Immune Ablation and Autologous Stem Cell Transplantation for Aggressive Multiple Sclerosis: Presented at ECTRIMS

By Chris Berrie
PRAGUE, CZECH REPUBLIC -- October 22, 2007 -- Immunoablative therapy plus autologous stem cell transplantation (ASCT) completely abrogates relapses and MRI events related to ongoing inflammation for up to 5 years, researchers reported here at the 23rd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
Mark S. Freedman, MD, Steering Committee Member and Professor of Neurology, University of Ottawa, and Director, Multiple Sclerosis Research Unit, Ottawa Hospital-General Campus, Ottawa, Canada, presented the 5-year interim analysis from a 3-year phase 2 study.
"If we completely remove the diseased immune system, we should halt ongoing immune-mediated damage, because we would have removed the mistake," Dr. Freedman said during his presentation on October 13. Furthermore, the purified stem cells should be capable of restoring a functional immune system, and might even be capable of stimulating repair.
Therefore, Dr. Freedman and colleagues conducted a study to determine if immunoablative therapy and ASCT induces long-lasting MS progression-free responses in patients with active and progressive disease who have a poor prognosis.
They enrolled patients aged 18 to 50 years with active MS with relapses or progression and sustained accumulated impairment. Patients had a high risk of progression, an Expanded Disability Status Scale (EDSS) from 3 to 6, and evidence of current disease activity, and had undergone at least 1 year of other standard MS therapy.
The main steps of the protocol included stem cell mobilization: cyclophosphamide 4.5 g/m², followed by granulocyte-colony stimulating factor (G-CSF) 10 mcg/kg/day for 10 days; leukophoresis and CD34+ stem cell collection. The immunoablation comprised: busulfan 9.6 mg/kg; cyclophosphamide 200 mg/kg, and rabbit ATG 5 mg/kg; with the ASCT carried out with G-CSF 5 mcg/kg/day.
Due to patient safety considerations (one early death due to busulfan-induced complications), busulfan dosing was later modified from 1 mg/kg/dose every 6 hours for 16 doses to 0.8 (0.6 in future) mg/kg IV for 16 doses, to avoid first pass effects and to minimize liver toxicity, Dr. Freedman noted.
Treatment failure was defined according to any two of the following: significant and sustained EDSS progression; at least two relapses at any time; and Gd+-enhancing lesions on any two consecutive MRI. However, the researchers' original definition of treatment success no longer holds due to difficulties in patient enrolment, particularly into the control arm.
The 25 patients available for evaluation were aged 26 to 41 years, MS duration of 30 to 128 months, had an EDSS score pre-ASCT of 3 to 6.5, and one to five relapses in the previous 2 years.
To date, no patient has experienced any attacks since undergoing ASCT. Although mild EDSS progression has been seen in four patients (one being a control subject, +1/1.5), a further three patients have shown EDSS improvements (-2 to -4), while in the remainder of subjects EDSS scores remained being stable. Dr. Freedman also indicated that the individual patient EDSS progression or improvement appear to be related to EDSS at baseline (progression only with EDSS 5.5 or greater).
For MRI lesions, Dr. Freedman said, "We have been without a single new Gd-enhancing or re-enhancing lesion post-transplantation. In fact, not a single new T2 lesion has developed in any patient since [ASCT]."
Finally, he gave some particular examples of the evidence of specific, but delayed, clinical improvements seen in some of the Kurtzke functional subscores. "This does suggest to us that in the absence of ongoing inflammation, the brain may be capable of some repair, and maybe this had been stimulated by the transplanted autologous bone-marrow-derived stem cells."
Funding for this study was provided by Bayer Schering Pharma AG.
[Presentation title: Immune Ablation and Autologous Stem Cell Transplantation for Aggressive Multiple Sclerosis: Interim 5-Year Report. Abstract 73]
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