247 Form

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Medical Policy Hematopoietic Cell Transplantation in the Treatment of Germ Cell Tumors Table of Contents • Policy: Commercial • Coding Information
• Information Pertaining to All Policies
• Policy: Medicare • Description
• References
• Authorization Information • Policy History

Policy Number: 247

BCBSA Reference Number: 8.01.35 (For Plan internal use only) NCD/LCD: N/A Related Policies
None

Policy Commercial Members: Managed Care (HMO and POS), PPO, and Indemnity
Medicare HMO BlueSM and Medicare PPO BlueSM Members

Single autologous hematopoietic cell transplantation (HCT) may be considered MEDICALLY NECESSARY as salvage therapy for germ cell tumors: • In individuals with favorable prognostic factors that have failed a previous course of conventional- dose salvage chemotherapy, OR
• In individuals with unfavorable prognostic factors* as initial treatment of first relapse (ie, without a course of conventional-dose salvage chemotherapy) and in individuals with platinum-refractory disease.

Tandem autologous HCT or transplant with sequential high-dose chemotherapy may be considered MEDICALLY NECESSARY for the treatment of testicular tumors either as salvage therapy or with platinum-refractory disease.

Autologous HCT is considered INVESTIGATIONAL as a component of first-line treatment for germ-cell tumors.

Allogeneic HCT is considered INVESTIGATIONAL to treat germ cell tumors, including, but not limited, to its use as therapy after prior failed autologous HCT.

• Individuals with favorable prognostic factors include those with a testis or retroperitoneal primary site, a complete response to initial chemotherapy, low levels of serum markers, and low-volume disease.

  ** Individuals with unfavorable prognostic factors are those with an extra testicular primary site, an

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incomplete response to initial therapy, high levels of serum markers, high-volume disease, or relapsing mediastinal nonseminomatous germ cell tumors.

The favorable and unfavorable prognostic factors above are derived from the current National Comprehensive Cancer Network guidelines and DeVita et al’s textbook Cancer: Principles and Practice of Oncology (2015, pp. 988-1004).

Prior Authorization Information
Inpatient • For services described in this policy, precertification/preauthorization IS REQUIRED for all products if the procedure is performed inpatient.
Outpatient • For services described in this policy, see below for products where prior authorization might be required if the procedure is performed outpatient.

Outpatient Commercial Managed Care (HMO and POS) Prior authorization is required. Commercial PPO and Indemnity Prior authorization is required. Medicare HMO BlueSM Prior authorization is required. Medicare PPO BlueSM Prior authorization is required.

Requesting Prior Authorization Using Authorization Manager Providers will need to use Authorization Manager to submit initial authorization requests for services. Authorization Manager, available 24/7, is the quickest way to review authorization requirements, request authorizations, submit clinical documentation, check existing case status, and view/print the decision letter. For commercial members, the requests must meet medical policy guidelines.
To ensure the service request is processed accurately and quickly: • Enter the facility’s NPI or provider ID for where services are being performed. • Enter the appropriate surgeon’s NPI or provider ID as the servicing provider, not the billing group.

Authorization Manager Resources Refer to our Authorization Manager page for tips, guides, and video demonstrations. CPT Codes / HCPCS Codes / ICD Codes Inclusion or exclusion of a code does not constitute or imply member coverage or provider reimbursement. Please refer to the member’s contract benefits in effect at the time of service to determine coverage or non-coverage as it applies to an individual member.

Providers should report all services using the most up-to-date industry-standard procedure, revenue, and diagnosis codes, including modifiers where applicable.

The following codes are included below for informational purposes only; this is not an all-inclusive list.

The above medical necessity criteria MUST be met for the following codes to be covered for Commercial Members: Managed Care (HMO and POS), PPO, Indemnity, Medicare HMO Blue and Medicare PPO Blue:

CPT Codes CPT codes: Code Description 38241 Hematopoietic progenitor cell (HPC); autologous transplantation HCPCS Codes

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

The following CPT codes are considered investigational for Commercial Members: Managed Care (HMO and POS), PPO, Indemnity, Medicare HMO Blue and Medicare PPO Blue:

CPT Codes CPT codes: Code Description 38240 Hematopoietic progenitor cell (HPC); allogeneic transplantation per donor HCPCS Codes HCPCS codes: Code Description S2142 Cord blood derived stem-cell transplantation, allogeneic

Description Germ Cell Tumors Germ cell tumors are composed primarily of testicular neoplasms as well as ovarian and extragonadal germ cell tumors (no primary tumor in either testis or ovary). Germ cell tumors are classified by their histology, stage, prognosis, and response to chemotherapy.

The most common testicular germ cell tumors are seminomas; all other histologic types are collectively referred to as nonseminomatous tumors. Nonseminomatous tumor types include embryonal cell tumor, yolk sac tumor, and teratomas. Malignant germ cell tumors of ovarian origin are classified as dysgerminomas or nondysgerminomas. Similarly, nondysgerminomas include immature teratomas, embryonal cell tumors, yolk sac tumor, polyembryoma, and mixed germ cell tumors.

Staging Stage depends on location and extent of the tumor, using the American Joint Committee on Cancer’s TNM system. TNM stages, modified by serum concentrations of markers for tumor burden (S0 to 3) when available, are grouped by similar prognoses. Markers used for germ cell tumors include human β- chorionic gonadotropin, lactate dehydrogenase, and a-fetoprotein. However, most patients with pure seminoma have normal a-fetoprotein concentrations. For testicular tumors, stages IA to B tumors are limited to the testis (no involved nodes or distant metastases) and no marker elevations (S0); stages IIA to C have increasing size and number of tumor-involved lymph nodes, and at least 1 marker moderately elevated above the normal range (S1), and stages IIIA to C have distant metastases and/or marker elevations greater than specified thresholds (S2 to 3). Germ cell tumors also are divided into good-, intermediate-, or poor-risk categories based on histology, site, extent of the primary tumor, and serum marker levels. Good-risk pure seminomas can be at any primary site but are without nonpulmonary visceral metastases or marker elevations. Intermediate-risk pure seminomas have nonpulmonary visceral metastases with or without elevated human chorionic gonadotropin and/or lactate dehydrogenase. There are no poor-risk pure seminomas, but mixed histology tumors and seminomas with elevated a-fetoprotein (due to the mixture with nonseminomatous components) are managed as nonseminomatous germ cell tumors. Good- and intermediate-risk nonseminomatous germ cell tumors have testicular or retroperitoneal tumors without nonpulmonary visceral metastases, and either S1 (good-risk) or S2 (intermediate) levels of marker elevations. Poor-risk tumors have mediastinal primary tumors, or nonpulmonary visceral metastases, or the highest level (S3) of marker elevations.

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Hematopoietic Cell Transplantation Hematopoietic cell transplantation (HCT) 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.

   Conditioning for Hematopoietic Cell Transplantation

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

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

   Reduced-Intensity Conditioning Allogeneic Hematopoietic Cell Transplantation Reduced-intensity conditioning (RIC) refers to the pretransplant use of lower doses of cytotoxic drugs or less intense regimens of radiotherapy than are used in traditional full-dose myeloablative conditioning treatments. Although the definition of RIC 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. RIC 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.

   Summary Description

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Therapy for germ cell tumors is generally dictated by several factors, including disease stage, tumor histology, primary site of tumor, and response to chemotherapy. Patients with unfavorable prognostic factors may be candidates for hematopoietic cell transplantation (HCT).

Summary of Evidence For individuals who have previously untreated germ cell tumors who receive autologous HCT as first-line therapy, the evidence includes randomized controlled trials (RCTs). Relevant outcomes are overall survival (OS), disease-specific survival (DSS), and treatment-related mortality and morbidity. Results from RCTs have shown that autologous HCT as initial therapy for germ cell tumors did not significantly improve outcomes compared with alternative therapy (eg, standard-dose chemotherapy). Study sample sizes were relatively small and might have been underpowered to detect differences between groups. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have relapsed or refractory germ cell tumors who receive autologous HCT, the evidence includes an RCT and several case series. Relevant outcomes are OS, DSS, and treatment- related mortality and morbidity. The single published RCT did not find improved outcomes with high-dose chemotherapy (HDC) and autologous HCT compared with standard-dose HCT. Case series had a wide range of sample sizes. Progression-free and OS rates varied by prior treatment experience, prognostic factors, number of high-dose chemotherapy and autologous stem cell transplantation cycles, and whether additional consolidation treatment such as radiation therapy was included. However, 2- and 3-year progression-free survival rates of 50% to 60% have consistently been achieved. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have germ cell tumors who receive tandem autologous transplantation and sequential HDC, the evidence includes an RCT, several retrospective cohort studies, and a comparative effectiveness review. Relevant outcomes are OS, DSS, and treatment-related mortality and morbidity. The RCT reported a higher rate of treatment-related mortality with sequential HDC compared with single HDC. However, 5 -year survival outcomes did not differ significantly between groups. Overall, the available studies have included heterogeneous patient populations, in different salvage treatment settings (ie, first vs. subsequent salvage therapy), and have lacked a universally accepted prognostic scoring system to risk-stratify patients. Tandem autologous transplant or transplant with sequential HDC has not shown a benefit in patients with primary mediastinal germ cell tumors. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have germ cell tumors who receive allogeneic HCT, the evidence includes a case report. Relevant outcomes are OS, DSS, and treatment-related mortality and morbidity. There were no RCTs or nonrandomized comparative studies evaluating allogeneic HCT for germ cell tumors. One 2007 case report has described successful treatment of a refractory mediastinal germ cell tumor with allogeneic HCT. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Policy History Date Action 2/2026 Annual policy review. References updated. Policy statements unchanged. 10/2025 Clarified coding information 3/2025 Annual policy review. References updated. Policy statements unchanged. 3/2024 Annual policy review. References updated. Policy statements unchanged. 9/2023 Policy clarified to include prior authorization requests using Authorization Manager.
3/2023 Annual policy review. Minor editorial refinements to policy statements; intent unchanged. 2/2022 Annual policy review. Description, summary, and references updated. Policy statements unchanged.

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3/2021 Annual policy review. Description, summary, and references updated. Policy statements unchanged. Clarified coding information.
10/2020 Clarified coding information 5/2020 Policy clarified to include the definition of favorable and unfavorable prognostic factors. 4/2020 Bone marrow harvesting codes were removed. Outpatient prior authorization is not required.
3/2020 Annual policy review. Description, summary, and references updated. Policy statements unchanged. 3/2019 Annual policy review. Description, summary, and references updated. Policy statements unchanged. 1/2019 Outpatient prior authorization is required for all commercial products including Medicare Advantage. Effective 1/1/2019. 4/2018 Annual policy review. Policy statement on tandem autologous HCT or transplant with sequential high-dose chemotherapy clarified. 4/1/2018. 3/2017 Annual policy review. Title changed. New references added. 3/1/2017 6/2015 Annual policy review. New references added. 1/2015 Clarified coding information. 6/2014 Updated Coding section with ICD10 procedure and diagnosis codes, effective 10/2015. 6/2013 Annual policy review. New references added. 12/2012 Updated to add new CPT code 38243. 11/2011-4/2012 Medical policy ICD 10 remediation: Formatting, editing and coding updates. No changes to policy statements.
12/1/2011 Updated - Investigational (not covered) criteria.
9/01/2010 Medical Policy 247 effective 9/01/2010 Describing covered and non-covered indications. Information Pertaining to All Blue Cross Blue Shield Medical Policies Click on any of the following terms to access the relevant information: Medical Policy Terms of Use Managed Care Guidelines Indemnity/PPO Guidelines Clinical Exception Process Medical Technology Assessment Guidelines

References

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3. Daugaard G, Skoneczna I, Aass N, et al. A randomized phase III study comparing standard dose BEP with sequential high-dose cisplatin, etoposide, and ifosfamide (VIP) plus stem-cell support in males with poor-prognosis germ-cell cancer. An intergroup study of EORTC, GTCSG, and Grupo Germinal (EORTC 30974). Ann Oncol. May 2011; 22(5): 1054-1061. PMID 21059637
4. Motzer RJ, Nichols CJ, Margolin KA, et al. Phase III randomized trial of conventional-dose chemotherapy with or without high-dose chemotherapy and autologous hematopoietic stem-cell rescue as first-line treatment for patients with poor-prognosis metastatic germ cell tumors. J Clin Oncol. Jan 20 2007; 25(3): 247-56. PMID 17235042
5. Droz JP, Kramar A, Biron P, et al. Failure of high-dose cyclophosphamide and etoposide combined with double-dose cisplatin and bone marrow support in patients with high-volume metastatic nonseminomatous germ-cell tumours: mature results of a randomised trial. Eur Urol. Mar 2007; 51(3): 739-46; discussion 747-8. PMID 17084512

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9. Adra N, Abonour R, Althouse SK, et al. High-Dose Chemotherapy and Autologous Peripheral-Blood Stem-Cell Transplantation for Relapsed Metastatic Germ Cell Tumors: The Indiana University Experience. J Clin Oncol. Apr 01 2017; 35(10): 1096-1102. PMID 27870561
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11. Baek HJ, Park HJ, Sung KW, et al. Myeloablative chemotherapy and autologous stem cell transplantation in patients with relapsed or progressed central nervous system germ cell tumors: results of Korean Society of Pediatric Neuro-Oncology (KSPNO) S-053 study. J Neurooncol. Sep 2013; 114(3): 329-38. PMID 23824533
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15. Lotz JP, Bui B, Gomez F, et al. Sequential high-dose chemotherapy protocol for relapsed poor prognosis germ cell tumors combining two mobilization and cytoreductive treatments followed by three high-dose chemotherapy regimens supported by autologous stem cell transplantation. Results of the phase II multicentric TAXIF trial. Ann Oncol. Mar 2005; 16(3): 411-8. PMID 15659420
16. Secondino S, Badoglio M, Rosti G, et al. High-dose chemotherapy with autologous stem cell transplants in adult primary non-seminoma mediastinal germ-cell tumors. A report from the Cellular Therapy and Immunobiology working party of the EBMT. ESMO Open. Sep 2024; 9(9): 103692. PMID 39241498
17. Agrawal V, Abonour R, Abu Zaid M, et al. Survival outcomes and toxicity in patients 40 years old or older with relapsed metastatic germ cell tumors treated with high-dose chemotherapy and peripheral blood stem cell transplantation. Cancer. Oct 15 2021; 127(20): 3751-3760. PMID 34260067
18. Lazarus HM, Stiff PJ, Carreras J, et al. Utility of single versus tandem autotransplants for advanced testes/germ cell cancer: a center for international blood and marrow transplant research (CIBMTR) analysis. Biol Blood Marrow Transplant. Jul 2007; 13(7): 778-89. PMID 17580256
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24. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Testicular Cancer, v1.2026. https://www.nccn.org/professionals/physician_gls/pdf/testicular.pdf. Accessed December 8, 2025.
25. Kanate AS, Majhail NS, Savani BN, et al. Indications for Hematopoietic Cell Transplantation and Immune Effector Cell Therapy: Guidelines from the American Society for Transplantation and Cellular Therapy. Biol Blood Marrow Transplant. Jul 2020; 26(7): 1247-1256. PMID 32165328