Medical Policy

This document addresses hematopoietic stem cell transplantation for pediatric solid tumors including neuroblastoma, primitive neuroectodermal tumors (PNETs) of the central nervous system, ependymoma, pineoblastoma, Ewing sarcoma, Wilms’ tumor, osteosarcoma, retinoblastoma, and rhabdomyosarcoma. These types of solid tumors generally develop in children; however, some may also present in adulthood.

Note: For additional information and criteria for umbilical cord transplantation, see:

• TRANS.00016 Umbilical Cord Blood Progenitor Cell Collection, Storage and Transplantation

Neuroblastoma

Medically Necessary:

An autologous hematopoietic stem cell transplantation is considered medically necessary as the initial treatment for high-risk neuroblastoma.

A planned autologous tandem* hematopoietic stem cell transplantation is considered medically necessary as the initial treatment for high-risk neuroblastoma.

An autologous hematopoietic stem cell transplantation is considered medically necessary as a treatment for primary refractory or recurrent neuroblastoma in individuals who have not previously undergone treatment with hematopoietic stem cell transplantation.

A repeat autologous hematopoietic stem cell transplantation due to primary graft failure or failure to engraft is considered medically necessary.

Hematopoietic stem cell harvesting** for an anticipated but unscheduled transplant is considered medically necessary in individuals with neuroblastoma who meet the criteria above when the treating physician documents that a future transplant is likely.

*Tandem transplantation refers to a planned infusion (transplant) of previously harvested hematopoietic stem cells with a repeat hematopoietic stem cell infusion (transplant) that is performed within 6 months of the initial transplant. This is distinguished from a repeat transplantation requested or performed more than 6 months after the first transplant, and is used as salvage therapy after failure of initial transplantation or relapsed disease.

**Hematopoietic stem cell harvesting does not include the transplant procedure.

Investigational and Not Medically Necessary:

An autologous hematopoietic stem cell transplantation is considered investigational and not medically necessary for individuals who do not meet the above criteria.

An allogeneic (ablative or non-myeloablative) hematopoietic stem cell transplantation is considered investigational and not medically necessary as a treatment of neuroblastoma.

A planned tandem allogeneic (ablative or non-myeloablative) hematopoietic stem cell transplantation as a treatment of neuroblastoma is considered investigational and not medically necessary.

A second or repeat autologous hematopoietic stem cell transplantation due to persistent, progressive or relapsed disease is considered investigational and not medically necessary.

Hematopoietic stem cell harvesting for a future but unscheduled transplant is considered investigational and not medically necessary when the criteria above are not met.

Primitive Neuroectodermal Tumors (PNETs) of the Central Nervous System, Ependymoma and Pineoblastoma

Medically Necessary:

An autologous hematopoietic stem cell transplantation with or without associated radiotherapy, is considered medically necessary for the treatment of PNETs (such as medulloblastoma), arising in the central nervous system, ependymoma or pineoblastoma.

A repeat autologous hematopoietic stem cell transplantation due to primary graft failure or failure to engraft is considered medically necessary.

Hematopoietic stem cell harvesting for an anticipated but unscheduled transplant is considered medically necessary in individuals with PNET, ependymoma or pineoblastoma who meet the criteria above when the treating physician documents that a future transplant is likely.

Investigational and Not Medically Necessary:

An allogeneic (ablative or non-myeloablative [mini transplant]) hematopoietic stem cell transplantation is considered investigational and not medically necessary for the treatment of PNETs (such as medulloblastoma), arising in the central nervous system, ependymoma or pineoblastoma.

A planned tandem allogeneic or autologous hematopoietic stem cell transplantation is considered investigational and not medically necessary for the treatment of PNETs (such as medulloblastoma), arising in the central nervous system, ependymoma or pineoblastoma.

A second or repeat autologous hematopoietic stem cell transplantation due to persistent, progressive or relapsed disease is considered investigational and not medically necessary.

Hematopoietic stem cell harvesting for a future but unscheduled transplant is considered investigational and not medically necessary when the criteria above are not met.

Other High-Risk Solid Tumors of Childhood (Ewing Sarcoma, Wilms’ Tumor, Osteosarcoma, Retinoblastoma, and Rhabdomyosarcoma)

Medically Necessary:

An autologous hematopoietic stem cell transplantation is considered medically necessary as a treatment for Ewing sarcoma (including extraosseous Ewing, peripheral neuroepithelioma and Askin's tumor).

A syngeneic allogeneic (ablative or non-myeloablative) hematopoietic stem cell transplantation is considered medically necessary as a treatment for Ewing sarcoma (including extraosseous Ewing, peripheral neuroepithelioma and Askin's tumor).

A repeat autologous or allogeneic (ablative or non-myeloablative) hematopoietic stem cell transplantation due to primary graft failure or failure to engraft is considered medically necessary.

Hematopoietic stem cell harvesting for an anticipated but unscheduled transplant is considered medically necessary in individuals with Ewing sarcoma who meet the criteria above when the treating physician documents that a future transplant is likely.

An autologous hematopoietic stem cell transplantation is considered medically necessary as a treatment for stage IVa and stage IVb retinoblastoma.

Investigational and Not Medically Necessary:

An allogeneic (ablative or non-myeloablative [mini transplant]) or autologous hematopoietic stem cell transplantation is considered investigational and not medically necessary for all other pediatric solid tumors, including but not limited to: Wilms’ tumor (nephroblastoma), osteosarcoma, and rhabdomyosarcoma.

An autologous hematopoietic stem cell transplantation is considered investigational and not medically necessary for retinoblastoma other than stage IVa or stage IVb.

An allogeneic (ablative or non-myeloablative [mini transplant]) is considered investigational and not medically necessary for retinoblastoma.

An allogeneic (ablative or non-myeloablative) hematopoietic stem cell transplantation is considered investigational and not medically necessary as a treatment of all high risk pediatric solid tumors relapsing after prior therapy with high-dose chemotherapy and autologous hematopoietic stem cell transplantation.

A planned tandem allogeneic or autologous hematopoietic stem cell transplantation is considered investigational and not medically necessary as a treatment of all high risk pediatric solid tumors of childhood.

A second or repeat autologous or allogeneic (ablative or non-myeloablative) hematopoietic stem cell transplantation due to persistent, progressive or relapsed disease is considered investigational and not medically necessary.

Hematopoietic stem cell harvesting for a future but unscheduled transplant is considered investigational and not medically necessary when the criteria above are not met.

Summary

High-dose chemotherapy with hematopoietic stem cell transplantation (HSCT) is used to treat various pediatric solid tumors, with stem cells sourced from the member (autologous), an identical twin (syngeneic), or a donor (allogeneic). While HSCT shows promising outcomes for high-risk neuroblastoma, particularly with tandem autologous transplants, its effectiveness varies across other cancers. Ewing sarcoma and retinoblastoma show potential benefit, whereas Wilms’ tumor, osteosarcoma, and rhabdomyosarcoma do not consistently demonstrate survival advantages. For PNETs, medulloblastoma, and other central nervous system (CNS) tumors, HSCT can reduce the need for radiotherapy and may preserve cognitive outcomes in young children, though treatment-related toxicities remain significant and further research is needed.

Discussion

Hematopoietic stem cell transplantation typically uses high-dose chemotherapy with cytotoxic agents using doses several times greater than the standard therapeutic dose. In some cases, whole body or localized radiotherapy is also given and is considered part of high-dose chemotherapy when applicable. The rationale for high-dose chemotherapy is that many cytotoxic agents act according to a steep dose-response curve. Thus, small increments in dosage will result in relatively large increases in tumor cell destruction. Increasing the dosage also increases the incidence and severity of adverse effects related primarily to bone marrow ablation. These complications may include opportunistic infections, hemorrhage, or organ failure. Bone marrow ablation is the most significant side effect of high-dose chemotherapy and requires infusion of hematopoietic stem cells (primitive cells capable of replication and formation into mature blood cells) to repopulate the marrow. The potential donors of stem cells include:

1. Autologous - Stem cells harvested from the individual’s own bone marrow prior to the cytotoxic therapy.
2. Syngeneic - Stem cells harvested from an identical twin.
3. Allogeneic - Stem cells harvested from a histocompatible donor. (Note: this document does not require a specific level of histocompatibility be present as part of the medical necessity evaluation).

Donor stem cells, either autologous or allogeneic, can be collected from either the bone marrow or the peripheral blood. Stem cells may be harvested from the peripheral blood using a pheresis procedure. To increase the number of stem cells in the peripheral circulation, donors may be pretreated with a course of chemotherapy or hematopoietic growth factors, or both.

Another source of stem cells is blood harvested from the umbilical cord and placenta shortly after delivery of neonates. Although cord blood is an allogeneic source, these stem cells are antigenically “naïve” and thus, are associated with a lower incidence of rejection or graft versus host disease.

The best stem cell source for a particular individual depends upon their disease, treatment history, and the availability of a compatible donor. In choosing the source, clinicians must balance the risks of graft failure and re-infusion of malignant cells in autologous procedures against the risks of graft rejection, and graft versus host disease in allogeneic procedures.

While the intensity of the regimens used for conditioning in conventional high-dose chemotherapy varies, collectively they have been termed “myeloablative.” Several less intense conditioning regimens have been developed recently and rely on immunosuppression rather than cytotoxic effects to permit engraftment of donor cells. These regimens, collectively termed “non-myeloablative” also vary in intensity with substantial overlap between the ranges for “myeloablative” and “non-myeloablative” regimens.

Studies have shown that donor allogeneic stem cells can engraft in recipients using less-intensive conditioning regimens that are sufficiently immunosuppressive to permit graft-host tolerance. This results in a stable mixed donor-host hematopoietic chimerism. Once chimerism has developed, a further infusion of donor leukocytes may be given to eradicate malignant cells by inducing a graft vs. tumor effect.

Non-myeloablative allogeneic transplants, also referred to as “mini-transplant” or “reduced intensity conditioning” (RIC), are thought to be potentially as effective as conventional high-dose chemotherapy followed by an allogeneic stem cell transplantation, but with decreased morbidity and mortality related to the less intense chemotherapy conditioning regimen. Consequently, for individuals with malignancies who are eligible for conventional high-dose chemotherapy followed by allogeneic stem cell transplantation, conditioning with milder, non-myeloablative regimens represents a technical modification of an established procedure.

Tandem high-dose or non-myeloablative chemotherapy with autologous or allogeneic stem cell support involves two sequential cycles of high-dose chemotherapy, with or without total body irradiation. Each cycle is followed by re-infusion of stem cells. Although high-dose chemotherapy can achieve temporary disease control, many individuals with advanced malignancies eventually relapse, indicating the presence of residual neoplastic cells. The rationale for tandem transplantation is that repeated cycles of myeloablative or non-myeloablative chemotherapy, with stem cell support for each cycle, may enhance eradication of remaining tumor cells and improve long-term outcomes.

Neuroblastoma

Since the early 1980s, multiple studies have evaluated autologous HSCT for high-risk neuroblastoma. Early randomized data from the European Neuroblastoma Study Group showed improved progression-free survival compared with chemotherapy alone, though interpretation was limited by small sample size and lack of post-transplant therapy (European Neuroblastoma Study Group, 1984). Subsequent phase I/II studies confirmed better disease-free and event-free survival versus historical controls despite variations in regimens and timing of analysis.

The Children’s Cancer Group phase II study (CCG-3891) demonstrated the feasibility of tandem autologous transplants, with 67% of participants remaining event-free and a 3-year event-free survival (EFS) of 58% (Grupp, 2000). George and colleagues reported similar long-term outcomes, with 5- and 7-year progression-free survival (PFS) of 47% and 45% and overall survival (OS) of 60% and 53%, respectively (George, 2006). In a large, randomized trial, Berthold and colleagues found higher EFS with autologous HSCT compared with maintenance therapy (47% vs 31%; p=0.022) but no significant OS benefit (Berthold, 2005). Likewise, Matthay (2009) demonstrated improved 5-year EFS with transplantation compared with chemotherapy alone (30% vs. 19%; p=0.04).

In a comprehensive European case series, Ladenstein and colleagues (2008) summarized outcomes from 4098 HSCT procedures over 28 years, showing that allogeneic transplantation was rarely used and associated with higher mortality, while 5-year OS was 37% after autologous and 25% after allogeneic transplant.

Several additional studies have examined the use of high-dose ^131I-metaiodobenzylguanidine (MIBG) therapy for relapsed or refractory neuroblastoma in conjunction with hematopoietic stem cell support to mitigate myelosuppression. Johnson (2011) reported that stem cell support shortened the duration of hematologic toxicity to a median of 15 days, while Matthay (2012) noted that stem cell rescue was typically required about 14 days after MIBG administration. Similarly, Polishchuk (2011) found that autologous stem cell infusion after MIBG improved hematologic recovery and supported its use as an effective salvage approach.

Kletzel and colleagues (2002) conducted a single-center prospective pilot study to evaluate the feasibility and potential benefit of triple-tandem high-dose chemotherapy with peripheral-blood stem-cell (PBSC) rescue followed by local irradiation in children with high-risk neuroblastoma. Between 1995 and 2000, 25 newly diagnosed and 1 relapsed participant were enrolled. After intensive induction chemotherapy and surgery, 22 children were eligible for the consolidation phase. Of these, 17 completed all three high-dose therapy cycles with PBSC rescue, 2 completed two cycles, and 3 completed one. One participant died of sepsis during treatment and another from complications of graft failure; 2 later developed prolonged pancytopenia, with 1 case showing evidence of myelodysplasia. At a median follow-up of 38 months, the estimated 3-year EFS and OS rates were 57% ± 11% and 79% ± 10%, respectively. The investigators concluded that this regimen was technically feasible and associated with acceptable toxicity in a small cohort. However, the lack of a control group, small sample size, and variation in adjunctive therapies (anti-GD2 antibody and 13-cis-retinoic acid) limit the strength of inference regarding survival benefit.

A Cochrane Review by Yalcin and colleagues (2015) evaluated three randomized controlled trials consisting of 739 children. The efficacy of myeloablative therapy was compared to conventional therapy for treatment of high-risk neuroblastoma. Initially, there was a statistically significant difference in EFS in favor of myeloablative therapy over conventional chemotherapy or no further treatment (three studies, 739 participants; hazard ratio [HR] 0.78; 95% confidence interval [CI], 0.67 to 0.90). Also, there was a statistically significant difference in OS in favor of myeloablative therapy over conventional chemotherapy or no further treatment (two studies, 360 participants; HR 0.74; 95% CI, 0.57 to 0.98). When additional follow-up data were subsequently obtained, the difference in EFS remained statistically significant (three studies, 739 participants; HR 0.79; 95% CI, 0.70 to 0.90), but the difference in OS was no longer statistically significant (two studies, 360 participants; HR 0.86; 95% CI, 0.73 to 1.01). The authors concluded that, based on the currently available evidence, myeloablative therapy seemed to work in terms of EFS. However, there was no evidence of effect for OS with the inclusion of additional follow-up data.

In a 2019 randomized clinical trial by Park and colleagues, the authors investigated whether a tandem autologous transplant improves EFS for individuals with newly diagnosed high-risk neuroblastoma compared to a single transplant. The study’s primary outcome was EFS from the time of randomization to when a first event occurred (that is; relapse, progressive disease, second malignancy, or death). Additional outcomes included the assessment of response at the end of the induction therapy and local recurrence (which was to be reported separately). There were 652 participants enrolled in the study. A total of 207 participants chose not to be randomized, 62 participants were ineligible for randomization, and 1 participant did not receive protocol therapy. This left 355 participants randomized to either tandem transplant (n=176) or single transplant (n=179). The protocol therapy included 3 phases: induction, consolidation, and post consolidation. For the 652 eligible participants, the 3-year EFS from enrollment or initiation of treatment was 51.1%. For the 355 randomized participants, the 3-year EFS from the time of randomization was 54.9%. Three years after randomization, the EFS for participants in the tandem transplant group was 61.6% and 48.4% for participants in the single transplant group. This study had limitations including the large number of participants who were not randomized leading to a potential selection bias. The EFS rates associated with tandem transplant are only relevant within the context of the total therapy delivered. Other delivered therapies may suggest differing EFS. There were 10% of participants who did not continue beyond the induction phase. While this study showed a better EFS in the participants who received tandem transplant, the findings may not represent all participants with high-risk neuroblastoma.

In a 2021 retrospective review by Khan and colleagues, the authors reported the survival and toxicity of high-risk individuals with neuroblastoma following treatment with a single autologous stem cell transplant. The study analyzed outcomes for 99 individuals. With a median follow-up of 50.2 months, there were 20 individuals who died due to disease progression, 4 individuals who died due to septicemia, 1 death related to renal failure, and 1 death due to viral pneumonia (overall mortality 26/99 = 26%). Median time of relapse from diagnosis was 15 months with the majority (n=37) relapsing within 2 years of diagnosis. OS for 3 years was 68.5% with 3-year EFS of 48.3%. There were no significant differences in survival rates for those who received total body radiation compared to those who did not (54.4% and 44.9% respectively).

A 2022 retrospective review by Suwannaying and colleagues reported on the outcomes of participants with high-risk neuroblastoma who received conventional chemotherapy (n=116) or HSCT (n=53). For those who received conventional chemotherapy, 5-year OS was 39.8%, 5-year EFS was 17.1%. For those who received HSCT, 5-year OS was 48.7%, 5-year EFS was 36%.

Collectively, these studies support autologous HSCT as an effective consolidation strategy that improves EFS in high-risk neuroblastoma and as a supportive therapy to facilitate high-dose or radiolabeled treatment, although consistent gains in OS remain modest.

Primitive Neuroectodermal Tumors (PNETs) of the Central Nervous System, Ependymoma and Pineoblastoma

HSCT has been evaluated as a component of therapy for PNETs of the CNS, including medulloblastoma and supratentorial PNET (sPNET). Dhall and colleagues (2008) reported outcomes in children younger than 3 years of age with nonmetastatic medulloblastoma treated with five cycles of induction chemotherapy followed by myeloablative chemotherapy and autologous HSCT. Nearly all participants completed induction and consolidation therapy, and most achieved complete radiographic response. Among those with gross total resection, 5-year EFS and OS were 64% and 79%, respectively, while for those with residual disease, 5-year EFS and OS were 29% and 57%. Treatment-related mortality was 19%, but craniospinal irradiation was avoided in more than half of the children, with the majority of survivors maintaining neurocognitive function and quality of life.

Dunkel and colleagues (2010b) examined the use of high-dose chemotherapy followed by autologous HSCT in 25 individuals with previously irradiated recurrent medulloblastoma. The regimen included carboplatin, thiotepa, and etoposide. Despite three treatment-related deaths, 6 participants were event-free survivors with durable remission at a median follow-up of more than 12 years, demonstrating the potential for long-term disease control in a subset of relapsed cases.

Chintagumpala and colleagues (2009) evaluated high-dose chemotherapy with autologous HSCT after risk-adapted craniospinal irradiation in 16 children and adolescents with newly diagnosed sPNET. Among average-risk participants, 5-year EFS and OS were 75% and 88%, while in high-risk participants they were 60% and 58%, respectively. The authors concluded that HSCT allowed for dose reduction of craniospinal irradiation without compromising disease control or survival outcomes.

Dufour and colleagues (2014) investigated tandem high-dose chemotherapy with autologous HSCT followed by conventional craniospinal radiotherapy in 24 children with newly diagnosed high-risk medulloblastoma or sPNET. At a median follow-up of 4.4 years, 5-year EFS and OS for those with metastatic medulloblastoma were 72% and 83%, with no treatment-related deaths. The authors concluded that tandem high-dose chemotherapy supported by HSCT is feasible and effective but emphasized the need for larger, prospective studies.

Zacharoulis and colleagues (2007) evaluated high-dose chemotherapy with autologous HSCT in 29 children younger than 10 years with newly diagnosed ependymoma treated on the “Head Start” protocols. After intensive induction and marrow-ablative consolidation chemotherapy, the estimated 5-year EFS and OS were 12% and 38%, respectively. Although survival outcomes were limited, the study underscored the role of HSCT as a potential option in refractory or high-risk ependymoma, warranting continued investigation into its long-term safety and efficacy.

A 2017 retrospective study by Raleigh and colleagues reported the outcomes of 222 children with newly diagnosed embryonal brain tumors treated with adjuvant craniospinal radiation compared to treatment with high-dose chemotherapy, stem cell transplant and delayed craniospinal radiation. There were 105 children who received adjuvant craniospinal radiation followed by chemotherapy. High-dose chemotherapy regimens incorporating stem cell transplant were given to 64 children and the remainder (n=32) received craniospinal radiation without upfront radiation therapy, high-dose chemotherapy, or stem cell transplantation. OS for those who received adjuvant craniospinal radiation was 66% and PFS was 67%. For those who received high-dose chemotherapy/stem cell transplants, OS was 61% and PFS was 62%. At the last follow-up, 31 children from the high-dose chemotherapy/stem cell transplant group had not received definitive or salvage radiotherapy. In this study, delaying radiation in very young children resulted in similar outcomes compared to upfront craniospinal radiation, thus avoiding neurocognitive radiation effects. The authors note prospective studies are necessary before eliminating radiation from treatment.

A 2024 study by Ahn and colleagues reported treatment outcomes and complications for participants with medulloblastoma who received radiotherapy and maintenance chemotherapy (n=24) (standard risk group) or chemotherapy and tandem high-dose chemotherapy with autologous stem cell rescue (n=35) (high risk group). The median follow-up time was 8.2 (5.0-11.4) years in the chemotherapy group and 5.4 (2.1-8.5) years in the autologous stem cell rescue group. In the standard risk group, the estimated 5-year EFS was 86.0% (95% CI, 72.5 to 100) and OS was 95.7% (95% CI, 87.7 to 100). In the high risk group, the 5-year EFS was 66.4% (95% CI, 52.0 to 84.8) and OS was 68.3% (95% CI, 53.8 to 86.7). There were 9 participants in the high risk group who had sepsis before high-dose chemotherapy, including 1 who had meningitis without mortality. During tandem high-dose chemotherapy, acute toxicities were reported for infectious diseases and were more frequent in the second cycle of high-dose chemotherapy. There was 1 participant who had hepatic veno-occlusive disease during the first round of high-dose chemotherapy and 2 participants during the second round. One participant died from myelopathy after the first high-dose chemotherapy with autologous stem cell rescue and 3 participants died during the second high-dose chemotherapy with autologous stem cell rescue. While tandem high-dose chemotherapy with autologous stem cell rescue showed favorable EFS and OS, there was a higher incidence of hematologic toxicities.

Specialty consensus opinion suggests autologous HSCT may be useful under specific circumstances to treat childhood ependymomas or pineoblastomas.

Taken together, these studies suggest that high-dose chemotherapy followed by autologous HSCT can achieve durable survival and, in some cases, permit reduction or delay of craniospinal radiation, particularly in very young children with PNETs. However, treatment-related mortality and relapse remain concerns, and larger prospective studies are needed to clarify the role of HSCT within contemporary, risk-adapted treatment protocols. The role of triple transplantation regimen requires further study before it can be considered a standard treatment. 

Ewing Sarcoma

A case series of 33 individuals with recurrent or progressive Ewing sarcoma studied treatment outcomes of HSCT with different preparatory regimens. Two of the individuals received autologous bone marrow, 1 received autologous bone marrow and stem cells, 29 received autologous peripheral blood stem cells, and 1 received an allogeneic bone marrow transplant due to an unsuccessful autologous harvest. EFS was 42.5% (95% CI, 26-59%) at 2 years and 38.2% at 5 years (95% CI, 21-55%). Although this treatment demonstrated the potential for long-term survival with high-dose therapy for recurrent or refractory Ewing sarcoma, it was associated with significant toxicity. One treatment-related death was reported and 2 participants experienced grade IV infections. The authors concluded that a prospective randomized clinical trial of high-dose therapy in this group of individuals is needed (McTiernan, 2006).

Gardner and colleagues (2008) reported results for 116 individuals with Ewing sarcoma who underwent autologous HSCT (80 [69%] as first-line therapy and 36 [31%] for recurrent disease) between 1989 and 2000. Five-year probabilities of PFS in individuals who received HSCT as first-line therapy were 49% (95% CI, 30-69%) for those with localized disease at diagnosis and 34% (95% CI, 22-47%) for those with metastatic disease at diagnosis. For those with localized disease at diagnosis and recurrent disease, 5-year probability of PFS was 14% (95% CI, 3-30%). The authors concluded that PFS rates after autologous HSCT were comparable to rates seen in those with similar disease characteristics treated with conventional therapy.

Wilms’ Tumor

Most individuals with Wilms’ tumor respond to standard therapies. However, individuals with adverse prognostic factors and relapsed disease often have poor outcomes and EFS of less than 15% (Dallorso, 2008). Various case series and reviews note the lack the prospective randomized trials for this small number of high-risk individuals who experience relapse.

There have been reports of autologous stem cell transplantation use in reinduction and consolidation treatment for high-risk recurrent Wilms’ tumors. In a study by Dallorso and colleagues (2008), 20 consecutive children were treated with various reinduction regimens and autologous stem cell transplant. At a median of 25 months, 3-year disease-free survival (DFS) was 56 ± 12%; OS 55 ± 13% and EFS 53 ± 12%. There were 8 treatment failures with re-relapse in 5 children, and progressive disease while on reinduction in 3 children. One child died as a result of treatment-related toxicities.

In a series reported by Campbell (2004), 13 individuals with relapsed Wilms’ tumor were treated with a single or double cycle of autologous stem cell transplant. At a median follow-up of 30 months, 7 individuals were alive with no evidence of disease, and the 4-year estimated EFS was 60% (95% CI, 0.40 to 6.88) while the OS estimated rate at 4 years was 73% (95% CI, 0.40 to 6.86).

Presson and colleagues (2010) performed a meta-analysis of 100 participants from six studies to determine characteristics that predict survival in relapsed Wilms’ tumors treated with autologous hematopoietic stem cell rescue. These results were then compared to survival data for 118 participants treated with chemotherapy. Four-year OS in the group treated with combined autologous hematopoietic stem cell rescue was 54.1% (95% CI: 42.8-64.1%). The participants who only relapsed in the lungs had higher 4-year survival rates of 77.7% (58.6% to 88.8%) compared to those who relapsed in other sites and/or suffered multiple relapses 41.6% (24.8% to 57.6%). Lung-only relapse was considered a favorable prognostic factor; however, there was no absolute advantage for those treated with salvage chemotherapy. Four-year survival rates among stage I-II disease were about 30% higher with chemotherapy than transplantation, but results of both treatments were comparable for stage III-IV disease. The authors concluded that salvage chemotherapy is typically the better choice for relapsed Wilms' tumors; however, autologous hematopoietic stem cell rescue could be considered for stage III-IV cases with a lung-only relapse.

In 2013, Ha and colleagues studied EFS and OS from published cases describing relapsed Wilms' tumor outcomes. The authors identified 19 articles: 5 reporting results following high dose chemotherapy without autologous stem cell rescue (601 treated individuals, 6 reported results after high-dose chemotherapy with autologous stem-cell rescue [101 treated individuals], and 8 studies comparing both approaches [125 treated individuals]). Study results suggested an advantage to high dose chemotherapy with autologous stem cell rescue with a hazard ratio (HR) for EFS of 0.87 (95% CI, 0.67-1.12) and 0.94 (0.71-1.24) for OS. The authors concluded that  …“great deal of uncertainty concerning the role of HDT in patients having relapsed after treatment for their Wilms’ tumour” and proposed a worldwide randomized trial to improve the level of certainty in the evidence base.

Osteosarcoma

Small case series and reports (Fagioli, 2002; Fagioli, 2003; Sauerbrey, 2001) have evaluated the use of autologous HSCT for treatment of osteosarcoma. Overall, outcomes generally indicated that autologous HSCT induced short remissions but long-term survival benefits appeared to be lacking.

A small phase II study by Arpaci and colleagues (2005) evaluated 22 participants with stage IIB high-grade osteosarcoma. Treatment consisted of two cycles of induction chemotherapy that included cisplatin, doxorubicin, and ifosfamide followed by high dose chemotherapy and autologous peripheral blood stem cell transplantation. Post engraftment, participants underwent limb-sparing surgery (LSS) followed by three to six cycles of chemotherapy. The median follow-up, total duration of treatment, and the time to surgery were 23.7 months, 5.96 months, and 3.03 months, respectively. At the time of last follow-up, metastasis had occurred in 5 of 22 participants (23%). During follow-up, 3 participants developed lung metastases, 1 participant developed local disease recurrence with lung metastasis, and 1 developed lung metastases and multiple bone metastases. A total of 17 participants remained alive and free of disease at time of last follow-up and 3 participants had died of disease progression. OS rates were reported as 100% in the first year, 92% in the second year, 83% in the third year and 75% in the fourth year and after. DFS rates were 94% and 70% in the first and second years, respectively. The authors indicated that based on their study results a phase III randomized study was needed.

Boye and colleagues (2014) evaluated high-dose chemotherapy and stem cell rescue for the primary treatment of metastatic and pelvic osteosarcoma. Between May 1996 and August 2004, 71 individuals participated in a single arm phase II study. Only 29 participants (43%) received the planned two courses of high dose chemotherapy and 10 (15%) received one course. Fourteen participants (20%) had progression of disease before study protocol completion. Median EFS was 18 months. The estimated 5-year EFS was 27%. Median OS was 34 months, and estimated 5-year OS was 31%. When participants who did not receive high-dose chemotherapy (HDCT) due to disease progression were excluded, there was no difference in EFS (p=0.72) or OS (p=0.49) between those who did or did not receive high-dose chemotherapy. The authors concluded that high dose chemotherapy with carboplatin and etoposide with stem cell rescue is not a treatment option for high-risk osteosarcoma.

A 2023 retrospective review by Kang and colleagues reported on the effectiveness of high-dose chemotherapy with autologous stem cell transplant in children with relapsed osteosarcoma. Records were reviewed for 40 children. With a median follow-up of 67.5 months, the 5-year OS was 51%. There were 25 participants who achieved CR with salvage therapy; 15 of whom received high-dose chemotherapy/autologous stem cell transplant. The 5-year OS was 82.4% for those who achieved OS. For the participants who achieved OS and had high-dose chemotherapy/autologous stem cell transplant, the 5-year OS was 83.9% and was 80.0% for those who did not receive high-dose chemotherapy/autologous stem cell transplant. The authors noted that receipt of high-dose chemotherapy/autologous stem cell transplant did not significantly improve outcomes.

Retinoblastoma

Retinoblastoma is a rare intraocular malignancy of childhood that can be deadly without treatment. A variety of treatment options have been evaluated for including autologous hematopoietic stem cell transplantation.

Dunkel and colleagues (2010a) described a multi-center retrospective case series of 8 children diagnosed with stage IVb retinoblastoma. Induction protocols varied between centers and included cyclophosphamide, carboplatin or both with a topoisomerase inhibitor in all cases. Five of the 8 children were treated with high-dose chemotherapy and autologous hematopoietic stem cell rescue after attaining either a major or complete response to induction chemotherapy. Four of the 5 subsequently were also treated with external beam radiation therapy and 1 also received intrathecal radioimmunotherapy. Two children survived event-free at 40 and 101 months and the remaining 3 died of their disease. The child surviving event-free at 40 months had been irradiated post high-dose chemotherapy and the child surviving at 101 months had not received radiation therapy. Due to this study’s small sample size, treatment heterogeneity, and potential for retrospective bias, these findings should be considered hypothesis-generating.

Dunkel and colleagues (2010c) performed a multi-center retrospective review of 13 individuals with trilateral retinoblastoma. Trilateral retinoblastoma refers to the development of a primary intra-cranial primitive neuro-ectodermal tumor in an individual with intra-ocular retinoblastoma (Dunkel, 2010b). Nine children were treated with high-dose chemotherapy with autologous HSCT. Seven children received a high-dose thiotepa based chemotherapy regimen, 2 received high-dose cyclophosphamide and melphalan, and 1 child received both regimens (tandem transplant). Five of these children survived event-free with a median follow-up time of 77 months from diagnosis of the disease and the remaining 4 died of the disease.

In a systematic literature review, Jaradat and colleagues (2012) investigated the role of high-dose chemotherapy followed by stem cell transplantation in the treatment of metastatic or relapsed, trilateral or bilateral advanced retinoblastoma, and in those with tumor at the surgical margin of the optic nerve and/or extrascleral extension. The authors located 15 studies (101 individuals) that met the inclusion criteria. Following treatment for metastatic and relapsed disease, 44 of 77 individuals (57.1%) were alive with no evidence of disease at the time of follow-up. A higher rate of local relapse occurred with CNS metastases (73.1%), which dropped to 47.1% for those who received thiotepa. In individuals with trilateral or bilateral advanced retinoblastoma, 5of 7 (71.4%) with reported outcome data were alive with no evidence of disease at the time of follow-up. In individuals with tumor at the surgical margin of the optic nerve with or without extrascleral extension, 6 of 7 (85.7%) were alive with no evidence of disease at the time of follow-up. The authors concluded that durable tumor control is possible in individuals with non-CNS metastases, trilateral or bilateral advanced retinoblastoma, and in those with tumor at the surgical margin of the optic nerve and/or extrascleral extension.

Friedman and colleagues (2013) retrospectively analyzed long-term medical outcomes in 19 survivors of extra-ocular retinoblastoma treated between 1992 and 2009. All survivors had received intensive multimodality therapy for their extra-ocular disease after management of their primary intra-ocular disease, including conventional chemotherapy (n=19, 100%), radiotherapy (n=15, 69%), and/or high-dose chemotherapy and autologous stem cell transplant (n=17, 89%). From the onset of diagnosis of extra-ocular retinoblastoma, the median follow-up was 7.8 years. The most common long-term non-visual outcomes were hearing loss (n=15, 79%), short stature (n=7, 37%), and secondary malignancies (SMN), n=6, 31%). Sixty-eight percent developed two or more non-visual long-term outcomes of any grade. With the exception of short stature, which was not graded for severity, grade 3-4 outcomes were limited to: ototoxicity (n=8; n=4 require hearing aids), SMNs (n=6), and unequal limb length (n=1). Five survivors who developed SMNs carried a known RB1 mutation. SMNs developed at a median of 11.1 years after initial diagnosis and 2 individuals died of their SMN. Long-term cardiac, pulmonary, hepatobiliary, or renal conditions were not observed. The authors concluded that longer comprehensive follow-up is needed to fully assess treatment-related health conditions in this population.

In 2022, Dunkel and colleagues published the results from a prospective, international trial in which 57 participants with metastatic retinoblastoma were treated with intensified therapy. The study included 19 participants with locoregional disease (stage II or III), 18 with stage IVa disease (hematogenous metastasis), and 20 with stage IVb disease (CNS extension). All participants received induction chemotherapy. Those with stage II or III retinoblastoma also received radiation therapy. All participants with stage IVa or IVb disease received high-dose chemotherapy and autologous HSCT after induction. Stage IVa or IVb participants with residual disease after chemotherapy also received radiation therapy. While the authors note limitations regarding missing data and lack of information regarding previously administered treatment, for stage II and stage III retinoblastoma, 1-year EFS was 88.1%. One-year EFS was 82.6% for stage IVa and 28.3% for stage IVb. There were 2 treatment-related deaths and 47 grade 3 or greater adverse events. Six participants developed secondary malignancies. The authors concluded that intensive multimodality treatment is highly effective for stage II, stage III, and stage IVa retinoblastoma.

A 2023 study reported the outcomes of autologous HSCT for participants with stage IVa metastatic retinoblastoma. In this retrospective review, Sait and colleagues discussed 24 participants (some who had been included in the Dunkel 2010a study discussed above) who received high-dose chemotherapy and autologous HSCT. Four participants had recurrences and died from the disease. With a median follow-up of 7.1 years, 16 participants remained in remission and free of retinoblastoma concluding that intensive multimodality therapy supported by autologous HSCT can be curative for retinoblastoma.

Given the rarity of certain stages of retinoblastoma, there may not be many randomized clinical trials of autologous hematopoietic stem cell transplantation conducted for this condition. Several case series (Tsuruta, 2011; Uppuluri, 2019) show complete remission following autologous HSCT for retinoblastoma and improvement in net health outcomes. Current literature has shown promising results from the use of autologous stem cell transplantation for stage IVa or IVb retinoblastoma. Expert opinion encourages the use of a single HSCT to support intensive treatment of advanced retinoblastoma.

Rhabdomyosarcoma

Weigel and colleagues (2001) reviewed and summarized published data on the role of autologous HSCT in the treatment of metastatic or recurrent rhabdomyosarcoma. Their analysis included results for 389 participants in 22 studies. Based on all of the data analyzing EFS and OS, they concluded that HSCT provided no significant in treating this condition.

Klingebiel and colleagues (2008) prospectively compared the efficacy of two high-dose chemotherapy treatments followed by autologous stem cell rescue versus an oral maintenance treatment in 96 children with stage IV soft tissue sarcoma (88 of whom had recurrent rhabdomyosarcoma). Five-year OS probability for the whole group was 0.52 ± 0.14, for the children who received oral maintenance therapy (n=51), and 0.27 ± 0.13 for the transplant group (n=45, p=0.03). For those with recurrent rhabdomyosarcoma, 5-year OS probability was 0.52 ± 0.16 with oral maintenance therapy versus 0.15 ± 0.12 with transplant (p=0.001). The authors concluded that transplant has failed to improve prognosis in metastatic soft tissue sarcoma but that oral maintenance therapy could be a promising alternative.

In a 2022 retrospective review by Schober and colleagues, the authors analyzed the role of allogeneic HSCT for participants with rhabdomyosarcoma compared to standard-of-care regimens. Results for 50 participants were reviewed (15 HLA-matched and 35 not HLA-matched). There were no significant differences in median EFS, OS, and transplant-related mortality. The authors noted no survival benefits of those who received HSCT compared to matched controls.

Other Solid Tumors

No randomized controlled trials of autologous bone marrow transplantation have been published to date for high-risk pediatric solid tumors except neuroblastoma. Several small phase I/II or case control studies have been performed. Most of these studies include different tumor types, multiple prior treatments, and different bone marrow transplant regimens, making conclusions and comparisons difficult. While some studies may indicate a benefit for transplant, other trials have found no difference.

A 2020 single-arm, single-center study by Ma and colleagues evaluated the feasibility and effectiveness of tandem high-dose chemotherapy and autologous stem cell transplant to minimize the use of radiotherapy in very young children with non-metastatic malignant brain tumors. This was an extension of a previous trial to allow for a larger cohort of participants and a longer follow-up time. The study enrolled 20 participants under the age of 3 years. All participants had a diagnosis of malignant brain tumor (4 had anaplastic ependymoma, 4 had medulloblastoma, 4 had PNET, 3 had choroid plexus carcinoma, 2 had high-grade glioma, 1 had immature teratoma, 1 had malignant fibrous histiocytoma, and 1 had atypical teratoid/rhabdoid tumor). Following six cycles of induction chemotherapy, participants received tandem high-dose chemotherapy and autologous stem cell transplantation. Only those individuals with post-operative gross residual tumor at older than 3 years received radiotherapy. After the first session of high-dose chemotherapy and autologous stem cell transplantation, 18 participants went on to phase two and received the second high-dose chemotherapy and autologous stem cell transplantation. Of those 18 who received the second transplant, 2 died from toxicity, 4 participants had relapse or disease progression. There were 17 participants who remained alive at a median of 7.8 years from diagnosis. Of the survivors, 9 did not receive radiotherapy, 6 received radiotherapy alone, and 2 had relapse following tandem high-dose chemotherapy and autologous stem cell transplant. The 5-year OS was 85%, EFS rate was 70%, and radiotherapy-free survival rate was 75%. EFS rate was 37.5% in those with gross residual tumor compared to 91.7% in those without gross residual tumor. While clinicians try to minimize the use of radiotherapy, particularly craniospinal radiotherapy due to the risk of functional impairment of the developing brain and late adverse effects, tandem high-dose chemotherapy and autologous stem cell transplant has a different set of risks. HSCT often produces severe toxicity and higher treatment-related mortality, particularly during a second transplant. The single-arm and single-center design, along with treatment of a diverse set of CNS tumors makes it difficult to make generalizations about tandem high-dose chemotherapy and autologous stem cell transplant in very young individuals with malignant brain tumors. Multi-center, prospective, randomized controlled trials are needed to compare toxicity and efficacy of treatment strategies.

Poor Graft Function

Poor graft function or graft failure is one of the major causes of morbidity and mortality after hematopoietic stem cell transplantation. Poor graft function is defined as slow or incomplete recovery of blood cell counts following a stem cell transplant or decreasing blood counts after initially successful hematopoietic engraftment following a stem cell transplant. There are several options for the management of poor graft function. Stem cell “boost” is a non-standardized term used to describe an infusion of additional hematopoietic stem cells to an individual who has undergone a recent hematopoietic stem cell transplantation and has poor graft function (Larocca, 2006). The infusion of additional hematopoietic stem cells may mitigate graft failure or rejection with or without immunosuppression. This process may include the collection of additional hematopoietic stem cells from a donor and infusion into the transplant recipient. Note that a "boost" is distinct from a repeat transplant and that there may be separate medical necessity criteria for a repeat transplant.

Allogeneic Hematopoietic Stem Cell Transplantation

Studies using allogeneic of HSCT for pediatric solid tumors are either lacking or associated with a higher risk of transplant-related mortality.

Overview

In 2020, the American Society for Transplantation and Cellular Therapy (ASTCT, Kanate, 2020) published guidelines on indications for hematopoietic cell transplant and immune effector cell therapy. Definitions used for classifying indications for hematopoietic cell transplant were: standard of care (S); standard of care, clinical evidence available (C); standard of care, rare indication (R); Developmental (D); and not generally recommended (N). Indications for hematopoietic cell transplantation in “pediatric patients” (generally age below 18 years of age) include the following classifications for solid tumors:

1. Ewing’s sarcoma, high risk or relapse (D for allogeneic and S for autologous)
2. Soft tissue sarcoma, high risk or relapse (D for allogeneic and D for autologous)
3. Neuroblastoma, high risk or relapse (D for allogeneic and S for autologous)
4. Wilms’ tumor, relapse (N for allogeneic and C for autologous)
5. Osteosarcoma, high risk (N for allogeneic and C for autologous)
6. Medulloblastoma, high risk (N for allogeneic and C for autologous)
7. Other malignant brain tumors (N for allogeneic and C for autologous)

Neuroblastoma

The use of single autologous hematopoietic stem cell transplantation has become widely accepted as a treatment option for children with high-risk neuroblastoma. Encouraging results have been reported on the use of tandem autologous hematopoietic stem cell transplantation for the initial treatment of high-risk neuroblastoma. Currently, some transplant centers use tandem autologous hematopoietic stem cell as the preferred treatment for high-risk neuroblastoma. There is insufficient evidence to support the use of three or more autologous HSCTs for neuroblastoma. A large retrospective review that included allogeneic HSCT for high-risk neuroblastoma (Ladenstein, 2008) indicated that allogeneic HSCTs failed to produce a survival benefit over autologous HSCT and was associated with a higher risk of transplant related mortality.

PNETs of the Central Nervous System, Ependymoma and Pineoblastoma

The use of single autologous HSCT is supported by case series demonstrating EFS. In addition, specialty consensus opinion suggests autologous HSCT may be useful under specific circumstances to treat childhood ependymomas or pineoblastomas.

Ewing Sarcoma

Case series demonstrate a survival benefit with the use of a single autologous HSCT for Ewing Sarcoma.

Wilms’ Tumor

The use of HSCT for Wilms’ tumor failed to show a survival benefit.

Osteosarcoma

The use of HSCT for osteosarcoma has failed to show a survival benefit.

Retinoblastoma

Given the rarity of stage IVa and IVb retinoblastoma it is unlikely that randomized clinical trials of autologous HSCT will be conducted for this condition.

Rhabdomyosarcoma

The use of HSCT for rhabdomyosarcoma has failed to show a survival benefit.

Neuroblastoma

Neuroblastoma is a rare solid cancerous tumor that forms in nerve cells of infants and young children. There are approximately 650 cases diagnosed each year in the United States. Neuroblastomas can originate in nerve tissues of the neck, chest, abdomen, or pelvis, but they most often originate in the tissues of the adrenal gland.

Peripheral neuroblastomas arise within the sympathetic nervous system and can present as a neck, mediastinal, abdominal, or pelvic mass. Peripheral neuroblastomas may be categorized as low, intermediate and high-risk based on patient age, the stage of the tumor and the amplification of the MYCN gene. Treatment typically consists of initial induction chemotherapy to reduce tumor burden, followed by surgery and local irradiation, followed by consideration of high-dose chemotherapy.

Central Nervous System Embryonal Tumors

CNS embryonal tumors are the most common malignant brain tumors in children. They account for 20% to 25% of primary CNS tumors in children. Embryonal tumors include supratentorial PNETs, medulloblastoma, neuroblastoma arising in the CNS, ependymoblastoma, medulloepithelioma, ganglioneuroblastoma, and atypical teratoid/rhabdoid tumor. Classification is based on both histopathologic characteristics of the tumor and location in the brain. Medulloblastoma is the most common type of CNS embryonal tumor.

Ependymoma

Ependymoma is a neuroepithelial tumor that may arise throughout the CNS, but is typically contiguous with the ventricular system. In children the tumor typically arises intracranially, while in adults a spinal cord location is more common. Ependymomas are distinct from ependymoblastomas due to their more mature histological differentiation. For this reason, ependymomas are not formally considered a member of the PNET family. Ependymomas comprise about 9% of all brain and spinal cord tumors in children which represents about 200 cases per year in the United States.

Pineoblastoma

A pineoblastoma is a fast growing type of brain tumor that occurs in or around the pineal gland, near the center of the brain. This type of tumor closely resembles a PNET, except for location and is considered by some to be a variant of a PNET. These types of tumors are rare and comprise 0.2% of all brain tumors.

Ewing Sarcoma

Ewing sarcoma is a cancer that occurs primarily in the bone or soft tissue. Ewing sarcoma can occur in any bone, but is most often found in the extremities and can involve muscle and the soft tissues around the tumor site. Ewing sarcoma cells can also spread (metastasize) to other areas of the body including the bone marrow, lungs, kidneys, heart, adrenal gland, and other soft tissues. This type of bone tumor accounts for about 30% of pediatric bone cancers. Ewing sarcoma most often occurs in children between the ages of 5 and 20.

Wilms’ Tumor

Wilms’ tumor is the most frequent tumor of the kidney in children and infants. There are approximately 650 cases diagnosed each year in the United States. Most incidences of Wilms tumor develop in healthy children, but approximately 10% of those children have been reported to have a congenital anomaly. Treatment may include surgery, chemotherapy and radiation therapy.

Osteosarcoma

Osteosarcoma is a cancer of the bone that destroys tissue and weakens the bone. It starts in immature bone cells that normally form new bone tissue. There are approximately 450 cases of osteosarcoma diagnosed in the United States each year.

Retinoblastoma

Retinoblastoma is an uncommon childhood tumor. It arises in the retina and is the most common primary tumor of the eye in children with approximately 200-300 cases diagnosed each year. If left untreated, mortality is 100% but with current therapy has at least a 90% cure rate. Once disease has spread beyond the eye, survival rates drop significantly (5-year DFS is less than 10% in those with extraocular disease).

Rhabdomyosarcoma

Rhabdomyosarcoma is a cancerous tumor that originates in the soft tissues of the body, including the muscles, tendons, and connective tissues. The most common sites for this tumor include the head, neck, bladder, vagina, arms, legs, and trunk. Embryonal rhabdomyosarcoma, the most common type, usually occurs in children under 6 years of age. Alveolar rhabdomyosarcoma occurs in older children and accounts for about 20 percent of all cases. Rhabdomyosarcoma is the most common soft tissue sarcoma in childhood. In the United States, about 250 children are diagnosed with rhabdomyosarcoma each year.

Ablative: A very high dose of a treatment, calculated to kill a tumor.

Bone marrow: A spongy tissue located within flat bones, including the hip and breast bones and the skull. This tissue contains stem cells, the precursors of platelets, red blood cells, and white cells.

Chemotherapy: Medical treatment of a disease, particularly cancer, with drugs or other chemicals.

Chimerism: Cell populations derived from different individuals and may be mixed or complete.

Complete response/remission (CR): The disappearance of all signs of cancer in response to treatment. This does not always mean the cancer has been cured; also called a complete response.

Cytotoxic: Destructive to cells.

Event-free survival: Refers to the length of time after primary treatment for a cancer that an individual is free of complications or events that treatment was intended to prevent or delay. This may include return of the cancer or the onset of other symptoms. EFS is used in clinical trials as a way to measure how well a new treatment works.

Failure to engraft: When the hematopoietic stem cells infused during a stem cell transplant do not grow and function adequately in the bone marrow.

Graft versus host disease: A life-threatening complication of bone marrow transplants in which the donated marrow causes an immune reaction against the recipient’s body.

Hematopoietic stem cells: Primitive cells capable of replication and formation into mature blood cells in order to repopulate the bone marrow.

High-dose or myeloablative chemotherapy (HDC): The administration of cytotoxic agents using doses several times greater than the standard therapeutic dose.

HLA (human leukocyte antigen): A group of protein molecules located on bone marrow cells that can provoke an immune response.

International Neuroblastoma Staging System (INSS) High Risk Neuroblastoma:

1. INSS Stage 2A/2B tumors in children older than 1 year, and in whom the tumor has both unfavorable Shimada classification and MYCN gene amplification
2. INSS Stage 3 tumors in infants younger than 1 year, and in whom the tumor has MYCN gene amplification
3. INSS Stage 3 tumors in children older than 1 year and in whom the tumor demonstrates either MYCN gene amplification or unfavorable Shimada classification
4. INSS Stage 4 tumors in infants younger than 18 months at diagnosis and in whom the tumor demonstrates MYCN gene amplification
5. INSS Stage 4 tumors in children older than 18 months with or without MYCN gene amplification
6. INSS Stage 4S tumor in infants younger than 1 year of age at diagnosis and in whom the tumor demonstrates MYCN gene amplification

Non-myeloablative chemotherapy: Less intense chemotherapy conditioning regimens, which rely more on immunosuppression than cytotoxic effects to permit engraftment of donor cells.

Partial response: A decrease in the size of a tumor, or in the extent of cancer in the body, in response to treatment. Also called partial remission.

Primary graft failure: When the hematopoietic stem cells infused during a stem cell transplant do not grow and function adequately in the bone marrow.

Primary refractory disease: Cancer that does not respond at the beginning of treatment; also called resistant disease.

Relapse: After a period of improvement, the return of signs and symptoms of cancer.

Tandem: Planned infusion (transplant) of previously harvested hematopoietic stem cells with a repeat hematopoietic stem cell infusion (transplant) that is performed within six months of the initial transplant. This is distinguished from a repeat transplantation requested or performed more than six months after the first transplant, and is used as salvage therapy after failure of initial transplantation or relapsed disease.

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member’s contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services may be Medically Necessary when criteria are met for autologous transplants:

When services are Investigational and Not Medically Necessary for autologous transplants:
For the procedure and diagnosis codes listed above when criteria are not met, for the following diagnosis codes, or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

When services may be Medically Necessary when criteria are met for allogeneic transplants:

When services are Investigational and Not Medically Necessary for allogeneic transplants:
For the procedure and diagnosis codes listed above when criteria are not met, for the following diagnoses, or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

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49. Zacharoulis S, Levy A, Chi SN, et al. Outcome for young children newly diagnosed with ependymoma, treated with intensive induction chemotherapy followed by myeloablative chemotherapy and autologous stem cell rescue. Pediatr Blood Cancer. 2007; 49(1):34-40.

Government Agency, Medical Society, and Other Authoritative Publications:

1. Centers for Medicare and Medicaid Services. National Coverage Determination: Stem Cell Transplantation. NCD #110.23. Effective October 7, 2024. Available at: http://www.cms.hhs.gov/mcd/index_list.asp?list_type=ncd. Accessed on October 03, 2025.
2. 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 Transplantation. 2020; 26(7):1247-1256.
3. National Cancer Institute. Available at: http://www.cancer.gov/publications/pdq/information-summaries. Accessed on October 03, 2025.
   • Childhood Brain and Spinal Cord Tumors (PDQ^®). Updated December 19, 2023.
   • Childhood Medulloblastoma and Other Central Nervous System Embryonal Tumors Treatment (PDQ). Updated April 11, 2025.
   • Childhood Soft Tissue Sarcoma Treatment (PDQ). Updated April 21, 2025.
   • Ewing Sarcoma and Undifferentiated Small Round Cell Sarcomas of Bone and Soft Tissue Treatment (PDQ). Updated November 27, 2024.
   • Neuroblastoma Treatment (PDQ). Updated April 28, 2025.
   • Osteosarcoma and Undifferentiated Pleomorphic Sarcoma of Bone Treatment (PDQ). Updated December 2, 2024.
   • Retinoblastoma Treatment (PDQ). Updated April 3, 2024.
   • Wilms Tumor and Other Childhood Kidney Tumors Treatment (PDQ). Updated April 15, 2025.
4. NCCN Clinical Practice Guidelines in Oncology^™: ^© 2025 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: http://www.nccn.org/index.asp. Accessed on October 03, 2025.
   • Bone Cancer (V1.2026). September 11, 2025.
   • Central Nervous System Cancers (V2.2025). August 28, 2025.
   • Soft Tissue Sarcoma (V1.2025). May 2, 2025.
5. Yalcin B, Kremer LCM, Caron HN, van Dalen EC. High-dose chemotherapy and autologous hematopoietic stem cell rescue for children with high-risk neuroblastoma. Cochrane Database Syst Rev. 2015;(10):CD006301.

1. American Cancer Society. Available at: http://www.cancer.org/. Accessed on October 03, 2025.
2. National Cancer Institute. Stem cell transplants in cancer treatment. Updated October 5, 2023. Available at: http://www.cancer.gov/cancertopics/factsheet/Therapy/bone-marrow-transplant. Accessed on October 03, 2025.

Hematopoietic Stem Cell Transplantation
Mini Transplant
Non-Myeloablative Stem Cell Transplant
Peripheral Blood Stem Cell
Reduced Intensity Conditioning (RIC)
Reduced Intensity Transplantation
Stem Cell Support (SCS)
Stem Cell Transplant (SCT)

Applicable to Commercial HMO members in California: When a medical policy states a procedure or treatment is investigational, PMGs should not approve or deny the request. Instead, please fax the request to Anthem Blue Cross Grievance and Appeals at fax # 818-234-2767 or 818-234-3824. For questions, call G&A at 1-800-365-0609 and ask to speak with the Investigational Review Nurse.

Federal and State law, as well as contract language, including definitions and specific contract provisions/exclusions, take precedence over Medical Policy and must be considered first in determining eligibility for coverage. The member’s contract benefits in effect on the date that services are rendered must be used. Medical Policy, which addresses medical efficacy, should be considered before utilizing medical opinion in adjudication. Medical technology is constantly evolving, and we reserve the right to review and update Medical Policy periodically.

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