1. Bone Marrow Failure Syndrome
   • Aplastic anemia, including congenital and acquired
   • Diamond-Blackfan anemia (DBA)
   • Fanconi’s anemia (FA)
   • Paroxysmal nocturnal hemoglobinuria (PNH)
2. Immunodeficiencies
   • Hemophagocytic Lymphohistiocytosis (HLH)
   • Severe Combined Immunodeficiency (SCID)
   • Wiskott-Aldrich Syndrome (WAS)
   • X-linked lymphoproliferative syndrome
   • Chediak-Higashi syndrome
   • Primary granulocyte dysfunction
   • Chronic granulomatous disease
3. Storage disorders
   • Hurler Syndrome (MPS I)
   • Hunter Syndrome (MPS II)
   • Maroteaux-Lamy Syndrome (MPS VI)
   • SanFilippo’s (MPS III)
   • Gaucher disease
4. Leukodystrophies
   • Adrenoleukodystrophy (ALD)
   • Globoid Cell Leukodystrophy (GBL; Krabbe's disease)
   • Metachromatic Leukodystrophy (MLD)
5. Hemoglobinopathies
   • Sickle Cell Disease
   • Thalassemia (homozygous beta-thalassemia)
6. Infantile malignant osteopetrosis (Albers-Schonberg disease or marble bone disease)
7. Other autosomal recessive disorders
   • Leukocyte adhesion deficiencies
   • Kostmann’s syndrome (severe congenital neutropenia, infantile genetic agranulocytosis)

A repeat allogeneic (ablative or non-myeloablative) stem cell transplantation due to primary graft failure or failure to engraft is considered medically necessary.

Investigational/Not Medically Necessary:

Allogeneic (ablative and non-myeloablative) stem cell transplantation is considered investigational/not medically necessary for the treatment of all genetic diseases not listed above including, but not limited to cystic fibrosis, and all acquired anemias not specifically identified above as medically necessary.

Autologous stem cell transplantation is considered investigational/not medically necessary for the treatment of all genetic diseases including, but not limited to cystic fibrosis and all acquired anemias.

A planned tandem allogeneic bone marrow transplantation or autologous bone marrow transplantation is considered investigational/not medically necessaryfor all genetic diseases and for all acquired anemias. 

A second or repeat allogeneic (ablative or non-myeloablative) transplant due to persistent, progressive or relapsed disease is considered investigational/not medically necessary.

Elective or prophylactic bone marrow/peripheral blood stem cell harvesting in anticipation of a possible transplant is considered investigational/not medically necessary.

Patient Selection Criteria for all diagnoses

For all diseases listed above for which the transplant has been identified as medically necessary, the patient must:

1. demonstrate chemosensitivity if applicable and
2. be medically compliant and free of an active substance abuse problem and
3. be free of any active comorbid disease which would significantly reduce short term life expectancy including, but not limited to one or more of the following:
   • Bilirubin > 2 mg/dl
   • INR > 1.6 unless on oral anticoagulants
   • Serum creat ≥ 2.0 mg/dL; children should have a GFR of > 70 ml/min/1.73m²
   • MUGA or ECHO with EF < 45% **
   • FEV1 or DLCO ≤ 50% of predicted value ***
   • Karnofsky or Lansky score < 70% or ECOG performance score ≤ 2.

** A left ventricular shortening fraction considered in the normal range at the ordering institution may be substituted in the pediatric population.

*** Pulmonary function tests are generally not performed in pediatric patients given the difficulty in cooperating with the test.  Provided the child has an adequate oxygen saturation on room air, a transplant program would consider the child eligible as far as his lung function is concerned.

Disease Specific Criteria

Aplastic Anemia Criteria:

• A suitably HLA matched donor and one of the following:
  • ≤55 yrs do not need to have failed immunosuppressive therapy
  • >55 yrs, or non-HLA identical donor, have to have failed immunosuppressive therapy

Sickle Cell Criteria:

• A suitably HLA matched donor and
• Pediatric pts <16 yrs with homozygous SS disease or S-B thalassemia and who have had at least one of the following complications:
  • Stroke or CNS hemorrhage
  • Clinical evidence of progressive neurologic deterioration, e.g., abnormal cerebral MRI and arteriogram and impaired neuropsychiatric testing
  • Sickle cell lung disease and/or recurrent acute chest syndrome requiring hospitalization and exchange transfusions
  • Sickle cell nephropathy

Thalassemia Criteria:

• Thalassemia major only
• A suitably HLA matched donor, and
• Patient ≤ 30 yrs, and
• The presence of minimal or no portal fibrous or active hepatitis
  

There is sufficient evidence in the medical literature to support the use of high-dose or non-myeloablative chemotherapy and stem cell transplant when the above criteria, as applicable, are met.

At this time, there is not sufficient evidence in the peer-reviewed medical literature, in terms of long-term safety and efficacy, to support the use of stem cell transplantation, for the indications listed as investigational/not medically necessary. The majority of studies performed to date are either case reports, retrospective reviews, or phase II studies with short follow up, no control groups and heterogeneous patient populations. There have been no large-scale prospective trials that have demonstrated improved outcomes.

Genetic Diseases

Over the last 20 years, there has been a growing body of literature describing the application of allogeneic transplantation to correct inborn errors of metabolism. In these disorders, a single gene defect leads to the absence of a key protein, which leads to the clinical phenotype of the disease. Allogeneic hematopoietic cell transplantation provides a means of replacing the missing protein, potentially improving the clinical phenotype. The most significant experience has been in the treatment of mucopolysaccharidoses and leukodystrophies, although case reports have described transplantation therapy for many other genetic disorders.

For certain genetic diseases and aplastic anemias, the need for a preparative regimen prior to transplantation therapy is variable.

In 2004, Spencer and Jaffe hypothesized about the use of autologous umbilical cord stem cell transplant and gene therapy to treat cystic fibrosis. However, there have been no prospective randomized trials to assess the efficacy and safety to support the use of stem cell transplantation for this indication.

Acquired Anemias

Aplastic anemia is a noncontagious disease that occurs when the bone marrow stops making a sufficient quantity of blood cells as the body needs. The generally accepted thinking about aplastic anemia is that the patient’s immune system is reacting against the bone marrow, interfering with its ability to make blood cells. Stem cells are no longer being replaced and the remaining stem cells are working less effectively, so the levels of red cells, white cells and platelets begin to drop. If blood levels drop too low, a person can experience fatigue (low red cells), bleeding under the skin, in the mouth and from the nose, or heavy periods (low platelets), and/or an increase in the number and severity of infections (low white cells).

High-dose chemotherapy (HDC) involves the administration of cytotoxic agents using doses several times greater than the standard therapeutic dose. In some cases, whole body or localized radiotherapy is also given and is included in the term HDC when applicable. The rationale for HDC is that many cytotoxic agents act according to a steep dose-response curve.  Thus, small increments in dosage will result in relatively large increases in tumor cell kill.  Increasing the dosage also increases the incidence and severity of adverse effects related primarily to bone marrow ablation (e.g., opportunistic infections, hemorrhage, or organ failure). Bone marrow ablation is the most significant side effect of HDC. As a result, HDC is accompanied by a re-infusion of hematopoietic stem cells, which are primitive cells capable of replication and formation into mature blood cells, in order to repopulate the marrow. The potential donors of stem cells include:

1.    Autologous - Stem cells can be harvested from the patient’s own bone marrow prior to the cytotoxic therapy

2.    Syngeneic - Stem cells harvested from an identical twin

3.    Allogeneic - Stem cells harvested from a healthy, histocompatible donor

Donor stem cells, either autologous or allogeneic, can be collected from either the bone marrow or the peripheral blood. Stem cells may be harvested from the peripheral blood using a pheresis procedure. To increase the number of stem cells in the peripheral circulation, autologous donors may be pretreated with a course of chemotherapy or hematopoietic growth factors, or both.

In addition, blood harvested from the umbilical cord and placenta shortly after delivery of neonates contains stem and progenitor cells. Although cord blood is an allogeneic source, these stem cells are antigenically “naïve” and thus, are associated with a lower incidence of rejection or graft versus host disease.

Immunologic compatibility between donor and patient is a critical factor for achieving a good outcome of allogeneic bone marrow transplantation. 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 the long arm of chromosome 6. Depending upon the disease being treated, an acceptable donor will match the patient at all or most of the HLA loci. Compatibility between donor and recipient tissue should be assessed using high resolution typing.

The most appropriate stem cell source for a particular patient depends upon his or her disease, treatment history, and the availability of a compatible donor. The most appropriate source of stem cells for each patient must balance the risks of graft failure and reinfusion of malignant cells in autologous procedures, the risks of graft rejection, and graft versus host disease in allogeneic procedures.

While the intensity of the regimens used for conditioning in conventional HDC varies, collectively they have been termed “myeloablative.” Several less intense conditioning regimens have been developed recently and rely more on immunosuppression than cytotoxic effects to permit engraftment of donor cells. These regimens, collectively termed “non-myeloablative”, also vary in intensity with substantial overlap between the ranges for “myeloablative” and “non-myeloablative” regimens. Studies have shown that donor allogeneic stem cells can engraft in recipients using less-intensive conditioning regimens that are sufficiently immunosuppressive to permit graft-host tolerance. This manifests as a stable mixed donor-host hematopoietic chimerism. Once chimerism has developed, a further infusion of donor leukocytes may be given to eradicate malignant cells by inducing a graft vs. tumor effect. Non-myeloablative allogeneic transplants, also referred to as “mini-transplant” or “transplant lite”, are thought to be potentially as effective as conventional HDC followed by an allogeneic stem cell transplantation (AlloBMT), but with decreased morbidity and mortality related to the less intense non-myeloablative chemotherapy conditioning regimen. Consequently, for patients with malignancies who are eligible for conventional HDC/AlloBMT, conditioning with milder, non-myeloablative regimens (NM-AlloBMT) represents a technical modification of an established procedure.

Tandem high-dose or non-myeloablative chemotherapy with autologous and/or allogeneic stem cell support is the planned administration of more than one cycle of high-dose chemotherapy, alone or with total body irradiation, each of which is followed by re-infusion of stem cells. Despite treatment with high-dose chemotherapy, many patients with advanced malignancies eventually relapse, indicating the presence of residual neoplastic cells. The hypothesis is that eradication of residual tumor cells can be achieved using multiple cycles of myeloablative or non-myeloablative chemotherapy with stem cell support.

Aplastic anemia: the bone marrow is unable to make blood cells

AlloSCT: allogeneic stem cell transplant

AuSCT: autologous stem cell transplant

Chest syndrome: a sudden breathing problem in some sickle cell patients

Conditioning: a preparative regimen of chemotherapy given as part of a bone marrow / peripheral blood stem cell transplant protocol; may be myeloablative, non-myeloablative or tandem

Consolidation: repetitive cycles of treatment during the immediate post-remission period; used especially for leukemia; also known as intensification therapy

Cytotoxic: destructive to cells

ECOG:  Eastern Cooperative Oncology Group

Failure to engraft:  When the bone marrow infused during a bone marrow transplant does not take or is not accepted by the patient

Gaucher disease: a rare disease where there is a deficiency of the enzyme glucocerebrosidase

Graft-versus-host disease (GVHD): the condition that results when the immune cells of a transplant (usually of bone marrow) react against the tissues of the person receiving the transplant

HDC: high-dose chemotherapy

HDC/AlloSCS: high-dose chemotherapy with allogeneic stem cell support

HDC/AuSCS: high-dose chemotherapy with autologous stem cell support

Immunodeficiency: inability to produce a normal complement of antibodies or sensitized T-cells in response to specific antigens

Induction chemotherapy: use of chemotherapy as initial treatment before surgery or radiotherapy of a malignancy

Infantile malignant osteopetrosis: a hereditary disorder characterized by extreme density, hardness and fragility of the bones with partial or complete obliteration of the marrow cavities

Kostmann's syndrome: an inherited disorder, causing low white blood cell counts and infection, noted during infancy

Leukodystrophy: any of several inherited diseases characterized by degeneration of the white matter of the brain

Non-myeloablative chemotherapy: less intense chemotherapy conditioning regimens, which rely more on immunosuppression than cytotoxic effects to permit engraftment of donor cells

Paroxysmal nocturnal hemoglobinuria (PNH): is a rare disease characterized by aplastic anemia, thrombosis, and red urine in the morning due to a breakdown of red blood cells

Primary graft failure:  When the bone marrow infused during a bone marrow transplant does not take or is not accepted by the patient

Refractory: not readily yielding to treatment

Relapse: the return of symptoms and signs of a disease after a period of improvement

Remission: a complete (CR) or partial (PR) disappearance of the signs and symptoms of disease in response to treatment; the period during which a disease is under control; a remission, however, is not necessarily a cure

Salvage chemotherapy: use of chemotherapy in a patient with recurrence of a malignancy following initial treatment, in hope of a cure or prolongation of life

Severe combined immunodeficiency (SCID): disorders where both immune cells and special immune proteins needed to fight disease are missing

Sickle cell disease: inherited blood disease with red blood cells shaped like sickles

Thalassemia: a group of inherited anemias affecting the hemoglobin chain genes

Wiskott-Aldrich syndrome: an inherited, usually fatal, childhood immunodeficiency disease

X-linked lymphoproliferative syndrome: a rare genetic disease of males transmitted from the mother in which the person's white blood cells are unable to fight infections

The following codes for treatments and procedures applicable to this policy are included below for informational purposes.  Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member’s contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services may be Medically Necessary when criteria are met:

CPT

HCPCS

ICD-9 Procedure

ICD-9 Diagnosis

When services are Investigational/Not Medically Necessary:

For the procedure and diagnosis codes listed above, when criteria are not met or when the code describes a procedure indicated in the Policy section as investigational/not medically necessary.

When services are also Investigational/Not Medically Necessary:

CPT

ICD-9 Procedure

ICD-9 Diagnosis

Peer Reviewed Publications:

1. Bacigalupo A, Locatelli F, Lanino E, et al. Fludarabine, cyclophosphamide and anti-thymocyte globulin for alternative donor transplants in acquired severe aplastic anemia: a report from the EBMT-SAA Working Party. Bone Marrow Transplant. 2005; 36(11): 947-950.
2. Braunlin EA, Stauffer NR, Peters CH, et al. Usefulness of bone marrow transplantation in the Hurler syndrome. Am J Cardiol. 2003; 92(7):882-886.
3. Buckley RH, Schiff SE, Schiff RI, et al. Hematopoietic stem cell transplantation for the treatment of severe combined immunodeficiency. N Engl J Med. 1999; 340(7):506-516.
4. Burt RK, Traynor AE. Hematopoietic stem cell transplantation: a new therapy for autoimmune disease. The Oncologist. 1999; 4:77-83.
5. Carreras E, Saiz A, Marin C, et al. CD34+ selected autologous peripheral blood stem cell transplantation for multiple sclerosis: report of toxicity and treatment results at one year of followup in 15 patients. Haematologica. 2003; 88:306-313.
6. D'Andrea AD, Dahl N, Guinan EC, Shimamura A. Marrow Failure. American Society of Hematology. Hematology. 2002; 58-72.
7. Davies SM. Hematopoietic cell transplantation for immunodeficiencies and genetic diseases. Clinical Oncology Web Book, 3rd edition. Chapter 94:1-10. 
8. Deeg HJ, Amylon MD, Harris RE, et al. Marrow transplants from unrelated donors for patients with aplastic anemia: minimum effective dose of total body irradiation. Biol Blood Marrow Transplant. 2001; 7:208-215.
9. Euler HH, Marmont AM, Bacigalupo A, et al. Early recurrence or persistence of autoimmune disease after unmanipulated autologous stem cell transplantation. Blood. 1996; 88(9):3621-3625.
10. Good RA, Verjee T. Historical and current perspectives on bone marrow transplantation for prevention and treatment of immunodeficiencies and autoimmunities. Biol Blood Marrow Transplant. 2001; 7:123-135.
11. Henter JI, Samuelson-Horne A, Arico M, et al. Treatment of hemophagocytic lymphohistiocytosis with HLH-94 immunochemotherapy and bone marrow transplantation. Blood. 2002; 100(7):2367-2373.
12. Hongeng S, Pakakasama S, Chaisiripoomkere W, et al. Outcome of transplantation with unrelated donor bone marrow in children with severe thalassemia. Bone Marrow Transplant. 2004; 33(4):377-379.
13. Horwitz ME, Barrett AJ, Brown MR, et al. Treatment of chronic granulomatous disease with nonmyeloablative conditioning and T-cell-depleted hematopoietic allograft. N Engl J Med. 2001; 344(12):881-888.
14. Iannone R, Casella JF, Ruchs EJ, et al. Results of minimally toxic non-myeloablative transplantation in patients with sickle cell anemia and beta thalassemia. Biol Blood Marrow Transplant. 2003; 9(8):519-528.
15. Imashuku S, Kohdera T, Teramura T, et al. Advances in the management of hemophagocytic lymphohistiocytosis. Int J Hematol. 2000; 72:1-11.
16. Krivit W, Shapiro EG, Peters C, et al. Hematopoietic stem-cell transplantation in globoid-cell leukodystrophy. N Engl J Med. 1998; 338(16):1119-1126.
17. Locatelli F, Rocha V, Reed W, et al. Related umbilical cord blood transplantation in patients with thalassemia and sickle cell disease. Blood. 2003; 101(6):2137-2143.
18. McSweeney PA, Nash RA, Sullivan KM, et al. High-dose immunosuppressive therapy for severe systemic sclerosis: initial outcomes. Blood. 2002; 1000(5):1602-1610.
19. Muenzer J, Fisher A. Advances in the treatment of mucopolysaccharidosis type I. N Engl J Med. 2004; 350(919):1932-1934.
20. Myers LA, Patel DD, Puck JM, Buckley RH. Hematopoietic stem cell transplantation for severe combined immunodeficiency in the neonatal period leads to superior thymic output and improved survival. Blood. 2002; 99(3):872-878.
21. Openshaw H, Lund BT, Kashyap A, et al. Peripheral blood stem cell transplantation in multiple sclerosis with busulfan and cyclophosphamide conditioning: report of toxicity and immunological monitoring. Biol Blood Marrow Transplant. 2000; 6:568-575.
22. Peters C, Shapiro EG, Anderson J, et al. Hurler Syndrome: II. Outcome of HLA-genotypically identical sibling and HLA-haploidentical related donor bone marrow transplantation in fifty-four children. Blood. 1998; 91(7):2601-2608. 
23. Schulz AS, Classen CF, Mihatsch WA, et al. HLA-haploidentical blood progenitor cell transplantation in osteopetrosis. Blood. 2002; 99(9):3458-3460.
24. Spencer H, Jaffe A. The potential for stem cell therapy in cystic fibrosis. J R Soc Med. 2004; 97 Suppl 44:52-56.
25. Staba SL, Escolar ML, Poe M, et al. Cord-blood transplants from unrelated donors in patients with Hurler's syndrome. N Engl J Med. 2004; 350(19):1960-1969.
26. Storb RF, Lucarelli G, McSweeney PA, Childs RW. Hematopoietic cell transplantation for benign hematologic disorders and solid tumors. American Society of Hematology. Hematology. 2003; 372-397.
27. Trigg ME. Milestones in the development of pediatric hematopoietic stem cell transplantation--50 years of progress. Pediatr Transplant. 2002; 6(6):465-474.
28. Van Laar JM, Tyndall A. Intense immunosuppression and stem-cell transplantation for patients with severe rheumatic autoimmune disease: a review. Cancer Control. 2003; 10(1):57-65.
29. Vermylen C. Hematopoietic stem cell transplantation in sickle cell disease. Blood Rev. 2003; 17(3):163-166.
30. Walters MC, Nienhuis AW, Vichinsky E. Novel therapeutic approaches in sickle cell disease. American Society of Hematology Education Program Book. Hematology. 2002; 10-34.
31. Wedderburn LR, Abinun M, Palmer P, Foster HE. Autologous hematopoietic stem cell transplantation in juvenile idiopathic arthritis. Arch Dis Child. 2003; 88:201-205.

Government Agency, Medical Society, and Other Authoritative Publications:

1. Blue Cross and Blue Shield Association. High-Dose Lymphoablative Therapy (HDLT) with or without Stem-Cell Rescue for Treatment of Severe Autoimmune Diseases. TEC Assessment. 2002; 16(14).
2. Centers for Medicare and Medicaid Services. National Coverage Determination for Stem Cell Transplantation. NCD #110.8.1. Effective March 15, 2005. Available at:
   http://www.cms.hhs.gov/MCD/viewncd.asp?ncd_id=110.8.1&ncd_version=4 &basket=ncd%3A110%2E8%2E1%3A4%3AStem+Cell+Transplantation. Accessed on March 2, 2007.   

1. National Cancer Institute. Bone Marrow Transplantation and Peripheral Blood Stem Cell Transplantation: Questions and Answers. Reviewed August 31, 2004. Available at:  http://www.cancer.gov/cancertopics/factsheet/Therapy/bone-marrow-transplant. Accessed on March 2, 2007.
2. National Library of Medicine. Medline Plus. Updated March 2, 2007. Bone Marrow Transplantation. Available at:  http://www.nlm.nih.gov/medlineplus/bonemarrowtransplantation.html. Accessed on March 2, 2007.
3. National Multiple Sclerosis Society. Research. Bone Marrow Transplantation and MS. Available at:  http://www.nationalmssociety.org/research.asp. Accessed on March 2, 2007.
4. National Library of Medicine. Clinical Trials. Available at:  http://clinicaltrials.gov/. Accessed on October 18, 2006.
5. The Lupus Foundation of America. Available at:  http://www.lupus.org/. Accessed on March 2, 2007. 

Mini Transplant

Non-Myeloablative Stem Cell Transplant

Peripheral Blood Stem Cell

Stem Cell Support (SCS)

Stem Cell Transplant (SCT)

Federal and State law, as well as contract language, including definitions and specific contract provisions/exclusions, take precedence over Medical Policy and must be considered first in determining eligibility for coverage. The member's contract benefits in effect on the date that services are rendered must be used. Medical Policy, which addresses medical efficacy, should be considered before utilizing medical opinion in adjudication. Medical technology is constantly evolving, and we reserve the right to review and update Medical Policy periodically. No part of this publication may be reproduced, stored in a retrieval system or transmitted, in any form or by an means, electronic, mechanical, photocopying, or otherwise, without permission from the health plan.

©CPT Only - American Medical Association