348 Form

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Medical Policy Stem Cell Therapy for Peripheral Arterial Disease Table of Contents • Policy: Commercial • Coding Information
• Information Pertaining to All Policies
• Policy: Medicare • Description
• References
• Authorization Information • Policy History

Policy Number: 348

BCBSA Reference Number: 8.01.55 (For Plans internal use only) NCD/LCD: NA Related Policies
• Orthopedic Applications of Stem Cell Therapy, #254 • Progenitor Cell Therapy for the Treatment of Damaged Myocardium due to Ischemia, #652 Policy Commercial Members: Managed Care (HMO and POS), PPO, and Indemnity
Medicare HMO BlueSM and Medicare PPO BlueSM Members

Treatment of peripheral arterial disease, including critical limb ischemia, with injection or infusion of stem cells from concentrated bone marrow, expanded in vitro, stimulated from peripheral blood, or from an allogeneic source, is considered INVESTIGATIONAL. 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) This is not a covered service. Commercial PPO and Indemnity This is not a covered service. Medicare HMO BlueSM This is not a covered service. Medicare PPO BlueSM This is not a covered service.

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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 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 0263T Intramuscular autologous bone marrow cell therapy, with preparation of harvested cells, multiple injections, one leg, including ultrasound guidance, if performed; complete procedure including unilateral or bilateral bone marrow harvest 0264T Intramuscular autologous bone marrow cell therapy, with preparation of harvested cells, multiple injections, one leg, including ultrasound guidance, if performed; complete procedure excluding bone marrow harvest 0265T Intramuscular autologous bone marrow cell therapy, with preparation of harvested cells, multiple injections, one leg, including ultrasound guidance, if performed; unilateral or bilateral bone marrow harvest only for intramuscular autologous bone marrow cell therapy.

Description Peripheral Arterial Disease Peripheral arterial disease (PAD) is a common atherosclerotic syndrome associated with significant morbidity and mortality.1, A less common cause of PAD is Buerger disease (also called thromboangiitis obliterans), which is a nonatherosclerotic segmental inflammatory disease that occurs in younger patients and is associated with tobacco use.2, The development of PAD is characterized by narrowing and occlusion of arterial vessels and eventual reduction in distal perfusion. Critical limb ischemia is the end stage of lower-extremity PAD in which severe obstruction of blood flow results in ischemic pain at rest, ulcers, and a significant risk for limb loss. Physiology Two endogenous compensating mechanisms may occur with occlusion of arterial vessels: capillary growth (angiogenesis) and development of collateral arterial vessels (arteriogenesis).3, Capillary growth is mediated by the hypoxia-induced release of chemokines and cytokines such as vascular endothelial growth factor and occurs by sprouting of small endothelial tubes from preexisting capillary beds. The resulting capillaries are small and cannot sufficiently compensate for a large, occluded artery. Arteriogenesis with collateral growth is, in contrast, initiated by increasing shear forces against vessel walls when blood flow is redirected from the occluded transport artery to the small collateral branches, leading to an increase in the diameter of preexisting collateral arterioles.

The mechanism underlying arteriogenesis includes the migration of bone marrow-derived monocytes to the perivascular space. The bone marrow-derived monocytes adhere to and invade the collateral vessel wall. It is not known if the expansion of the collateral arteriole is due to the incorporation of stem cells into the wall of the vessel or to cytokines released by monocytic bone marrow cells that induce the proliferation of resident endothelial cells. It has been proposed that bone marrow-derived monocytic cells may be the putative circulating endothelial progenitor cells. Notably, the same risk factors for advanced

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ischemia (diabetes, smoking, hyperlipidemia, advanced age) are also risk factors for a lower number of circulating progenitor cells.

Treatment Use of autologous stem cells freshly harvested and allogeneic stem cells are reported to have a potential role in the treatment of PAD.4, Stem cells can be administered in a variety of routes, derived from different progenitors, and be grouped with different co-factors, many of which are being studied in order to determine the best clinical option for patients. The primary outcome in stem cell therapy trials regulated by the U.S. Food and Drug Administration (FDA) is amputation-free survival, defined as time to major amputation and/or death from any cause. Other outcomes for critical limb ischemia include the Rutherford criteria for limb status, healing of ulcers, the Ankle-Brachial Index (ABI), transcutaneous oxygen pressure, and pain-free walking. The ABI measures arterial segmental pressures on the ankle and brachium and indexes ankle systolic pressure against brachial systolic pressure (normative range, 0.95 to 1.2 mm Hg). Summary Peripheral arterial disease (PAD) is a common atherosclerotic syndrome associated with significant morbidity and mortality. Critical limb ischemia (CLI) is the end stage of lower-extremity PAD in which severe obstruction of blood flow results in ischemic pain at rest, ulcers, and a significant risk for limb loss. Use of autologous stem cells freshly harvested and allogeneic stem cells are reported to have a role in the treatment of PAD. For individuals who have peripheral arterial disease (PAD) who receive stem cell therapy, the evidence includes small, randomized trials and systematic reviews. Relevant outcomes are overall survival, symptoms, change in disease status, morbid events, functional outcomes, quality of life, and treatment- related morbidity. The current literature on stem cells as a treatment for critical limb ischemia (CLI) due to PAD consists primarily of phase 2 studies using various cell preparation methods and methods of administration. A meta-analysis of the trials with the lowest risk of bias has shown no significant benefit of stem cell therapy for overall survival, amputation-free survival, or amputation rates. Three randomized controlled trials (RCTs) have been published that used granulocyte-macrophage colony-stimulating factor (GM-CSF)-mobilized peripheral blood mononuclear cells (PBMNC). The route of administration of cell therapy and the primary outcomes differed between studies. In the trial that added cell therapy to guideline- based care, there were no significant differences in progression-free survival and frequency of limb amputation at 1 year of follow-up. There was a substantial rate of subsequent surgical intervention in both arms. Well-designed RCTs with a larger number of subjects and low risk of bias are needed to evaluate the health outcomes of these various procedures. Several are in progress, including multicenter randomized, double-blind, placebo-controlled trials. More data on the safety and durability of these treatments are also needed. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome. Policy History Date Action 3/2026 Annual policy review. Policy updated with literature review through November 24, 2025; reference added. Policy statement unchanged 3/2025 Annual policy review. Description, summary, and references updated. Policy statements unchanged. 3/2024 Annual policy review. Description, summary, and references updated. Policy statements unchanged. 3/2023 Annual policy review. Description, summary, and references updated. Policy statements unchanged. 2/2022 Annual policy review. Policy statements unchanged. 3/2021 Annual policy review. Description, summary, and references updated. Policy statements unchanged.

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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. 3/2018 Annual policy review. Description, summary, and references updated. Policy statements unchanged. 12/2017 Annual policy review.
Policy statement updated to describe specific sources of stem cells. Effective 12/1/2017. 3/2016 Annual policy review. New references added. 12/2015 Added coding language. 7/2015 Annual policy review. New references added. 6/2013 Annual policy review. New references added. 5/1/12 New policy describing ongoing non-coverage. 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. Krishna SM, Moxon JV, Golledge J. A review of the pathophysiology and potential biomarkers for peripheral artery disease. Int J Mol Sci. May 18 2015; 16(5): 11294-322. PMID 25993296
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6. Xie B, Luo H, Zhang Y, et al. Autologous Stem Cell Therapy in Critical Limb Ischemia: A Meta-Analysis of Randomized Controlled Trials. Stem Cells Int. 2018; 2018: 7528464. PMID 29977308
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8. PMID 31113463
9. Pu H, Huang Q, Zhang X, et al. A meta-analysis of randomized controlled trials on therapeutic efficacy and safety of autologous cell therapy for atherosclerosis obliterans. J Vasc Surg. Apr 2022; 75(4): 1440- 1449.e5. PMID 34788653
10. Moazzami B, Mohammadpour Z, Zabala ZE, et al. Local intramuscular transplantation of autologous bone marrow mononuclear cells for critical lower limb ischaemia. Cochrane Database Syst Rev. Jul 08 2022; 7(7): CD008347. PMID 35802393
11. Procházka V, Gumulec J, Jalůvka F, et al. Cell therapy, a new standard in management of chronic critical limb ischemia and foot ulcer. Cell Transplant. 2010; 19(11): 1413-24. PMID 20529449
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13. PMID 21951607

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12. Skóra J, Pupka A, Janczak D, et al. Combined autologous bone marrow mononuclear cell and gene therapy as the last resort for patients with critical limb ischemia. Arch Med Sci. Apr 25 2015; 11(2): 325-
13. PMID 25995748
14. Gupta PK, Krishna M, Chullikana A, et al. Administration of Adult Human Bone Marrow-Derived, Cultured, Pooled, Allogeneic Mesenchymal Stromal Cells in Critical Limb Ischemia Due to Buerger's Disease: Phase II Study Report Suggests Clinical Efficacy. Stem Cells Transl Med. Mar 2017; 6(3): 689-699. PMID 28297569
15. Dubský M, Husáková J, Bem R, et al. Comparison of the impact of autologous cell therapy and conservative standard treatment on tissue oxygen supply and course of the diabetic foot in patients with chronic limb-threatening ischemia: A randomized controlled trial. Front Endocrinol (Lausanne). 2022; 13: 888809. PMID 36105404
16. Henderson, F. C., Sarel, I., Tuchman, K., Lewis, S., & Hsiang, Y. (2024). Angiogenic Precursor Cell Treatment of Critical Limb Ischemia Decreases Ulcer Size, Amputation and Death Rate: Re- Examination of phase II ACP NO-CLI Trial Data. Journal ISSN, 2766, 2276.
17. Teraa M, Sprengers RW, Schutgens RE, et al. Effect of repetitive intra-arterial infusion of bone marrow mononuclear cells in patients with no-option limb ischemia: the randomized, double-blind, placebo- controlled Rejuvenating Endothelial Progenitor Cells via Transcutaneous Intra-arterial Supplementation (JUVENTAS) trial. Circulation. Mar 10 2015; 131(10): 851-60. PMID 25567765
18. Peeters Weem SM, Teraa M, den Ruijter HM, et al. Quality of Life After Treatment with Autologous Bone Marrow Derived Cells in No Option Severe Limb Ischemia. Eur J Vasc Endovasc Surg. Jan 2016; 51(1): 83-9. PMID 26511056
19. Walter DH, Krankenberg H, Balzer JO, et al. Intraarterial administration of bone marrow mononuclear cells in patients with critical limb ischemia: a randomized-start, placebo-controlled pilot trial (PROVASA). Circ Cardiovasc Interv. Feb 01 2011; 4(1): 26-37. PMID 21205939
20. Powell RJ, Comerota AJ, Berceli SA, et al. Interim analysis results from the RESTORE-CLI, a randomized, double-blind multicenter phase II trial comparing expanded autologous bone marrow- derived tissue repair cells and placebo in patients with critical limb ischemia. J Vasc Surg. Oct 2011; 54(4): 1032-41. PMID 21684715
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24. McDermott MM, Ferrucci L, Tian L, et al. Effect of Granulocyte-Macrophage Colony-Stimulating Factor With or Without Supervised Exercise on Walking Performance in Patients With Peripheral Artery Disease: The PROPEL Randomized Clinical Trial. JAMA. Dec 05 2017; 318(21): 2089-2098. PMID 29141087
25. Horie T, Yamazaki S, Hanada S, et al. Outcome From a Randomized Controlled Clinical Trial - Improvement of Peripheral Arterial Disease by Granulocyte Colony-Stimulating Factor-Mobilized Autologous Peripheral-Blood-Mononuclear Cell Transplantation (IMPACT). Circ J. Jul 25 2018; 82(8): 2165-2174. PMID 29877199
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28. Tendera M, Aboyans V, Bartelink ML, et al. ESC Guidelines on the diagnosis and treatment of peripheral artery diseases: Document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteries: the Task Force on the Diagnosis and Treatment of Peripheral Artery Diseases of the European Society of Cardiology (ESC). Eur Heart J. Nov 2011; 32(22): 2851-906. PMID 21873417
29. Aboyans V, Ricco JB, Bartelink MEL, et al. 2017 ESC Guidelines on the Diagnosis and Treatment of Peripheral Arterial Diseases, in collaboration with the European Society for Vascular Surgery (ESVS): Document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteries Endorsed by: the European Stroke Organization (ESO)The Task Force for the Diagnosis and Treatment of Peripheral Arterial Diseases of the European Society of Cardiology (ESC) and of the European Society for Vascular Surgery (ESVS). Eur Heart J. Mar 01 2018; 39(9): 763-816. PMID 28886620
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