation in patients with chronic granulomatous disease: a prospective multicentre study. Lancet. Feb 1 2014; 383(9915):436-48. PMID 24161820

39. Filipovich AH. Hematopoietic cell transplantation for correction of primary immunodeficiencies. Bone Marrow Transplant. Aug 2008; 42(suppl 1):S49-52. PMID 18724301

40. Hassan A, Booth C, Brightwell A, et al. Outcome of hematopoietic stem-cell transplantation for adenosine deaminase deficient severe combined immunodeficiency. Blood. Oct 25 2012; 120(17):3615-24; quiz 3626. PMID 22791287.

41. Filipovich AH, Stone J, Tomany SC, et al. Impact of donor type on outcome of bone marrow transplantation for Wiskott-Aldrich syndrome: collaborative study of the International Bone Marrow Transplant Registry and the National Marrow Donor Program. Blood. Mar 15 2001; 97(6):1598-603. PMID 11238097

42. Moratto D, Giliani S, Bonfim C, et al. Long-term outcome and lineage-specific chimerism in 194 patients with Wiskott-Aldrich syndrome treated by hematopoietic cell transplantation in the period 1980-2009: an international collaborative study. Blood. Aug 11 2011; 118(6):1675-84. PMID 21659547

43. Marsh RA, Bleesing JJ, Chandrakasan S, et al. Reduced-Intensity Conditioning Hematopoietic Cell Transplantation Is an Effective Treatment for Patients with SLAM-Associated Protein Deficiency/X-linked Lymphoproliferative Disease Type 1. Biol Blood Marrow Transplant. Jun 9 2014. PMID 24923536

44. Mehta P. Metabolic diseases. In: Mehta P, ed. Pediatric Stem-cell Transplantation. Sudbury, MA: Jones and Bartlett Publishers; 2004:233-58.

45. Guffon N, Bertrand Y, Forest I, et al. Bone marrow transplantation in children with Hunter syndrome: outcome after 7 to 17 years. J Pediatr. May 2009; 154(5):733-7. PMID 19167723

46. Vellodi A, Young E, New M, et al. Bone marrow transplantation for Sanfilippo disease type B. J Inherit Metab Dis. 1992; 15(6):911-8. PMID 1293388

47. Bordigoni P, Vidailbet M, Lena M, et al. Bone marrow transplantation for Sanfilippo syndrome. In: Hobbs JR, ed. Correction of Certain Genetic Diseases by Transplantation. London: Cogent; 1989:114-9.

48. Boelens JJ, Prasad VK, Tolar J, et al. Current international perspectives on hematopoietic stem-cell transplantation for inherited metabolic disorders. Pediatr Clin North Am. Feb 2010; 57(1):123-45. PMID 20307715

49. Prasad VK, Kurtzberg J. Transplant outcomes in mucopolysaccharidoses. Semin Hematol. Jan 2010; 47(1):59-69. PMID 20109613

50. Rovelli AM. The controversial and changing role of haematopoietic cell transplantation for lysosomal storage disorders: an update. Bone Marrow Transplant. Jun 2008; 41(suppl 2):S87-9. PMID 18545253

51. Aldenhoven M, Wynn RF, Orchard PJ, et al. Long-term outcome of Hurler syndrome patients after hematopoietic cell transplantation: an international multicenter study. Blood. Mar 26 2015; 125(13):2164-72. PMID 25624320

52. Boelens JJ, Wynn RF, O’Meara A, et al. Outcomes of haematopoietic cell transplantation for MPS-1 in Europe: a risk factor analysis for graft failure. Bone Marrow Transplant. Aug 2007; 40(3):225-33. PMID 17529997

53. Hansen MD, Filipovich AH, Davies SM, et al. Allogeneic hematopoietic cell transplantation (HSCT) in Hurler’s syndrome using a reduced intensity preparative regimen. Bone Marrow Transplant. Feb 2008; 41(4):349-53. PMID 18026148

54. Mynarek M, Tolar J, Albert MH, et al. Allogeneic hematopoietic SCT for alpha-mannosidosis: an analysis of 17 patients. Bone Marrow Transplant. Aug 18 2012; 47(3):352-9. PMID 21586746

55. Miller WP, Rothman SM, Nascene D, et al. Outcomes after allogeneic hematopoietic cell transplantation for childhood cerebral adrenoleukodystrophy: the largest single-institution cohort report. Blood. Aug 18 2011; 118(7):1971-8. PMID 21586746

56. Steward CG. Hematopoietic stem-cell transplantation for osteopetrosis. Pediatr Clin N Am. Feb 2010; 57(1):171-80. PMID 20307717

57. Driessen GJ, Gerritsen EJ, Fischer A, et al. Long-term outcome of hematopoietic stem-cell transplantation in autosomal recessive osteopetrosis: an EBMT report. Bone Marrow Transplant. Oct 2003; 32(7):657-63. PMID 13130312

58. Majhail NS, Farnia SH, Carpenter PA, et al. Indications for autologous and allogeneic hematopoietic cell transplantation: guidelines from the American Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant. Nov 2015; 21(11):1863-9. PMID 26256941

59. Killick SB, Bown N, Cavenagh J, et al. Guidelines for the diagnosis and management of adult aplastic anaemia. Br J Haematol. Jan 2016; 172(2):187-207. PMID 26568159

60. Barone A, Lucarelli A, Onofrillo D, et al. Diagnosis and management of acquired aplastic anemia in childhood. Guidelines from the Marrow Failure Study Group of the Pediatric Haemato-Oncology Italian Association (AIEOP). Blood Cells Mol Dis. Jun 2015; 55(1):40-7. PMID 25976466

61. Allogeneic Bone Marrow Transplantation for Neuroblastoma, Thalassemia, Sickle Cell Anemia, and Polycythemia Vera. Chicago, Illinois: Blue Cross Blue Shield Association – Technology Evaluation Center Evaluation Program (1988 December):398-407.

62. Allogeneic Bone Marrow Transplantation for Lysosomal Storage Disorders. Chicago, Illinois: Blue Cross Blue Shield Association – Technology Evaluation Program (1992 December):303-23.

63. Allogeneic Bone Marrow Transplantation for the Treatment of Sickle Cell Anemia. Chicago, Illinois: Blue Cross Blue Shield Association – Technology Assessment Program (1997 January) 11(27):1-30.

64. Allogeneic Hematopoietic Stem-Cell Transplantation for Genetic Diseases and Acquired Anemias. Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2018 January) Therapy 8.01.22.

Policy History:

Date Reason
5/15/2018 Document updated with literature review. Coverage unchanged. References reorganized and 19, 58-59 were added; none removed.
6/1/2017 Reviewed. No changes.
6/1/2016 Document updated with literature review. Coverage unchanged. Rationale significantly revised.
7/15/2015 Document updated with literature review. Coverage unchanged. Title changed from Stem-Cell Transplant for Genetic Diseases and Acquired Anemias.
6/1/2014 Document updated with literature review. The following was changed: reorganized and expanded multiple coverage indications/conditions, including: 1) hemoglobulinopathies (adding history of prior stroke or at increased risk of stroke or end-organ damage for sickle cell anemia and homozygous for beta-thalassemia with example); 2) bone marrow failure syndromes (adding examples of hereditary or acquired forms); 3) primary immunodeficiencies (including absent or defective T-cell function, natural killer function, neutrophil function); 4) inherited metabolic disease (adding lysosomal and peroxisomal storage disorders with examples); and 5) genetic disorders affecting skeletal tissue (adding examples of infantile malignant osteopetrosis). The following coverage statements were added: 1) hematopoietic progenitor cell boost is considered experimental, investigational and/or unproven. and 2) expanded coverage to consider a) short tandem repeat (STR) markers medically necessary when used in pre- or post-stem-cell support testing of the donor and recipient DNA profiles as a way to assess the status of donor cell engraftment following allogeneic SCS for specific genetic diseases and acquired anemias listed; b) all other uses of STR markers experimental, investigational and/or unproven, if not listed in the coverage section. Description and Rationale significantly revised.
4/1/2010 New medical document originating from: SUR703.017, Peripheral/Bone Marrow Stem-cell Transplantation (PSCT/BMT) for Non-Malignancies; SUR703.018, Peripheral/Bone Marrow Stem-cell Transplantation (PSCT/BMT) for Malignancies; SUR703.022, Cord Blood as a Source of Stem-cells (CBSC); SUR703.023, Donor Leukocyte Infusion (DLI); and SUR703.024, Tandem/Triple High-Dose Chemoradiotherapy with Stem-cell Support for Malignancies. Stem-cell transplant continues to be medically necessary when stated criteria are met. [NOTE: A link to the medical policies with the following titles can be found at the end of the medical policy SUR703.002, Stem-Cell Reinfusion or Transplantation Following Chemotherapy (General Donor and Recipient Information): Peripheral/Bone Marrow Stem-cell Transplantation (PSCT/BMT) for Non-Malignancies; Peripheral/Bone Marrow Stem-cell Transplantation (PSCT/BMT) for Malignancies; Cord Blood as a Source of Stem-cells; Donor Leukocyte Infusion (DLI); and Tandem/Triple High-Dose Chemoradiotherapy with Stem-cell Support for Malignancies.

Archived Document(s):

Back to Top