Stem Cell Therapy | Mellon Center Approach | Cleveland Clinic

Q: What are the types of stem cell therapy?

A: Stem cells are primitive cells that are capable of self-renewal (i.e., to divide to replenish their population); are pluripotent (i.e., able to differentiate into different mature cells); and are able to create, maintain, or repair tissues. There are several general categories of stem cells, including:

Two general stem-cell-based therapeutic strategies have been considered in MS:1

This document addresses AHSCT and MSC transplantation separately.

A: AHSCT is a multi-step procedure, which includes:

Mobilization typically is performed as an outpatient. Conditioning, PBHSC infusion, and initial recovery usually are performed during an approximately 1-month hospitalization in a specialized transplant unit.

A: A sizable number of case series, uncontrolled phase 2 clinical trials, and randomized clinical trials have demonstrated, in aggregate, potent efficacy of AHSCT in patients with active relapsing MS, including marked reduction in relapses, MRI lesion activity, and brain volume loss (after initial acceleration).1-3 In two analyses, the rate of no evidence of disease activity at 2 years was 70-90% in AHSCT case series and trials compared to 15-50% in clinical trials of MS disease modifying therapies (DMTs).4,5 A sizable proportion of patients treated with AHSCT demonstrate improvement in disability, for example, 64% at 4 years in a recent case series.6 Disease control often is durable, lasting up to 15 years or more without the need for ongoing disease modifying therapy (DMT) in many patients.7 Nonetheless, some patients require resumption of standard DMTs at some point after AHSCT, particularly with lower intensity non-myeloablative conditioning regimens.

The potent efficacy is attributed to immunoablative conditioning that depletes pathogenic immune cells; the durability of benefit is attributed more normal regulatory function and T-cell and B-cell repertoires following immune reconstitution.4

A: Early toxicity is common in patients undergoing AHSCT and potentially includes MS relapse during mobilization and conditioning, complications of leukapheresis, side effects of cytotoxic agents comprising the conditioning regimen (e.g., nausea or infertility), complications of myelosupression (e.g., infection or bleeding complications), and engraftment syndrome after re-infusion of PBHSCs (fever, rash, pulmonary edema, liver or renal impairment, and encephalopathy). Patients typically are hospitalized for approximately 1 month when undergoing conditioning and transplantation, and for initial recovery. Previous estimates of overall transplant-related mortality in MS were 2% or more. The current estimate is 0.2-0.3% for AHSCT performed after 2012.4 The improved safety is due to increased experience with the procedure, refinement of the protocol, and better selection of patients with lower risk of complications.

After recovery, adverse effects are rare and include infection (principally related to herpes zoster) and secondary autoimmune disorders. One potential advantage is that after AHSCT patients typically do not need ongoing MS DMT, with the associated cumulative risk of adverse effects.

A: The estimated cost for uncomplicated AHSCT is approximately $150,000. One potential advantage is that after recovery patients typically do not need ongoing MS DMT, with the associated cumulative cost. Nevertheless, most health insurance plans do not cover AHSCT, so obtaining coverage often is difficult.

A: Patients most likely to benefit from AHSCT are young (approximately 55 years or less), with relatively recent disease onset (approximately 10 years or less), still ambulatory, with highly active MS with recent clinical relapses or MRI lesion activity, and continued disease activity despite treatment with approved DMTs especially high-efficacy DMTs. Both the American Society for Blood and Marrow Transplantation 2 and National MS Society3 have published policy statements that AHSCT is a reasonable option in such patients, who are at high risk for disability.

A: Because of the complexity of the AHSCT procedure and the need for appropriate patient selection and follow-up, AHSCT for MS should be performed by centers with expertise and experience in transplant and that are affiliated with centers with experience and expertise in management of MS.1-3We advise patient not to undergo AHSCT in free-standing transplant clinics, especially in the absence of a detailed plan for follow-up and management of medical and neurologic issues post-transplant.

A: Because of the uncertain efficacy and safety of AHSCT compared to approved DMTs for MS, the Mellen Center is participating in the ongoing Best Available Therapy Versus Autologous Hematopoietic Stem Cell Transplant for Multiple Sclerosis (BEAT-MS) clinical trial sponsored by the National Institute of Allergy and Infectious Diseases and the Immune Tolerance Network (ClinicalTrials.gov Identifier: NCT04047628). This multicenter, randomized, rater-blinded trial compares the efficacy, safety, cost-effectiveness, and immunologic effects of AHSCT versus high-efficacy DMTs in participants with highly active, treatment-refractory, relapsing MS.

Because of unanswered questions regarding the efficacy of AHSCT in MS and substantial associated risk, our priority is to enroll patients for whom AHSCT is being considered into the BEAT-MS trial. We will consider AHSCT outside of the BEAT-MS trial for selected patients for whom AHSCT appears indicated but who are not eligible to participate in the study.

A: Typically, transplant physicians monitor and manage transplant-related adverse effects for the first 6 months following uncomplicated AHSCT (longer if there are complications). After 6 months following uncomplicated AHSCT, transplant-related adverse effects are rare. Patients need to be monitored primarily for symptoms or other findings suggesting infection or secondary autoimmune disorders. Long-term MS disease monitoring is similar to typical MS, with clinical visits and periodic MRIs.

A: Several analyses demonstrated that AHSCT has modest or no efficacy in preventing or reversing progressive disability worsening in the absence of recent relapses or MRI lesion activity. Conversely, the risk of adverse effects and transplant-related mortality are increased in progressive MS due to greater neurologic disability, older age, and increased likelihood of comorbidities. Many of the transplant-related deaths in recent series were patients with progressive MS.4 As a result, AHSCT generally is not advised for patients with non-active progressive MS and/or severe disability.

A: A recent publication reported potent efficacy of non-myeloablative AHSCT in preventing relapses, improving disability, and improving quality of life in 11 patients with aquaporin-4-positive neuromyelitis optica spectrum disorders (NMOSD).8 There now are 3 medications with regulatory approval to treat NMOSD plus several other medications used off-label. The findings from this small uncontrolled case series suggests AHSCT might be an option for patients with NMOSD who do not achieve adequate disease control from the available medication options. Rigorous formal clinical trials are needed to more definitively assess the efficacy and safety of AHSCT in NMOSD. We have not performed AHSCT for NMOSD at Cleveland Clinic.

A: Studies of various stem cell approaches to directly replace myelin-forming cells have been proposed (e.g., transplantation of oligodendrocyte progenitor cells or induced pluripotent stem cells), but none has been completed.1 To date, the most experience is with transplantation of mesenchymal stem cells (MSCs), pluripotent stromal cells present in a perivascular niche in a variety of tissues. In addition to their ability to differentiate into mesodermal lineage derivatives (e.g., bone, cartilage, connective tissue, and adipose tissue), MSCs appear to function to limit inflammatory tissue damage and promote tissue repair, including in the central nervous system, through elaboration of a large number of soluble immunomodulatory and trophic factors. These properties have led to a large number of studies investigating the potential benefit of MSC transplantation to treat a wide variety of inflammatory and tissue injury conditions.1 There also are a large number of commercial stem cell clinics offering MSC transplantation for a wide range of conditions.

A: A sizable number of preliminary trials of MSC transplantation in MS have been reported,1 including one conducted at the Mellen Center.9 These studies had different study populations, cell products, routes of administration, and study protocols, making it difficult to generalize the results. In aggregate, the studies reported good safety and tolerability, and some provided preliminary evidence of benefit. A recent study utilizing cell production procedures intended to augment production of neurotrophic factors by the MSCs and multiple intrathecal administrations, reported more prominent efficacy.10

Despite the sizable number of studies of MSC transplantation, there are a many unanswered technical questions, including the best tissue source (e.g., bone marrow, adipose tissue, or placenta/umbilical cord), whether the cells should be autologous (i.e., from the patient) or allogeneic (i.e., from someone without MS), the optimal cell culture methods to maximize yield and stimulate characteristics that increase therapeutic potency, whether the cells can be cryopreserved (frozen and stored) or need to be harvested directly from culture, dose (i.e., how many MSCs are administered), dosing schedule (i.e., for how long the therapeutic benefit lasts and how often the MSCs need to be administered), and optimal route of administration (i.e., intravenous, intrathecal, or both), among other issues. Because of these unanswered technical questions, MSC transplantation currently is an experimental treatment and should not be performed outside of rigorous formal clinical trials

A: There are a large number of commercial stem cell clinics in the U.S. and other countries offering treatments marketed as stem cells and presumed to be predominantly MSCs, on a fee-for service basis. However, because of the lack of quality control, lack of regulatory oversight, and lack of any validation of their efficacy or safety, we strongly advise patients not to pursue stem cell treatments at commercial stem cell clinics, outside of rigorous formal clinical trials. Many of these operations are potentially fraudulent.

Although MSC transplantation generally has been well-tolerated and safe in formal clinical trials, complications have been reported when administered in commercial stem cell clinics, including among other reports severe loss of vision following intravitreal injection11 and malignant spinal cord neoplasm following intrathecal injection.12

In addition, a number of concerns regarding commercial stem cell clinics have been raised: 13,14

A: Patient who undergo MSC transplantation should be monitored for symptoms or other findings indicating potential complications, including local or systemic infection, ectopic tissue formation, neoplasia, and arachnoiditis (following intrathecal administration). Long-term MS disease monitoring is similar to typical MS, with clinical visits and periodic MRIs.

Last Updated: 10 DEC 2020

Approach last updated: February 14, 2021

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Stem Cell Therapy | Mellon Center Approach | Cleveland Clinic