Hematopoietic Cell Transplantation for CNS Embryonal Tumors and Ependymoma

POLICY NUMBER

A.8.01.28

DESCRIPTION

High-dose chemotherapy with hematopoietic cell transplantation (HCT) has been investigated as a possible therapy in pediatric patients with brain tumors, particularly in those with high-risk disease. The use of HCT has allowed for a reduction in the dose of radiation needed to treat both average- and high-risk disease with a goal of preserving the quality of life and intellectual functioning.

Central Nervous System Embryonal Tumors

Classification of brain tumors is based on both histopathologic characteristics of the tumor and location in the brain. Central nervous system (CNS) embryonal tumors are more common in children and are the most common brain tumor in childhood. Medulloblastomas account for 20% of all childhood CNS tumors.

Recurrent childhood CNS embryonal tumors are not uncommon, and depending on which type of treatment the patient initially received, autologous hematopoietic cell transplantation (HCT) may be an option. For patients who receive high-dose chemotherapy and autologous HCT for recurrent embryonal tumors, the objective response is 50% to 75%; however, long-term disease control is obtained in fewer than 30% of patients and is primarily seen in patients with a first relapse of localized disease at the time of the relapse.

Ependymoma

Ependymoma is a neuroepithelial tumor that arises from the ependymal lining cell of the ventricles and is, therefore, usually contiguous with the ventricular system. An ependymoma tumor typically arises intracranially in children, while in adults a spinal cord location is more common. Ependymomas have access to the cerebrospinal fluid and may spread throughout the entire neuroaxis. Ependymomas are distinct from ependymoblastomas due to their more mature histologic differentiation.

Hematopoietic Cell Transplantation

Hematopoietic cell transplantation (HCT) is a procedure in which hematopoietic cells are intravenously infused to restore bone marrow and immune 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 (autologous HCT) or a donor (allogeneic HCT [allo-HCT]). These cells can be harvested from bone marrow, peripheral blood, or umbilical cord blood shortly after delivery of neonates. Cord blood transportation is discussed in detail in the  Placental and Umbilical Cord Blood as a Source of Stem Cells medical policy.

Immunologic compatibility between infused hematopoietic stem cells and the recipient is not an issue in autologous HCT. In allogeneic stem cell transplantation, immunologic compatibility between donor and patient is a critical factor for achieving a successful outcome. Compatibility is established by typing of human leukocyte antigens (HLA) using cellular, serologic, or molecular techniques. HLA refers to the gene complex expressed at the HLA-A, -B, and -DR (antigen-D related) loci on each arm of chromosome 6. An acceptable donor will match the patient at all or most of the HLA loci.

Conditioning for Hematopoietic Cell Transplantation

Conventional Conditioning

The conventional (“classical”) practice of allo-HCT involves administration of cytotoxic agents (e.g., cyclophosphamide, busulfan) with or without total body irradiation at doses sufficient to cause bone marrow ablation in the recipient. The beneficial treatment effect of this procedure is due to a combination of the initial eradication of malignant cells and subsequent graft-versus-malignancy effect mediated by non-self-immunologic effector cells. While the slower graft-versus-malignancy effect is considered the potentially curative component, it may be overwhelmed by existing disease in the absence of pretransplant conditioning. Intense conditioning regimens are limited to patients who are sufficiently medically fit to tolerate substantial adverse effects. These include opportunistic infections secondary to loss of endogenous bone marrow function and organ damage or failure caused by cytotoxic drugs. Subsequent to graft infusion in allo-HCT, immunosuppressant drugs are required to minimize graft rejection and graft-versus-host disease, which increases susceptibility to opportunistic infections.

The success of autologous HCT is predicated on the potential of cytotoxic chemotherapy, with or without radiotherapy, to eradicate cancerous cells from the blood and bone marrow. This permits subsequent engraftment and repopulation of the bone marrow with presumably normal hematopoietic stem cells obtained from the patient before undergoing bone marrow ablation. Therefore, autologous HCT is typically performed as consolidation therapy when the patient’s disease is in complete remission. Patients who undergo autologous HCT are also susceptible to chemotherapy-related toxicities and opportunistic infections before engraftment, but not graft-versus-host disease.

Reduced-Intensity Conditioning Allogeneic Hematopoietic Cell Transplantation

Reduced-intensity conditioning (RIC) refers to the pretransplant use of lower doses of cytotoxic drugs or less intense regimens of radiotherapy than are used in traditional full-dose myeloablative conditioning treatments. Although the definition of reduced-intensity conditioning is variable, with numerous versions employed, all regimens seek to balance the competing effects of relapse due to residual disease and non-relapse mortality. The goal of RIC is to reduce disease burden and to minimize associated treatment-related morbidity and non-relapse mortality in the period during which the beneficial graft-versus-malignancy effect of allogeneic transplantation develops. Reduced-intensity conditioning regimens range from nearly total myeloablative to minimally myeloablative with lymphoablation, with intensity tailored to specific diseases and patient condition. Patients who undergo RIC with allo-HCT initially demonstrate donor cell engraftment and bone marrow mixed chimerism. Most will subsequently convert to full-donor chimerism. In this policy, the term reduced-intensity conditioning will refer to all conditioning regimens intended to be nonmyeloablative.

Autologous HCT allows for the escalation of chemotherapy doses above those limited by myeloablation and has been tried in patients with high-risk brain tumors in an attempt to eradicate residual tumor cells and improve cure rates. The use of allo-HCT for solid tumors does not rely on the escalation of chemotherapy intensity and tumor reduction, but rather on a graft-versus-tumor effect. Allo-HCT is not commonly used in solid tumors and may be used if an autologous source cannot be cleared of tumor or cannot be harvested.

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 Code of Federal Regulation (CFR), Title 21, parts 1270 and 1271. Hematopoietic stem cells are included in these regulations.

POLICY

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.

Embryonal Tumors of the Central Nervous System

Autologous Hematopoietic Cell Transplantation

Autologous hematopoietic cell transplantation may be considered medically necessary to treat recurrent embryonal tumors of the CNS.

Autologous hematopoietic cell transplantation may be considered medically necessary as consolidation therapy for previously untreated embryonal tumors of the central nervous system (CNS) that show partial or complete response to induction chemotherapy, or stable disease after induction therapy (see Policy Guidelines).

Tandem autologous hematopoietic cell transplantation is investigational to treat embryonal tumors of the CNS.

Allogeneic Hematopoietic Cell Transplantation

Allogeneic hematopoietic cell transplantation is investigational to treat embryonal tumors of the CNS.

Ependymoma

Autologous, tandem autologous, and allogeneic hematopoietic cell transplantation are investigational to treat ependymoma.

POLICY EXCEPTIONS

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 from the Plan’s Utilization Review Vendor.

POLICY GUIDELINES

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

Residual tumor is defined as a tumor that does not achieve a complete response after initial therapy. This includes partial responses (i.e., those less than complete but greater than or equal to 50% response) and refractory disease (i.e., less than a 50% response).

In general, use of autologous hematopoietic cell transplantation for previously untreated medulloblastoma has shown no survival benefit for those individuals considered to be at average risk (i.e., age older than 3 years, without metastatic disease, and with total or near-total surgical resection [<1.5 cm² residual tumor]) compared with conventional therapies.

Other CNS tumors include astrocytoma, oligodendroglioma, and glioblastoma multiforme. These tumors arise from glial cells, not neuroepithelial cells. These tumors are considered in the Autologous Hematopoietic Stem-Cell Transplantation for Malignant Astrocytomas and Gliomas medical policy.

Due to their neuroepithelial origin, peripheral neuroblastoma and Ewing sarcoma may be considered primitive neuroectodermal tumors. These peripheral tumors are considered in the  Hematopoietic Cell Transplantation for Solid Tumors of Childhood medical policy.

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 Mental Health Disorders, 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 medical necessity, “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.

POLICY HISTORY

3/25/2004: See policy "High-Dose Chemotherapy with Hematopoietic Stem Cell Support for Malignancies" prior to 3/25/2004, separate policy developed and aligned with BCBSA policy # 8.01.28 per approval by Medical Policy Advisory Committee (MPAC).

6/25/2004: Code Reference section completed.

11/18/2004: Review by MPAC, no changes.

10/26/2005: Code Reference section updated, CPT codes 38230, G0355 - G0364 added to the covered table, 38204, 86812 - 86822 added to the non-covered table, J9000 - J9999 deleted, ICD9 procedure codes 41.01, 41.09 added to the covered table, 41.02, 41.03 added to the non-covered table.

3/21/2006: Coding updated. CPT4/HCPCS revisions added to policy.

5/21/2007: Policy reviewed, description of syngeneic and allogeneic donor types added. No change to policy statements.

12/20/2007: Coding updated per 2008 CPT/HCPCS revisions.

5/21/2008: Policy reviewed, no changes.

04/26/2010: Title changed from “High-Dose Chemotherapy with Autologous Stem-Cell Support for Primitive Neuroectodermal Tumors (PNET) of the CNS and Ependymoma” to “Hematopoietic Stem-Cell Transplantation for CNS Embryonal Tumors and Ependymoma.” The term “PNET” was changed to “embryonal tumors” throughout the policy. Policy description updated. Policy statement changed to state that autologous consolidation therapy in patients with previously untreated embryonal tumors showing complete or partial response to, or stable disease after, induction therapy is now considered medically necessary. Supporting explanation added to the policy guidelines. Policy statement reworded and ependymoma and embryonal CNS tumors are addressed separately. FEP and State and School Employee verbiage added to the Policy Exceptions section. Added new CPT codes 86825 and 86826. Removed CPT codes 86812, 86813, 86816, 86817, 86821, and 86822 from the non-covered table. Added HCPCS S2140 and S2142 to the non-covered table. Deleted HCPCS G0265, G0266, and G0267 from the code section as these codes were deleted on 12/31/2007.

12/28/2010: Policy reviewed; no changes.

01/17/2012: Policy reviewed; no changes.

03/13/2013: Policy reviewed; no changes.

03/07/2014: Policy reviewed; no changes.

12/11/2014: Policy reviewed; description updated regarding survival rates. Policy statements unchanged.

08/26/2015: Code Reference section updated to add ICD-10 codes, updated the code descriptions for 38240 and 38242; removed deleted code CPT 96445 and replaced with CPT code 96446.

03/21/2016: Policy description updated regarding FDA regulations. Policy statements unchanged.

05/25/2016: Policy number A.8.01.28 added.

09/30/2016: Code Reference section updated to add the following new ICD-10 procedure codes: 30240G2, 30243G2, 30240G3, 30243G3, 30240G4, 30243G4, 30240Y2, 30243Y2, 30240Y3, 30243Y3, 30240Y4, and 30243Y4.

01/31/2017: Policy updated to change "hematopoietic stem cell transplantation" to "hematopoietic cell transplantation." Policy description updated. Policy statements unchanged.

12/21/2017: Code Reference section updated to add new 2018 CPT code 38222. Revised descriptions for CPT codes 38220 and 38221 effective 01/01/2018. Removed deleted ICD-10 procedure codes 30240G1, 30243G1, 30240Y1, 30243Y1 and ICD-9 procedure codes 41.02, 41.03, 41.05, and 41.08.

02/13/2018: Policy description updated. Policy statements unchanged.

03/14/2019: Policy description revised to remove treatment information. Policy statements unchanged. Code Reference section updated to remove deleted CPT code 86822 and HCPCS code G0364.

09/27/2019: Code Reference section updated to add new ICD-10 procedure codes 30240U2, 30243U2, 30240U3, 30243U3, 30240U4, and 30243U4, effective 10/01/2019.

02/24/2020: Policy description updated regarding hematopoietic cell transplantation and conditioning for hematopoietic cell transplantation. Policy statements unchanged. Policy Guidelines updated regarding related policies.

03/05/2021: Policy reviewed. Policy statements unchanged. Policy Guidelines updated to change "Nervous/Mental Conditions" to "Mental Health Disorders" and "Medically Necessary" to "medical necessity."

12/30/2021: Code Reference section updated to make note of deleted ICD-10 procedure codes.

02/17/2022: Policy reviewed; no changes.

11/29/2022: Code Reference section updated to remove deleted ICD-10 procedure codes 30240G0, 30240Y0, 30240G2, 30240G3, 30240G4, 30240U2, 30240U3, 30240U4, 30240Y2, 30240Y3, and 30240Y4.

03/01/2023: Policy description updated. Policy statements unchanged. Policy Guidelines updated to change "patients" to "individuals."

12/21/2023: Code Reference section updated to revise the code description for CPT code 96446, effective 01/01/2024.

02/26/2024: Policy reviewed; no changes.

04/07/2025: Policy reviewed; no changes.

SOURCE(S)

Blue Cross Blue Shield Association Policy # 8.01.28

CODE REFERENCE

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.

Covered Codes

Investigational Codes

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