Latest Review Date: March 2024

Category: Surgery                                                                

POLICY:

Allogeneic stem cell transplantation may be considered medically necessary for selected individuals with the following disorders:

Hemoglobinopathies

1. Sickle cell anemia for children or young adults with a history either of prior stroke or at increased risk of stroke or end organ damage. Factors associated with a high risk of stroke or end organ damage include:

• Recurrent acute chest syndrome
• Recurrent vaso-occlusive crises resulting in frequent pain that does not respond or has an inadequate response to standard of care, such as hydroxyurea, new-targeted therapies, or chronic transfusion therapies.
• Red blood cell alloimmunization on chronic transfusion therapy.

2. Homozygous beta-thalassemia (i.e., thalassemia major)

Bone Marrow Failure Syndromes

• Severe aplastic anemia, including hereditary (e.g., Fanconi’s anemia or Diamond-Blackfan syndrome) 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)

Inherited Metabolic Disease

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

Genetic Disorders Affecting Skeletal Tissue

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

DESCRIPTION OF PROCEDURE OR SERVICE:

Numerous inherited and acquired conditions are potentially severe and/or progressive, for which allogeneic HCT has been used to alter the natural history of the disease or potentially offer a cure.

Genetic Diseases and Acquired Anemias

Hemoglobinopathies

Thalassemia’s result from mutations in the globin genes, resulting in reduced or absent hemoglobin production, reducing oxygen delivery. The supportive treatment of beta-thalassemia major requires life-long red blood cell transfusions, which lead to progressive iron overload and the potential for organ damage and impaired cardiac, hepatic and endocrine function. Sickle cell disease (SCD) 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. SCD 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 individuals with SCD has been demonstrated as 42 years for males and 48 for females.

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.

Bone Marrow Failure Syndromes

Aplastic anemia in children is rare, and is most often 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 or acute myelogenous leukemia. Most individuals with FA succumb to the complications of severe aplastic anemia, leukemia or solid tumors, with a median survival of 30 years of age.

Dyskeratosis Congenita is characterized by marked telomere dysregulation with clinical features of reticulated skin hyperpigmentation, nail dystrophy and oral leukoplakia. 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 anemia. Shwachman-Diamond has clinical features that include pancreatic exocrine insufficiency, skeletal abnormalities, and cytopenias, with some individuals developing aplastic anemia. As with other bone marrow failure syndromes, individuals are at increased risk of myelodysplastic syndrome and malignant transformation, especially acute myelogenous leukemia. Diamond-Blackfan anemia is characterized by absent or decreased erythroid precursors in the bone marrow with 30% of inidividuals also having a variety of physical anomalies.

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. Recent literature has identified gene therapy and gene editing as potential future treatments for Diamond-Blackfan anemia and other hereditary bone marrow failure syndromes.

Primary Immunodeficiencies

The primary immunodeficiencies (PID) 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. The most severe defects (collectively known as severe combined immunodeficiency or [SCID]) cause an absence or dysfunction of T-lymphocytes, and sometimes B-lymphocytes and natural killer cells.

Treatment

Without treatment, individuals with SCID usually die by 12 to 18 months of age. With supportive care, including prophylactic medication, the life span of these individuals 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 transplant is the only definitive cure, and the treatment of choice for SCID and other PID including Wiskott-Aldrich syndrome and congenital defects of neutrophil function.

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. Lysosomal storage disorders are caused by specific enzyme deficiencies that result in defective lysosomal acid hydrolysis of endogenous macro-molecules 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. 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 (IMD); however, these drugs do not cross the blood-brain barrier, which results in 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. The donor-derived cells can migrate and engraft in many organ systems, giving rise to different types of cells, for example, microglial cells in the brain and Kupffer cells in the liver.

Allogeneic HCT has been used primarily to treat the IMD that belongs to the lysosomal and peroxisomal storage disorders, as listed in Table 1. The first stem cell transplant for an IMD was in 1980 in an individual with Hurler syndrome. Since that time, over 1,000 transplants have been performed worldwide.

Table 1. Lysosomal and Peroxisomal Storage Disorders

Category	Diagnosis	Other Names
Mucopolysaccharidoses	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. Osteopetrosis is a heterogeneous group of heritable disorders, resulting in several different types of variable severity. The most severely affected individuals are those with infantile malignant osteopetrosis. Individuals 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 individuals die before the age of 6 years, often of recurrent infections.

Treatment

HCT is the only curative therapy for this fatal disease.

Hematopoietic Cell Transplantation

Hematopoietic cell transplantation (HCT) refers to a procedure in which hematopoietic stem cells are infused to restore bone marrow function in individuals who receive bone marrow toxic doses of cytotoxic drugs with or without whole body radiation therapy.  Allogeneic HCT refers to the use of hematopoietic progenitor cells obtained from a donor. They can be harvested from bone marrow, peripheral blood, or umbilical cord blood and placenta shortly after delivery of neonates.  Although cord blood is an allogeneic source, the stem cells in it are antigenically “naïve” and thus are associated with a lower incidence of rejection or graft-versus-host disease (GVHD). Cord blood is discussed in greater detail in medical policy #439: Placenta/Umbilical Cord Blood as a Source of Stem Cells.

Immunologic compatibility between infused stem cells and the recipient is a critical factor for achieving a good outcome of allogeneic HCT. 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 HLA A, B, and DR loci on each arm of chromosome 6. Depending on the disease being treated, an acceptable donor will match the individual at all or most of the HLA loci (with the exception of umbilical cord blood).

Preparative Conditioning for Allogeneic HCT

The conventional practice of allogeneic HCT involves administration of myelotoxic agents (e.g., cyclophosphamide, busulfan) with or without total body irradiation at doses sufficient to cause bone marrow failure. Reduced-intensity conditioning (RIC) refers to chemotherapy regimens that seek to reduce adverse effects secondary to bone marrow toxicity. These regimens partially eradicate the individual’s hematopoietic ability, thereby allowing for relatively prompt hematopoietic recovery (e.g., 28 days or less) even without a transplant. Individuals who undergo RIC with allogeneic HCT initially demonstrate donor cell engraftment and bone marrow mixed chimerism. Most will subsequently convert to full-donor chimerism. A number of different cytotoxic regimens, with or without radiotherapy, may be used for RIC allotransplantation. They represent a continuum in their intensity, from nearly totally myeloablative, to minimally myeloablative with lymphoablation.

HCT for autoimmune disease, such as rheumatoid arthritis or MS, is considered in Medical Policy #485: Hematopoietic Cell Transplantation for Autoimmune Disease.

KEY POINTS:

The most recent literature update was performed through March 13, 2024.

Summary of Evidence

For individuals who have a hemoglobinopathy, bone marrow failure syndrome, primary immunodeficiency, inherited metabolic syndrome disease, 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. The exception has been the use of allo-HCT in the inherited metabolic diseases like Hunter, Sanfilippo, and Morquio syndromes. Allo-HCT is likely to improve health outcomes in select individuals with certain inherited and acquired diseases. The evidence is sufficient to determine that the technology results in an 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 individuals with Hunter, Sanfilippo, or Morquio syndromes does not result in improvements in neurologic, neuropsychologic, and neurophysiologic function. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Practice Guidelines and Position Statements

American Society of Hematology (ASH)

The American Society of Hematology published eight recommendations for the treatment of sickle cell disease utilizing stem cell transplant in September 2021. The guidelines are based on updated and original systematic reviews of evidence conducted under the direction of the Mayo Evidence-Based Practice Research Program. The panel followed best practices for guideline development recommended by the Institute of Medicine and the Guidelines International Network using the Grading of Recommendations Assessment Development and Evaluation (GRADE) approach. The recommendations include:

1. HLA-matched related HSCT rather than standard of care (hydroxyurea (HU)/transfusion) in individuals with SCD who have experienced an overt stroke or have an abnormal transcranial Doppler ultrasound (TCD).
2. For individuals with frequent pain, the ASH guideline panel suggests using related matched allogeneic transplantation rather than standard of care.
3. For individuals with recurrent episodes of ACS, the ASH guideline panel suggests using matched related allogeneic transplantation over standard of care.
4. For individuals with SCD with an indication for HSCT who lack an MSD, the ASH guideline panel suggests using transplants from alternative donors in the context of a clinical trial.
5. For allogeneic HSCT, the ASH guideline panel suggests using either total-body irradiation (TBI) ≤400 cGy or chemotherapy-based conditioning regimens.
6. For children with SCD who have an indication for allogeneic HSCT and an MSD, the ASH guideline panel suggests using myeloablative conditioning over RIC that contains melphalan/fludarabine regimens and for adults with SCD who have an indication for allogeneic HSCT and an MSD, the ASH guideline panel suggests nonmyeloablative conditioning over RIC that contains melphalan/fludarabine regimens.
7. In individuals with an indication eligible for HSCT, the ASH guideline panel suggests using allogeneic transplantation at an earlier age rather than an older age.
8. The ASH guideline panel suggests the use of HLA-identical sibling cord blood when available (and associated with an adequate cord blood cell dose and good viability) over bone marrow (BM).

American Society for Blood and Marrow Transplantation

In 2015, the American Society for Blood and Marrow Transplantation published consensus guidelines on the use of hematopoietic cell transplantation (HCT) to treat specific conditions in and out of the clinical trial settings. Specific to this review Table 2 provides the allogeneic guidelines for specific indications. Each indication is given a rating, which include:

•  Standard of care, where indication for HCT is well defined and supported by evidence.
•  Standard of care, clinical evidence available, where large clinical trials and observational studies are not available but HCT has been shown to be effective therapy.
•  Standard of care, rare indication, for rare diseases where HCT has demonstrated effectiveness but large clinical trials and observational studies are not feasible.
•  Developmental, for diseases where pre-clinical and/or early phase clinical studies show HCT to be a promising treatment option.
•  Not generally recommended, where available evidence does not support the routine use of HCT.

Table 2. Recommendations for Use of Allogeneic HCT to Treat Genetic Diseases and Acquired Anemias

Indications	Allogeneic HCT <18 Years
Severe aplastic anemia, new diagnosis	S
Severe aplastic anemia, relapse/refractory	S
Fanconi anemia	R
Dyskeratosis Congenita	R
Blackfan-Diamond anemia	R
Sickle cell disease	C
Thalassemia	S
Congenital amegakaryocytic thrombocytopenia	R
Severe combined immunodeficiency	R
T-cell immunodeficiency, severe combined immunodeficiency variants	R
Wiskott-Aldrich syndrome	R
Hemophagocytic disorders	R
Lymphoproliferative disorders	R
Severe congenital neutropenia	R
Chronic granulomatous disease	R
Other phagocytic cell disorders	R
Immunodysregulation polyendocrinopathy enteropathy X-linked syndrome	R
Juvenile rheumatoid arthritis	D
Systemic sclerosis	D
Other autoimmune and immune dysregulation disorders	R
Mucopolysaccharidoses (MPS-I and MPS-VI)	R
Other metabolic diseases	R
Osteopetrosis	R
Globoid cell leukodystrophy (Krabbe)	R
Metachromatic leukodystrophy	R
Cerebral X-linked adrenoleukodystrophy	R
Indications	Allogeneic HCT >18 Years
Severe aplastic anemia, new diagnosis	S
Severe aplastic anemia, relapse/refractory	S
Fanconi anemia	R
Dyskeratosis Congenita	R
Sickle cell disease	C
Thalassemia	D
Hemophagocytic syndromes, refractory	R
Mast cell diseases	R
Common variable immunodeficiency	R
Wiskott-Aldrich syndrome	R
Chronic granulomatous disease	R
Multiple sclerosis	N
Systemic sclerosis	N
Rheumatoid arthritis	N
Systemic lupus erythematosus	N
Crohn’s disease	N
Polymyositis-dermatomyositis	N

C: clinical evidence available; D: developmental; HCT: hematopoietic cell transplantation; N: not generally recommended; R: standard of care, rare indication; S: standard of care.

British Committee for Standards in Haematology

In 2020, the British Committee for Standards in Haematology published guidelines on the diagnosis and management of adult aplastic anemia. The following key recommendations on hematopoietic cell transplant (HCT) were included in the guidelines:

• Matched sibling donor (allogeneic) HCT is the treatment of choice for severe aplastic anemia; however, for individuals aged 40 to 50 years, individuals need to be assessed for comorbidities before being considered for HCT.
• For adults, unrelated donor HCT should be considered if individuals fail to respond to a single course of immunosuppressive therapy.
• Although there have been improvements in outcomes after alternative donor HCT, these transplants are still experimental and expert consultation should be sought before considering their use.

U.S. Preventive Services Task Force Recommendations

Not applicable.

KEY WORDS:

Aplastic Anemia, Hematopoietic Stem Cell Transplant (HSCT), Inborn Errors of Metabolism, Mucolipidosis, Mucopolysaccharidosis, Osteopetrosis, Severe Combined Immunodeficiency’s (SCID), Sickle Cell Disease, Thalassemia, Hemoglobinopathies, Primary Immunodeficiency’s, Inherited Metabolic Disease,  Bone Marrow Failure Syndromes, Fanconi Anemia, allogeneic hematopoietic cell transplantation , allo-HCT, Diamond-Blackfan syndrome, dyskeratosis congenita, Shwachman-Diamond syndrome, Hunter Syndrome, Sanfilippo Syndrome, Morquio Syndrome, Maroteaux-Lamy syndrome, Hurler syndrome, adrenoleukodystrophy, ALD

APPROVED BY GOVERNING BODIES:

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.  Hematopoietic stem cells are included in these regulations.

BENEFIT APPLICATION:

Coverage is subject to member’s specific benefits.  Group-specific policy will supersede this policy when applicable.

ITS: Home Policy provisions apply

FEP: Special benefit consideration may apply.  Refer to member’s benefit plan. 

CURRENT CODING: 

CPT Codes:

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
38230	Bone marrow harvesting for transplantation; allogeneic
38240	Bone marrow or blood-derived peripheral stem-cell transplantation; allogeneic
38242	Management/transplant preparation/infusion of hematopoietic progenitor cells code range

HCPCS:

S2140	Cord blood harvesting for transplantation, allogeneic
S2142	Cord blood-derived stem-cell transplantation, allogeneic
S2150	Bone marrow or blood-derived stem cells (peripheral or umbilical), allogeneic or autologous, harvesting, transplantation, and related complications; including: pheresis and cell preparation/storage; marrow ablative therapy; drugs, supplies, hospitalization with outpatient follow-up; medical/surgical, diagnostic, emergency, and rehabilitative services; and the number of days of pre and post-transplant care in the global definition

REFERENCES:

1. 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):1087-1094.
2. 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):2164-2172.
3. 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):811-820.
4. 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. Dec 2014; 20(12):2066-2071.
5. Askmyr MK, Fasth A and Richter J.  Towards a better understanding and new therapeutics of osteopetrosis.  Br J Haematol 2008; 140(6):597-609.
6. Aspesi A, Borsotti C, Follenzi A. Emerging Therapeutic Approaches for Diamond Blackfan Anemia. Curr Gene Ther. 2018;18(6):327-335.
7. Bacigalupo A. Bone marrow transplantation for acquired severe aplastic anemia. Hematol Oncol Clin North Am. Dec 2014; 28(6):1145-1155.
8. 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):40-47.
9. 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 2012; 120(2):473-476.
10. Bernaudin F, Socie G, Kuentz M, et al. Long-term results of related, myeloablative stem cell transplantation to cure sickle cell disease. Blood 2007; 110(7):2749-2756.
11. Bhatia M and Walters MC. Hematopoietic cell transplantation for thalassemia and sickle cell disease: past, present and future. Bone Marrow Transplant 2008; 41:109-117.
12. Boelens JJ, Prasad VK, Tolar J, et al. Current international perspectives on hematopoietic stem cell transplantation for inherited metabolic disorders. Pediatr Clin North Am 2010; 57(1):123-145.
13. 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. 2007; 40(3):225-233.
14. Bordigoni P, Vidailbet M, et al. Bone marrow transplantation for Sanfilippo syndrome. In Hobbs JR, ed. Correction of Certain Genetic Disease by Transplantation. London: Cogent, 114-119.
15. Burroughs LM, Petrovic A, Brazauskas R, et al. Excellent outcomes following hematopoietic cell transplantation for Wiskott-Aldrich syndrome: a PIDTC report. Blood. Jun 04 2020; 135(23): 2094-2105. 
16. Cancio, M., Troullioud Lucas, A. G., Bierings, M., Klein, E., de Witte, M. A., Smiers, F. J., Bresters, D., Boelens, J. J., & Smetsers, S. E. (2024). Predictors of outcomes in hematopoietic cell transplantation for Fanconi anemia. Bone marrow transplantation, 59(1), 34–40. doi.org/10.1038/s41409-023-02121-1
17. Cesaro S, Oneto R, Messina C, et al. Hematopoietic stem cell transplantation for Shwachman-Diamond disease: a study from the European Group for Blood and Marrow Transplantation. Br J Haematol 2005; 131(2):231-236.
18. Cesaro S, Pillon M, Sauer M, et al. Long-term outcome after allogeneic hematopoietic stem cell transplantation for Shwachman Diamond syndrome: a retrospective analysis and a review of the literature by the Severe Aplastic Anemia Working Party of the European Society for Blood and Marrow Transplantation (SAAWP-EBMT). Bone Marrow Transplant. Sep 2020; 55(9): 1796-1809.
19. Chiesa R, Wang J, Blok HJ, et al. Hematopoietic cell transplantation in chronic granulomatous disease: a study of 712 children and adults. Blood. Sep 03 2020; 136(10): 1201-1211.
20. Driessen GJA, Gerritsen EJA, Fischer A, et al. Long-term outcome of hematopoietic stem cell transplantation in autosomal recessive osteopetrosis: an EBMT report. Bone Marrow Transplant 2003; 32:657-663.
21. Dufour C and Svahn J. Fanconi anaemia: New strategies. Bone Marrow Transplant 2008; 41: S90-S95.
22. 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):565-573.
23. El Gohary G, El Fakih R, de Latour R, et al. Haploidentical hematopoietic stem cell transplantation in aplastic anemia: a systematic review and meta-analysis of clinical outcome on behalf of the severe aplastic anemia working party of the European group for blood and marrow transplantation (SAAWP of EBMT). Bone Marrow Transplant. Oct 2020; 55(10): 1906-1917.
24. 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 2001; 97:1598-1603.
25. Filipovich AH.  Hematopoietic cell transplantation for correction of primary immunodeficiency’s. Bone Marrow Transplant 2008; 42:S49-52.
26. Gadalla SM, Sales-Bonfim C, Carreras J, et al. Outcomes of allogeneic hematopoietic cell transplantation in patients with dyskeratosis ulticente. Biol Blood Marrow Transplant. Aug 2013; 19(8):1238-1243.
27. Gennery AR and Cant AJ. Advances in hematopoietic stem cell transplantation for primary immunodeficiency.  Immunol Allergy Clin N Am 2008; 28:439-456.
28. Gluckman E, Wagner JE. Hematopoietic stem cell transplantation in childhood inherited bone marrow failure syndrome. Bone Marrow Transplant. 2008; 41(2):127-132.
29. Guffon N, Bertrand Y, Forest I et al. Bone marrow transplantation in children with Hunter syndrome: outcome after 7 to 17 years. J Pediatr 2009; 154(5):733-737.
30. 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 multicenter study. Lancet. Feb 1 2014; 383(9915):436-448.
31. Hansen MD, Filipovich AH, Davies SM, et al. Allogeneic hematopoietic cell transplantation (HCT) in Hurler’s syndrome using a reduced intensity preparative regimen.  Bone Marrow Transplant 2008; 41:349-353.
32. Hassan A, Booth C, Brightwell A et al. Outcome of hematopoietic stem cell transplantation for adenosine deaminase deficient severe combined immunodeficiency. Blood 2012; 120(17):3615-3624; quiz 3626.
33. 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.
34. IOM (Institute of Medicine). 2011. Clinical Practice Guidelines We Can Trust. Washington, DC: The National Academies Press. 
35. Kanate AS, Majhail NS, Savani BN, et al. Indications for Hematopoietic Cell Transplantation and Immune Effector Cell Therapy: Guidelines from the American Society for Transplantation and Cellular Therapy. Biol Blood Marrow Transplant. 2020;26(7):1247-56.
36. Kanter Julie, Liem Robert I., Bernaudin Françoise, et al. American Society of Hematology 2021 guidelines for sickle cell disease: stem cell transplantation. Blood Adv (2021) 5 (18): 3668–3689.
37. Killick SB, Bown N, Cavenagh J, et al. Guidelines for the diagnosis and management of adult aplastic anemia. Br J Haematol. Jan 2016; 172(2):187-207.
38. Kim H, Lee JH, Joo YD et al. A randomized comparison of cyclophosphamide vs. reduced dose cyclophosphamide plus fludarabine for allogeneic hematopoietic cell transplantation in patients with aplastic anemia and hypoplastic myelodysplastic syndrome. Ann Hematol 2012; 91(9):1459-1469. 
39.  Kulasekararaj A, Cavenagh J, Dokal I, Foukaneli T, Gandhi S, Garg M, et al. Guidelines for the diagnosis and management of adult aplastic anaemia: A British Society for Haematology Guideline. Br J Haematol. 2024;204(3):784–804. doi.org/10.1111/bjh.19236
40. 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):1072-1078.
41. MacMillan ML, Walters MC, Gluckman E. Transplant outcomes in bone marrow failure syndromes and hemoglobinopathies. Semin Hematol 2010; 47(1):37-45.
42. Mahmoud HK, Elhaddad AM, Fahmy OA, et al. Allogeneic hematopoietic stem cell transplantation for non-malignant hematological disorders. J Adv Res. May 2015; 6(3):449-458.
43. 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):1863-1869.
44. 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. Oct 2014; 20(10):1641-1645.
45. Mathews V, Srivastava A, Chandy M. Allogeneic stem cell transplantation for thalassemia major. Hematol Oncol Clin North Am. Dec 2014; 28(6):1187-1200.
46. Mehta P, Locatelli F, Stary J et al. Bone marrow transplantation for inherited bone marrow failure syndromes. Pediatr Clin N Am 2010; 57(1):147-170.
47. Mehta P. Hematopoietic stem cell transplantation for hemoglobinopathies (Chapter 16). In: Pediatric stem cell transplantation 2004. Jones and Bartlett Publishers; Sudbury, MA. Pp. 259-279.
48. Mehta P. Hematopoietic stem cell transplantation for inherited bone marrow failure syndromes. (Chapter 17). In: Pediatric stem cell transplantation 2004. Jones and Bartlett Publishers; Sudbury, MA. Pp. 281-316.
49. Mehta P. Metabolic diseases (Chapter 15). In: Pediatric stem cell transplantation 2004. Jones and Bartlett Publishers; Sudbury, MA. Pp. 233-258.
50. Mehta P. Metabolic diseases. In: Mehta P, ed. Pediatric Stem Cell Transplantation. Sudbury, MA: Jones and Bartlett Publishers; 2004: 233-258.
51. Miano M, Dufour C. The diagnosis and treatment of aplastic anemia: a review. Int J Hematol. Jun 2015; 101(6):527-535.
52. Miller WP, Rothman SM et al. Outcomes after allogenic hematopoietic cell transplantation for childhood cerebral adrenoleukodystrophy; the largest single institution cohort report. Blood 2011 Aug 18; 118(7):1970-1978.
53. 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 2011; 118(6): 1675-1684.
54. Myers K, Hebert K, Antin J, et al. Hematopoietic Stem Cell Transplantation for Shwachman-Diamond Syndrome. Biol Blood Marrow Transplant. Aug 2020; 26(8): 1446-1451.
55. Mynarek M, Tolar J, Albert MH, et al. Allogeneic hematopoietic SCT for alpha-mannosidosis: an analysis of 17 patients. Bone Marrow Transplant. Mar 2012; 47(3):352-359.
56. 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.
57. 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.
58. Oringanje C, Nemecek E, Oniyangi O. Hematopoietic stem cell transplantation for people with sickle cell disease. Cochrane Database Syst Rev. Jul 03 2020; 7: CD007001.
59. Porta F, Forino C, De Martiis D, et al. Stem cell transplantation for primary immunodeficiencies.  Bone Marrow Transplant 2008; 41:S83-S86.
60. Porta F, Forino C, De Martiis D, et al. Stem cell transplantation for primary immunodeficiencies. Bone Marrow Transplant. 2008; 41(suppl 2):S83-86.
61. Prasad VK and Kurtzberg J. Emerging trends in transplantation of inherited metabolic diseases. Bone Marrow Transplant 2008; 41:99-108.
62. Prasad VK and Kurtzberg J. Transplant outcomes in mucopolysaccharidoses. Semin Hematol 2010; 47(1):59-69.
63. Prasad VK, Kurtzberg J. Emerging trends in transplantation of inherited metabolic diseases. Bone Marrow Transplant. 2008; 41(2):99-108.
64. Rovelli AM. The controversial and changing role of haematopoietic cell transplantation for lysosomal storage disorders: An update. Bone Marrow Transplant 2008; 41:S87-S89.
65. Roy V, Perez WS, Eapen M, et al. Bone marrow transplantation for Diamond-Blackfan anemia. Biol Blood Marrow Transplant 2005; 11(8):600-608.
66. Smiers F, Krishnamurti L, Lucarelli G. Hematopoietic stem cell transplantation for hemoglobinopathies: current practice and emerging trends. Pediatr Clin N Am 2010; 57(1):181-205.
67. Smith AR, Gross TG, Baker KS. Transplant outcomes for primary immunodeficiency disease. Semin Hematol 2010; 47(1):79-85.
68. Steward CG. Hematopoietic stem cell transplantation for osteopetrosis. Pediatr Clin N Am 2010; 57(1):171-180.
69. Szabolcs P, Cavazzana-Calvo M, Fischer A et al. Bone marrow transplantation for primary immunodeficiency diseases. Pediatr Clin N Am 2010; 57(1):207-37.
70. Vellodi A, Young E, et al. Bone marrow transplantation for Sanfilippo disease type B. J Inherit Metab Disease 1992; 15(6): 911-918.
71. Wagner JE, Eapen M, MacMillian ML et al.  Unrelated donor bone marrow transplantation for the treatment of Fanconi anemia. Blood 2007; 109(5):2256-2262. 
72. Walters MC, Patience M, Leisenring W, et al. Bone marrow transplantation for sickle cell disease. N Engl J Med 1996; 335:369-376.
73. Walters MC, Storb R, Patience M, et al. Impact of bone marrow transplantation for symptomatic sickle cell disease: an interim report. Multicenter investigation of bone marrow transplantation for sickle cell disease. Blood 2000; 95:1918-1924.
74. Yabe M, Morio T, Tabuchi K, et al. Long-term outcome in patients with Fanconi anemia who received hematopoietic stem cell transplantation: a retrospective nationwide analysis. Int J Hematol. 2021.
75. 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. 2005; 130(1):99-106. 
76. Zielińska P, Noster I, Wieczorkiewicz-Kabut A, et al. Allogeneic hematopoietic stem cell transplantation for acquired severe aplastic anemia: a summary of a 20-year experience. Pol Arch Intern Med. 2023; 133: 16448. doi:10.20452/pamw.16448

POLICY HISTORY:

Medical Policy Group, June 2009 (2)

Medical Policy Administration Committee, July 2009

Available for comment July 1-August 14, 2009

Medical Policy Group, September 2009 (3)

Medical Policy Administration Committee, October 2009

Available for comment October 3-November 17, 2009

Medical Policy Panel, September 2010

Medical Policy Group, February 2011 (2)

Medical Policy Panel, September 2011

Medical Policy Group, September 2011 (2): Key Points, References updated

Medical Policy Group, December 2011 (3): 2012 Code Verbiage updates added to code 38208, 38209, 38230; Added new Codes 38232, & 86812-86822

Medical Policy Group, October 2012 (4): 2012 Update to Key Points and References

Medical Policy Panel, September 2013

Medical Policy Group, September 2013 (3):  Updates to Description, Key Points and References; no change in policy statement

Medical Policy Group, October 2013 (3): Removed ICD-9 Procedure codes; no change in policy statement.

Medical Policy Group, January 2014 (1): 2014 Coding Update: added current codes Q2049 and Q2050 to coding section; new codes are included in the chemotherapy drug code range

Medical Policy Panel, September 2014

Medical Policy Group, September 2014 (3): 2014 Updates to Key Points & References; no change in policy statement

Medical Policy Panel, February 2016

Medical Policy Group, March 2016 (2):  Updates to Description, Key Points, Key Words, Approved by Governing Bodies, Current Coding:  removed CPT codes 86812–86822, Q0083-Q0085, Q2049, Q2050, J9000-J9999, and References; no change in policy statement.

Medical Policy Panel, October 2017

Medical Policy Group, October 2017 (7): 2017 Updates to Title, Key Points, and References. No change in Policy Statement.

Medical Policy Panel, January 2018

Medical Policy Group, February 2018 (7): Updates to Description, Key points, Key Words, and References. No change in Policy Statement.

Medical Policy Panel, January 2019

Medical Policy Group, February 2019 (3): 2019 Updates to Key Points, and Key Words: added: Diamond-Blackfan Syndrome, Dyskeratosis Congenita, Shwachman-Diamond Syndrome, Hunter Syndrome, Sanfilippo Syndrome, Morquio Syndrome, Maroteaux-Lamy Syndrome, Hurler Syndrome, Adrenoleukodystrophy, and ALD. No changes to policy statement or intent.

Medical Policy Panel, January 2020

Medical Policy Group, January 2020 (3): 2020 Updates to Key Points. No changes to policy statement or intent.

Medical Policy Panel, January 2021

Medical Policy Group, February 2021 (3): 2021 Updates to Key Points and References. Policy statement updated to remove “not medically necessary,” no change to policy statement or intent. Medical Policy Panel, February 2022

Medical Policy Group, February 2022 (3): 2022 Updates to Key Points, Practice Guidelines and Position Statements, and References. Policy clarification for sickle cell anemia to specify factors associated with a high risk of stroke or end organ damage to meet medical necessity for allogeneic stem cell transplant.

Medical Policy Group, March 2023 (3): 2023 Updates to Key Points, Practice Guidelines and Position Statements, Benefit Applications, and References. Reviewed by consensus. No new published peer-reviewed literature available that would alter the coverage statement in this policy.

Medical Policy Group, March 2024 (3): 2024 Updates to Description, Key Points, Benefit Applications, and References. Reviewed by consensus. No new published peer-reviewed literature available that would alter the coverage statement in this policy.

This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.

The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.

As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.

The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:

1. The technology must have final approval from the appropriate government regulatory bodies;

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;

3. The technology must improve the net health outcome;

4. The technology must be as beneficial as any established alternatives;

5. The improvement must be attainable outside the investigational setting.

Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:

1. In accordance with generally accepted standards of medical practice; and

2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and

3. Not primarily for the convenience of the patient, physician or other health care provider; and

4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.