Coverage Policy Manual
Policy #: 2001025
Category: Medicine
Initiated: January 1993
Last Review: February 2024
  HDC & Allogeneic Stem &/or Progenitor Cell Support for Primitive Neuroectodermal Tumors (PNET) & Ependymoma

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.
 
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 tumor is not uncommon and depending on which type of treatment the patient initially received, autologous HSCT may be an option. For patients who receive high-dose chemotherapy and autologous HSCT for recurrent embryonal tumors, objective response is 50–75%; however, long-term disease control is obtained in fewer than 30% of patients and is primarily seen in patients in first relapse with localized disease at the time of relapse (Mueller, 2009).
 
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. In children, the tumor typically arises intracranially, 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 is a procedure in which hematopoietic stem 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.
 
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.
 
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 (GVHD), which increases susceptibility to opportunistic infections.
 
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 review, 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 a tumor or cannot be harvested.
 
Note: Due to their neuroepithelial origin, peripheral neuroblastoma and Ewing’s sarcoma may be considered PNETs. However, these peripheral tumors are considered in separate policies. Policy No. 2000048 addresses high dose chemotherapy and autologous stem-cell transplant for Ewing’s Sarcoma and policy No. 2006003 handles high dose chemotherapy and allogeneic stem-cell transplant for Ewing’s Sarcoma. Policy No. 2001034 addresses high dose chemotherapy and autologous stem-cell transplant for peripheral neuroblastoma and other solid tumors of childhood and Policy No. 2011055 addresses high dose chemotherapy and allogeneic stem-cell transplant for peripheral neuroblastoma and other solid tumors of childhood.
 
Regulatory Status
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/
Coverage:
Effective November 2020
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
High dose chemotherapy with allogeneic bone marrow, stem cell or progenitor cell support does not meet primary coverage criteria that there be scientific evidence for treatment of embryonal tumors of the CNS (i.e. medulloblastoma, medulloepithelioma, supratentorial PNETs (pineoblastoma, cerebral neuroblastoma, ganglioneuroblastoma), ependymoblastoma, and atypical teratoid/rhabdoid tumor (AT/RT)) or ependymoma.
 
Allogeneic transplant after previous high dose chemotherapy with autologous stem cell support does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
Effective Prior to November 2020
 
High dose chemotherapy with allogeneic bone marrow, stem cell or progenitor cell support does not meet primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the treatment of primitive neuroectodermal tumors (pineoblastoma, cerebral neuroblastoma, ganglioneuroblastoma), ependymoblastoma, atypical teratoid/rhabdoid tumors or ependymoma.
 
For contracts without primary coverage criteria, high dose chemotherapy with allogeneic bone marrow, stem cell or progenitor cell for the treatment of primitive neuroectodermal tumors (pineoblastoma, cerebral neuroblastoma, ganglioneuroblastoma), ependymoblastoma, atypical teratoid/rhabdoid tumors or ependymoma is considered investigational.  Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective prior to September 2011
High dose chemotherapy with allogeneic bone marrow, stem cell or progenitor cell support meets primary coverage criteria for effectiveness and is covered for:
    • initial treatment of high risk disease;
    • for recurrent disease;
    • for primary refractory disease.
 
Non-myeloablative allogeneic “mini” transplant as primary treatment of Neuroblastoma is not covered based on benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For contracts without primary coverage criteria, non-myeloablative allogeneic “mini” transplant as primary treatment of Neuroblastoma is considered investigational, and is not covered.  Investigational services are an exclusion in the member certificate of coverage.
 
Tandem transplants are not covered based on a specific exclusion in the member benefit contract.

Rationale:
Treatment of neuroblastoma using HDC was addressed in 2 Blue Cross Blue Shield Association Technology Evaluation Center Evaluations in 1987 and 1988.  At that time, the importance of N-myc oncogene amplification as a risk factor was not appreciated. Since that time, many studies have been published on HDC for neuroblastoma, particularly in patients with high-risk, primarily Stage IV, disease. Two clinical settings have been investigated: one, for initial treatment of patients presenting with high-risk, typically Stage IV, disease, and second, for salvage therapy in patients with primary refractory or recurrent disease. Although there have been no randomized studies of HDC in patients with Stage IV disease, case series data suggest that HDC with either autologous or allogeneic stem-cell support yields 25%–50% 2-year progression-free survival (PFS) in those treated before disease progression, and 7%–25% PFS in those treated after disease progression.  Due to the challenges of promptly finding a compatible allogeneic stem-cell donor, autologous stem cells may be used more commonly.
 
Most recently, the Children’s Cancer Group (CCG) compared health outcomes of 379 patients randomized to HDC plus total body irradiation or to conventional-dose chemotherapy for initial treatment of high-risk neuroblastoma (defined as stages II-III with N-myc amplification). With a median follow-up of 43 months, event-free survival was significantly better among patients treated with HDC compared to conventional-dose chemotherapy (39% versus 22% at 3 years, respectively; p<0.034). Overall survival of the 2 treatment arms did not differ in this study. Adverse prognostic factors included stage IV disease; amplification of the N-myc oncogene; elevated serum ferritin; and poor response to induction therapy.  [Note: In this study, 258 of the patients were further randomized to either receive or not receive 13-cis-retinoic acid maintenance therapy. Event free survival was reportedly significantly improved in the cis-retinoic acid treatment in this study; a subsequent randomized study in similar patients did not report a similar survival benefit.]
 
Several alternative treatment strategies are being studied in attempts to increase event-free and overall survival, especially in the high-risk patient population. One approach is administration of tandem or triple cycles of high-dose regimens, each followed by stem-cell infusion. Another is the use of targeted radiotherapy or radio-immunotherapy using I131-metaiodobenzylguanidine (I131MIBG) or a similar agent shortly before administration of myeloablative chemotherapy. Yet a third strategy is to reduce tumor-cell contamination of bone marrow and peripheral blood stem-cell harvests by in vivo cytoreduction or positive cell- collection techniques. The evidence on these methods is limited to a few small clinical series, so the true effects of these alternatives on health outcomes currently cannot be assessed.
 
The policy regarding use of allogeneic transplant for salvage after a prior failed autologous transplant is based on a 1999 Blue Cross Blue Shield Association Technology Evaluation Center Assessment.  At that time, only 1 relevant article was identified in the published literature, a single case report of a child with neuroblastoma. A search of the more recent literature did not identify any additional studies on this topic.
 
2011 Update
This policy was revised to include discussion of high dose chemotherapy and allogeneic stem and/or progenitor support for primitive neuroectodermal tumors (PNET) and ependymoma which includes central nervous system neuroblastomas. Peripheral neuroblastoma is discussed in policy No. 2011055.  A search of the MEDLINE database through July 2011 was conducted.  The literature on the use of high dose chemotherapy with allogeneic bone marrow, stem cell or progenitor cell support for the treatment of CNS embryonal tumors consists of rare case reports with mixed results (Matsuda, 1998) (Lundberg, 1992) (Secondino, 2008).  More data on this treatment is needed.
 
2013 Update
A literature search was conducted using the MEDLINE database through September 2013.  No new information was identified that would prompt a change in the coverage statement.
 
2014 Update
A literature search conducted through March 2014 did not reveal any new information that would prompt a change in the coverage statement.
 
A literature search conducted through October 2014 did not reveal any new information that would prompt a change in the coverage statement.
 
2016 Update
A literature search conducted through October 2016 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Central Nervous System Embryonal Tumors
Standard therapy for CNS embryonal tumors often involves craniospinal irradiation, in addition to surgical resection and chemotherapy. In pediatric patients, craniospinal irradiation is associated with impairments in neurodevelopmental outcomes, with risks increasing in younger age groups, particularly in those under the age of 3. A focus of research in pediatric CNS tumor treatments has been finding methods to reduce radiation exposure to the developing brain without conferring unacceptably high recurrence risks. Therefore, a relevant outcome in evaluating hematopoietic stem cell transplant (HSCT) for CNS embryonal tumors is whether the use of HSCT allows radiation dose reduction.
 
Newly Diagnosed Central Nervous System Embryonal Tumors
The evidence describing outcomes after HSCT for newly-diagnosed CNS embryonal tumors consists of relatively small case series, some of which enrolled patients prospectively. While most studies report outcomes for specific tumor types, a number include multiple tumor types.
 
In one study that grouped CNS embryonal tumors, Odagiri and colleagues reported outcomes for 24 patients treated for various CNS embryonal tumors on the basis of high- or average-risk prognosis. (Odagiri, 2014). Among all patients included, 16, 4, 3, and 1, respectively, had medulloblastoma, PNET, atypical teratoid/rhabdoid tumor (ATRT), and pineoblastoma. Nine patients were considered “average risk” based on the presence of all of the following: age 3 years or older at diagnosis, nonmetastatic disease, and had undergone gross total resection; the remaining 16 patients were considered “high risk.” High risk patients received HSCT, in addition to craniospinal irradiation and chemotherapy. Craniospinal irradiation for the high risk group was in the same doses as for the average risk group for patients with nonmetastatic disease (23.4 Gy for those 5 years and older and 18 Gy for those under 5 years, with a boost of 54 Gy for all ages), with higher doses for those with metastatic disease (30-36 Gy, with a boost of %4 Gy). In the average risk group (n = 9), the 5-year progression free survival (PFS) and overall survival (OS) rates were 71.1% and 88.9%, respectively. In the high risk group (n=15), the 5-year PFS and OS rates were 66.7% and 71.1%, respectively. Survival rates did not differ significantly between the average and high risk groups.
 
Supratentorial Primitive Neuroectodermal Tumor
In a study including 26 adult and pediatric patients with sPNET treated with a variety of modalities, Lester and colleagues evaluated factors prognostic for OS and disease-free survival (DFS), including treatment with HSCT (Lester, 2014). Compared with treatment with standard chemotherapy, HSCT was associated with a nonsignificant tendency toward improved DFS (hazard ratio [HR] 0.4, 95% CI 0.1 to 1.0, P=0.07) and improved OS (HR 0.3, 95% CI 0.1 to 1.0, P=0.05). However, these results are confounded by higher rates of HSCT use in children, who had better OS and DFS overall.
 
Clinical Trials
A search of the clinica trials database did not reveal any new or additional clinical trials other than previously identified.
 
2017 Update
A literature search conducted through October 2017 did not reveal any new information that would prompt a change in the coverage statement.  
 
2018 Update
A literature search was conducted through November 2018.  There was no new information identified that would prompt a change in the coverage statement.  The key identified literature is summarized below.
 
American Society for Blood and Marrow Transplantation
The American Society for Blood and Marrow Transplantation published consensus guidelines on the use of HCT to treat specific conditions, in both clinical trial and clinical practice settings (ASBMT, 2015). Per this review, clinical evidence is available to support autologous HCT in pediatric patients (<18 years) with medulloblastoma.  Stem cell transplantation is not generally recommended using allogeneic HCT for medulloblastomas.  The guidelines did not address HCT in treating ependymomas.
 
2019 Update
Annual policy review completed with a literature search using the MEDLINE database through November 2019. No new literature was identified that would prompt a change in the coverage statement.
 
2020 Update
Annual policy review completed with a literature search using the MEDLINE database through October 2020. The key identified literature is summarized below.
 
Tandem HSCT
Sung et al reported on prospective follow-up for 13 children with AT/RT who received tandem HDC and autologous HCT (Sung, 2016). Five of the children were less than three years old; the remaining eight were three years or older. Tandem HDC and autologous HCT were administered after six cycles of induction chemotherapy with radiotherapy deferred until age three unless the tumor showed relapse or progression in the younger children. Reduced-dose radiotherapy was administered either after two cycles of induction chemotherapy or after surgery with tandem HDC, and autologous HCT was performed after six cycles of induction chemotherapy in the older children. All five younger children died from disease progression. Four of the 8 older children remained progression-free, with a median follow-up of 64 months.
 
Dufour et al reported outcomes for patients with newly diagnosed high-risk medulloblastoma and sPNET treated with tandem HDC and autologous HCT support followed by conventional craniospinal radiotherapy (Dufour, 2014). Twenty-four children older than age 5 years were treated from 2001 to 2010, 21 with newly diagnosed high-risk medulloblastoma (disseminated medulloblastoma or medulloblastoma with residual tumor volume >1.5 cm2 or MYCN amplification) and three with sPNET. Patients received two courses of conventional chemotherapy, followed by two courses of high-dose thiotepa followed by stem cell rescue and craniospinal radiotherapy. Twenty-three patients received two courses of HDC, while one patient received only one course of high-dose thiotepa due to seizures. Median follow-up was 4.4 years (range, 0.8-11.3 years). Three-year EFS and OS rates were 79% (95% CI, 59% to 91%) and 82% (95% CI, 62% to 93%), respectively, while 5-year EFS and OS rates were 65% (95% CI, 45% to 81%) and 74% (95% CI, 51% to 89%), respectively.
 
Sung et al reported on the results of reduced-dose craniospinal radiotherapy followed by double-tandem HDC with autologous HCT in 20 children older than 3 years of age with high-risk medulloblastoma (17 with metastatic disease, 3 with postoperative residual tumor >1.5 cm2 without metastasis) (Sung, 2013). The tumor relapsed or progressed in four patients, and two died of treatment-related toxicity during the second transplant. Fourteen (70%) patients remained event-free at a median follow-up of 46 months (range, 23-82 months) from diagnosis. Late adverse events, evaluated at a median of 36 months (range, 12-68 months) after tandem, HCT included hypothyroidism, growth hormone deficiency, sex hormone deficiency, hearing loss, and renal tubulopathy.
 
Little evidence is available on the use of tandem autologous HCT for CNS embryonal tumors. The single-arm studies are very small but appear to report OS and EFS rates comparable with single autologous HCT. Tandem transplants may allow reduced doses of craniospinal irradiation, but most studies used standard-dose irradiation, making the relative benefit of tandem autologous HCT uncertain. The evidence is insufficient to determine that the technology results in a meaningful improvement in the net health outcome.
 
Ependymoma
The literature on autologous HCT for the treatment of ependymoma primarily consists of small case series. Sung et al reported the results of double-tandem HDC with autologous HCT in 5 children younger than 3 years of age with newly diagnosed anaplastic ependymoma (Sung, 2012). All patients were alive at a median follow-up of 45 months (range, 31-62 months) from diagnosis, although the tumor progressed at the primary site in 1 patient. No significant endocrine dysfunction occurred except for hypothyroidism in one patient, and significant neurologic injury from primary surgical treatment in another patient. The results of this very small case series indicate that treatment with tandem HCT is feasible in very young children with anaplastic ependymoma and that this strategy might also be an option to improve survival in these patients without unacceptable long-term toxicity.
 
Mason et al reported on a case series of 15 patients with recurrent ependymoma (Mason, 1998). Five patients died of treatment-related toxicities, eight died from a progressive disease, and one died of unrelated causes. After 25 months, 1 patient remained alive but with tumor recurrence. The authors concluded that their high-dose regimen of thiotepa and etoposide was not an effective treatment of ependymoma. Grill et al similarly reported a disappointing experience in 16 children treated with a thiotepa-based high-dose regimen (Grill, 1996).
 
A small 2007 series reported 5-year EFS and OS rates of 12% and 38%, respectively, among 29 children younger than 10 years of age who received autologous HCT after intensive induction chemotherapy to treat newly diagnosed ependymoma (Zacharoulis, 2007). Importantly, the radiation-free survival rate was only 8% in these cases. The results of these series, although limited in size, would suggest HCT is not superior to other previously reported chemotherapeutic approaches.
 
For individuals who have ependymoma who receive autologous HCT, the evidence includes relatively small case series. The relevant outcomes are OS, DSS, and TRM and morbidity. The available case series do not report higher survival rates for patients with ependymoma treated with HCT compared with standard therapies. The evidence is insufficient to determine that the technology results in a meaningful improvement in the net health outcome.
 
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through October 2021. No new literature was identified that would prompt a change in the coverage statement.
 
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through October 2022. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Dufour et al reported on outcomes for children 5 years and older with newly diagnosed high-risk medulloblastoma treated with high-dose chemotherapy plus autologous HCT, followed by conventional CSI from an open-label, multicenter, single-arm study (Dufour, 2021). Medulloblastoma was considered high-risk in the presence of metastatic disease, greater than 1.5 cm2 residual disease, if unfavorable histopathology was present, or MYCN or MYC genes were amplified. Fifty-one patients (median age at diagnosis, 8 years; range 5 to 19 years) were included in the study. All children received postoperative induction chemotherapy (etoposide and carboplatin), followed by 2 high-dose thiotepa courses with autologous HCT. The median time between diagnosis and onset of radiation therapy was 146 days (range, 117 to 210 days) and in 16 (34%) out of 47 patients, this delay was greater than 150 days. Median follow-up was 7.1 years (range, 3.4 to 9.0 years). At 3 years, PFS and OS rates were 78% (95% CI, 65% to 88%) and 84% (95% CI, 72% to 92%), respectively. At 5 years, PFS and OS rates were 76% (95% CI, 63% to 86%) and 76% (95% CI, 63% to 86%), respectively. No treatment-related deaths were reported. The authors concluded that the treatment regimen of high-dose chemotherapy plus autologous HCT and conventional CSI resulted in a high survival rate in children with newly diagnosed high-risk medulloblastoma.
 
Reddy et al studied the impact of high-dose chemotherapy with autologous HCT and early radiation therapy in patients with atypical teratoid or rhabdoid tumors in a nonrandomized cohort study (Reddy, 2020). After surgery, the study regimen consisted of 2 courses of multiagent chemotherapy, followed by 3 courses of high-dose chemotherapy with autologous HCT and radiation therapy. Patients who were younger than 36 months of age (n=54) were included in primary analysis and compared with a historical cohort who received a different combination of multiagent chemotherapy followed by radiation therapy, but no HCT support (Reddy, 2020; Geyer, 2005). Median follow-up time was 4.7 years (95% CI, 4.2 to 5.3 years) (Reddy, 2020). Treatment with the study regimen significantly reduced the risk of EFS events in patients younger than 36 months compared with the historical cohort (HR, 0.43; 95% CI, 0.28 to 0.66; p<.0005). Four-year EFS and OS for the entire cohort of patients (N=65), including patients older than 36 months, were 37% (95% CI, 25% to 49%) and 43% (95% CI, 31% to 55%), respectively. Treatment-related deaths occurred in 4 patients.
 
In 2015, the American Society for Blood and Marrow Transplantation (now referred to as the American Society for Transplantation and Cellular Therapy) published consensus guidelines on the use of HCT to treat specific conditions, in both clinical trial and clinical practice settings (Majhail, 2015). These guidelines were updated in 2020 (Kanate, 2020). Neither the 2015 nor the 2020 guidelines address HCT in treatment of ependymomas. The tumors addressed in this review for which the Society has provided recommendations are listed below:
 
Recommendations for Use of Allogenic Hematopoietic Cell Transplantation in Pediatric patients (<18 years):
Neuroblastoma, high-risk or relapse
    • 2015 Recommendation: Developmental
    • 2020 Recommendation: Developmental
Medulloblastoma, high-risk
    • 2015 Recommendation: Not generally recommended
    • 2020 Recommendation: No generally recommended
Other malignant brain tumors
    • 2015 Recommendation: Not generally recommended
    • 2020 Recommendation: Not generally recommended
 
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through October 2023. No new literature was identified that would prompt a change in the coverage statement.
 
2024 Update
Annual policy review completed with a literature search using the MEDLINE database through January 2024. No new literature was identified that would prompt a change in the coverage statement.

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