Hematopoietic stem cell transplantation for progressive multiple sclerosis: failure of a total body irradiation–based conditioning regimen to prevent disease progression in patients with high disability scores

Abstract

There were 21 patients with rapidly progressive multiple sclerosis (MS) treated on a phase 1/2 study of intense immune suppressive therapy and autologous hematopoietic stem cell (HSC) support with no 1-year mortality. Following transplantation, one patient had a confirmed acute attack of MS. Neurologic progression defined by the expanded disability status scale (EDSS) did not increase in disability by 1.0 or more steps in any of 9 patients with a pretransplantation EDSS of 6.0 or less. In 8 of 12 patients with high pretransplantation disability scores (EDSS > 6.0), progressive neurologic disability as defined by at least a 1-point increase in the EDSS has occurred and was manifested as gradual neurologic deterioration. There were 2 patients with a pretransplantation EDSS of 7.0 and 8.0 who died from complications of progressive disease at 13 and 18 months following treatment. Our experience suggests that intense immune suppression using a total body irradiation (TBI)-based regimen and hematopoietic stem cell transplantation (HSCT) are not effective for patients with progressive disease and high pretransplantation disability scores. Further studies are necessary to determine the role of intense immune suppressive therapy and HSC support in ambulatory patients with less accumulated disability and more inflammatory disease activity. Specifically, more patients and longer follow-up would be required in patients with an EDSS of 6.0 or less before drawing conclusions on this subgroup.

Hematopoietic Stem Cell Therapy for Multiple Sclerosis: Top 10 Lessons Learned

“…Either agent may cause dose-dependent neurotoxicity, aggravate MS associated CNS damage or prevent the ability of the CNS to recover from an insult by damaging the endogenous regenerative mechanism in the brain. HSCT after total body irradiation has been associated with poorer MS outcomes [14,45] and this could be attributed to these mechanisms. In the future, a risk-adapted treatment approach could tailor the optimum conditioning regimen dose intensity to the risks of neurotoxicity and to the aggressiveness of the MS.…”

“…However, it was observed that these patients (with an Expanded Disability Status Scale [EDSS] score≥6.0) had poor outcomes compared with patients who entered HSCT with less disability [14]. A review of data from the EBMT registry that stratified patients by age and duration of MS, showed markedly better outcomes for recipients who were younger than 40 years of age and had been diagnosed within the last 5 years compared with older patients who had longstanding MS [18].…”

“…& Patients undergoing HSCT for a malignancy who also have concurrent MS [10][11][12] & The initial prospective phases 1 and 2 cohort trials [13][14][15][16][17] & Reports of registry [18] based data for the treatment of MS This information is summarized in a number of review articles [19,20].…”

“…The 2 most commonly used stem cell mobilization regimens used to collect HSC from MS patients are granulocyte-colony stimulating factor (G-CSF) administered concurrently with steroids and cyclophosphamide followed by G-CSF. Sole administration of G-CSF can induce an MS relapse [13,14,22], however, this can be prevented by concurrent steroid or chemotherapy administration. These drugs offer the additional benefit of providing transient immunosuppression, which helps control the MS until the stem cell transplant.…”

“…Initially some groups used conditioning regimens containing total body irradiation [13,14], however, most centers have subsequently adopted multi-drug chemotherapy regimens. Thus, experience with total body irradiation is limited to less than 100 MS patients.…”