BlueCross and BlueShield of Montana Medical Policy/Codes
Stem-Cell Transplant for Genetic Diseases and Acquired Anemias
Chapter: Surgery: Procedures
Current Effective Date: December 27, 2013
Original Effective Date: December 27, 2013
Publish Date: September 27, 2013
Description

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.  While the manifestations of these diseases relate to the accumulation of metabolites in the reticuloendothelial cells, fibroblasts, or nervous system, the enzymatic defect may be corrected by an alloSCT (allogeneic stem cell transplant).

Aplastic Anemia (severe or very severe) is characterized by a great reduction of red blood cells and hemoglobin as a result of hypoplastic or aplastic bone marrow.  Fanconi's anemia and Diamond-Blackfan Syndrome are congenital forms.  Acquired aplastic anemia may be secondary to drug or toxin exposure.

Beta-Thalassemia is hereditary hemolytic anemia (loss of hemoglobin concentration in the blood cells) caused by a diminished synthesis of the beta chain within the hemoglobin, usually found in people of Mediterranean decent.  Beta-Thalassemia is also known as Homozygous Beta-Thalassemia, Thalassemia Major, and Cooley's Disease.

Chediak-Higashi Syndrome (CHS) or Chediak-Steinbrick-Higashi Syndrome (CSHS) is an abnormality in the granulation of the leukocyte nucleus structure resulting in partial albinism, neurologic disorders, and changes in vision, damage to liver, spleen, lymph system, and increased susceptibility to infection.

Hemophagocytic Lymphohistiocytosis (HLH) is an overproduction of infection-fighting cells causing inflammation and damage to bone marrow, lymph nodes, liver, spleen, skin, and membranes surrounding the brain or spinal cord.

Hypereosinophilic Syndrome (HES) is an increased number of eosinophilic leukocytes resulting in infiltration into the bone marrow, heart, and other organs.  HES may be considered as pre-leukemic.

Kostmann's Syndrome is a severe congenital neutropenia in which neutrophils fail to reach a mature and functional state.

Leukocyte Adhesion Deficiency (LAD) is a disorder affecting the glycoproteins (located on the surface of phagocytic cells) which are responsible for the ability of leukocytes to adhere to antigens and migrate into sites of infection and inflammation.

Mucolipidoses (ML) is another group of storage diseases (resembling Mucopolysaccharidoses) that share symptoms.  However, different origins result in damage to different organs or systems of the body.  Gaucher's Disease, Metachromatic Leukodystrophy, Globoid Cell Leukodystrophy, and Adrenoleukodystrophy are four origins of ML.

Mucopolysaccharidoses (MPS) is a group of storage diseases caused by a disorder in the metabolism of mucopolysaccharides (which is excreted in the urine and infiltrated into connective tissue).  Thus, there is damage and defects of bone, cartilage, and connective tissues.  Examples of these conditions are Hunter's Syndrome, Hurler's Syndrome, Sanfilippo Syndrome, and Maroteaux-Lamy variants.

Osteopetrosis or Infantile Malignant Osteopetrosis (progressively worse) is a congenital disease that prevents formation of bone marrow and results in abnormal bone development, stunted growth, abnormal dental development, and fragile bones.  This disease is known as Albers-Schönberg Syndrome or Marble Bone Disease.

Severe Combined Immunodeficiency Syndrome (SCIDS) is a primary immune deficiency characterized by a severe defect in both the T- and B-lymphocyte systems resulting in the onset of one or more serious infections within the first months of life.  The infections can be life threatening and may include pneumonia, meningitis, or bloodstream infections.  SCIDS include Adenosine Deaminase Deficiency, Bare Lymphocyte Syndrome, and Omenn's Syndrome.

Shwachman-Diamond Syndrome (SDS) is a rare disorder affecting:

  • The pancreas, which fails to produce enzymes necessary for digestion,
  • Bone marrow, causing a reduction in the number or malfunction of leukocytes leading to more frequent infections.

Sickle Cell Disease (SCD) is a chronic hemolytic anemia occurring almost exclusively in Blacks.  It is characterized by abnormally shaped (sickle-like) red blood cells, resulting from inheritance of the sickle cell trait.

Wiskott-Aldrich Syndrome (WAS) is a genetic X-linked immunodeficiency disorder characterized by thrombocytopenia (small number of platelets), eczema, melena, and susceptibility to recurrent bacterial infections.

X-Linked Lymphoproliferative Syndrome (XLP) is an extremely rare inherited (primary) immunodeficiency disorder characterized by a defective immune response to infection by the Epstein-Barr virus.  Approximately one half of individuals with XLP syndrome experience severe, life threatening mononucleosis causing an abnormal increase of white blood cells that results in severe liver damage and/or failure, aplastic anemia, and/or thrombocytopenia.  This disorder is inherited as an X-linked recessive trait, and is usually expressed in males only.

Policy

Each benefit plan or contract defines which services are covered, which are excluded, and which are subject to dollar caps or other limits.  Members and their providers have the responsibility for consulting the member's benefit plan 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 or contract, the benefit plan or contract will govern.

Coverage

Coverage for evaluation of and subsequent single treatment by stem-cell transplant (SCT) (using bone marrow, peripheral blood, or umbilical cord blood as a stem-cell source), derived from a specific donor category, and following a chemotherapy regimen for treatment of genetic diseases and acquired anemias is identified in the grid below.

Allogeneic

May be considered medically necessary for the following:

  • Hemophagocytic Lymphohistiocytosis (HLH);
  • X-Linked Lymphoproliferative Syndrome (XLP);
  • Wiskott-Aldrich Syndrome (WAS);
  • Sickle Cell Disease (SCD) for children or young adults with either a history of prior stroke, or at increased risk of stroke or end-organ damage, and with an HLA-identical, related donor. Factors associated with a high risk of stroke or end-organ damage include: recurrent chest syndrome, recurrent vaso-occlusive crises, red blood cell alloimmunization on chronic transfusion therapy;
  • Severe Combined Immunodeficiency Syndrome (SCIDS);
  • Osteopetrosis or Infantile Malignant Osteopetrosis;
  • Mucopolysaccharidoses (MPS) for patients who are neurologically intact;
  • Mucolipidoses (ML) for patients who have failed conventional therapy (e.g., diet, enzyme replacement) and who are neurologically intact;
  • Leukocyte Adhesion Deficiency (LAD);
  • Kostmann’s Syndrome;
  • Beta-Thalassemia;
  • Aplastic Anemia for patients with platelets less than 20 x 109/L, granulocytes less than 0.5 x 109/L, and reticulocytes less than 1% (corrected for hematocrit) and who have failed antithymocyte globulin therapy.

Is considered experimental, investigational and unproven for the following:

  • Chediak-Higashi Syndrome (CHS) or Chediak-Steinbrick-Higashi Syndrome (CSHS);
  • Shwachman-Diamond Syndrome (SDS);
  • Hypereosinophilic Syndrome (HES).

Autologous

 

Is considered experimental, investigational and unproven for the following:

  • Chediak-Higashi Syndrome (CHS) or Chediak-Steinbrick-Higashi Syndrome (CSHS);
  • Shwachman-Diamond Syndrome (SDS);
  • Hypereosinophilic Syndrome (HES);
  • Hemophagocytic Lymphohistiocytosis (HLH);
  • X-Linked Lymphoproliferative Syndrome (XLP);
  • Wiskott-Aldrich Syndrome (WAS);
  • Sickle Cell Disease (SCD);
  • Severe Combined Immunodeficiency Syndrome (SCIDS);
  • Osteopetrosis or Infantile Malignant Osteopetrosis;
  • Mucopolysaccharidoses (MPS);
  • Mucolipidoses (ML);
  • Leukocyte Adhesion Deficiency (LAD);
  • Kostmann’s Syndrome;
  • Beta-Thalassemia;
  • Aplastic Anemia.

Tandem or Triple Stem-Cell Transplant

Is considered experimental, investigational and unproven. 

Donor Leukocyte Infusion

Is considered experimental, investigational and unproven. 

Rationale

The quality of life after high-dose chemotherapy (HDC) followed by hematopoietic stem-cell (HSC) (i.e., blood or marrow) transplant is of utmost importance.  In aplastic anemia and malignancies, there is the expectation of improved status after HDC and HSC.  Conversely, quality of life outcomes (measured by growth, skeletal development dysfunction, and neuropsychological) for patients with storage diseases is gradually being defined.  Because of these long-term problems, non-malignant or maldevelopment indications for HDC and HSCs should not be reviewed with criteria similar to that for malignancies.

This policy is based on three Blue Cross Blue Shield (BCBSA) Technology Evaluation Center (TEC) Assessments from 1988, 1992 and 1997.  The conclusions of these TEC Assessments are summarized below.

The 1988 BCBSA TEC Assessment addressed allogeneic BMT (bone marrow transplant) in the treatment of thalassemia.  Sixty-five percent of 173 reported homozygous beta-thalassemia patients treated with allogeneic BMT and immuno-suppression survived up to 34 months with sustained engraftment and no need of further therapy.  Although transfusions and desferoxamine administration can extend life expectancy they are not curative and the disease will be eventually fatal.  Allogeneic BMT is therefore apparently curative in 65% of beta-thalassemia patients.

The 1992 BCBSA TEC Assessment examined the benefits and risks of allogeneic BMT for the treatment of lysosomal storage genetic disorders.  BMT does not appear to be a cure for these disorders, but there is little doubt that the natural history of these disorders is altered by successful BMT.  BMT has prolonged functional life in some cases by up to five years.

The chance of a good outcome is best when done as early in the course of the disease as possible. Much of the damage to the organs, especially in the skeletal system and the CNS, is irreversible.  Also, it is felt that the ability of the CNS to establish new synaptic connections are greater diminished after the age of three (Cowan, 1991). 

It is difficult to evaluate many of the diseases individually, in that few transplants have been done for some of the rarer diseases.  However, it is possible to generalize from the classes of diseases where a larger number of transplants have been done to those where only a few have been performed.  The theoretical issues are the same for the difference disorders, only the specific enzyme involved will differ. 

Despite its challenges and risks, BMT has had some positive results, especially when performed early in a disease’s course.  It has an increased chance for success with newborns, whose naturally suppressed immune systems lower the risk of transplant rejection.   

The 1997 BCBSA TEC Assessment examined the benefits and risks of allogeneic BMT for the treatment of sickle cell anemia in two distinct patient groups:

  • children or young adults with homozygous sickle cell anemia and a history of stroke; and
  • children or young adults with homozygous sickle cell anemia with severe symptoms that increase the risk of stroke or end-organ damage.

Four papers were reviewed reporting the results of children and young adults with symptomatic sickle cell disease who had received bone marrow allografts from HLA-identical related donors. The studies were relatively small uncontrolled clinical series that included patients who varied with regard to disease state and prognostic factors.  Although the reported studies are not controlled investigations, the consistency of the results with regard to evidence of stable engraftment of donor hematopoietic cells, non-recurrence of sickle cell manifestations, and recovery of organ function does permit a conclusion concerning the effect of BMT on health outcome.

The evidence suggests that allogeneic BMT is a curative treatment for sickle cell disease.  It is the only treatment option that offers the potential for long-term disease-free survival.  Disease-free survival rates ranged from 73–100% with follow-up periods ranging from a median of 16 months to 37 months.  Clinical and hematological evidence of improvement after BMT, including absence of vaso-occlusive episodes, recovery of organ function, stabilization of cerebrovascular disease and stable engraftment of donor hematopoietic cells was observed.  In contrast, the alternatives of chronic transfusion and hydroxyurea are palliative rather than curative.

For patients with a prior history of stroke, the incidence of recurrent stroke after treatment with BMT was 5% (1/19); estimated risk while undergoing chronic transfusion therapy is 10% and hydroxyurea has not been shown to have an effect on the prevention of stroke.  Based on the data reviewed, BMT treatment-related mortality rates ranged from 0–9%.  When the data are pooled, aggregate treatment related mortality is calculated at 5% for the 65 total patients.  BMT-associated morbidity included primarily GVHD (graft-versus-host-disease) and neurological complications.  Acute GVHD was reported at rates between 4% and 40%, while chronic GVHD ranged from 14–21%.  GVHD was responsible for two patient deaths.  Neurological symptoms, including one death due to intracerebral hemorrhage, were observed in 22% of children who had a stroke prior to transplantation, the subset of patients reported to be at increased risk for neurological complications.  However, the incidence of neurological complications appears to be decreasing with changes in the treatment protocol.  Patients treated in the earlier phase of Walters et al. series (1995 and 1996) experienced higher rates of neurological complication as compared to those treated after the introduction of a prophylactic regimen.

Given the severe and chronic debilitation associated with sickle cell disease, the data suggest that the benefit of treatment can outweigh the risk of BMT-associated morbidity and mortality in patients with severe, symptomatic homozygous sickle cell anemia, including children with or without a history of stroke.

Allogeneic Stem-Cell Transplant for Chediak-Higashi Syndrome or Chediak-Steinbrick-Higashi Syndrome, Shwachman-Diamond Syndrome, and Hypereosinophilic Syndrome is considered experimental, investigational, and unproven due to lack of adequate evidence of safety and effectiveness documented in published, peer-reviewed medical literature.

Autologous, Tandem or Triple Stem-Cell Transplant, and Donor Leukocyte Infusion (DLI) for genetic diseases and acquired anemias are considered experimental, investigational, and unproven due to lack of adequate evidence of safety and effectiveness documented in published, peer-reviewed medical literature.

Coding

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 vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps. 

ICD-9 Codes

41.00, 41.01, 41.02, 41.03, 41.04, 41.05, 41.06, 41.07, 41.08, 41.09, 41.91, 99.25, 99.74, 99.79, 272.7, 277.5, 279.12, 279.2, 282.41, 282.42, 282.49, 282.60, 282.61, 282.62, 282.63, 282.64, 282.68, 282.69, 284.01, 284.09, 284.89, 284.9 

Procedural Codes: 36511, 38204, 38205, 38206, 38207, 38208, 38209, 38210, 38211, 38212, 38213, 38214, 38215, 38220, 38221, 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, 86849, 86950, 86985, 88240, 88241, S2140, S2142, S2150
References
  1. 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.
  2. Allogeneic Bone Marrow Transplantation for Lysosomal Storage Disorders. Chicago, Illinois: Blue Cross Blue Shield Association – Technology Evaluation Program (1992 December):303-23.
  3. 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.
  4. Desnick, R.J., Schuchman, E.H. Enzyme Replacement and Enhancement Therapies: Lessons from Lysosomal Storage Disorders. Nature Reviews - Genetics (2002) 3:954-66.
  5. Donor Leukocyte Infusion for Hematologic Malignancies that Relapse after Allogeneic Stem Cell Transplant. BCBSA Medical Policy Reference Manual (2005 September) Medicine: 2.03.03.
  6. High-Dose Chemotherapy and Allogeneic Stem-Cell Support for Genetic Diseases and Acquired Anemias.  Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2007 December) Therapy 8.01.22.
History
September 2013  New 2013 BCBSMT medical policy.
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Stem-Cell Transplant for Genetic Diseases and Acquired Anemias