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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 cancer patients who receive bone-marrow-toxic doses of cytotoxic drugs, with or without whole-body radiotherapy. Hematopoietic stem cells may be obtained from the transplant recipient (i.e., autologous HSCT) or from a donor (i.e., allogeneic HSCT). They can be harvested from bone marrow, peripheral blood, or umbilical cord blood shortly after delivery of neonates. Although cord blood is an allogeneic source, the stem cells in it are antigenically “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 the Placental and Umbilical Cord Blood as a Source of Stem Cells policy.
Immunologic compatibility between infused hematopoietic stem cells and the recipient is not an issue in autologous-HSCT. However, immunologic compatibility between donor and patient is a critical factor for achieving a good outcome of allogeneic-HSCT. Compatibility is established by typing 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 patient at all or most of the HLA loci.
Conventional Preparative Conditioning for Hematopoietic SCT
The conventional (“classical”) 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. The beneficial treatment effect in this procedure is due to a combination of initial eradication of malignant cells and subsequent graft-versus-malignancy (GVM) effect that develops after engraftment of allogeneic stem cells within the patient’s bone marrow space. While the slower GVM effect is considered to be the potentially curative component, it may be overwhelmed by extant disease without the use of pretransplant conditioning. However, intense conditioning regimens are limited to patients who are sufficiently fit medically to tolerate substantial adverse effects that include pre-engraftment opportunistic infections secondary to loss of endogenous bone marrow function and organ damage and failure caused by the cytotoxic drugs. Furthermore, in any allogeneic HSCT, immune suppressant drugs are required to minimize graft rejection and GVHD, which also increases susceptibility of the patient to opportunistic infections.
The success of autologous HSCT is predicated on the ability of cytotoxic chemotherapy with or without radiation to eradicate cancerous cells from the blood and bone marrow. This permits subsequent engraftment and repopulation of bone marrow space with presumably normal hematopoietic stem cells obtained from the patient prior to undergoing bone marrow ablation. As a consequence, autologous HSCT is typically performed as consolidation therapy when the patient’s disease is in complete remission. Patients who undergo autologous HSCT are susceptible to chemotherapy-related toxicities and opportunistic infections prior to engraftment, but not GVHD.
Reduced-Intensity Conditioning for Allogeneic HSCT
Reduced-intensity conditioning (RIC) refers to the pretransplant use of lower doses or less intense regimens of cytotoxic drugs or radiation than are used in conventional full-dose myeloablative conditioning treatments. The goal of RIC is to reduce disease burden, but also to minimize as much as possible associated treatment-related morbidity and non-relapse mortality (NRM) in the period during which the beneficial GVM effect of allogeneic transplantation develops. Although the definition of RIC remains arbitrary, with numerous versions employed, all seek to balance the competing effects of NRM and relapse due to residual disease. RIC regimens can be viewed as a continuum in effects, from nearly totally myeloablative to minimally myeloablative with lymphoablation, with intensity tailored to specific diseases and patient condition. 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, which may be supplemented with donor lymphocyte infusions to eradicate residual malignant cells. For the purposes of this policy, the term reduced-intensity conditioning will refer to all conditioning regimens intended to be nonmyeloablative, as opposed to fully myeloablative (conventional) regimens.
Primary Systemic Amyloidosis
The primary amyloidoses comprise a group of diseases with an underlying clonal plasma cell dyscrasia. They are characterized by the extracellular deposition of pathologic, insoluble protein fibrils with a beta-pleated sheet configuration that exhibit a pathognomonic red-green birefringence when stained with Congo red dye and examined under polarized light. These diseases are classified on the basis of the type of amyloidogenic protein involved, as well as by the distribution of amyloid deposits. In systemic amyloidosis, the unnatural protein is produced at a site that is remote from the site(s) of deposition, whereas in localized disease, the protein is produced at the site of deposition. Light-chain amyloidosis (AL), the most common type of systemic amyloidosis, has an incidence similar to that of Hodgkin’s lymphoma or chronic myelogenous leukemia, estimated at 5 to 12 people per million annually. The median age at diagnosis is around 60 years. The amyloidogenic protein in AL amyloidosis is an immunoglobulin (Ig) light chain or light-chain fragment that is produced by a clonal population of plasma cells in the bone marrow. While the plasma cell burden in AL amyloidosis is typically low, ranging from 5%–10%, this disease also may occur in association with multiple myeloma in 10%–15% of patients. Deposition of AL amyloidogenic proteins causes organ dysfunction, most frequently in the kidneys, heart, and liver, although the central nervous system and brain may be affected.
Historically, this disease has had a poor prognosis, with a median survival from diagnosis of about 12 months, although outcomes have improved with the advent of combination chemotherapy with alkylating agents and autologous-HSCT. Emerging approaches include the use of immunomodulating drugs such as thalidomide or lenalidomide, and the proteasome inhibitor bortezomib. Regardless of the approach chosen, treatment of AL amyloidosis is aimed at rapidly reducing the production of amyloidogenic monoclonal light chains by suppressing the underlying plasma cell dyscrasia, with supportive care to decrease symptoms and maintain organ function. The therapeutic index of any chemotherapy regimen is a key consideration in the context of underlying organ dysfunction.
Waldenstrom macroglobulinemia (WM) is a B-cell malignancy that accounts for 1%–2% of hematologic malignancies, with an estimated 1,500 new cases annually in the United States. The median age of WM patients at presentation is 63 to 68 years, with men comprising 55%–70% of cases. Median survival of WM ranges from 5 to10 years, with age, hemoglobin concentration, serum albumin level, and beta-2 microglobulin level as predictors of outcome. The Revised European American Lymphoma (REAL) and World Health Organization (WHO) classification, and a consensus group formed at the Second International Workshop on WM, recognize WM primarily as a lymphoplasmacytic lymphoma (LPL) with an associated immunoglobulin M (IgM) monoclonal gammopathy. The definition also requires the presence of a characteristic pattern of bone marrow infiltration with small lymphocytes demonstrating plasmacytic differentiation with variable cell surface antigen expression. The Second International Workshop indicated no minimum serum concentration of IgM is necessary for a diagnosis of WM.
Treatment of WM is indicated only in symptomatic patients, and should not be initiated solely on the basis of serum IgM concentration. Clinical and laboratory findings that indicate the need for therapy of diagnosed WM include hemoglobin concentration <100 g/L; platelet count <100 x 109/L; significant adenopathy or organomegaly; symptomatic Ig-related hyperviscosity (>50 g/L); severe neuropathy; amyloidosis; cryoglobulinemia; cold-agglutinin disease; or evidence of disease transformation. Primary chemotherapeutic options have included alkylating agents (chlorambucil, cyclophosphamide, melphalan), purine analogues (cladribine, fludarabine), and monoclonal antibody agents (rituximab), alone or in various combinations. Plasma exchange is indicated for acute treatment of symptomatic hyperviscosity.
No 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.
Autologous hematopoietic stem-cell transplantation may be considered medically necessary to treat primary systemic amyloidosis.
Allogeneic hematopoietic stem-cell transplantation is considered investigational to treat primary systemic amyloidosis.
Autologous hematopoietic stem-cell transplantation may be considered medically necessary as salvage therapy of chemosensitive Waldenstrom macroglobulinemia.
Allogeneic hematopoietic stem-cell transplantation is considered investigational to treat Waldenstrom Macroglobulinemia.
For 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.
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.
Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of 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. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.
The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.
1/2004: Interim policy, High-dose chemotherapy with autologous stem-cell support considered investigational to treat primary amyloidosis or Waldenstrom's macroglobulinemia
3/25/2004: Reviewed by MPAC, "High-dose chemotherapy with autologous stem-cell support to treat primary systemic amyloidosis" changed to medically necessary, "High-dose chemotherapy with autologous stem-cell support to treat Waldenstrom’s macroglobulinemia" remains investigational
5/5/2004: Code Reference section completed
8/18/2004: Code Reference section updated, CPT 38215 note added covered codes, CPT chemotherapy administration code range added covered codes, CPT 96520, 96530, 96545 added covered codes, ICD-9 procedure code 41.07, 99.25 added covered codes, HCPCS chemotherapy drug range added covered codes, HCPCS Q0083, Q0084, Q0085 added covered codes, HCPCS S2150 note added covered codes, non-covered table added, CPT 38205, 38240, 38242 added non-covered codes, ICD-9 procedure code 41.05, 41.08, 41.91 added non-covered codes
11/18/2004: Reviewed by MPAC; no changes
10/27/2005: Code Reference sections updated; Covered table: CPT codes 38230 added; ICD-9 procedure 41.09 added; HCPCS codes G0355, G0356, G0357, G0358, G0359, G0360, G0361, G0362, G0363, G0364 added; J9000-J9999 deleted; Non-Covered table: CPT-4 code 38204, 86812, 86816, 86817, 86821, 86822 added, ICD-9 Procedure 41.02, 41.03 added
3/21/2006: Coding updated. CPT4/HCPCS 2006 revisions added to policy
8/31/2006: Policy reviewed, no changes
9/12/2006: Coding updated. ICD9 2006 revisions added to policy
9/18/2007: Policy reviewed, no changes
12/19/2007: Coding updated per 2008 CPT/HCPCS revisions
9/26/2008: Allogeneic SCT added to policy statements as investigational. Policy description updated. "High Dose Chemotherapy" removed from policy title. Term "stem-cell support" replaced with "stem-cell transplantation"
8/19/2009: Policy reviewed, no changes
4/13/2010: "Support to Treat" was changed to "Transplantation" in the Policy Title. Policy description was updated regarding conventional and reduced-intensity conditioning. FEP and State and School Employee verbiage added to Policy Exceptions section. Added new CPT Codes 86825 and 86826 to the Non-covered table. HCPCS G0265, G0266 and G0267 deleted from Covered table due to codes were deleted as of 12-31-2007. ICD-9 diagnosis code 277.3 deleted from covered table due to code was deleted as of 9-30-2006.
05/09/2011: Policy statement revised to state that autologous hematopoietic stem-cell transplantation may be considered medically necessary as salvage therapy of chemosensitive Waldenstrom macroglobulinemia. Allogeneic hematopoietic stem-cell transplantation remains investigational to treat Waldenstrom macroglobulinemia.
05/08/2012: Policy reviewed; no changes.
04/16/2013: Policy reviewed; no changes.
03/17/2014: Policy reviewed; no changes.
03/30/2015: Policy description updated. Policy statements regarding primary systemic amyloidosis updated to change "stem-cell transplantation" to "hematopoietic stem-cell transplantation." Policy guidelines updated to add medically necessary and investigative definitions. Sources section updated.
08/26/2015: Code Reference section updated to add ICD-10 codes, updated the code descriptions for 38240 and 38241; removed deleted HCPCS code G0363, and removed deleted code CPT 96445 and replaced with CPT code 96446.
Blue Cross Blue Shield Association policy # 8.01.42
Blue Cross Blue Shield Association policy # 8.01.54
This 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.