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Progenitor cell therapy describes the use of multipotent cells of various cell lineages (autologous or allogeneic) for tissue repair and/or regeneration. Progenitor cell therapy is being investigated for the treatment of damaged myocardium resulting from acute or chronic cardiac ischemia and for refractory angina.
Ischemia is the most common cause of cardiovascular disease and myocardial damage in the developed world. Despite impressive advances in treatment, ischemic heart disease is still associated with high morbidity and mortality. Current treatments for ischemic heart disease seek to revascularize occluded arteries, optimize pump function, and prevent future myocardial damage. However, current treatments are unable to reverse existing damage to heart muscle. Treatment with progenitor cells (i.e., stem cells) offers potential benefits beyond those of standard medical care, including the potential for repair and/or regeneration of damaged myocardium. Potential sources of embryonic and adult donor cells include skeletal myoblasts, bone marrow cells, circulating blood-derived progenitor cells, endometrial mesenchymal stem cells (MSCs), adult testis pluripotent stem cells, mesothelial cells, adipose-derived stromal cells, embryonic cells, induced pluripotent stem cells, and bone marrow MSCs, all of which are able to differentiate into cardiomyocytes and vascular endothelial cells.
The mechanism of benefit after treatment with progenitor cells is not entirely understood. Differentiation of progenitor cells into mature myocytes and engraftment of progenitor cells into areas of damaged myocardium has been suggested in animal studies using tagged progenitor cells. However, there is controversy concerning whether injected progenitor cells actually engraft and differentiate into mature myocytes in humans to a degree that might result in clinical benefit. It also has been proposed that progenitor cells may improve perfusion to areas of ischemic myocardium. Basic science research also suggests that injected stem cells secrete cytokines with antiapoptotic and pro-angiogenesis properties. Clinical benefit may result if these paracrine factors limit cell death from ischemia or stimulate recovery. For example, myocardial protection can occur through modulation of inflammatory and fibrogenic processes. Alternatively, paracrine factors may affect intrinsic repair mechanisms of the heart through neovascularization, cardiac metabolism, and contractility, increase in cardiomyocyte proliferation, or activation of resident stem and progenitor cells. The relative importance of these proposed paracrine actions depends on the age of the infarct (eg, cytoprotective effects in acute ischemia and cell proliferation in chronic ischemia). Investigation of the specific factors induced by administration of progenitor cells is ongoing.
There also are various potential delivery mechanisms for donor cells, encompassing a wide range of invasiveness. Donor cells can be delivered via thoracotomy and direct injection into areas of damaged myocardium. Injection of progenitor cells into the coronary circulation also is done using percutaneous, catheter-based techniques. Finally, progenitor cells may be delivered intravenously via a peripheral vein. With this approach, the cells must be able to target damaged myocardium and concentrate at the site of myocardial damage.
Adverse effects of progenitor cell treatment include the risks of the delivery procedure (e.g., thoracotomy, percutaneous catheter-based) and risks of the donor cells themselves. Donor progenitor cells can differentiate into fibroblasts rather than myocytes. This may create a substrate for malignant ventricular arrhythmias. There is also a theoretical risk that tumors, such as teratomas, can arise from progenitor cells, but the actual risk in humans is currently unknown.
The U.S. Food and Drug Administration (FDA) regulates human cells and tissues intended for implantation, transplantation, or infusion through the Center for Biologics Evaluation and Research, under Code of Federal Regulation (CFR) title 21, parts 1270 and 1271. Hematopoietic cells are included in these regulations. FDA marketing clearance is not required when autologous cells are processed on site with existing laboratory procedures and injected with existing catheter devices. Several cell products are expanded ex-vivo and require FDA approval.
MyoCell® (Bioheart, Sunrise, FL) comprises patient autologous skeletal myoblasts that are expanded ex vivo and supplied as a cell suspension in a buffered salt solution for injection into the area of damaged myocardium. MyoCell® SDF-1 (Bioheart) is similar to MyoCell®, but before injection, myoblast cells are genetically modified to release excess stromal-derived factor-1 (SDF-1). Increased SDF-1 levels at the site of myocardial damage may accelerate recruitment of native stem cells to increase tissue repair and neovascularization. For both products, myoblast isolation and expansion occur at a single reference laboratory (Bioheart); both products are therefore subject to FDA approval. Currently, neither product has been cleared by the FDA. Implantation may require use of a unique catheter delivery system (eg, MyoCath [Bioheart]) that has been cleared by the FDA.
An allogeneic human mesenchymal stem cell (hMSC) product (Prochymal®; Osiris Therapeutics) is under investigation for the treatment of acute myocardial infarction (AMI). Prochymal® (also referred to as Provacel®; Osiris) is a highly purified preparation of ex vivo cultured adult hMSCs isolated from the bone marrow of healthy young adult donors. Prochymal® has been granted fast track status by the FDA for Crohn disease and graft-versus-host disease (GVHD), and has orphan drug status for GVHD from FDA and the European Medicines Agency.
Ixmyelocel-T (Vericel, formerly Aastrom Biosciences) is an autologous bone marrow-derived multicellular therapy produced by expanding bone marrow mononuclear cells. Ixmyelocel-T was cleared for marketing by FDA through the orphan drug process for the treatment of ischemic dilated cardiomyopathy, based on results of a phase 2b study.
MultiStem® (Athersys) is an allogeneic bone marrow-derived adherent adult stem-cell product. MultiStem® was cleared for marketing by FDA through the orphan drug process for GVHD and has received authorization from FDA for a phase 2 trial for treatment of AMI with an adventitial delivery system. In September 2016, under a Special Protocol Assessment of FDA, Athersys received approval of the design and analysis for its phase 3 trial (MultiStem Administration for Stroke Treatment and Enhanced Recovery Study-2 [MASTERS-2]) on the use of MultiStem® for treating patients who had experienced an ischemic stroke.
POLICYProgenitor cell therapy, including but not limited to skeletal myoblasts or hematopoietic stem cells, is considered investigational as a treatment of damaged myocardium.
Infusion of growth factors (i.e., granulocyte colony stimulating factor [GCSF]) is considered investigational as a technique to increase the numbers of circulating hematopoietic stem cells as treatment of damaged myocardium.
The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.
Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.
POLICY HISTORY7/15/2004: Approved by Medical Policy Advisory Committee (MPAC)
10/5/2004: Code Reference section completed
3/15/2006: Policy reviewed, no changes
7/22/2008: Policy reviewed, no changes
8/10/2009: Policy Title revised to add "Progenitor" and "due to Ischemia", Policy Description Section updated to add research information on various types of autologous cell tranplantation and adverse effects of treatment with progenitor cells, Verbage, " Investigational for all uses", added to Non-Covered ICD-9 Diagnosis codes Section.
07/16/2010: Policy reviewed; no changes.
08/02/2011: Policy reviewed; no changes.
07/17/2012: Policy reviewed. Deleted "Autologous" from the policy title and statement. Deleted outdated references from the Sources section.
09/03/2013: Policy reviewed; no changes.
08/06/2014: Policy reviewed; description updated regarding products. Policy statement unchanged.
08/14/2015: Code Reference section updated for ICD-10.
10/22/2015: Policy description updated. Policy statements unchanged. Investigative definition updated in policy guidelines section.
06/06/2016: Policy number A.2.02.18 added.
01/16/2017: Policy description updated regarding FDA regulation and products. Policy statements unchanged.
SOURCE(S)Blue Cross Blue Shield Association policy # 2.02.18
CODE REFERENCEThis may not be a comprehensive list of procedure codes applicable to this policy.
There are no specific codes for this procedure, either describing the laboratory component of processing the harvested autologous cells, or for the implantation procedure. The laboratory component may be reported with the stem cell procedure codes (38204, 38206, 38207, 38208, 38209, 38210, 38211, 38212, 38213, 38214, 38215, 38230, 38241). In some situations, the implantation may be an added component of a scheduled coronary artery bypass graft (CABG); in other situations, the implantation may be performed as a unique indication for a cardiac catheterization procedure.
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