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A number of inherited and acquired conditions have the potential for severe and/or progressive disease. For some conditions, allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been used to alter the natural history of the disease or potentially offer a cure.
Hematopoietic Stem-Cell Transplantation
Hematopoietic stem-cell transplantation (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 radiotherapy. Allogeneic HSCT 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. Cord blood is discussed in a separate policy, Placental and Umbilical Cord Blood as a Source of Stem Cells.
Immunologic compatibility between infused hematopoietic stem cells and the recipient is a critical factor for achieving a good outcome with allogeneic HSCT. Compatibility is established by typing of human leukocyte antigen (HLA) using cellular, serologic, or molecular techniques. HLA refers to the tissue type expressed at the HLA-A, -B, and -DR (antigen-D related) loci on each arm of 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).
Preparative Conditioning for Allogeneic Hematopoietic SCT
The conventional practice of allogeneic HSCT involves administration of cytotoxic agents (e.g., cyclophosphamide, busulfan) with or without total body irradiation at doses sufficient to destroy endogenous hematopoietic capability in the recipient. Reduced-intensity conditioning (RIC) refers to chemotherapy regimens that seek to reduce adverse effects secondary to bone marrow toxicity. These regimens partially eradicate the patient’s hematopoietic ability, thereby allowing for relatively prompt hematopoietic recovery. Patients who undergo RIC with allogeneic HSCT 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 almost totally myeloablative to minimally myeloablative with lymphoablation, with intensity tailored to specific diseases and patient condition.
Genetic Diseases and Acquired Anemias
The thalassemias 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 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 allogeneic 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. 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 males and 48 for females. Three major therapeutic options are available: chronic blood transfusions, hydroxyurea, and allogeneic HSCT, 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, 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 patients with Fanconi anemia succumb to the complications of severe aplastic anemia, leukemia, or solid tumors, with a median survival of 30 years of age. In Fanconi anemia, HSCT is currently the only treatment that definitively restores normal hematopoiesis. Excellent results have been observed with the use of HLA-matched sibling allogeneic HSCT, with cure of the marrow failure and amelioration of the risk of leukemia.
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.
Mutations 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 patients developing aplastic anemia. As with other bone marrow failure syndromes, patients 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 patients also having a variety of physical anomalies.
The primary immunodeficiencies are a genetically heterogeneous group of diseases that affect distinct components of the immune system. More than 120 gene defects have been described, causing more than 150 disease phenotypes. 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. 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 transplant is the only definitive cure, and the treatment of choice for SCID and other primary immunodeficiencies, 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 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. 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 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 HSCT has been primarily used to treat the inherited metabolic diseases that belong to the lysosomal and peroxisomal storage disorders, as listed in the table below. The first stem-cell transplant for an inherited metabolic disease was in 1980 in a patient with Hurler syndrome. Since that time, more than 1,000 transplants have been performed worldwide.
Category Diagnosis Other Names Mucopolysaccharidosis (MPS) MPS I Hurler, Scheie, H-S Sphingolipiodsis Fabry Glycoproteinosis Aspartylglucosaminuria Other lipidoses Niemann-Pick disease C Glycogen storage GSD type II Pompe Multiple enzyme deficiency Galactosialidosis Cystinosis Peroxisomal storage disorders Adrenoleukodystrophy ALD
Hurler, Scheie, H-S
Niemann-Pick disease C
GSD type II
Multiple enzyme deficiency
Peroxisomal storage disorders
Infantile Malignant Osteopetrosis
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 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, often of recurrent infections. HSCT is the only curative therapy for this fatal disease.
Hematopoietic stem-cell transplantation for autoimmune disease, such as rheumatoid arthritis or multiple sclerosis, is considered separately in Hematopoietic Stem-Cell Transplantation for Autoimmune Diseases medical policy.
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.
POLICYNo benefits will be provided for a covered transplant procedure or a transplant evaluation unless the Member receives prior authorization through case management from Blue Cross & Blue Shield of Mississippi.
Allogeneic hematopoietic stem cell transplantation is considered medically necessary for select patients with the following disorders:
Bone Marrow Failure Syndromes
(See Guideline 1.)
Inherited Metabolic Disease
(See Guideline 2.)
Genetic Disorders Affecting Skeletal Tissue
POLICY EXCEPTIONSFor Federal Employee Program (FEP) subscribers, the Service Benefit Plan includes specific conditions in which autologous or allogeneic blood or marrow stem cell transplants would be considered eligible for coverage.
For State and School Employee subscribers, all bone marrow/stem cell transplants must be certified as medically necessary by the Plan’s Utilization Review Vendor. No benefits will be provided for any transplant procedure unless prior approval for the transplant is obtained.
The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.
The following lists the immunodeficiencies that have been successfully treated by allogeneic hematopoietic stem cell transplantation (allo-HSCT).
In the inherited metabolic disorders, allo-HSCT has been proven effective in some cases of Hurler, Maroteaux-Lamy, and Sly syndromes, childhood onset cerebral X-linked adrenoleukodystrophy, globoid cell leukodystrophy, metachromatic leukodystrophy, alpha-mannosidosis, and aspartylglucosaminuria. Allogeneic HSCT is possibly effective for fucosidosis, Gaucher types 1 and 3, Farber lipogranulomatosis, galactosialidosis, GM1 gangliosidosis, mucolipidosis II (I-cell disease), multiple sulfatase deficiency, Niemann-Pick, neuronal ceroid lipofuscinosis, sialidosis, and Wolman disease. Allogeneic HSCT has not been effective in Hunter, Sanfilippo, or Morquio syndromes.
The experience with reduced-intensity conditioning and allo-HSCT for the diseases listed in this policy has been limited to small numbers of patients and has yielded mixed results, depending upon the disease category. In general, the results have been most promising in the bone marrow failure syndromes and primary immunodeficiencies. In the hemoglobinopathies, success has been hampered by difficulties with high rates of graft rejection, and in adult patients, severe graft-versus-host-disease. Several phase 2/3 trials are ongoing examining the role of this type of transplant for these diseases, as outlined in the Ongoing and Unpublished Clinical Trials.
Medically Necessary is defined as those services, treatments, procedures, equipment, drugs, devices, items or supplies furnished by a covered Provider that are required to identify or treat a Member's illness, injury or Nervous/Mental Conditions, and which Company determines are covered under this Benefit Plan based on the criteria as follows in A through D:
A. consistent with the symptoms or diagnosis and treatment of the Member's condition, illness, or injury; and
B. appropriate with regard to standards of good medical practice; and
C. not solely for the convenience of the Member, his or her Provider; and
D. the most appropriate supply or level of care which can safely be provided to Member. When applied to the care of an Inpatient, it further means that services for the Member's medical symptoms or conditions require that the services cannot be safely provided to the Member as an Outpatient.
For the definition of Medically Necessary, “standards of good medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. BCBSMS makes no payment for services, treatments, procedures, equipment, drugs, devices, items or supplies which are not documented to be Medically Necessary. The fact that a Physician or other Provider has prescribed, ordered, recommended, or approved a service or supply does not in itself, make it Medically Necessary.
POLICY HISTORY3/25/2004: See policy "Allogeneic Stem Cell Transplant" prior to 3/25/2004, separate policy developed and aligned with BCBSA policy # 8.01.22
8/19/2004: Code Reference section completed
11/18/2004: Reviewed by MPAC; no changes
10/27/2005: Code Reference section updated; CPT-4 codes 38204, 38205, 38207, 38208, 38209, 38210, 38211, 38212, 38213, 38214, 38215, 38230 added; ICD-9 Procedures 41.02, 41.03, 41.05, 41.08 added; HCPCS G0355, G0356, G0357, G0358, G0359, G0360, G0361, G0362, G0363, G0364 added, J9000-J9999 deleted
03/10/2006: Coding updated. CPT4/HCPCS 2006 revisions added to policy.
09/12/2006: Coding updated. ICD9 2006 revisions added to policy
12/21/2006: Policy reviewed, no changes
9/18/2007: Code reference section updated. ICD-9 2007 revisions added to policy
12/20/2007: Coding updated per 2008 CPT/HCPCS revisions
9/28/2009: Code reference section updated. New ICD-9 diagnosis code 285.3 added to covered table. ICD-9 procedure code 284.8 deleted from covered table due to code was deleted as of 9-30-2007. HCPC codes G0265, G0266 and G0267 deleted from covered table due to codes were deleted as of 12-31-2007.
06/04/2010: The title changed from “High Dose Chemotherapy and Allogeneic Stem-Cell Support for Genetic Diseases and Acquired Anemias” to “Allogeneic Hematopoietic Stem-Cell Transplantation for Genetic Diseases and Acquired Anemias.” Policy description was revised to include detailed information regarding genetic diseases and acquired anemias. Table inserted describing Lysomal and Peroxisomal Storage Disorders. Policy statement section revised to include medically necessary indications for allogeneic hematopoietic stem cell transplantation. FEP and State and School Employee verbiage added to Policy Exceptions section. Added new CPT Codes 86825 and 86826 to the Covered Codes Table.
10/21/2010: Policy reviewed; no changes.
10/05/2011: Policy reviewed; no changes.
11/30/2012: Policy reviewed; no changes.
11/15/2013: Policy reviewed; no changes.
11/13/2014: Policy reviewed; description updated regarding bone marrow failure syndromes. Policy statement regarding bone marrow failure syndromes updated to include aplastic anemia.
08/21/2015: Code Reference section update to add ICD-10 codes. Revised the descriptions for CPT codes 38240 and 38242; removed deleted CPT code G0363; removed deleted code CPT 96445 and replaced with CPT code 96446. Removed ICD-9 procedure code 99.25 and ICD-9 diagnosis code 288.0.
06/09/2016: Policy number added. Policy description updated regarding FDA regulations. Medically necessary policy statement updated to change "allogeneic bone marrow transplants" to "allogeneic hematopoietic stem cell transplantation." Policy guidelines section updated to add guidelines for primary immunodeficiencies and inherited metabolic disease. Added medically necessary definition.
09/30/2016: Code Reference section updated to add the following new ICD-10 procedure codes: 30233G2, 30233G3, 30233G4, 30233Y2, 30233Y3, 30233Y4, 30243G2, 30243G3, 30243Y2, 30243Y3, and 30243Y4. Added new ICD-10 diagnosis code D47.Z2.
SOURCE(S)Blue Cross Blue Shield Association policy # 8.01.22
CODE REFERENCEThis may not be a comprehensive list of procedure codes applicable to this policy.
The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of this document.