March 23, 2011 — Long-term results of a small phase 1/2 study show that hemopoietic stem cells were effective, even life-saving, for some patients with aggressive multiple sclerosis (MS), researchers say.
Among 35 patients included in the trial who underwent hemopoietic stem cell transplantation (HSCT), the rate of disease progression-free survival at 15 years was 44% for those with active lesions in the central nervous system on magnetic resonance imaging (MRI) and 10% for those without active lesions.
"HSCT is not a therapy for the general population of patients with MS but should be reserved for aggressive cases, still in the inflammatory stage of the disease, and for the malignant form, in which it can be life-saving," the researchers, with corresponding author Vasilios K. Kimiskidis, MD, from the Department of Neurology at George Papanicolaou Hospital in Thessaloniki, Greece, conclude.
|Dr. Vasilios K. Kimiskidis|
"HSCT has an impressive and sustained effect in suppressing disease activity on MRI," they write.
Results of this single-center study were published in the March 22 issue of Neurology.
"Impressive and Sustained Effect"
The researchers launched this unblinded trial in 1995 to study the effect of intense immunosuppressive chemotherapy followed by HSCT. They performed the study on the basis of reports of this strategy in experimental autoimmune encephalomyelitis (an animal model of MS), they write, and "the simple rationale that a renewed state of immune tolerance might be attained if the aberrant immune system was completely eradicated and replaced by a pristine, expectantly nonautoreactive, system generated from an autologous hemopoietic stem cell graft purged of autoimmune cells."
A previous report on these 35 patients by this group showed an 80% probability of disease progression-free survival at 5 years, they write. "Moreover, a major suppressive effect on disease activity was noted in brain MRI, while the procedure was associated with 3% mortality" (Best Pract Res Clin Hematol. 2004;17:247-262).
In the current study, the authors looked at long-term results with this "still disputable therapy" at a median follow-up of 11 years (range, 2 - 15 years).
Over follow-up, 5 patients died. One died of aspergillosis at 2 months after transplantation and 1 died at 2.5 years of pulmonary hemorrhage after use of a factor VIII inhibitor, probably transplant-related. In the final analysis, 3 more deaths had occurred: 1 from prostate cancer at 12 years and 2 from MS-related complications at 10 and 14 years after transplantation, respectively.
Sixteen patients had functional improvement on the Expanded Disability Status Scale (EDSS) of 0.5 to 5.5 points (median, 1 point) after transplantation. This improvement lasted for a median of 2 years, but 2 patients remained improved for 7 and 8 years, the authors report. Seven patients eventually progressed beyond their baseline disability, but in 7 others, scores have not yet exceeded those at baseline despite evidence of clinical activity, they write.
A life-saving response was seen in 1 patient with "malignant" MS, they add; full details of this case were previously reported (Mult Scler. 2008;14:278-283).
The progression-free survival rate was 25% at 15 years and was not affected by disease type, sex, method of immune conditioning, or EDSS score at the time of transplantation, the researchers note.
Median duration of progression-free survival was 5.4 years in patients with secondary and relapsing MS and 1.5 years in those with primary progressive disease (P = .338). Patients who were 35 years of age or younger and had a short interval between diagnosis and transplantation appeared to have better outcomes.
Patients with active MRI lesions had a progression-free survival rate of 44% at 15 years (median, 11 years; 95% confidence interval [CI], 0 - 22 years) vs 10% in patients without active lesions (median, 2.3 years; 95% CI, 0 - 6 years) (P = .01).
"A significant reduction in the number and volume of gadolinium-enhancing lesions was detected on MRI, which started after mobilization, became maximal after transplantation, and was thereafter sustained in time," the authors write.
Results similar to these were reported by the European Group for Blood and Marrow Transplantation in 178 patients from 45 centers, they add. That study showed the importance of selecting patients who are younger, are not too disabled, or were recently diagnosed in order to minimize mortality, which in Europe is estimated at 2% to 3% (Mult Scler. 2006;12:814-823).
"Because the mortality issue has remained of concern in the neurologic society and impeded adequate patient accrual in comparative studies, the superiority of HSCT over standard therapies has not yet been demonstrated in randomized trials, although more than 700 patients have been treated in phase 1/2 studies worldwide and good results have been claimed," the authors conclude. "Nevertheless, HSCT could be regarded as a salvage treatment of choice in 'malignant' MS, in which comparative trials cannot be done and in which HSCT may yield dramatic results."
Dr. Kimiskidis told Medscape Medical News that after the conclusion of the long-term follow-up of this initial cohort, they stopped recruiting patients as a single center and instead have joined in larger international coordinated efforts to investigate this approach further.
"It's clear that only a randomized, comparative trial will be able to answer this question conclusively," he said in an emailed comment. "Currently, there are a number of international collaborative efforts to this end, the results of which are eagerly awaited."
In the meantime, patients they would consider for HSCT are those in a relatively early phase of disease, "characterized by rapid clinical and radiological deterioration with active MRI lesions despite treatment with 1 or 2 lines of standard therapy," Dr. Kimiskidis added. "In these patients, the inflammatory component of the disease is particularly active and therefore they are expected to benefit most from the intense anti-inflammatory and immunosuppressive effects of HSCT."
In 2009, researchers led by Richard K. Burt, MD, from Northwestern University Feinberg School of Medicine in Chicago, Illinois, reported a phase 1/2 trial of HSCT in patients with relapsing-remitting MS. They showed that transplantation in these patients was safe and was associated with stabilization and, in some cases, reversal of disability (Lancet Neurol. 2009;8:244-253). A phase 3 trial was planned.
Dr. Kimiskidis reports that he serves on the editorial advisory board of the journal Epileptic Disorders and as a consultant for Novartis and Merck Serono. Disclosures for coauthors appear in the paper.
Neurology. 2011;76:1066-1070. Abstract
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Cite this: Stem Cells May Improve Survival in Aggressive MS - Medscape - Mar 23, 2011.