Latest Review Date:  January 2024

Category:  Surgery                                                                

POLICY:

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

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.

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’s sarcoma,
• Recurrent or refractory* Ewing's sarcoma, and
• Metastatic retinoblastoma.

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

• Rhabdomyosarcoma,
• Wilms tumor,
• Osteosarcoma, and
• Retinoblastoma without metastasis

POLICY GUIDELINES:

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

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

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.

Salvage transplantation is defined as a hematologic cell transplantation (HCT), either autologous, allogeneic, or RIC (Reduced Intensity Conditioning)-allogeneic. This treatment is used as a second-line therapy after failure of primary therapy of any type. Salvage transplantation is sometimes referred to as a “rescue” transplant. It implies that the initial therapy has failed. A salvage second HCT is often an autologous HCT if the prior therapy is chemotherapy. If the prior therapy is a failed autologous transplant a salvage second HCT would more likely be an allogeneic HCT or an RIC-allogeneic HCT. Typically, salvage transplantation is done after enough time has elapsed to identify that the primary therapy was unsuccessful, so the interval between the two transplants would be longer.

Tandem transplantation is defined as a HCT procedure where the initial intent for therapy involves two sequential HCTs. The “tandem” involves a very short pre-planned interval between the two transplants, as well as the therapeutic intent to do two transplants from the outset of therapy. These may be autologous followed by a second autologous (auto-auto) transplantation, autologous followed by allogeneic (auto-allo) transplantation, or autologous followed by RIC-allogeneic (auto–RIC-allo) transplantation.

Notes: Other solid tumors of childhood include germ cell tumors, which are considered in Medical Policy# 412: Hematopoietic Cell Transplantation in the Treatment of Germ Cell Tumor. For solid tumors classified as embryonal tumors arising in the central nervous system see Medical Policy #404: Hematopoietic Cell Transplantation for Central Nervous System Embryonal Tumors and Ependymoma and for central nervous system tumors derived from glial cells (i.e., astrocytoma, oligodendroglioma, or glioblastoma multiforme) see Medical Policy# 372: Autologous Stem Cell Transplantation for Malignant Astrocytomas and Gliomas.

DESCRIPTION OF PROCEDURE OR SERVICE:

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 (RMS), osteosarcoma, and retinoblastoma.

General Treatment

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

Descriptions of pediatric-onset solid tumors addressed herein 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.

Individuals 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, 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 occurs frequently 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 (PFS) 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

Stage	Description
1	Localized tumor with complete gross excision, with or without microscopic residual disease; lymph nodes negative for tumor
2A	Localized tumor with incomplete gross excision; lymph nodes negative for tumor
2B	Localized tumor with or without complete gross excision, with ipsilateral lymph nodes positive for tumor
3	Unresectable unilateral tumor infiltrating across the midline, with or without regional lymph node involvement; or localized unilateral tumor with contralateral regional lymph node involvement; or midline tumor with bilateral extension by infiltration or by lymph node involvement
4	Any primary tumor with dissemination to distant lymph nodes, bone, bone marrow, liver, skin, and/or other organs, except as defined for stage 4S
4S	Localized primary tumor as defined for stage 1, 2A, or 2B, with dissemination limited to skin, liver, and/or bone marrow (marrow involvement less than 10%), limited to children younger than 1 year of age

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

 The International Neuroblastoma Risk Group (2009) 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
L1	Localized tumor not involving vital structures as defined by the list of image-defined risk factors and confined to one body compartment
L2	Locoregional tumor with presence of one or more image-defined risk factors
M	Distant metastatic disease (except stage MS)
MS	Metastatic disease in children younger than 18 months with metastases confined to skin, liver, and/or bone marrow

Treatment

In general, most individuals  with low-stage disease have excellent outcomes with minimal therapy, and with International Neuroblastoma Staging System stage-1 disease (INSS), most individuals 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 multi-agent 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 clearly established. Individuals at high risk have historically had very low (<15%) long-term OS. 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 the time of diagnosis, and the extent of disease and age of the individual at recurrence.

Ewing’s Sarcoma Family of Tumors

Ewing’s sarcoma family of tumors (ESFT) encompasses a group of tumors that have in common 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’s sarcoma of bone, extraosseous Ewing’s, peripheral primitive neuroectodermal tumor (pPNET), 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’s 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 radiation (dependent on tumor size and location), followed by adjuvant chemotherapy. Multiagent chemotherapy, surgery, and radiotherapy have improved the PFS in individuals with localized disease to 60% to 70%.  The presence of metastatic disease is the most unfavorable prognostic feature, and the outcome for individuals presenting with metastatic disease is poor, with 20% to 30% PFS. Other adverse prognostic factors that may categorize an individual as having “high-risk” Ewing are tumor location (e.g., individuals with pelvic primaries have worse outcomes), larger tumor size, and older age of the individual. However, “high-risk” Ewing has not always been consistently defined in the literature.

Rhabdomyosarcoma

Rhabdomyosarcoma (RMS), 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 has increased between 1975 and 2017 from 53% to 71% in children younger than 15 years and from 30% to 52% in individuals 15 to 19 year-olds.

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, post-relapse mortality is very high. The prognosis of 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 (NWTS) system, which is based on surgical evaluation before chemotherapy (see Table 3).

Table 3: National Wilms Tumor Study Staging

Stage	Description
I	(a) Tumor is limited to the kidney and completely excised; (b) The tumor was not ruptured before or during removal; (c) The vessels of the renal sinus are not involved beyond 2 mm (d) There is no residual tumor apparent beyond the margins of excision
II	(a) Tumor extends beyond the kidney but is completely excised (b) No residual tumor is apparent at or beyond the margins of excision (c) Tumor thrombus in vessels outside the kidney is stage II if the thrombus is removed en bloc with the tumor
III	Residual tumor confined to the abdomen: (a) Lymph nodes in the renal hilum, the periaortic chains, or beyond are found to contain tumor (b) Diffuse peritoneal contamination by the tumor (c) Implants are found on the peritoneal surfaces (d) Tumor extends beyond the surgical margins either microscopically or grossly (e) Tumor is not completely resectable because of local infiltration into vital structures
IV	Presence of hematogenous metastases or metastases to distant lymph nodes
V	Bilateral renal involvement at the time of initial diagnosis

Treatment

In the United States, NWTS/COG protocols are based on primary resection for unilateral tumors, followed by escalating levels of chemotherapy and radiation depending on tumor stage and other prognostic factors. Tumor histology, tumor stage, molecular and genetic markers (e.g., 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 radiation, and current cure rates exceed 85%. Between 10% and 15% of individuals with favorable histology and 50% of individuals with anaplastic tumors, experience tumor progression or relapse.

Similar risk-adapted strategies are being tested for the 15% of individuals who experience relapse. Success rates after relapse range from 25% to 45%. For individuals with adverse prognostic factors (histologically anaplastic tumors, relapse <6 to 12 months after nephrectomy, second or subsequent relapse, relapse within the radiation field, bone or brain metastases), EFS 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 individuals with localized disease include site and size of the primary tumor, 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 individuals who had a complete resection of metastatic pulmonary tumors and a 20% survival rate for individuals 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 non-heritable (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 (i.e., disease metastatic to the central nervous system) has been lethal in virtually all cases reported.

The strategy for non-metastatic disease depends on the disease extent, but may include focal therapies (e.g., 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.

Hematopoietic Cell Transplantation for Solid Tumors

Hematopoietic cell transplantation (HCT) is a procedure in which hematopoietic stem cells are infused to restore bone marrow function in cancer individuals 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 from 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. The use of cord blood is discussed in Medical Policy #439: Placental/Umbilical Cord Blood as a Source of Stem Cells.

Immunologic compatibility between infused hematopoietic stem cells and the recipient is not an issue in autologous HCT. However, immunologic compatibility between donor and individual 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 refers 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.

KEY POINTS:

The most recent literature review was performed through November 30, 2023.

Summary of Evidence

For individuals who have high-risk or relapsed peripheral neuroblastoma who receive single or tandem autologous HCT, the evidence includes randomized controlled trials (RCTs), systematic reviews with meta-analyses of those trials, and observational studies. Relevant outcomes are  overall survival (OS), disease-specific survival (DSS), and treatment-related mortality (TRM) and morbidity. In the pooled analysis, individuals with high-risk neuroblastoma treated with first-line therapy with single autologous HCT with myeloablative conditioning had significantly improved event-free survival (EFS) compared with standard therapy. Similarly, non-randomized comparative studies, single-arm studies, and case series evaluating tandem autologous HCT showed improvements in EFS for children with high-risk neuroblastoma. A recent RCT found that tandem autologous HCT resulted in statistically significantly better EFS compared with single HCT. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have high-risk Ewing sarcoma who receive tandem autologous HCT, the evidence includes an RCT, single-arm studies, and case series. Relevant outcomes are OS, DSS, and TRM and morbidity. Although early non-randomized studies were promising, more recent prospective non-randomized study results have been inconsistent regarding whether HCT extends survival compared with typical conventional therapy. An RCT comparing consolidation with HDC plus autologous HCT to standard chemotherapy plus whole lung irradiation in individuals with Ewing sarcoma with pulmonary and/or pleural metastases did not find a significant improvement in EFS in the group that received HCT. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have high-risk Ewing sarcoma who receive single autologous HCT, the evidence includes randomized controlled trials, single-arm studies, and case series. Relevant outcomes are OS, DSS, and TRM and morbidity. Clinical input has been obtained from specialty societies and academic medical centers which had a general agreement of medical necessity regarding the use of single autologous HCT for high-risk Ewing sarcoma. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have rhabdomyosarcoma (RMS) who receive single autologous HCT, the evidence includes a systematic review and non-randomized comparative studies. Relevant outcomes are OS, DSS, and TRM and morbidity. Available studies have not demonstrated improvements in OS or EFS with autologous HCT. Additional research is needed to demonstrate a benefit with autologous HCT for pediatric RMS. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have Wilms tumor who receive single autologous HCT, the evidence includes retrospective studies and meta-analysis. Relevant outcomes are OS, DSS, and TRM and morbidity. In the meta-analysis, overall 4-year survival rates were similar between individuals receiving HCT and receiving chemotherapy. There was a trend suggesting that individuals with lung-only stage 3 or 4 relapse might benefit from autologous HCT. However, the overall body of evidence is limited. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have osteosarcoma who receive single autologous HCT, the evidence includes case series, a prospective single-arm study, and a retrospective study. Relevant outcomes are OS, DSS, and TRM and morbidity. An interim analysis of the prospective single-arm study showed that individuals receiving autologous HCT were experiencing lower EFS rates than historical controls, resulting in all individuals being enrolled in the standard of care chemotherapy. Conversely, a retrospective study found favorable EFS and OS rates with HDC plus autologous HCT in individuals with non-metastatic osteosarcoma with low-degree necrosis after neoadjuvant chemotherapy. The overall body of evidence is limited. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have localized retinoblastoma who receive single autologous HCT, there are no studies. Relevant outcomes are OS, DSS, and TRM and morbidity. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have metastatic retinoblastoma who receive single autologous HCT, the evidence includes small case series and case reports and prospective and retrospective studies. Relevant outcomes are OS, DSS, and TRM and morbidity. Results from the limited data have suggested that autologous HCT may prolong EFS and OS, particularly in individuals without CNS involvement (stage 4A disease). Given the poor prognosis for this indication with conventional therapies, the incremental improvement with autologous HCT might be considered a significant benefit. However, the overall body of evidence is limited. Additionally, clinical input has been obtained from specialty societies and academic medical centers which had a general agreement of medical necessity regarding the use of single autologous HCT for metastatic retinoblastoma. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Practice Guidelines and Position Statements

American Society for Transplantation and Cellular Therapy

In 2020, the American Society for Transplantation and Cellular Therapy published consensus guidelines for clinically appropriate indications for HCT based on best prevailing evidence. Indications for HCT in pediatric patients with the solid tumors types addressed in this review are outlined in Table 4.

Table 4: Indications for Hematopoietic Cell Transplant in Pediatric Patients with Solid Tumors

Indication and Disease Status	Allogeneic HCTa	Autologous HCTa
Ewing sarcoma, high risk or relapse	D	S
Soft tissue sarcoma, high risk or relapse	D	D
Neuroblastoma, high risk or relapse	D	Sƅ
Wilms tumor, relapse	N	C
Osteosarcoma, high risk	N	C

Adapted from Kanate et al (2020).
HCT: hematopoietic cell transplantation.
a “Standard of care (S): This category includes indications that are well defined and are generally supported by evidence in the form of high quality clinical trials and/or observational studies (e.g., through CIBMTR or EBMT).” “Standard of care, clinical evidence available (C): This category includes indications for which large clinical trials and observational studies are not available. However, HCT/immune effector cell therapy (IECT) has been shown to be an effective therapy with acceptable risk of morbidity and mortality in sufficiently large single- or multi-center cohort studies. HCT/IECT can be considered as a treatment option for individual patients after careful evaluation of risks and benefits. As more evidence becomes available, some indications may be reclassified as ‘Standard of Care’.” “Developmental; (D): Developmental indications include diseases where pre-clinical and/or early phase clinical studies show HCT/IECT to be a promising treatment option. HCT/IECT is best pursued for these indications as part of a clinical trial. As more evidence becomes available, some indications may be reclassified as ‘Standard of Care, Clinical Evidence Available’ or ‘Standard of Care’.” “Not generally recommended (N): HCT/IECT is not currently recommended for these indications where evidence do not support the routine use of HCT/IECT. However, this recommendation does not preclude investigation of HCT/IECT as a potential treatment and may be pursued for these indications within the context of a clinical trial.
b Tandem autologous HCT recommended.

National Comprehensive Cancer Network

Current National Comprehensive Cancer Network guidelines or comments on HCT related to the cancers addressed in this review are summarized in Table 5. Other tumor types are not addressed in NCCN guidelines.

Table 5: NCCN Guidelines

Guideline	Tumor Type	Year	NCCN Comments
Bone cancer	Osteosarcoma	v.1.2024	"The safety and efficacy of HDT/HCT in patients with locally advanced, metastatic, or relapsed osteosarcoma have also been evaluated. In the Italian Sarcoma Group study, treatment with carboplatin and etoposide was followed by stem cell rescue, combined with surgery-induced complete response in chemosensitive disease. Transplant-related mortality was 3.1%. The 3-year OS and DFS rates were 20% and 12%, respectively. The efficacy of this approach in patients with high-risk disease is yet to be determined in prospective randomized studies."
Bone cancer	Ewing sarcoma	v.1.2024	“High dose chemotherapy followed by stem cell transplant (HDT/SCT) has been evaluated in patients with localized as well as metastatic disease. HDT/SCT has been associated with potential survival benefit in patients with non-metastatic disease. However, studies that have evaluated HDT/SCT in patients with primary metastatic disease have shown conflicting results…. HDT/SCT has been associated with improved long-term survival in patients with relapsed or progressive Ewing sarcoma in small, single-institution studies. The role of this approach is yet to be determined in prospective randomized studies.”
Soft tissue sarcoma	Rhabdomyosarcoma	v.2.2023	HCT not addressed
Wilms tumor (nephroblastoma)	Wilms tumor	v.2.2023	HCT not addressed

DFS: disease-free survival; HCT: hematopoietic cell transplantation; HDT: high-dose therapy; NCCN: National Comprehensive Cancer Network; OS: overall survival

U.S. Preventive Services Task Force Recommendations

Not applicable.

KEY WORDS:

Ewing’s Sarcoma, High-Dose Chemotherapy, Solid Tumors of Childhood, Neuroblastoma, Osteosarcoma, Retinoblastoma, Stem-Cell Transplant, Wilms’ Tumor, Rhabdomyosarcoma, hematopoietic cell transplantation, HCT, tandem, autologous

APPROVED BY GOVERNING BODIES:

Not applicable.

BENEFIT APPLICATION:

Coverage is subject to member’s specific benefits.  Group-specific policy will supersede this policy when applicable.

ITS: Home Policy provisions apply

FEP:  Special benefit consideration may apply.  Refer to member’s benefit plan. 

CPT Codes:

38204	Management of recipient hematopoietic cell donor search and cell acquisition
38205	Blood-derived hematopoietic progenitor cell harvesting for transplantation, per collection, allogeneic
38206	Blood-derived hematopoietic progenitor cell harvesting for transplantation, per collection, autologous
38208	Transplant preparation of hematopoietic progenitor cells; thawing of previously frozen harvest, without washing; per donor
38209	; thawing of previously frozen harvest, with washing; per donor
38210	;specific cell depletion with harvest, T cell depletion
38211	;tumor cell depletion
38212	;red blood cell removal
38213	;platelet depletion
38214	;plasma (volume) depletion
38215	;cell concentration in plasma, mononuclear, or buffy coat layer
38220	Diagnostic bone marrow; aspiration(s)
38221	Diagnostic bone marrow; biopsy(ies)
38222	Diagnostic bone marrow; biopsy(ies) and aspiration(s)
38230	Bone marrow harvesting for transplantation; allogeneic
38232	;autologous
38240	Bone marrow or blood-derived peripheral stem-cell transplantation: allogeneic
38241	;autologous
86812-86821	Histocompatibility studies code range (e.g., for allogeneic transplant)

                     

HCPCS:

S2140	Cord blood harvesting for transplantation, allogeneic
S2142	Cord blood-derived stem-cell transplantation, allogeneic
S2150	Bone marrow or blood-derived peripheral stem-cell harvesting and transplantation, allogeneic or autologous, including pheresis, high-dose chemotherapy, and the number of days of post-transplant care in the global definition (including drugs; hospitalization; medical surgical, diagnostic and emergency services)

REFERENCES:

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28. IOM (Institute of Medicine). 2011. Clinical Practice Guidelines We Can Trust. Washington, DC: The National Academies Press.
29. Kanate AS, Majhail NS, Savani BN, et al. Indications for Hematopoietic Cell Transplantation and Immune Effector Cell Therapy: Guidelines from the American Society for Transplantation and Cellular Therapy. Biol Blood Marrow Transplant. Jul 2020; 26(7): 1247- 1256.
30. Khoury JD. Ewing sarcoma family of tumors. Adv Anat Pathol. Jul 2005; 12(4): 212-20.  
31. Kletzel M, Katzenstein HM, Haut PR et al. Treatment of high-risk neuroblastoma with triple-tandem high-dose therapy and stem-cell rescue: results of the Chicago Pilot II Study. J Clin Oncol. May 1 2002; 20(9):2284-2292.
32. Klingebiel T, Boos J, Beske F, et al. Treatment of children with metastatic soft tissue sarcoma with oral maintenance compared to high dose chemotherapy: Report of the HD CWS-96 trial. Pediatr Blood Cancer. Apr 2008; 50(4):739-745.
33. Koscielniak E, Klingebiel TH, Peters C, et al. Do patients with metastatic and recurrent rhabdomyosarcoma benefit from high-dose therapy with hematopoietic rescue? Report of the German/Austrian Pediatric Bone Marrow Transplantation Group. Bone Marrow Transplant. Feb 1997; 19 (3): 227-231.
34. Kremens B, Gruhn B, Klingebiel T, et al. High-dose chemotherapy with autologous stem rescue in children with nephroblastoma. Bone Marrow Transplant. Dec 2002; 30(12):893-898.
35. Kremens B, Wieland R, Reinhard H, et al. High-dose chemotherapy with autologous stem cell rescue in children with retinoblastoma. Bone Marrow Transplant. Feb 2003; 31(4):281-284.
36. Kullendorff CM, Bekassy AN. Salvage treatment of relapsing Wilms’ tumour by autologous bone marrow transplantation. Eur J Pediatr Surg. Jun 1997; 7(3):177-179.
37. Ladenstein R, Pötschger U, Hartman O et al. 28 years of high-dose therapy and SCT for neuroblastoma in Europe: lessons from more than 4000 procedures. Bone Marrow Transplant. Jun 2008; 41(suppl 2):S118-127.
38. Laprie A, Michon J, Hartmann O, et al. High-dose chemotherapy followed by locoregional irradiation improves the outcome of patients with international neuroblastoma staging system Stage II and III neuroblastoma with MYCN amplification. Cancer. Sep 01 2004; 101(5):1081-1089.
39. LaQuaglia MP, Gerstle JT. Advances in the treatment of pediatric solid tumors: A 50-year perspective. J Surg Oncol. Oct 2022; 126(5): 933-942.
40. Loschi S, Dufour C, Oberlin O, et al. Tandem high-dose chemotherapy strategy as first-line treatment of primary disseminated multifocal Ewing sarcomas in children, adolescents and young adults. Bone Marrow Transplant. Aug 2015; 50(8):1083-1088.
41. Majhail NS, Farnia SH, Carpenter PA, et al. Indications for autologous and allogeneic hematopoietic cell transplantation: guidelines from the American Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant. Nov 2015; 21(11):1863-1869.
42. Malogolowkin MH, Hemmer MT, Le-Rademacher J, et al. Outcomes following autologous hematopoietic stem cell transplant for patients with relapsed Wilms' tumor: a CIBMTR retrospective analysis. Bone Marrow Transplant. Nov 2017; 52(11):1549-1555.
43. Matsubara H, Makimoto A, Higa T, et al. A multidisciplinary treatment strategy that includes high-dose chemotherapy for metastatic retinoblastoma without CNS involvement. Bone Marrow Transplant. Apr 2005; 35(8):763-766.
44. Matthay K, Reynolds CP, Seeger RC, et al. Long-term results for children with high-risk neuroblastoma treated on a randomized trial of myeloablative therapy followed by 13-cis-retinoic acid: A Children’s Oncology Group study. J Clin Oncol. Mar 1 2009; 27(7):1007-1013.
45. Matthay KK, Villablanca JG, Seeger RC, et al. Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. Children’s Cancer Group. N Engl J Med. Oct 14 1999; 341(16):1165-1173.
46. McDowell HP, Foot AB, Ellershaw C et al. Outcomes in paediatric metastatic rhabdomyosarcoma: results of the International Society of Paediatric Oncology (SIOP) study MMT-98. Eur J Cancer. Jun 2010; 46(9):1588-1595.
47. Metzger ML, Dome JS. Current therapy for Wilms' tumor. Oncologist. Nov-Dec 2005; 10(10):815-826.
48. Meyers PA, Krailo MD, Ladanyi M et al. High-dose melphalan, etoposide, total-body irradiation, and autologous stem-cell reconstitution as consolidation therapy for high-risk Ewing's sarcoma does not improve prognosis. J Clin Oncol. Jun 1 2001; 19(11):2812-2820.
49. Meyers PA. High-dose therapy with autologous stem cell rescue for pediatric sarcomas. Curr Opin Oncol. Mar 2004; 16(2):120-125.
50. Monclair T, Brodeur GM, Ambros PF, et al. The International Neuroblastoma Risk Group (INRG) staging system: an INRG Task Force report. J Clin Oncol. Jan 10 2009; 27(2):298-303.
51. Mullassery D, Farrelly P, Losty PD. Does aggressive surgical resection improve survival in advanced stage 3 and 4 neuroblastoma? A systematic review and meta-analysis. Pediatr Hematol Oncol. Nov 2014; 31(8):703-716.
52. National Cancer Institute (NCI). Physician Data Query (PDQ): Childhood rhabdomyosarcoma treatment. 2022; www.cancer.gov/types/soft-tissue-sarcoma/hp/odontoameloblastosarcomata. 
53. National Cancer Institute (NCI). Physician Data Query (PDQ): Osteosarcoma and Malignant fibrous histiocytoma of bone treatment. Nov 28, 2023; www.cancer.gov/types/bone/hp/osteofibrochondrosarcoma. 
54. National Cancer Institute (NCI). Physician Data Query (PDQ): Retinoblastoma treatment: health professional version. 2023; www.cancer.gov/types/retinoblastoma/hp/retinocerebelloangiomatosis. 
55. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Wilms Tumor (Nephroblastoma). Version 1.2023. www.nccn.org/professionals/physician_gls/pdf/wilms_tumor.pdf. 
56. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Bone Cancer. Version 1.2024. www.nccn.org/professionals/physician_gls/pdf/bone.pdf. 
57. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Soft Tissue Sarcoma. Version 2.2023. www.nccn.org/professionals/physician_gls/pdf/sarcoma.pdf. 
58. Park JR, Kreissman SG, London WB, et al. Effect of Tandem Autologous Stem Cell Transplant vs Single Transplant on Event-Free Survival in Patients With High-Risk Neuroblastoma: A Randomized Clinical Trial. JAMA. Aug 27 2019; 322(8): 746-755.
59. Pasqualini C, Dufour C, Goma G, et al. Tandem high-dose chemotherapy with thiotepa and busulfan-melphalan and autologous stem cell transplantation in very high-risk neuroblastoma patients. Bone Marrow Transplant. Feb 2016; 51(2):227-231.
60. Pein F, Michon J, Valteau-Couanet D et al. High-dose melphalan, etoposide, and carboplatin followed by autologous stem-cell rescue in pediatric high-risk recurrent Wilms’ tumor: a French Society of Pediatric Oncology study. J Clin Oncol. Oct 1998; 16(10):3295-3301.
61. Presson A, Moore TB, Kempert P. Efficacy of high-dose chemotherapy and autologous stem cell transplant for recurrent Wilms’ tumor: a meta-analysis. J Pediatr Hematol Oncol. Aug 2010; 32(6):454-461.
62. Pritchard J, Cotterill SJ, Germond SM, et al. High dose melphalan in the treatment of advanced neuroblastoma: Results of a randomized trial (ENSG-1) by the European Neuroblastoma Study Group. Pediatr Blood Cancer. Apr 2005; 44(4):348-357.
63. Proust-Houdemont S, Pasqualini C, Blanchard P, et al. Busulfan-melphalan in high-risk neuroblastoma: the 30-year experience of a single institution. Bone Marrow Transplant. Aug 2016; 51(8):1076-1081.
64. Ratko TA, Belinson SE, Brown HM et al. Hematopoietic stem-cell transplantation in the pediatric population. Rockville, MD, 2012.
65. Rodriguez-Galindo C, Wilson MW, Haik BG et al.  Treatment of metastatic retinoblastoma.  Ophthalmology. Jun 2003; 110(6):1237-1240.
66. Shimada H, Ambros IM, Dehner LP, et al.  Terminology and morphologic criteria of neuroblastic tumors:  Recommendations by the International Neuroblastoma Pathology Committee.  Cancer. Jul 15 1999; 86(2):349-363.
67. Spreafico F, Bisogno G, Collini P, et al.  Treatment of high-risk relapsed Wilms tumor with dose-intensive chemotherapy, marrow-ablative chemotherapy, and autologous hematopoietic stem cell support:  Experience by the Italian association of pediatric hematology and oncology.  Pediatr Blood Cancer. Jul 2008; 51(1):23-28.
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69. Sung KW, Ahn HS, Cho B et al. Efficacy of tandem high-dose chemotherapy and autologous stem cell rescue in patients over 1 year of age with stage 4 neuroblastoma: the Korean Society of Pediatric Hematology-Oncology experience over 6 years (2000-2005). J Korean Med Sci. May 2010; 25(5):691-697.
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POLICY HISTORY:

Medical Policy Group, February 2010 (2)

Medical Policy Administration Committee, February 2010

Available for comment February 23-April 8, 2010

Medical Policy Group, December 2011 (3): 2012 Code Updates: Verbiage change to codes 38208, 38209 and 38230 & added code 38232

Medical Policy Panel, April 2012

Medical Policy Group, February 2013 (3): 2012 Updates to Policy, Key Points, and References in reference to tandem autologous hematopoietic stem cell transplants

Medical Policy Administration Committee, February 2013

Available for comment February 21 through April 7, 2013

Medical Policy Group, April 2013 (3): 2013 Update, no policy changes

Medical Policy Panel, April 2014

Medical Policy Group, April 2014 (3):  2014 Updates to Key Points & References; policy statement also updated to include clarification “Allogeneic (myeloablative or non-myeloablative) hematopoietic stem-cell transplantation for the treatment of pediatric solid tumors is considered not medically necessary and investigational”. 

Medical Policy Administration Committee May 2014

Available for comment May 1, through June 14, 2014

Medical Policy Panel, April 2015

Medical Policy Group, April 2015(2): 2015 Updates to Description, Key Points, and References; no change to policy statement.

Medical Policy Panel, May 2017

Medical Policy Group, May 2017(7): 2017 Updates to Title, Description, Key Points, and References; Policy Statement- updated to include coverage for metastatic retinoblastoma; removed word “Stem” and 2013 verbiage from policy statement.

Medical Policy Administration Committee, June 2017

Available for comment June 16 through July 30, 2017

Medical Policy Group, December 2017: Annual Coding Update 2018. Added new CPT code 38222 effective 1/1/18 to the Current Coding section. Updated verbiage for revised CPT codes 38220 and 38221. Created Previous Coding section and moved deleted CPT code 86822 to this section.

Medical Policy Panel, March 2018

Medical Policy Group, March 2018 (7): 2018 Updates to Key Points and References; no change to policy statement.

Medical Policy Panel, January 2019

Medical Policy Group, February 2019 (3): 2019 Updates to Description, Key Points, Practice Guidelines and Position Statements, References and Key Words: added: hematopoietic cell transplantation, HCT, tandem, and autologous. No changes to policy statement or intent.

Medical Policy Panel, January 2020

Medical Policy Group, March 2020 (3): 2020 Updates to Description and Key Points. Added Policy Guidelines section. No changes to policy statement or intent.

Medical Policy Panel, January 2021

Medical Policy Group, February 2021 (3): 2021 Updates to Key Points, Practice Guidelines and Position Statements, and References. Policy statement updated to remove “not medically necessary,” no change to policy statement or intent.

Medical Policy Panel, January 2022

Medical Policy Group, February 2022 (3): 2022 Updates to Key Points, Practice Guidelines and Position Statements, and References. No changes to policy statement or intent.

Medical Policy Panel, January 2023

Medical Policy Group, January 2023 (3): 2023 Updates to Description, Key Points, Practice Guidelines and Position Statements, and References. Removed Previous Coding section. No changes to policy statement or intent.

Medical Policy Panel, January 2024

Medical Policy Group, January 2024 (3): Updates to Policy Guidelines, Description, Key Points, Benefits Application and References. No changes to policy statement or intent.

This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.

The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.

As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.

The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:

1. The technology must have final approval from the appropriate government regulatory bodies;

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;

3. The technology must improve the net health outcome;

4. The technology must be as beneficial as any established alternatives;

5. The improvement must be attainable outside the investigational setting.

Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:

1. In accordance with generally accepted standards of medical practice; and

2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and

3. Not primarily for the convenience of the patient, physician or other health care provider; and

4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.