Medical Policy
Subject: Other Stem Cell Therapy
Document #: TRANS.00035Publish Date: 10/01/2021
Status: ReviewedLast Review Date: 05/13/2021
Description/Scope

This document addresses uses of stem cell therapy for the prevention and treatment of health conditions, including but not limited to, peripheral vascular disease, and orthopedic, autoimmune, inflammatory, and degenerative conditions. Stem cell therapy involves the use of stem cells (usually in the form of an injection or infusion) to repair damaged cells and body tissues.

This document does not address: stem cell therapy used for disorders affecting the hematopoietic system that are inherited, acquired, or result from myeloablative treatment (that is: FDA-approved products derived from stem cells that are approved for limited use in individuals with disorders involving the hematopoietic system), including transplantation of allogeneic stem cells to reconstitute hematopoiesis in individuals with either bone marrow failure or genetic disease affecting blood cell production or function, or transplantation of autologous or allogeneic stem cells to allow reconstitution of hematopoiesis in individuals who might benefit from intensive radiochemotherapy for the treatment of malignant disease (for example, acute myeloid leukemia). FDA-approved stem cell products are listed on the FDA website here: https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/approved-cellular-and-gene-therapy-products.

First identified in the hematopoietic system, stem cells are likely to be present in many other tissues. Stem cells can be derived from human embryos or somatic tissues in the adult or they can be created by inducing greater potency in an already differentiated somatic cell. Examples of adult stem cells (also called somatic stem cells or tissue-specific stem cells) not used for hematopoietic indications include, but are not limited to, mesenchymal (also called stromal stem cells), neural, epithelial, epidermal, and follicular. Extraction sources of adult stem cells include, but are not limited to, blood, bone marrow, adipose tissue, umbilical cords, placentas, and amniotic fluid. Other types of stem cells transplanted include peripheral bone marrow mononuclear cells [PBMNCs], and bone marrow mononuclear cells [BMMNCs].

Notes:

Position Statement

Investigational and Not Medically Necessary:

Stem cell therapy, including but not limited to mesenchymal stem cell therapy is considered investigational and not medically necessary for the prevention and treatment of all conditions including but not limited to peripheral vascular disease, and orthopedic, autoimmune, inflammatory and degenerative conditions.

Note: This document does not address stem cell therapy used for disorders affecting the hematopoietic system that are inherited, acquired, or result from myeloablative treatment, or hematopoietic stem cell transplantation.

Rationale

Mesenchymal Stem Cell Therapy

Orthopedic Conditions

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 suitable for harvesting, and the potential of graft failure. Alternative regenerative technologies, which could minimize or avoid these issues while regenerating damaged tissue are being actively investigated.

Various agents and techniques to procure and expand mesenchymal stem cells (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 MSCs 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 involving the cartilage or ligaments is limited to pre-clinical studies, case series and small, randomized controlled trials. The efficacy and safety of these novel therapies have not been established in well-designed, 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.

A systematic review of preclinical studies published by Haddad and colleagues (2013) reviewed 19 articles that had used cell-based approaches to tissue-engineered menisci; cell types used included MSCs amongst others. The 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 MSCs (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 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.”

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 events were 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 MSC effect on outcomes from the HA effect since the control group received neither.

In 2013, Wong and colleagues conducted a randomized controlled trial (RCT) 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 concluded 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 an HA injection only. Outcomes of interest at intervals over the 2-year follow-up period 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 are needed to confirm the early results.

Vega and colleagues (2015) conducted a small, randomized, controlled trial comparing intra-articular injections of allogeneic bone marrow MSCs and HA in individuals with knee osteoarthritis (n=30). Each participant received either one injection of MSC or HA and were followed for 1 year. Assessed outcomes included evaluations of pain, disability, quality of life and articular cartilage quality as determined by MRI. The MSC group reported a medium to large treatment effect (effect size, 0.58-1.12) while the HA group reported a small treatment effect (effect size, 0.19-0.48). While the MSC group reported improved results over the HA group, it is noted that this is the first study to demonstrate the feasibility, safety and efficacy of the use of allogeneic MSCs in treating osteoarthritis. The authors note that further research is needed on how MSCs “relieve pain, promote regeneration, and become immune evasive.”

Jo and colleagues (2017) reported the results of a 2-year follow-up study that evaluated the safety and effectiveness of intra-articular injections of adipose tissue-derived MCSs (AD-MCSs) for the treatment of osteoarthritis of the knee. A total of 18 subjects with osteoarthritis of the knee were enrolled (15 female; 3 male; mean age, 61.8 ± 6.6 years [range, 52-72 years]). Participants in the low-, medium-, and high-dose groups received an intra-articular injection of 1.0 × 107, 5.0 × 107, and 1.0 × 108 AD MSCs into the knee, respectively. Clinical and structural evaluations were conducted using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and measurements of the size and depth of the cartilage defect, signal intensity of regenerated cartilage, and cartilage volume MRI. No treatment-related adverse events were reported during the 2-year period. An intra-articular injection of autologous AD MSCs enhanced knee function, as measured with the WOMAC, Knee Society clinical rating system (KSS), and Knee injury and Osteoarthritis Outcome Score (KOOS), and decreased knee pain, as measured with the visual analog scale (VAS), for up to 2 years regardless of the cell dosage. However, statistical significance was seen primarily in the high-dose group. Clinical outcomes tended to decline after 1 year in the low- and medium-dose groups, whereas those in the high-dose group remained level until 2 years. The structural outcomes gauged with MRI also showed similar trends. The authors concluded that this study demonstrated the safety and efficacy of the intra-articular injection of AD-MSCs into the osteoarthritic knee over 2 years. The authors acknowledged that this study highlighted potential concerns about the durability of clinical and structural outcomes and encouraged larger randomized clinical trials.

Ha and colleagues (2019) conducted a systematic review assessing the efficacy of intra-articular MSCs in terms of clinical outcomes including pain and function and cartilage repair in individuals with osteoarthritis of the knee. Clinical outcomes were evaluated using clinical scores, and cartilage repair was assessed using magnetic resonance imaging and second-look arthroscopy findings. A total of 17 studies met the inclusion criteria: 6 randomized controlled trials; 8 prospective observational studies; and 3 retrospective case-control studies. Of the 17 studies, 1 used umbilical cord blood-derived MSCs, 2 used adipose tissue-derived MSCs, 6 used adipose tissue-derived stromal vascular fraction and 8 studies used bone marrow-derived MSCs. All studies except for 2 reported improved clinical outcomes at final follow-up or significantly better clinical outcomes in the MSC group. With regard to cartilage repair, 9 of 11 studies reported an improvement in the state of the cartilage on magnetic resonance imaging. A total of 6 of 7 studies reported the presence of repaired tissue on second-look arthroscopy. The authors concluded that in many cases, intra-articular MSCs improve pain and function in knee osteoarthritis at short-term follow-up (< 28 months), however, the evidence of efficacy of intra-articular MSCs on both cartilage repair and clinical outcomes remains limited.

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 in the treatment of orthopedic conditions.

In 2020, the American College of Rheumatology (ACR) and the Arthritis Foundation (AF) released a joint guideline on the management of osteoarthritis of the hand, hip, and knee. The ACR and AF strongly recommend against stem cell injections in individuals with knee or hip osteoarthritis stating "there is concern regarding the heterogeneity and lack of standardization in available preparations of stem cell injections, as well as techniques used” (Kolasinski, 2020). In regards to hand osteoarthritis, no recommendation was made due to a lack of studies evaluating stem cell therapy as a treatment (Kolasinski, 2020). 

Neurodegenerative Diseases

Alzheimer’s Disease

Kim and colleagues (2015) conducted a phase I clinical trial in individuals (n=9) with mild-to-moderate Alzheimer's disease to evaluate the safety and dose-limiting toxicity of stereotactic brain injection of human umbilical cord blood-derived MSCs (hUCB-MSCs). The low- (n=3) and high-dose (n=6) cohorts received a total of 3.0 × 106 cells/60 μL and 6.0 × 106 cells/60 μL, respectively, into the bilateral hippocampi and right precuneus. None of the study participants demonstrated serious adverse reactions during the 24-month follow-up period. During the 12-week follow-up period, the most frequent acute adverse event was wound pain from the surgical procedure (n=9), followed by headache (n=4), dizziness (n=3), and postoperative delirium (n=3). No dose-limiting toxicity was reported. The authors concluded that the administration of hUCB-MSCs into the hippocampus and precuneus by stereotactic injection was feasible, safe, and well tolerated but additional trials are warranted to determine treatment efficacy.

Amylotrophic lateral sclerosis (ALS)

Mazzini and colleagues (2003) evaluated the feasibility and safety of a method of intraspinal cord implantation of autologous MSCs in 7 participants (4 females and 3 males; range: 23–74 years, mean age 46.6 ± 16.8 years) with ALS. The group had severe functional impairment of the lower limbs and mild functional impairment of the upper limbs without signs of respiratory failure. Participants were monitored by clinical evaluation which included the Norris score, ALS-FRS scale, bulbar score, and MRC strength scale. Respiratory assessment included clinical evaluation, arterial blood gas analysis, pulmonary function tests and nocturnal cardio-respiratory monitoring. The neurophysiological assessments consisted of somatosensory evoked potentials (SEP) and EMG. The neuro-radiological assessment included MRI of the spinal cord and brain before and after gadolinium DTA infusion. A clinical psychologist conducted a psychological evaluation. None of the participants experienced severe adverse events such as death, respiratory failure or permanent post-surgical neurological deficits. Minor adverse events included intercostal pain (n=4) which was reversible after a mean period of 3 days (range: 1–6) after surgery, and leg sensory dysesthesia (n=5) which resolved after a mean period of 6 weeks (range: 1–8) following surgery. None of the participants manifested bladder and bowel dysfunction, or leg motor deficit. There were no anesthetic complications. MRI with gadolinium DTA infusion carried out at 3 and 6 months post implantation demonstrated no evidence of structural changes of the spinal cord or signs of abnormal cell proliferation when compared with the baseline. SEPs from tibial nerve stimulation demonstrated a mild delay of the central conduction time 3 days after surgery but this normalized within 1 month following transplantation. All of the participants showed a good acceptance of the procedure and no significant modifications of the quality of life or the psychological status were observed. In all of the participants, muscular strength (MRC scale) declined during the 6 months before transplantation. However, at the third month post stem cell implantation a trend towards a slowing down of the linear decline of muscular strength was evident in 4 participants in the proximal muscle groups of the lower limbs, while a mild increase in strength was observed in the same muscle groups of 2 participants. While the authors concluded that the study seemed to demonstrate MSC transplantation into the spinal cord of humans is safe and well tolerated by individuals with ALS, the authors stated that additional controlled studies are needed to evaluate the efficacy of stem cell therapy in the treatment of ALS.

Parkinson’s Disease

Research exploring the feasibility of MSC transplantation as a treatment of Parkinson’s disease is ongoing. In one study (NCT00976430), researchers investigated the safety and efficacy of autologous MSCs in treating advanced Parkinson’s disease by harvesting and processing the stem cells from bone marrow and transplanting them via stereotactic techniques into the striatum of the subject. However, the study was terminated because an adequate number of participants could not be recruited in the set timeframe. Other studies exploring the use of MSCs as a treatment of Parkinson’s disease are ongoing but not yet completed or published. Information regarding these studies is available on the clinicaltrials.gov web site.

At this time, there is insufficient evidence from well-designed clinical trials to evaluate the clinical utility of MSC therapy in individuals with neurodegenerative diseases. 

Autoimmune Diseases

Celiac Disease

Ciccocioppo and colleagues (2016) reported the results of a study that investigated the feasibility, safety, and efficacy of serial infusions of autologous bone marrow-derived MSCs in a 51-year-old woman with type II refractory celiac disease. MSCs were separated, expanded, and characterized according to standard protocols. The researchers monitored the participant’s malabsorption indexes, mucosal architecture, and percentage of aberrant intraepithelial lymphocytes during study enrollment, at each infusion, and 6 months post treatment. Mucosal expression of interleukin (IL)-15 and its receptor was also monitored. The subject underwent 4 systemic infusions of 2×106 MSCs/kg body weight 4 months apart without adverse effects. During the treatment period, the participant experienced gradual and durable amelioration of her general condition, with normalization of stool frequency, body mass index, laboratory test results, and mucosal architecture. The expression of IL-15 and its receptor practically disappeared.  At this time, there is insufficient evidence from well-designed clinical trials to evaluate the clinical utility of MSC therapy in individuals with celiac disease. 

Multiple sclerosis

In a triple-blind, placebo-controlled study, Fernandez and colleagues (2018), investigated the safety and feasibility of the use of adipose-derived MSCs for the treatment of secondary-progressive multiple sclerosis. The cell samples were obtained from consenting participants by lipectomy and subsequently expanded. Study participants were randomized 1:1:1 to an intravenous (IV) infusion of placebo or one of two dose-groups (1x106 cells/kg or 4x106 cells/kg). The study was triple blinded (the treating physician, study participant and statisticians were unaware of treatment assignment). Participants were followed for 12 months. The researchers monitored safety using laboratory parameters, vital signs and spirometry. EDSS, MRI and other measures of possible treatment effects and adverse events were also recorded. A total of 34 subjects underwent lipectomy for adipose-derived MSC collection, were randomized and 30 were infused (11 placebo, 10 low-dose and 9 high-dose); 4 randomized participants were not infused due to karyotype abnormalities in the cell product. Measures of treatment effect demonstrated an inconclusive trend of efficacy. The mean EDSS score and the individual EDSS did not reflect any significant changes over the course of the study. Baseline MRI data was similar between the three groups. The researchers reported some non-statistically significant differences between the placebo and treatment groups for the evoked potentials parameters after 12 months of treatment. Tibial SEP central conduction time (N22-P39) and the motor evoked potential (MEP) central conduction time for the legs, reflected statistically significant diminishing latencies over time in placebo and the two treatment groups, but these differences were not statistically significant comparing placebo and both treatment groups. Visual evoked potential (VEP) and median nerve SEP (N13-N20) also demonstrated a trend of stabilization or amelioration of latencies over time in treatment groups, however, these differences did not reach statistical significance over the time. There were no significant changes in the cerebral spinal fluid from baseline to the 12-month follow-up. One serious adverse event was reported in the treatment arms (urinary infection, considered not related to study treatment). No other changes in safety parameters were reported. Although the results of the study did not demonstrate treatment efficacy, the authors found infusion of autologous adipose-derived MSCs safe and feasible in individuals with secondary-progressive multiple sclerosis.

Systemic Lupus Erythematosus (SLE)

Wang and colleagues (2014) conducted a multicenter clinical trial to assess the safety and efficacy of allogeneic umbilical cord MSC transplantation (MSCT) in subjects with active and refractory SLE. Researchers recruited 40 individuals with active SLE from four clinical centers. Allogeneic umbilical cord MSCs were infused intravenously on days 0 and 7. The primary endpoints were safety profiles. The secondary endpoints included major clinical response (MCR), partial clinical response (PCR) and relapse. Each participant was re-assessed at 1, 3, 6, 9 and 12 months post MSC transplantation. Evaluations performed at the follow-up visits included a physical examination, determination of Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score, British Isles Lupus Assessment Group (BILAG) analysis, serologic studies and evaluation of organ function. A total of 39 subjects (39/40, 97.5%) underwent umbilical cord MSC infusions twice with an interval of 1 week, and 1 participant (1/40, 2.5%) was exempted from the second MSC infusion due to uncontrolled disease progression. The overall survival rate was 92.5% (37 of 40 subjects). Umbilical cord MSCT was well tolerated, and no adverse events related to the transplantation were observed. During the 12 months of follow-up, an MCR was achieved in 13 participants (32.5%) and 11 participants (27.5%) achieved a PCR. Three individuals (12.55%) experienced disease relapse at 9 months and 4 participants (16.7%) experienced disease relapse at 9 months after a prior clinical response. The SLEDAI scores decreased significantly at 3, 6, 9 and 12 months follow-up. Total BILAG scores decreased at 3 months and continued to decrease at subsequent follow-up visits. BILAG scores for hematopoietic, renal and cutaneous systems improved. Among participants with lupus nephritis, 24-hour proteinuria diminished after transplantation, with statistically significant differences at 9 and 12 months. Serum creatinine and urea nitrogen declined to the lowest level at 6 months, but these values slightly increased at 9 and 12 months in 7 relapse cases. Additionally, serum levels of albumin and complement 3 rose after MSCT, peaked at 6 months and then slightly declined by the 9- and 12-month follow-up examinations. Serum antinuclear antibody and anti-double-stranded DNA antibody diminished after MSCT, with statistically significant differences at 3-month follow-up examinations. The authors concluded that the study results demonstrate that umbilical cord MSCT is a safe and effective treatment for individuals with SLE, but a repeated MSC infusion may be necessary after 6 months to avoid disease relapse. The authors also acknowledge that limitations of the study include its lack of a randomized controlled design and the lack of uniformity amongst the condition of the study participants.

In 2015, Wang and colleagues reported the results of a study that investigated whether double transplantations of MSCs is superior to single transplantation. Of the 58 refractory SLE subjects enrolled in the study, 30 were randomly given single MSCT, and the other 28 were given double MSCT. Participants were followed to determine rates of survival, disease remission, and relapse, as well as transplantation-related adverse events. Serologic features and changes in the SLEDAI were monitored. At more than 1 year follow-up, the results demonstrated that no remarkable differences between single and double allogeneic MSCT were found in terms of disease remission and relapse, amelioration of disease activity and serum indexes. This study demonstrated that single MSC transplantation at the dose of one million MSCs per kilogram of body weight was sufficient to induce disease remission for refractory SLE subjects. Although 95% of the participants had lupus nephritis at the time of enrollment, it is unclear whether MSC therapy can ameliorate renal pathology, aside from the improvements in renal function, because the pathological data on the participants at the time of enrollment was not available.

Crohn’s Disease

In a Phase I trial, Duijvestein and colleagues (2010) assessed the safety and feasibility of the use of autologous bone marrow-derived MSC treatment for luminal Crohn's disease refractory to steroids and immunomodulators. A total of 10 adult participants with refractory Crohn's disease underwent bone marrow aspiration under local anesthesia. Bone marrow MSCs were isolated and expanded ex-vivo. MSCs were assessed in- vitro for functionality and phenotype.  Nine participants received two doses of 1-2×106 cells/kg body weight, intravenously, 7 days apart. During follow-up, the participants were monitored for possible side effects and changes in the Crohn's disease activity index (CDAI). Colonoscopies were conducted at weeks 0 and 6, and mucosal inflammation was assessed using the Crohn's disease endoscopic index of severity. The study demonstrated a decline in CDAI by ≥ 70 from baseline in 3 participants at 6 weeks post treatment; conversely 3 participants required surgery due to worsening Crohn’s disease. None of the participants achieved remission. The subjects reported minor allergic reaction (10%), headache (30%), as well as taste and smell disturbances (90%) which were considered related to MSC infusion.

Zhang and colleagues (2018) investigated the efficacy and safety of umbilical MSCs for the treatment of Crohn’s disease. The Phase III clinical trial included 82 participants who were diagnosed with Crohn’s disease and had received steroid maintenance therapy for more than 6 months. A total of 41 participants were randomly selected to receive four peripheral IV infusions of 1×106 umbilical cord MSCs/kg, with one infusion per week. Participants were followed for 12 months. Assessment tools included the CDAI and Harvey-Bradshaw index (HBI). Corticosteroid dosage was also assessed. Twelve months post treatment, the CDAI, HBI, and corticosteroid dosage had decreased by 62.5 ± 23.2, 3.4 ± 1.2, and 4.2 ± 0.84 mg/day, respectively, in the umbilical cord-MSC group and by 23.6 ± 12.4, 1.2 ± 0.58, and 1.2 ± 0.35 mg/day, respectively, in the control group (p˂0.01, p˂0.05, and p˂0.05 for UC-MSC vs control, respectively). Fever after the administration of MSC infusion was reported in 4 participants. No serious adverse events were reported. The authors concluded that umbilical cord-MSCs were an effective treatment for Crohn’s disease that produced mild side effects. A limitation of this study was that it did not examine indicators of immune status or intestinal histopathology in the participants. Therefore, the mechanism by which stem cell therapy modifies Crohn’s disease remains unclear.

While small, preliminary studies investigating the use of MSC therapy as a treatment for Crohn’s disease may show promise, additional well-designed studies with larger populations and longer follow-up periods are needed before conclusions regarding the safety and efficacy of MSC therapy can be made.

Summary

MSCs isolated from bone marrow and other sites, display specific anti-inflammatory and immunomodulation properties and may be a tool for the treatment of various chronic diseases. While the results of some early trials have been promising, a number of questions remain (Goldberg, 2017; Viganò, 2016). The available data have not yet established that MSCs, when infused or transplanted, can regenerate by incorporating themselves into native tissue, survive, differentiate, and promote the preservation of injured tissue. In addition, the optimal source for MSCs has not been clearly identified. Randomized, controlled trials that are adequately powered and include long-term follow-up data are needed before conclusions regarding the safety, efficacy and clinical utility of MSC therapy for the treatment of chronic autoimmune, inflammatory, orthopedic and degenerative diseases can be made.

Bone Marrow Mononuclear Cell and Peripheral Blood Mononuclear Cell Therapies

Peripheral Vascular Disease

The use of autologous or allogeneic stem cell therapy as a treatment of peripheral vascular disease (PVD) has been the subject of many peer-reviewed published articles. Most of the available evidence is in the form of small case series studies with less than 30 subjects (Bartsch, 2006, 2007; Durdue, 2006; Huang, 2004; Kawamoto, 2009; Lara-Hernandez, 2010; Van Tongeren, 2008). There are a few studies with greater than 100 participants, but as with the smaller studies, most use case series methodology (Horie, 2010; Matoba, 2008). The studies themselves vary in follow-up duration, specific method of transplantation (for example, IV, intramuscular [IM], and intra-arterial [IA]), type of stem cells transplanted (PBMNCs, BMMNCs, or MSCs), and underlying etiology of the vascular disease (for example, diabetes, thromboangiitis obliterans [TAO], arteriosclerosis obliterans [ASO]). Additionally, some studies are limited to the treatment of lower limb PVD, while others include subjects with upper limb PVD as well. These case series tend to report positive impact of stem cell therapy with rare transplantation-related complications. However, there are significant concerns about these case series, which are prone to publication bias (only positive case series published) as well as the lack of prospective, randomized comparison groups.

Several nonrandomized trials have been reported for autologous stem cell treatments (Higashi, 2004; Katamata, 2007). Ondara and colleagues (2011) reported a study that was a re-analysis of data previously published by Horie (2010) and Matoba (2008). The authors reported that after adjustment for history of dialysis and Fontaine class, there were no significant differences between the treatment with BMMNC compared to PBMNC with respect to overall survival or amputation-free survival. They also reported that the negative prognostic factors affecting overall survival or amputation-free survival were the number of CD34-positive cells collected, history of dialysis, Fontaine class, male sex, and older age.

A double-blind placebo-controlled RCT has been published on the use of allogeneic stem cell therapy to treat PVD (Gupta, 2015). This small study involved 20 subjects with critical limb ischemia (CLI) who were unable to undergo traditional revascularization procedures. Data for 19 subjects were reported. Experimental group subjects received IM injections of allogeneic BMMNC (200 million in 15 ml) while control subjects received placebo infusions. All subjects were followed for at least 2 years, with blinding only up to the 6-month time point. No procedural-related adverse events were reported. Overall, 58 adverse events were reported, with 13 occurring in 6 experimental group subjects and 45 reported in 8 placebo group subjects. Of these, 25 were related to abnormalities in laboratory values, but the investigators did not attribute any of them to the BMMNC treatment. Another 14 events were related to complications of CLI. Significant increase in Ankle Brachial Pressure Index (ABPI) and ankle pressure were seen in the BMMNC group compared to the placebo group, with mean ABPI improvement of 0.214 and 0.004 respectively after 6 months (p=0.0018). The authors noted that no significant differences were seen between groups with regard to serum cytokine levels and blood lymphocyte profile, indicating that no T-cell proliferative response was elicited. The authors concluded that the use of allogeneic BMMNC is safe when injected via IM route at a dose of 2 million cells/kg body weight. They also state that improved ABPI and ankle pressure showed positive trend, warranting further studies.

There are several RCTs available addressing the use of autologous stem cell therapy to treat PVD. The first reported study included only 22 subjects with bilateral leg ischemia due to undisclosed etiology (Tateishi-Yuyama, 2002). For each subject, one leg was randomly selected to receive IM transplantation with BMMNC, the other was treated with IM PBMNC. At 24 weeks, legs injected with BMMNC were significantly improved compared to PBMNC with respect to ankle-brachial index (ABI) (p<0.0001), transcutaneous oxygen pressure (TcO2, p<0.0001), pain at rest (p=0.025), and pain-free walking (p=0.0001). The next study included 28 subjects with CLI due to advanced Type 2 diabetes (Huang, 2005). Study subjects were randomized to receive either stem cell therapy with PBMNCs administered via IM injection or IV prostaglandin therapy. The authors reported that there was significant improvement (p=0.05) in the stem cell group compared to the control group in terms of lower limb pain, ulcer healing, lower limb perfusion, ankle brachial index, and angiographic scores. The number of CLI-related amputations were also significantly better in the stem cell group (1 vs. 5, p=0.007). However, the study was not blinded, there was no placebo or sham intervention arm, and the study sample was very small. It is unclear whether the differences reported are attributable to the treatments given or other factors. Huang and colleagues (Huang, 2007) published an additional study that involved 150 subjects with TAO randomized to receive stem cell therapy with either PBMNCs or with BMMNCs via IM injection. Ankle-brachial index, skin temperature and pain at rest were all better in the PBMNC group. These findings contradict those reported by Tateishi-Yuyama, as discussed above (2002). An RCT conducted by Van Tongeren and others included 27 subjects with CLI of the legs due to undisclosed etiology (2008). Subjects were randomly assigned to receive BMMNC via either IM or a combination of IM/IA injections. At 12 months, 2 IM/IA group subjects had amputations vs. 7 in the IM only group. In the remaining participants, regardless of group, treatment resulted in significant improvements in pain-free walking distance, overall pain, and ABI.

Fadini and others published the results of a meta-analysis of previously published studies (2010). This analysis looked at the results of autologous stem cell therapy for PVD with regard to the endpoints of change in ABI, TcO2, pain-free walking time, ulcer healing and amputations. Significant improvements were reported for all the measures when all studies were analyzed. When only controlled studies were considered, no significant differences were found for ABI and TcO2. Outcomes were evaluated between subjects with ASO vs. TSO. For subjects with TAO compared to those with ASO, significant benefits were noted for changes in ABI (p=0.021), TcO2 (p=0.03), pain scale (p=0.003), and pain-free walking distance (p=0.019). When looking at the data comparing PBMNCs vs. BMMNCs, PBMNCs were significantly better at improving resting pain (p=0.006) and BMMNCs were better with regard to ulcer healing times (p=0.038). No other significant differences were noted. The route of administration was also evaluated, comparing IM vs. IM/IA. The authors reported that ABI and TcO2 were significantly improved in subjects receiving IM but not IM/IA administration. With the exception of ulcer healing time, all other measures demonstrated equal benefit between groups. There was insufficient data to evaluate ulcer healing times. The authors note that most studies evaluated were not properly designed to report on safety-related issues and systematic reporting of adverse events was rare.

A small RCT was published by Szabo and colleagues in 2013. The study involved 19 subjects with late-stage no-option PVD randomly assigned to undergo either standard of care or treatment with VesCell autologous stem cell therapy. Follow-up assessments were conducted at 1 and 3 months, and at 2 years. No adverse events were attributed to the treatment methods during the study. However, 80% of the control subjects and 50% of the VesCell group subjects experienced adverse events. At 3 months, the difference in limb loss between the two groups was statistically significant (p=0.01). At 2 years, major amputation-free proportion was 70% in treated group and 40% in control group. At 3 months, the average change in ABI was -0.01 in the control group, and +0.36 ± 0.11 (p=0.01). At 2 years, the average change from baseline was 0.62 ± 0.07, (p=0.001). TcO2 was significantly improved in the VesCell group only at the 3 month time point (6.06 ± 4.0 in the VesCell group vs. -3.5 ± 5.4 in the control group; p=0.03). These results are interesting, but the small sample size limits the utility of these findings.

The results of another randomized, double-blind, placebo controlled trial involving 160 subjects with CLI receiving autologous BMMNCs (n=81) vs. sham treatment (n=79) was published in 2015 (The JUVENTAS Trial, Teraa, 2015). In this study, all subjects completed the 6-month time point, and 79% (127/160) completed the planned 12-month study. No differences were reported between groups with regard to the primary outcome, with amputation rates of 19% and 13% in the BMMNC group and control group, respectively (p=0.31). Additionally, no significant differences were noted between groups with regard to the combined safety outcome (15% vs. 19%, relative risk [RR]=1.46), all-cause mortality (5% vs. 6%, RR=0.78), or combined risk for amputation or death (23% vs. 16%, RR=1.43). The authors concluded, “Repetitive inter-arterial infusion of autologous BMMNCs into the common femoral artery did not reduce major amputation rates in subjects with severe, non-revascularizable limb ischemia compared to placebo.”

A prospective observational case series study of 40 subjects with either systemic sclerosis (n=11) or ASO (n=29) who underwent implantation with autologous BMMNCs was reported (Takagi, 2014). The authors reported that there was a case of amputation in each group within 4 weeks after therapy. At 3 months, TcO2 significantly improved in subjects with systemic sclerosis (lcSSc, p<0.01) and those with ASO (p<0.05). At the 2 year follow-up, the limb amputation rate was 9.1% in the lcSSc group and 20.7% in the ASO group (p=0.36), and the recurrence rate was 18.2% in the lcSSc group and 17.2% in the ASO group (p=0.95). The authors concluded that “bone marrow mononuclear cell implantation is safe and effective for intractable digital ulcers in lcSSc and ASO and is a promising therapeutic option for peripheral digital ulcer patients.” However, this conclusion is significantly weakened when considering the methodological weaknesses of this small, open-label, nonrandomized study.

The most recent recommendations from the American Heart Association and the American College of Cardiology on the management of patients with lower extremity peripheral artery disease do not have any reference to the use of stem cell therapy for PVD (Bailey, 2019; Gerhard-Herman, 2017).

While the existing evidence to-date shows some potential benefit of autologous stem cell therapy for PVD, this evidence is from predominately small, uncontrolled, non-blind, nonrandomized studies. Furthermore, the data from available RCTs is somewhat contradictory. There are significant outstanding questions regarding optimal selection criteria for treatment candidate and cell type, method of administration, and whether or not similar benefits can be derived with the treatment of lower and upper extremities. Further investigation in the form of well-done, large scale, randomized controlled trials is needed to answer these questions and provide guidance for the use of stem cell therapy for PVD in the clinical setting.

Other Adult Stem Cell Therapies

The study of other adult stem cell types for stem cell therapy has been limited, with most studies using animal models. Scientists have discovered neuronal stem cells from the brain and spinal cord, and small studies are underway to test olfactory ensheathing glial cells for regenerating spinal cord tissue. Human teratocarcinoma cell line (hNT) cells have shown promise in animal models for treating ALS and stroke. Muscle-derived stem cells are being investigated in rat models for incontinence and cardiac damage. Other possible adult stem cells under investigation include liver stem cells, pancreatic stem cells, corneal limbal stem cells, and mammary stem cells. Stem cells are also being investigated from the salivary glands, skin, and heart. Although small clinical trials are underway, a great deal of research is needed to assess the safety and efficacy of adult stem cell therapies (NIH, 2018).

Exosome Therapy

Some clinics offer products marketed as containing exosomes (membrane bound extracellular vesicles produced by the endosomes of cells). The treatments are purportedly produced from stem cells, often placental derived mesenchymal stem cells. At this time, there are no FDA-approved exosome products, and no credible safety and efficacy data evaluating these marketed treatments. The FDA has issued a public safety notification on the risks of exosome products (FDA, 2019).

Background/Overview

Overview

Stem cell therapy, a component of regenerative medicine, involves the insertion (usually an infusion or injection) of stem cells into the body to repair body tissues. Sources of stem cells include a person’s own stem cells (such as those extracted from blood and tissues), another person’s stem cells, stem cells extracted from embryos, and stem cells extracted from pregnancy remains (amniotic fluid, placentas, umbilical cords or umbilical cord blood).

Stem cells are unspecialized cells that have the unique ability to self-renew through cell division or differentiate into specialized cells, such as red blood cells, brain cells, or muscle cells. They form the human body and replace damaged cells throughout a person’s lifespan. Stem cells are divided into four main classes: totipotent, pluripotent, multipotent, and unipotent.

Totipotent stem cells can form every cell type in the body, including placental and umbilical cord cells. The first cell of human life, the zygote, is a totipotent stem cell that divides to create more totipotent stem cells. After the first few days of embryonic development, totipotent stem cells cease to exist and give rise to pluripotent stem cells.

Pluripotent stem cells can form every cell type in the body except umbilical and placental cells. They are found in 3 to 5 day old embryos called blastocysts. Additionally, some pluripotent cells are found in fetal tissue after 8 weeks of development. Due to ethical concerns, the use of embryonic stem cells (totipotent and pluripotent) and fetal tissue stem cells for stem cell therapy has been controversial in the United States, with some states banning or limiting research. As an alternative, researchers have been working on the creation of induced pluripotent stem cells (iPSCs), which are specialized adult human cells reprogrammed to act like pluripotent embryonic stem cells. iPSCs are still in the investigative stages, and more research is needed before they can be used for stem cell therapy.

As human development continues, pluripotent cells cease to exist and give rise to multipotent stem cells that stay in the body throughout life. Multipotent stem cells form certain specialized cell types, usually the types needed to repair the tissue or organ where they reside, although some research suggests they may be able to transdifferentiate into other cell types. Multipotent stem cells can give rise to unipotent stem cells, which differentiate along only one lineage.

Multipotent and unipotent stem cells are referred to as adult stem cells (also called tissue-specific cells or somatic cells) and are found in many areas of the body. They are thought to reside in a specific location in the tissue called the “stem cell niche.” Researchers have identified many types of adult stem cells, including neural, epithelial, epidermal, hematopoietic, and mesenchymal. Currently, hematopoietic adult stem cell therapy for transplants is the only established use of stem cells. Researchers are investigating other types of adult stem cells, with the largest focus on mesenchymal stem cells.

Mesenchymal stem cells

Mesenchymal stem cells (MSCs) are non-hematopoietic, multipotent stem cells that can differentiate into a variety of cell types. The four major cell types are osteocytes (bone), myocytes (muscle), adipocytes (fat) and chondrocytes (cartilage). MSCs have immunomodulatory properties and secrete cytokines. MSCs remain in a quiescent (non-proliferative) state during most of their lifetime, pending stimulation by the signals triggered by tissue renewal, damage and remodeling processes. Because of their multi-lineage potential, immunomodulatory properties and ability to secrete anti-inflammatory molecules, MSCs may have the potential to treat various chronic autoimmune, inflammatory and degenerative diseases (Ullah, 2015).

MSCs have been isolated from various sites, including dermis, amniotic fluid, adipose tissue, endometrium, dental tissue, synovial fluid, placenta and umbilical cord tissue. Additionally, researchers have been able to culture hMSCs in specific media. The MSC population in red bone marrow is estimated at 1 per 105 nucleated cells. The incidence of MSCs in adults is 1 per 103 nucleated cells (Piccirilli, 2017). Counts in cord blood or peripheral blood are lower (Bonab, 2006). These tissue sources differ with respect to MSC cell density and differentiation capacity. Bone marrow-derived MSCs are considered the preferred source for bone repair and regeneration as there is better chondrogenic differentiation potential (Shao, 2015). 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. MSCs are used as a stand-alone therapy in the form of an injection or in combination with scaffolds (Viganò, 2016),

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

Currently, the risks of MSC therapy for the treatment of chronic, autoimmune, inflammatory and degenerative conditions 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.

MSC therapy is being investigated as a treatment of many chronic, autoimmune, inflammatory, severe pulmonary syndrome and degenerative conditions, including but not limited to the following diseases:

Bone Marrow Mononuclear Cell and Peripheral Blood Mononuclear Cell Therapies

Several medical conditions, including diabetes, TAO (also known as Buerger’s disease) and ASO, are known to lead to damage to the arteries and other blood vessels leading to the extremities. These conditions, collectively referred to as PVD, which is also known as peripheral artery disease (PAD), lead to impaired blood flow and oxygen delivery to the hands and feet, and eventually to tissue damage. In most cases, this condition is treated with surgical revascularization. However, in extreme cases surgery is not an option and a condition known as CLI develops. This leads to severe tissue damage and the only treatment option left is limb amputation.

Stem cell therapy has been proposed as a treatment for PVD. The theory is that implantation of stem cells from the bone marrow into the affected limbs could trigger the growth of new blood vessels, increasing blood flow to the extremities and treating complications that develop due to PVD. At this time, two approaches for stem cell therapy for PVD have been described in the medical literature. The first involves the direct harvesting of BMMNCs from the bone marrow. The other method involves administering a hormone called Granulocyte-Colony Stimulating Factor (G-CSF) to the person to be treated. This stimulates the bone marrow to produce mononuclear stem cells and release them into the blood stream. These cells, now called PBMNCs, are then collected as part of a blood sample collected from a vein. Regardless of the type of cells used, the collected stem cell samples are processed to isolate and multiply the cells, which are then transplanted back into the person being treated. Several different transplantation methods have been described in the scientific literature, including injection into a vein, artery, or muscle of the affected limb.

At this time the use of stem cell therapy for PVD is in the preliminary stages of investigation. There is much yet to be understood about this medical procedure before it should be widely used.

There are several products or services proposed for the processing of stem cells for PVD treatment, including the VesCell (TheraVitae, Bangkok , Thailand), and the MarrowStim P.A.D. kit™ (Biomet Biologics, Warsaw, Indiana).

Other Adult Stem Cell Types

In addition to mesenchymal stem cells, researchers have identified other adult stem cell types in the body. Examples include:

Challenges and Risks of Adult Stem Cell Therapy

While the concept of extracting and injecting adult stem cells may seem straightforward, scientists have identified many challenges and risks. Only limited numbers of adult stem cells are found in human tissues. They are difficult to isolate and do not self-renew in the laboratory as easily as embryonic stem cells. In addition, they are unpredictable and do not always differentiate into the desired cell type. Also, the intrinsic nature or external manipulation of stem cells can potentially form malignancies. There have been reports of unregulated stem cell therapy causing infection, blindness, tumor growth, paralysis, and the multiplication of an undesired stem cell type. As stem cell research continues, scientists are working on ways to mitigate these challenges and risks (FDA, 2019; NIH, 2018).

Regulation

The U.S. Food and Drug Administration (FDA) regulates tissues and human cells intended for implantation, infusion or transplantation via the Center for Biologics Evaluation and Research, under Code of Federal Regulation, title 21, parts 1270 and 1271. Currently, the only stem cell products approved by the FDA are hematopoietic progenitor cells from umbilical cord blood. In 2017, the FDA issued a warning to consumers stating some medical providers are using unapproved and unproven stem cell treatments that may be dangerous. They stated that to ensure safety, stem cell treatments should be FDA-approved or have an Investigational New Drug Application (IND), which is a clinical investigation plan the FDA has allowed to proceed.

Definitions

Bone marrow mononuclear stem cells: A type of bone marrow-derived cell from which blood vessels are created and repaired.

Differentiation: The multi-stage process by which an unspecialized stem cell gives rise to specialized cells.

Exosomes: Small, double-lipid membrane vesicles that are secreted from cells and encapsulate a portion of the parent cell cytoplasm. Exosomes shed into biofluids, including blood and urine.

Mesenchymal stem cells: A type of bone marrow-derived cell from which muscles are created.

Multipotent: Possessing the ability to produce more than one type of specialized cell of the body, but not all types of cells.

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

Stem cell therapy: A medical treatment that involves the implantation of stem cells into the body with the goal of growing new or repairing damaged or defective tissues and organs.  This type of treatment has been proposed for a wide variety of conditions, including Parkinson’s disease, heart disease, and spinal cord injury.

Transdifferentiation: The ability for adult stem cells to give rise to specialized cells other than those expected by the stem cell’s lineage.

Coding

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.

CPT

 

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 unilateral or bilateral 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

 

 

ICD-10 Diagnosis

 

 

All diagnoses

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

CPT

 

 

For the following procedures when specified as harvesting or administration of stem cells for therapy to repair damaged cells or body tissues:

17999

Unlisted procedure, skin, mucous membrane and subcutaneous tissue

20999

Unlisted procedure, musculoskeletal system, general

38205

Blood-derived hematopoietic progenitor cell harvesting for transplantation, per collection; allogeneic

38206

Blood-derived hematopoietic progenitor cell harvesting for transplantation, per collection; autologous

38230

Bone marrow harvesting for transplantation; allogeneic

38232

Bone marrow harvesting for transplantation; autologous

38999

Unlisted procedure, hemic or lymphatic system [when specified as bone marrow cell therapy or stem cell therapy such as IM, IV or IA for peripheral vascular disease]

64999

Unlisted procedure, nervous system

 

 

ICD-10 Procedure

 

30233AZ

Transfusion of embryonic stem cells into peripheral vein, percutaneous approach

30243AZ

Transfusion of embryonic stem cells into central vein, percutaneous approach

3E0Q0AZ

Introduction of embryonic stem cells into cranial cavity and brain, open approach

3E0Q3AZ

Introduction of embryonic stem cells into cranial cavity and brain, percutaneous approach

3E0R0AZ

Introduction of embryonic stem cells into spinal canal, open approach

3E0R3AZ

Introduction of embryonic stem cells into spinal canal, percutaneous approach

6A550ZV

Pheresis of hematopoietic stem cells, single

 

 

ICD-10 Diagnosis

 

 

Including, but not limited to, the following:

E08.51-E08.59

Diabetes mellitus due to underlying condition with circulatory complications

E09.51-E09.59

Drug or chemical induced diabetes mellitus with circulatory complications

E10.51-E10.59

Type 1 diabetes mellitus with circulatory complications

E11.51-E11.59

Type 2 diabetes mellitus with circulatory complications

E13.51-E13.59

Other specified diabetes mellitus with circulatory complications

G12.21

Amyotrophic lateral sclerosis

G20-G21.9

Parkinson’s disease, secondary parkinsonism

G30.0-G30.9

Alzheimer’s disease

G31.01-G31.9

Other degenerative diseases of nervous system, not elsewhere classified

G35

Multiple sclerosis

I70.201-I70.299

Atherosclerosis of native arteries of the extremities

I70.401-I70.499

Atherosclerosis of autologous vein bypass graft(s) of the extremities

I73.00-I73.9

Other peripheral vascular disease

K50.00-K51.919

Crohn’s disease [regional enteritis], ulcerative colitis

K52.3

Indeterminate colitis

K90.0

Celiac disease

M04.1-M04.9

Autoinflammatory syndromes

M15.0-M19.93

Osteoarthritis

M21.00-M21.079

Valgus deformity, not elsewhere classified

M21.10-M21.179

Varus deformity, not elsewhere classified

M21.70-M21.769

Unequal limb length (acquired)

M21.80-M21.869

Other specified acquired deformities of limbs

M21.90-M21.969

Unspecified acquired deformity of limb and hand

M23.000-M23.92

Internal derangement of knee

M24.10-M24.19

Other articular cartilage disorders

M24.20-M24.29

Disorder of ligament

M24.60-M24.69

Ankylosis of joint

M24.7

Protrusio acetabuli

M24.80-M24.89

Other specific joint derangements, not elsewhere classified

M24.9

Joint derangement, unspecified

M25.50-M25.59

Pain in joint

M32.0-M32.9

Systemic lupus erythematosus (SLE)

M75.00-M75.92

Shoulder lesions

M84.30XA-M84.9

Disorder of continuity of bone

M87.00-M87.9

Osteonecrosis

M91.0-M94.9

Chondropathies

S43.401A-S43.499S

Sprain of shoulder joint

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Government Agency, Medical Society, and Other Authoritative Publications:

  1. Bailey SR, Beckman JA, Dao TD, et al. ACC/AHA/SCAI/SIR/SVM 2018 Appropriate Use Criteria for peripheral artery intervention: a report of the American College of Cardiology Appropriate Use Criteria Task Force, American Heart Association, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, and Society for Vascular Medicine. J Am Coll Cardiol. 2019; 73(2):214-237.
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  3. Jaslok Hospital and Research Centre. Autologous Mesenchymal Stem Cell Transplant for Parkinson's Disease. NLM Identifier: NCT00976430. Last updated on August 14, 2018. Available at: https://clinicaltrials.gov/ct2/show/NCT00976430?term=NCT00976430&rank=1. Accessed on March 29, 2021.
  4. Kolasinski SL, Neogi T, Hochberg MC, et al. 2019 American College of Rheumatology/Arthritis Foundation Guideline for the Management of Osteoarthritis of the Hand, Hip, and Knee. Arthritis Care Res (Hoboken). 2020; 72(2):149-162.
  5. U.S. Food and Drug Administration (FDA). Regulatory considerations for human cells, tissues, and cellular and tissue-based products: minimal manipulation and homologous use guidance for industry and food and drug administration staff. Last updated on July 2020. Available at: https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Cellularand
    GeneTherapy/UCM585403.pdf
    . Accessed on March 29, 2021.
  6. U.S. Food and Drug Administration (FDA). FDA warns about stem cell therapies. Last updated September 3, 2019. Available at: https://www.fda.gov/consumers/consumer-updates/fda-warns-about-stem-cell-therapies. Accessed on March 29, 2021.
  7. U.S. Food and Drug Administration (FDA). Approved cellular and gene therapy products. Last updated March 27, 2021. Available at: https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/approved-cellular-and-gene-therapy-products. Accessed on March 29, 2021.
  8. U.S. Food and Drug Administration (FDA). Statement on stem cell clinic permanent injunction and FDA’s ongoing efforts to protect patients from risks of unapproved products. Last updated June 25, 2019. Available at: https://www.fda.gov/news-events/press-announcements/statement-stem-cell-clinic-permanent-injunction-and-fdas-ongoing-efforts-protect-patients-risks. Accessed on March 29, 2021.
  9. U.S. Food and Drug Administration (FDA). Public safety notification on exosome products. Last updated on December 6, 2019. Available at: https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/public-safety-notification-exosome-products. Accessed on March 29, 2021.
Websites for Additional Information
  1. International Society for Stem Cell Research. Available at: https://www.closerlookatstemcells.org/. Accessed on March 29, 2021.
  2. National Cancer Institute. Bone Marrow Transplantation and Peripheral Blood Stem Cell Transplantation. Reviewed August 12, 2013. Available at: http://www.cancer.gov/cancertopics/factsheet/Therapy/bone-marrow-transplant. Accessed on March 29, 2021. 
  3. U.S National Institute of Health. Stem Cell Information. Available at: http://stemcells.nih.gov/. Accessed on March 29, 2021.
Index

Adult Stem Cell Therapy
Bone Marrow
MarrowStim P.A.D. kit
Mesenchymal Stem Cell Therapy
Mononuclear
Regenexx®
Stem Cell Transplantation
VesCell

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

Document History

Status

Date

Action

  10/01/2021

Updated Coding section with 10/01/2021 ICD-10-PCS changes; removed open approach codes deleted 09/30/2021.

Reviewed

05/13/2021

Medical Policy & Technology Assessment Committee (MPTAC) review. Updated Background, References and Websites sections. Updated coding section with corrected diagnosis range G31.01-G31.9.

 

10/01/2020

Updated Coding section with 10/01/2020 ICD-10-CM changes; added M24.19, M24.29, M24.69, M24.89, M25.59.

Revised

05/14/2020

MPTAC review. Title changed to “Other Stem Cell Therapy.” Position Statement revised from “non-hematopoietic adult stem cell therapy” to “stem cell therapy.” Note in relation to scope added to Position Statement section. Updated the Description/Scope, Rationale, Background/Overview, Definitions, References, Websites for Additional Information, and Index sections. Updated Coding section to add codes 0263T, 0264T, 0265T, 38205, 38206, 6A550ZV and diagnosis codes previously addressed in TRANS.00036.

Revised

08/22/2019

MPTAC review. Title changed to “Non-Hematopoietic Adult Stem Cell Therapy.” Position Statement expanded to include non-hematopoietic adult stem cell therapy. Updated the Description/Scope, Rationale, Background/Overview, Definitions, Coding, References and Websites for Additional Information sections. Added Index section. 

Reviewed

03/21/2019

MPTAC review. Updated Rationale, Background/Overview, Definitions, References and Websites for Additional Information sections. 

Revised

01/24/2019

MPTAC review. Title changed to “Mesenchymal Stem Cell Therapy for the Treatment of Joint and Ligament Disorders, Autoimmune, Inflammatory and Degenerative Diseases”. Updated the Description/Scope, Rationale, Background/Overview, Definitions, References and Websites for Additional Information sections. Deleted Index section.  Updated Coding section to include removing 20930 for spinal surgery no longer addressed.

Reviewed

09/13/2018

MPTAC review Updated Rationale and References sections.

Reviewed

11/02/2017

MPTAC review. The document header wording updated from “Current Effective Date” to “Publish Date.” Updated Rationale, Background, References and Website sections.

 

03/06/2017

Revised note in Scope section to clarify that TRANS.00035 addresses bone graft products with added or exogenous MSCs and that bone graft products with endogenous MSCs are addressed in CG-SURG-45.

Reviewed

11/03/2016

MPTAC review. Removed the products Osteocel, Trinity Evolution and Elite and BIO4 from the rationale. Updated Description, Rationale, References, Website and Index sections.

Reviewed

08/04/2016

MPTAC review. Updated Description, Rationale, Background, References and Websites sections.

 

04/01/2016

Updated Coding section with corrected diagnosis code range for spondylosis; also removed ICD-9 codes.

Reviewed

08/06/2015

MPTAC review. Updated Description/Scope, Rationale, Coding, References, Websites and Index sections.

Reviewed

08/14/2014

MPTAC review. Updated Description/Scope, Rationale, References and Websites sections.

Reviewed

08/08/2013

MPTAC review. Updated Rationale, Background, References and Websites sections.

Reviewed

08/09/2012

MPTAC review. Rationale, Background, References and Websites updated.

 

01/01/2012

Updated Coding section with 01/01/2012 CPT changes.

Reviewed

08/18/2011

MPTAC review. Rationale, Background, References and Websites updated. Updated Coding section with 10/01/2011 ICD-9 changes.

Reviewed

08/19/2010

MPTAC review. Rationale, Background, References and Websites updated.

Reviewed

08/27/2009

MPTAC review. Rationale, websites and references updated.

New

08/28/2008

MPTAC review. Initial document development.


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