Hematopoietic Cell Transplantation for Solid Tumors of Childhood

POLICY NUMBER

A.8.01.34

DESCRIPTION

Hematopoietic cell transplantation (HCT) is a procedure in which hematopoietic stem cells are infused to restore bone marrow function in cancer patients who receive bone-marrow-toxic doses of drugs, with or without whole body radiotherapy. Stem cells may be obtained from the transplant recipient (autologous HCT) or harvested from a donor (allogeneic HCT). Stem cells may be harvested from bone marrow, peripheral blood, or umbilical cord blood shortly after delivery of neonates.

Solid Tumors of Childhood

Solid tumors of childhood arise from mesodermal, ectodermal, and endodermal cells of origin. Some common solid tumors of childhood are neuroblastoma, Ewing sarcoma/Ewing sarcoma family of tumors (ESFT), Wilms tumor, rhabdomyosarcoma, osteosarcoma, and retinoblastoma.

General Treatment The prognosis for pediatric solid tumors has improved more recently, mostly due to the application of multiagent chemotherapy and improvements in local control therapy (including aggressive surgery and advancements in radiotherapy). However, patients with metastatic, refractory, or recurrent disease continue to have poor prognoses, and these “high-risk” patients are candidates for more aggressive therapy, including autologous HCT, to improve event-free survival and overall survival.

Descriptions of pediatric-onset solid tumors that are addressed in this policy are as follows.

Peripheral Neuroblastoma Neuroblastoma is the most common extracranial solid tumor of childhood, with approximately 90% of cases presenting in children younger than 5 years of age. These tumors originate where sympathetic nervous system tissue is present, within the adrenal medulla or paraspinal sympathetic ganglia, but have diverse clinical behavior depending on a variety of risk factors.

Patients with neuroblastoma are stratified into prognostic risk groups (low, intermediate, and high) that determine treatment plans. Risk variables include age at diagnosis, clinical stage of disease, tumor histology, and certain molecular characteristics, including the presence of the MYCN oncogene. Tumor histology is categorized as favorable or unfavorable, according to the degree of tumor differentiation, the proportion of tumor stromal component, and index of cellular proliferation. It is well established that MYCN amplification is associated with rapid tumor progression and a poor prognosis, even in the setting of other coexisting favorable factors. Loss of heterozygosity (LOH) at chromosome arms 1p and 11q frequently occurs in neuroblastoma. Although 1p LOH is associated with MYCN amplification, 11q is usually found in tumors without this abnormality. Some recent studies have shown that 1p LOH and unbalanced 11q LOH are strongly associated with outcome in patients with neuroblastoma, and both are independently predictive of worse progression-free survival in patients with low- and intermediate-risk disease. Although the use of these LOH markers in assigning treatment in patients is evolving, they may prove useful to stratify treatment.

In the early 1990s, a uniform clinical staging system based on surgical resectability and distant spread, the International Neuroblastoma Staging System, was adopted by pediatric cooperative groups (see Table 1).

Table 1. International Neuroblastoma Staging System

The low-risk group includes patients younger than 1 year of age with stage 1, 2, or 4S with favorable histopathologic findings and no MYCN oncogene amplification. High-risk neuroblastoma is characterized by age older than one year, disseminated disease, MYCN oncogene amplification, and unfavorable histopathologic findings.

In 2009, the International Neuroblastoma Risk Group proposed a revised staging system, which incorporated pretreatment imaging parameters instead of surgical findings (see Table 2).

Table 2. International Neuroblastoma Risk Group Staging System

Stage Description

Treatment In general, most patients with low-stage disease have excellent outcomes with minimal therapy, and with International Neuroblastoma Staging System stage-1 disease, most patients can be treated by surgery alone. Most infants, even with disseminated disease, have favorable outcomes with chemotherapy and surgery.

For intermediate-risk disease, moderately intensive multiagent chemotherapy is the mainstay of therapy. Surgery is needed to obtain a diagnosis, and the extent of resection necessary to obtain an optimal outcome is not established. Patients at high-risk have historically had very low (<15%) long-term overall survival. Current therapy for high-risk disease typically includes an aggressive multimodal approach with chemotherapy, surgical resection, and radiotherapy.

Treatment of recurrent disease is determined by the risk group at diagnosis and the extent of disease and age of the patient at recurrence.

Ewing Sarcoma Family of Tumors

Ewing sarcoma family of tumors (ESFT) encompasses a group of tumors that share some degree of neuroglial differentiation and a characteristic underlying molecular pathogenesis (chromosomal translocation). The translocation usually involves chromosome 22 and results in fusion of the EWS gene with one of the members of the ETS (E26 transformation-specific) family of transcription factors, either FLI1 (90% to 95%) or ERG (5% to 10%). These fusion products function as oncogenic aberrant transcription factors. Detection of these fusions is considered to be specific for the ESFT and helps further validate the diagnosis. Included in ESFT are “classic” Ewing sarcoma of bone, extraosseous Ewing, peripheral primitive neuroectodermal tumor, and Askin tumors (chest wall).

Most commonly diagnosed in adolescence, ESFT can be found in bone (most commonly) or soft tissue; however, the spectrum of ESFT has also been described in various organ systems. Ewing is the second most common primary malignant bone tumor. The most common primary sites are the pelvic bones, the long bones of the lower extremities, and the bones of the chest wall.

Treatment Current therapy for Ewing sarcoma typically includes induction chemotherapy, followed by local control with surgery and/or radiotherapy (dependent on tumor size and location), followed by adjuvant chemotherapy. Multiagent chemotherapy, surgery, and radiotherapy have improved progression-free survival rates in patients with the localized disease to 60% to 70%. The presence of metastatic disease is the most unfavorable prognostic feature, and the outcome for patients presenting with metastatic disease is poor, with 20% to 30% progression-free survival. Other adverse prognostic factors that may categorize a patient as having “high-risk” Ewing are tumor location (e.g., patients with pelvic primaries have worse outcomes), larger tumor size, and older age of the patient. However, “high-risk” Ewing has not always been consistently defined in the literature.

Rhabdomyosarcoma

Rhabdomyosarcoma, the most common soft tissue sarcoma of childhood, shows skeletal muscle differentiation. The most common primary sites are the head and neck (e.g., parameningeal, orbital, pharyngeal), genitourinary tract, and extremities.

Treatment Specific treatment is based on tumor location, resection, and node status, and may involve surgery, radiotherapy, and chemotherapy. Five-year survival rates for rhabdomyosarcoma increased between 1975 and 2017 from 53% to 71% in children younger than 15 years and from 30% to 52% in patients 15 to 19 years of age.

Approximately 15% of children present with metastatic disease, and despite the introduction of new drugs and intensified treatment, the 5-year survival is 20% to 30% for this “high-risk” group. Similarly, postrelapse mortality is very high. The prognosis of the metastatic disease is affected by tumor histology, age at diagnosis, the site of metastatic disease, and the number of metastatic sites.

Wilms Tumor

Wilms tumor is the most common primary malignant renal tumor of childhood. In the United States, Wilms tumor is staged using the National Wilms Tumor Study system, which is based on surgical evaluation before chemotherapy (see Table 3).

Table 3. National Wilms Tumor Study Staging

StageDescription

Treatment In the United States, National Wilms Tumor Study and Children’s Oncology Group protocols are based on primary resection for unilateral tumors, followed by escalating levels of chemotherapy and radiotherapy depending on tumor stage and other prognostic factors. Tumor histology, tumor stage, molecular and genetic markers (eg, loss of heterozygosity at chromosome 16q), and age (>2 years) are all associated with increased risks of recurrence and death. Wilms tumors are highly sensitive to chemotherapy and radiotherapy, and current cure rates exceed 85%. Between 10% and 15% of patients with favorable histology and 50% of patients with anaplastic tumors, experience tumor progression or relapse.

Similar risk-adapted strategies are being tested for the 15% of patients who experience a relapse. Success rates after relapse range from 25% to 45%. For patients with adverse prognostic factors (histologically anaplastic tumors, relapse less than 6 to 12 months after nephrectomy, second or subsequent relapse, relapse within the radiation field, bone or brain metastases), the event-free survival is less than 15%.

Osteosarcoma

Osteosarcoma is a primary malignant bone tumor and the most common bone cancer in children and adolescents; it is characterized by infiltration of bone or osteoid by the tumor cells. Peak incidence occurs around puberty, most commonly in long bones such as the femur or humerus. Osteosarcomas are characterized by variants in the TP53 tumor suppressor gene.

The prognosis of osteosarcoma has greatly improved, with 5-year survival rates increasing between 1975 and 2020 from 40% to 72% in children younger than 15 years and from 56% to 71% in 15- to 19-year olds. Prognostic factors for patients with localized disease include site and size of the primary tumor, the presence of metastases at the time of diagnosis, resection adequacy, and tumor response to neoadjuvant chemotherapy.

Treatment For patients with recurrent osteosarcoma, the most important prognostic factor is surgical resectability. There is a 5-year survival rate of 20% to 45% in patients who had a complete resection of metastatic pulmonary tumors and a 20% survival rate for patients with metastatic tumors at other sites.

Retinoblastoma

Retinoblastoma is the most common primary tumor of the eye in children. It may occur as a heritable (25% to 30%) or nonheritable (70% to 75%) tumor. Cases may be unilateral or bilateral, with bilateral tumors almost always being the heritable type.

Treatment Treatment options depend on the extent of disease. Retinoblastoma is usually confined to the eye, and with current therapy, has a high cure rate. However, once disease spreads beyond the eye, survival rates drop significantly; 5-year disease-free survival is reported to be less than 10% in those with extraocular disease, and stage 4B disease (ie, disease metastatic to the central nervous system) has been lethal in virtually all cases reported.

The strategy for nonmetastatic disease depends on the disease extent, but may include focal therapies (eg, laser photocoagulation, cryotherapy, plaque radiotherapy), intravitreal chemotherapy, intra-arterial chemotherapy, systemic chemotherapy, enucleation, or a combination. For metastatic disease, intensive multimodal therapy with high-dose chemotherapy, with or without radiotherapy, is standard care.

Notes: Other solid tumors of childhood include germ cell tumors, which are considered separately in the Hematopoietic Stem Cell Transplantation as a Treatment of Germ Cell Tumors medical policy. For solid tumors classified as embryonal tumors arising in the central nervous system, see the Hematopoietic Stem-Cell Transplantation for CNS Embryonal Tumors and Ependymoma medical policy. For central nervous system tumors derived from glial cells (i.e., astrocytoma, oligodendroglioma, or glioblastoma multiforme), see the Autologous Hematopoietic Stem-Cell Transplantation for Malignant Astrocytomas and Gliomas medical policy.

Hematopoietic Cell transplantation

HCT is a procedure in which hematopoietic stem cells are infused to restore bone marrow function in cancer patients who receive bone-marrow-toxic doses of drugs, with or without whole body radiotherapy. Hematopoietic stem cells may be obtained from the transplant recipient (autologous HCT) or a donor (allogeneic HCT). 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 “naive” and thus are associated with a lower incidence of rejection or graft-versus-host disease.

Immunologic compatibility between infused hematopoietic stem cells and the recipient is not an issue in autologous HCT. However, immunologic compatibility between donor and patient is critical for achieving a good outcome of allogeneic HCT. Compatibility is established by typing of human leukocyte antigens using cellular, serologic, or molecular techniques. Human leukocyte antigens refer to the tissue type expressed at class I and class II loci on chromosome 6. Depending on the disease being treated, an acceptable donor (except umbilical cord blood) will match the patient at all or most human leukocyte antigens loci.

Cord blood is discussed in detail in the Placental and Umbilical Cord Blood as a Source of Stem Cell 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 Code of Federal Regulation 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.

Autologous hematopoietic cell transplantation may be considered medically necessary for:

• initial treatment of high-risk neuroblastoma,

• recurrent or refractory neuroblastoma,

• initial treatment of high-risk Ewing sarcoma, 

• recurrent or refractory Ewing sarcoma, and

• metastatic retinoblastoma.

Tandem autologous hematopoietic cell transplantation may be considered medically necessary for high-risk neuroblastoma.

Autologous hematopoietic cell transplantation is considered investigational as initial treatment of low- or intermediate-risk neuroblastoma, initial treatment of low- or intermediate-risk Ewing sarcoma, and for other solid tumors of childhood including, but not limited, to the following:

• Rhabdomyosarcoma

• Wilms tumor

• Osteosarcoma

• Retinoblastoma without metastasis.

Tandem autologous hematopoietic cell transplantation is considered investigational for the treatment of all other types of pediatric solid tumors except high-risk neuroblastoma, as noted above.

Allogeneic (myeloablative or nonmyeloablative) hematopoietic cell transplantation is considered investigational for treatment of pediatric solid tumors.

Salvage allogeneic hematopoietic cell transplantation for pediatric solid tumors that relapse after autologous transplant or fail to respond is considered investigational.

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.

This policy addresses peripheral neuroblastoma arising from the peripheral nervous system (ie, neuroblastoma, ganglioneuroblastoma, ganglioneuroma).

Hematopoietic cell transplantation refers to any source of stem cells, i.e., autologous, allogeneic, syngeneic, or umbilical cord blood.

Relapse is defined as tumor recurrence after a prior complete response.

Primary refractory disease is defined as a tumor that does not achieve a complete remission after initial standard-dose chemotherapy.

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 # 8.01.34 per approval by Medical Policy Advisory Committee (MPAC).

7/1/2004: Code Reference section completed.

11/18/2004: Reviewed by MPAC; no changes.

10/28/2005: Code Reference section updated; CPT-4 code 38230 added, ICD-9 procedure codes 41.01,41.02, 41.03, 41.09 added; HCPCS codes G0355, G0356, G0357, G0358, G0359, G0360, G0361, G0362, G0363, G0364 added, J9000-J9999 deleted.

3/16/2006: Coding updated. CPT4/HCPCS 2006 revisions added to policy.

5/21/2007: Policy reviewed, no changes.

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

5/9/2008: Policy reviewed, no changes.

10/6/2009: Code reference section updated. New ICD-9 diagnosis code 209.73 added to covered table. HCPC codes G0265, G0266 and G0267 deleted from covered table due to codes were deleted as of 12-21-2007. 

04/26/2010: Policy title and statement revised to remove “High-Dose Chemotherapy” and to change “Stem-Cell Support” to “Stem-Cell Transplantation.” Policy description updated with recent literature regarding solid tumors. Policy statement revised to indicate that multiple cycle high-dose chemotherapy and hematopoietic stem-cell support (i.e., tandem or multiple transplants) is considered investigational for treatment of neuroblastoma. The policy guidelines were updated based on this new policy statement. FEP and State and School Employee verbiage added to the Policy Exceptions section. Added new CPT codes 86825 and 86826.

02/23/2011: Policy statement revised to state specifically that “tandem autologous-autologous” HSCT is considered investigational and that “allogeneic (myeloablative or nonmyeloablative)” HSCT is considered investigational in treatment of pediatric solid tumors.

06/22/2011: Policy description and statement unchanged. Deleted outdated references from Sources section.

07/12/2012: Policy description updated. Policy statement revised to indicate that tandem autologous hematopoietic stem-cell transplantation may be considered medically necessary for high-risk neuroblastoma and remains investigational for all other indications. 

08/07/2013: Policy reviewed; no changes.

07/08/2014: Policy reviewed; description updated. Policy statement on salvage allogeneic hematopoietic stem-cell transplantation revised to remove "neuroblastoma or other" from the policy statement. It previously stated: Salvage allogeneic hematopoietic stem-cell transplantation for neuroblastoma or other pediatric solid tumors that relapse after autologous transplant or fail to respond is considered investigational.

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.

09/15/2015: Policy description updated regarding immunologic compatibility. Policy statements unchanged. Policy Guidelines section updated to add medically necessary and investigative definitions.

05/26/2016: Policy number A.8.01.34 added.

09/30/2016: Code Reference section updated to add the following new codes: ICD-10 procedure codes 30230G2, 30230G3, 30230G4, 30233G2, 30233G3, 30233G4, 30240G2, 30240G3, 30240G4, 30243G2, 30243G3, 30243G4, 30230Y2, 30230Y3, 30230Y4, 30233Y2, 30233Y3, 30233Y4, 30240Y2, 30240Y3, 30240Y4, 30243Y2, 30243Y3, and 30243Y4; and ICD-10 diagnosis codes C49.A0 - C49.A9.

08/01/2017: "Hematopoietic stem-cell transplantation" changed to "hematopoietic cell transplantation" throughout policy. Policy description updated regarding the International Neuroblastoma Risk Group Staging System, rhabdomyosarcoma, Wilms tumor, osteosarcoma, and retinoblastoma. Medically necessary policy statements regarding autologous HCT combined to list criteria and to add metastatic retinoblastoma. Combined investigational policy statements regarding autologous HCT and added "retinoblastoma without metastasis." Policy Guidelines updated to state that this policy addresses peripheral neuroblastoma; those arising from the peripheral nervous system.

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 30230G1, 30233G1, 30240G1, 30243G1, 30230Y1, 30233Y1, 30240Y1, and 30243Y1.

03/09/2018: Policy description updated. Policy statements unchanged. Policy Guidelines updated regarding peripheral neuroblastoma.

03/18/2019: Policy reviewed; no changes. Code Reference section updated to remove deleted CPT code 86822 and HCPCS code G0364.

09/26/2019: Code Reference section updated to add new ICD-10 procedure codes 30230U2, 30233U2, 30240U2, 30243U2, 30230U3, 30233U3, 30240U3, 30243U3, 30230U4, 30233U4, 30240U4, and 30243U4, effective 10/01/2019.

02/25/2020: Policy description updated regarding the International Neuroblastoma Staging System. Policy statements unchanged.

03/22/2021: Policy reviewed. Policy statements unchanged. Policy Guidelines updated to change "Nervous/Mental Conditions" to "Mental Health Disorders" and "Medically Necessary" to "medical necessity."

12/22/2021: Code Reference section updated to make note of deleted ICD-10 procedure codes.

02/18/2022: Policy reviewed; no changes.

11/29/2022: Code Reference section updated to remove deleted ICD-10 procedure codes 30230G0, 30240G0, 30230G2, 30240G2, 30230G3, 30240G3, 30230G4, 30240G4, 30230U2, 30240U2, 30230U3, 30240U3, 30230U4, 30240U4, 30230Y0, 30240Y0, 30230Y2, 30240Y2, 30230Y3, 30240Y3, 30230Y4, and 30240Y4.

03/02/2023: Policy reviewed; no changes.

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

02/27/2024: Policy description updated regarding rhabdomyosarcoma and osteosarcoma. Policy statements unchanged.

04/08/2025: Policy reviewed; no changes.

SOURCE(S)

Blue Cross Blue Shield Association policy # 8.01.34

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

CPT copyright American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association.