The Use of Autologous Stem Cells in the Rehabilitation of Multiple Sclerosis

Prior to 1993 there were no disease-modifying therapies (DMTs) for multiple sclerosis (MS). Rehabilitative techniques were the only available methods for managing this disease. [1] We used these techniques to substitute for progressive neurological loss and maintain function. In the fall of 1993 the first DMT for MS was approved by the U.S. FDA, and over the years since then more than a dozen increasingly efficacious DMTs have become available on the U.S. market. However, at best these DMTs offer only partial disease control; patients will typically continue to get worse.

It has been known for some time that MS was produced by a misdirected attack by a patient's immune system on the central nervous system (CNS). Thus, MS is considered an “immune mediated” disease. In the mid-1990 s we postulated that if we completely ablated an MS patient's immune system, followed by an autologous hematopoietic stem cell transplant (HSCT) rescue, which would reconstitute without the offending, programed “attack” T-cells, we should be able to stop the disease (suppressive phase). Then we could actually improve a patient's function with a subsequent rehabilitation program (improvement phase). Although Fassass et al. had tested this suppressive phase approach using carmustine, etoposide, cytarabine, and melphalan chemotherapy (BEAM) and antithymocyte globulin (ATG) [2] and Burt et. al. had used cyclophosphamide (Cy) plus total body irradiation (TBI) [3], we designed the suppressive phase of our pilot study as the first to use all three techniques: TBI, Cy, and ATG. Following this high dose immunosuppressive therapy (HDIT) we gave the patient previously-selected and cryopreserved peripheral blood CD34-selected stem cells as rescue. With the disease now stabilized, we then followed this with a customized rehabilitation program to actually improve the patient.

In our pilot study (1998 through 2001) we treated 26 MS patients, with all types of MS: relapsing-remitting (RRMS), secondary progressive (SPMS), primary progressive (PPMS), and progressive relapsing (PRMS). Our inclusion criteria were very broad, ranging from an Expanded Kurtzke Disability Scale (EDSS) of 5.0 to 8.0. Estimated survival was 91% and treatment failure was 27% at 3 years. [4] As a generalization, we found that the best results were in the patients who had the most active inflammatory disease (RRMS) and the lowest EDSS scores.

Those selected patients did so well, that when we designed our follow-up NIH-funded protocol (HALT-MS), we limited the subjects to RRMS patients with an EDSS range of 3.0 – 5.5, reduced the toxicity of the chemotherapeutic component by using BEAM, eliminated the TBI, and again followed the stable patients with an individualized rehabilitation program. At 3 years EDSS progression-free survival of these 25 subjects was 90.9% and MRI event-free survival was 100%. [5] Clearly, the combination of refined selection criteria and a more benign treatment regimen resulted in better outcome.

The rehabilitation program that followed all of these now-stabilized patients consisted of individualized components, designed to reduce disability and handicap, selected from a broad menu of rehabilitative strategies. Rather than giving the same rehabilitation program to every subject, highly individualized approaches were prescribed.

These strategies included:

• Pharmacological optimization: spasmolytic agents for controlling spasticity, walking enhancement with dalfampridine, fatigue management with modafinil or armodafinil, bladder control using oxybutynin or similar medications, and pain management using gabapentin or similar drugs.

• Exercise: Stretching exercises, resistive exercises, and aerobic conditioning.

• Orthoses: Foot-drop management with a low-friction toe cap or ankle-foot orthoses (AFO).

• Gait aids: Appropriate prescription of a cane, walker, wheel chair (manual or power) or scooter.

• Depression: Counseling and antidepressants.

• Cognitive impairment: Neuropsychological assessment followed by speech/language training.

• Employment issues: Management with vocational training and workplace accommodations.

In summary, we have now had almost 2 decades experience in using the very powerful treatment approach of HDIT/HSCT to suppress MS activity followed by an aggressive rehabilitative program to improve function. We have now treated more than 60 MS patients using this approach, and believe that it is presently the most effective treatment protocol for very aggressive, relapsing-remitting multiple sclerosis.

References:

[1] Kraft GH. Rehabilitation still the only way to improve function in multiple sclerosis. The Lancet. 1999 Dec 11;354(9195):2016 – 7.

[2] Fassass A, Anagnostopoulos A, Kazis A, et al. Peripheral blood stem cell transplantation in the treatment of progressive multiple sclerosis: first results of a pilot study. Bone Marrow Transplant. 1997 Oct;20(8):631 – 8.

[3] Burt RK, Traynor AE, Cohen B, et al. T cell-depleted autologous hematopoietic stem cell transplantation for multiple sclerosis: report on the first three patients. Bone Marrow Transplantation. 1998 Mar;21(6):537 – 41.

[4] Nash RA, Bowen JD, McSweeney PA, et al. High-dose immunosuppressive therapy and autologous peripheral blood stem cell transplantation for severe multiple sclerosis. Blood. 2003 Oct 1;102(7):2364 – 72.

[5] Nash RA, Hutton GJ, Racke MK, et al. High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation for relapsing-remitting multiple sclerosis (HALT-MS). JAMA Neurol. 2015 Feb;72(2):159 – 69.