TRANS.00035 Mesenchymal Stem Cell Therapy For … – anthem.com

This document addresses the use of mesenchymal stem cell (MSC) therapy for regeneration in orthopedic indications (for example, cartilage or bone).

MSCs are progenitor cells located in the bone marrow and other tissues that may develop into connective tissue and bone (Shen, 2005).MSC therapy refers to the procurement (through autologous or cadaveric allogeneic harvest) of MSCs, processing (such as, concentration and/or expansion of cells) and subsequent infusion or implantation of the MSCs into various anatomic areas to promote healing or regeneration of damaged cartilage or bone.

Note: For additional information please see the following related documents:

Investigational and Not Medically Necessary:

Mesenchymal stem cell therapy is considered investigational and not medically necessary for treatment of orthopedic indications.

Surgical repair of tendon, ligament, cartilage and bone defects has been the standard therapy, which may be augmented by autologous grafts, cadaveric allografts or synthetic grafts. However, there have been several limitations to the use of grafts in orthopedic therapy. For instance, autologous graft sources may be hampered by comorbid conditions, limited sites are suitable for harvesting, and the potential of graft failure is an ever-present risk of these procedures. Therefore, alternative regenerative technologies continue to be investigated.

Various agents and techniques to procure and expand MSCs to achieve sufficient numbers for infusion or implantation are being studied and implemented in proprietary processes for diverse orthopedic indications. The processing of cadaveric allogeneic donor MSCs typically involves proprietary techniques and a combination of MSCs with various transport mediums. In addition, it is not clear that mesenchymal stem cells procured from different tissue sources are functionally equivalent. There is a paucity of randomized controlled trials in humans to support the safety and efficacy of using MSC therapy for orthopedic indications, including cartilage and ligament repair and bone regeneration.

At this time, the medical evidence supporting the use of MSCs for orthopedic indications is limited to pre-clinical studies, case series and small, randomized controlled trials. This novel approach has not demonstrated an improved and durable health outcome benefit over standard therapies in robust, large randomized controlled trials with long-term follow-up.

Several preclinical studies have been conducted to evaluate the effectiveness of MSCs in tissue regeneration. Caudwell and colleagues (2014) conducted a systematic review of preclinical studies using MSC and scaffolds in the treatment of knee ligament regeneration. The authors concluded, based on their investigation of 21 articles, that preclinical evidence of ligamentous regeneration with MSC and scaffold use was established, but limited clinical evidence exists to support recently developed scaffolds. Furthermore, no consensus has been reached on the nature of scaffold material that is most suitable.

Lau and colleagues (2014) conducted a systematic review of preclinical and clinical studies. In preclinical studies, evidence from stem cells used as treatment in avascular necrosis of the femoral head demonstrated uniform improvement in osteogenesis and angiogenesis (sources of stem cells varied across studies chosen for inclusion). In clinical trials included for review, significant improvements in participant reported outcomes were demonstrated across studies but superior hip survivorship was not reported. Authors call for trials to determine "Dose and quality optimization" as well as demonstrable improvement in hip survivorship.

In the literature, there is a growing body of reports from the pre-clinical and clinical setting for the potential efficacy of MSC use in tissue regeneration for orthopedic indications. However, well-designed, large randomized comparative clinical trials are needed to demonstrate the efficacy and safety of MSC therapy for orthopedic indications. The variety of MSC sources, proprietary processing and different scaffolds make comparison of products challenging.

A systematic review of preclinical studies was published by Haddad and colleagues (2013) which reviewed 19 articles that had used cell-based approaches to tissue-engineered menisci; cell types used included MSCs amongst others. Authors stated that, "The diversity of studies made it impossible to adhere to full guidelines or perform a meta-analysis," but concluded that overall superior tissue integration and favorable biochemical properties were observed in regenerated tissues when compared to acellular techniques.

In 2011, Wakitani reported long-term follow-up of 45 articular cartilage repairs utilizing autologous bone marrow-derived mesenchymal stem cells (BMSCs) in 41 individuals. With a mean follow-up of 75 months (5 to 137 months), the authors reported no tumors or infections observed in the individuals who were treated between 1998 and November 2008. Although considered a low risk, the authors concluded that, "The possibility that the cells transplanted in joints move and injure other parts of the body remains unresolved" (Wakitani, 2011).

A pilot study was conducted by Wakitani and colleagues (2004) using autologous bone MSC therapy to repair nine full-thickness cartilage defects in the patello-femoral joints of 3 individuals. The assessment of clinical symptoms were rated with the International Knee Documentation Committee Subjective Knee Evaluation Form (IKDC score), with 0 being the worst and 100 being the best rating. IKDC scores improved for all 3 individuals during the follow-up period ranging from 7 to 20 months after receiving mesenchymal therapy. In all 3 cases, the investigators were unable to confirm the material covering the defects was in fact hyaline cartilage resulting from mesenchymal cell therapy.

In 2012, Lee and colleagues conducted a prospective, short-term comparative study to determine if knees with symptomatic cartilage defects treated with outpatient injections of MSCs and hyaluronic acid (HA; n=35) had better outcomes than an open-air implantation of MSCs (n=35). The outcome of interest was the International Cartilage Repair Society (ICRS) Cartilage Injury Evaluation Package and MRI results 1 year post-procedure. No adverse event was reported and significant improvement was seen across several domains of the ICRS evaluation package at final follow-up (mean 24 months). Although MRI results were promising, authors acknowledge that the sensitivity of MRIs in lesion identification was only estimated at 45%. A shortcoming of this study, aside from the small sample size and short-term data, is the inability to distinguish the MSCs effect on outcomes from the HA effect since the control group received neither.

Small randomized trials have been conducted, evaluating the efficacy of MSC use in orthopedic indications. A randomized, prospective, preliminary study was published in 2013 by Liebergall and colleagues. A total of 24 participants with distal tibial fractures were enrolled to evaluate time to union. Half of participants (n=12) were randomized into the treatment group and received MSCs (harvested from iliac crest bone marrow), platelet-rich plasma and demineralized bone matrix injections under fluoroscopy at the tibial fracture site in conjunction with standard orthopedic surgical intervention (nails or plates implanted for stabilization). The control group (n=12) received no additional intervention during their surgical procedure to stabilize the tibia. Author
s found that this minimally invasive procedure reduced time to union from 3 months (control group) to 1.5 months (treatment group) on average. The difference was statistically significant in the unblinded analysis (p<0.03) and significance fell in the blinded analysis (p<0.06). Authors concluded that this minimally invasive technique appears safe and efficient. However, no long-term data are available and superiority was not demonstrated in the unblinded analysis.

A systematic review by Khashan and colleagues (2013), sought to compare the evidence in the literature of cell-based grafts combined with bone extenders to autologous bone grafts. Their review addressed five key questions by examining results from 28 clinical trials. The authors ultimately determined that evidence for each key question was weak or absent and therefore insufficient to support the use of MSC therapy for spinal fusion.

A point of concern raised regarding the status of clinical evidence in tissue engineering, is the need for validated scoring for outcomes to provide standardized data collection set that will allow comparison of results from different trials. Additional studies are needed to establish validated scoring for histopathologic research. The use of mesenchymal products is unproven for use in spinal fusion and for intervertebral disc regeneration.

In 2013, Wong and colleagues conducted a randomized control trial evaluating 56 participants with unicompartmental, osteoarthritic, varus knees enrolled in either the stem cell recipient group (n=28) or the control group (n=28). The treatment group received intra-articular injections of MSCs and HA 3 weeks post-surgical intervention and the control group received HA only. Participants were re-evaluated at 6-, 12- and 24-month follow-up. The treatment group showed significantly better scores than the control group in Tegner (p=0.021), Lysholm (p=0.016), and IKDC (p=0.01) scores. MRI scans at 1 year follow-up showed significantly better Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) scores (p<0.001). Authors conclude that the investigated intervention demonstrated efficacy in short-term clinical and MOCART outcomes. However, data was insufficient to demonstrate clinical improvement and long-term efficacy and safety data.

In 2014, Vangsness and colleagues performed the first randomized, double-blind controlled clinical trial investigating the efficacy and safety of MSCs in the treatment of an orthopedic indication. A total of 55 participants from seven institutions who were eligible for a partial medial meniscectomy were enrolled and randomized into one of three treatment groups: Group A (n=17) received an injection of 50x106 allogeneic MSCs; Group B (n=18), received 150x106 MSCs; and the control group (n=19) received a HA injection only. Outcomes of interest at intervals over the 2-year follow-up included safety, meniscus regeneration, overall knee joint condition and clinical outcomes. No adverse events occurred and investigators found a significant increase in meniscal volume (p=0.022; determined by MRI) in both Groups A and B; no participants met the threshold for increased volume (15%) in the control group. Furthermore, both groups A and B reported a significant reduction in pain compared to the control group. Results of this small, Phase I/II clinical trial are promising for use of MSCs in knee-tissue regeneration. Data from larger trials is needed to confirm the early results.

In a systematic review by Longo and colleagues (2011), authors state that the use of MSC therapy for repair of tendon injuries is "At an early stage of development. Although these emerging technologies may develop into substantial clinical treatment options, their full impact needs to be critically evaluated in a scientific fashion."

Although preclinical studies, case series, and small, randomized trials suggest that MSC therapy may improve regeneration of bone or tissue in orthopedic indications, the lack of validated, comparable scoring, robust sample sizes and long-term follow-up data, preclude definitive conclusions regarding the net health benefit of MSC therapy. The available data has not yet established that MSCs, when infused or transplanted into an area, can: 1) truly regenerate by incorporating themselves into the native tissue, surviving, and differentiating or 2) promote the preservation of injured tissue and tissue remodeling. In addition, the optimal source for MSCs (for example from adipose tissue in bone marrow) has not been clearly identified.

The concentrated autologous MSC products are not regulated by the U.S. Food and Drug Administration (FDA). Currently there are no allogeneic MSC therapies or devices that are approved for marketing by the FDA.

However, there are products containing mesenchymal stem cells that are commercially available for orthopedic indications, which include:

MSCs are being investigated as a regenerative biologic agent because of their ability to differentiate into multiple tissue types and to self-renew. The MSC population in bone marrow is estimated at 1 in 3.1 x104 mononuclear cells, and is even lower in cord blood or peripheral blood (Bonab, 2006). Although other sources for MSCs have been identified, the bone marrow is currently the primary source of procurement.

MSC therapy has been proposed as a treatment option for orthopedic indications that include torn cartilage, osteoarthritis, and bone grafting. The proposed benefits of MSC therapy are improved healing and possible avoidance of surgical procedures with protracted recovery times.

Optimal materials or grafts that promote bone growth and healing require the following properties (Shen, 2005):

The American Academy of Orthopaedic Surgeons (2007) provides information on stem cells:

Bone marrow stromal cells are mesenchymal stem cells that, in the proper environment, can differentiate into cells that are part of the musculoskeletal system. They can help to form trabecular bone, tendon, articular cartilage, ligaments and part of the bone marrow.

At this point, stem cell procedures in orthopaedics are still at an experimental stage. Most procedures are performed at research centers as part of controlled clinical trials.

Currently, the risks of MSC therapy for the treatment of orthopedic indications are unknown. Insufficient data have been reported to allow a proper understanding of how this technology may affect individuals either in the short or long-term. Furthermore, there are known risks related to the various methods utilized to harvest MSCs from the bone marrow, including pain and hemorrhage.

Stem cells: A type of cell from which other types of cells develop.

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 are Investigational and Not Medically Necessary: When the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

Peer Reviewed Publications:

AlloStem Cellentra VCBM Osteocel Osteocel Plus Ovation Regenexx RegenexxAD RegenexxSD Trinity Elite Trinity Evolution

The use of specific product names is illustrative only. It is not in
tended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

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