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:
- Embryonic stem cells – the prototypic stem cells present in the inner cell mass of the blastocyst that give rise to all the cell types in the developing embryo
- Adult stem cells – various types of stem cells present in virtually all body tissues in the adult, including neural stem cells and oligodendrocyte progenitor cells in the adult central nervous system
- Induced pluripotent stem cells – stem cells generated from adult somatic cells through molecular reprogramming
Two general stem-cell-based therapeutic strategies have been considered in MS:1
- Anti-inflammatory strategies – typified by autologous hematopoietic stem cell transplantation (AHSCT)
- Repair-promoting strategies – typified by mesenchymal stem cell (MSC) transplantation
This document addresses AHSCT and MSC transplantation separately.
Q: What does AHSCT entail?
A: AHSCT is a multi-step procedure, which includes:
- Mobilization of autologous peripheral blood hematopoietic (blood-forming) stem cells (PBHSCs), typically by treatment with cyclophosphamide and granulocyte colony stimulating factor, harvest (collection by leukapheresis) and cryopreservation sometimes with selection of CD34+ cells. At Cleveland Clinic, we do not utilize CD34 selection for AHSCT for MS.
- Conditioning with high-dose chemotherapy. The ablative conditioning eliminates the existing immune cells and is the component of the protocol that represents MS disease therapy per se. Conditioning regimens all are immunoablative but range in intensity from low-intensity non-myeloablative regimens to high-intensity potently myeloablative regimens. The optimal intensity conditioning regimen currently is uncertain.1 The lower intensity non-myeloablative regimens are better tolerated but may have somewhat less potent or durable efficacy. Conversely, the highest intensity myeloablative regimens may have more potent or durable efficacy, but have greater risk. At Cleveland Clinic, we currently utilize BEAM (carmustine, etoposide, cytarabine, melphalan) plus anti-thymocyte globulin, an intermediate intensity conditioning regimen, for AHSCT for MS.
- Re-infusion of the PBHSC graft. The principal purpose of the transplant is to shorten the aplastic phase after conditioning and lessen the resultant adverse effects, though some data suggest that it might contribute to immune reconstitution with more normal regulatory function and self-tolerance.
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.
Q: How efficacious is AHSCT?
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
Q: What are the risks of AHSCT?
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.
Q: How expensive is AHSCT?
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.
Q: Who is most likely to benefit from AHSCT?
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.
Q: Where should AHSCT be performed?
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.
Q: Is the Cleveland Clinic performing ASHCT to treat MS?
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.
Q: What follow-up is needed following AHSCT?
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.
Q: Is AHSCT useful for patients with progressive MS?
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.
Q: Is AHSCT effective for neuromyelitis spectrum disorders?
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.
Q: Are there stem cell approaches that promote repair?
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.
Q: What is the status of MSC transplantation to treat MS?
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
Q: Should patients pursue MSC therapy at commercial stem cell clinics?
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
- Lack of follow-up or communication with the treating neurologist
- Lack of regulatory oversight and of compliance with federal regulations and FDA criteria for homologous use and minimal manipulation
- Ethical concerns
- Misrepresentation of an unproven therapy as practice of medicine or patient-funded research
- Lack of veracity of marketing claims about safety and efficacy
- Incomplete information regarding the type and integrity the cell product, procedures performed, potential risks
- Susceptibility of a vulnerable population to medical and financial harm
Q: What follow-up is needed after MSC transplantation?
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
- Scolding NJ, Pasquini M, Reingold SC, Cohen JA, on behalf of attendees at the International Conference on Cell-Based Therapies for Multiple Sclerosis. Cell-based therapeutic strategies for multiple sclerosis. Brain 2017;140:2776-2796.
- >Cohen JA, Baldassari LE, Atkins HL, et al. Autologous hematopoietic cell transplantation for treatment-refractory relapsing multiple sclerosis: position statement from the American Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant 2019;25:845-854.
- Miller AE, Chitnis T, Cohen BA, et al. Autologous hematopoietic stem cell transplant in multiple sclerosis. Recommendations of the National Multiple Sclerosis Society. JAMA Neurol 2020;doi:10.1001/jamaneurol.2020.4025.
- Muraro PA, Martin R, Mancardi GL, Nicholas R, Sormani MP, Saccardi R. Autologous haematopoietic stem cell transplantation for treatment of multiple sclerosis. Nature Reviews Neurology 2017;13:391-405.
- Sormani MP, Muraro PA, Saccardi R, Mancardi G. NEDA status in highly active MS can be more easily obtained with autologous hematopoietic stem cell transplantation than other drugs. Mult Scler J 2017;23:201-204.
- Burt RK, Balabanov R, Han X, et al. Association of nonmyeloablative hematopoietic stem cell transplantation with neurologic disability in patients with relapsing-remitting multiple sclerosis. JAMA 2015;313:275-284.
- Muraro PA, Pasquini M, Atkins HL, et al. Long-term outcomes after autologous hematopoietic stem cell transplantation for multiple sclerosis. JAMA Neurol 2017 74:459-469.
- Burt RK, Balabanov R, Han X, et al. Autologous nonmyeloablative hematopoietic stem cell transplantation for neuromyelitis optica. Neurology 2019;93:e1732-e1741.
- Cohen JA, Imrey PB, Planchon SM, et al. Pilot trial of intravenous autologous culture-expanded mesenchymal stem cell transplantation in multiple sclerosis. Mult Scler J 2018; 24:501-511.
- Harris VK, Stark J, Vyshkina T, et al. Phase I trial of intrathecal mesenchymal stem cell-derived neural progenitors in progressive multiple sclerosis. EBioMedicine 2018;29:23-30.
- Kuriyan AE, Albini TA, Townsend JH, et al. Vision loss after intravitreal injection of autologous "stem cells" for AMD. N Engl J Med 2017;376:1047-1053.
- Berkowitz AL, Miller MB, Mir SA, et al. Glioproliferative lesion on the spinal cord as a complication of "stem-cell tourism". N Engl J Med 2016;375:196-198.
- Sipp D, Robey PG, Turner L. Comment: Clear up this stem-cell mess. Nature (London) 2018;561:455-457.
- Julian K, Yuhasz N, Rai W, Salerno JA, Imitola J. Complications from “stem cell tourism” in neurology. Ann Neurol 2020;88:661-668.