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Prepublished online as a Blood First Edition Paper on May 22, 2003; DOI 10.1182/blood-2002-12-3908.
Submitted December 24, 2002
Accepted May 13, 2003
High-dose immunosuppressive therapy and autologous peripheral blood stem cell transplantation for severe multiple sclerosis
Richard A Nash*, James D Bowen, Peter A McSweeney, Steven Z Pavletic, Kenneth R Maravilla, Man-soo Park, Jan Storek, Keith M Sullivan, Jinan Al-Omaishi, John R Corboy, John DiPersio, George E Georges, Theodore A Gooley, Leona A Holmberg, C Fred LeMaistre, Harry Openshaw, Julie Sunderhaus, Rainer Storb, Joseph Zunt, and George H Kraft
Fred Hutchinson Cancer Research Center, Seattle, WA, USA; University of Washington, Seattle, WA, USA
University of Colorado Health Sciences Center, Denver, CO, USA
University of Nebraska Medical Center, Omaha, NE, USA
City of Hope National Medical Center, Duarte, CA, USA
Duke University Medical Center, Durham, NC, USA
Washington University, St. Louis, MO, USA
Texas Transplant Institute, San Antonio, TX, USA
* Corresponding author; email: rnash{at}fhcrc.org.
Twenty-six patients were enrolled in a pilot study of high-dose immunosuppressive therapy (HDIT) for severe multiple sclerosis (MS). Median baseline Expanded Disability Status Scale (EDSS) was 7.0 (5.0-8.0). HDIT consisted of total body irradiation, cyclophosphamide and antithymocyte globulin (ATG) and was followed by transplantation of autologous, G-CSF-mobilized CD34-selected stem cells. Regimen-related toxicities were mild. Because of bladder dysfunction, there were eight infectious events of the lower urinary tract. One patient died from EBV-PTLD associated with a change from horse-derived to rabbit-derived ATG in the HDIT regimen. An engraftment syndrome characterized by noninfectious fever +/- rash developed in 13 of the first 18 patients and was associated in some cases with transient worsening of neurological symptoms. Two significant adverse neurologic events occurred, including a flare of MS during mobilization and an episode of irreversible neurological deterioration after HDIT associated with fever. With a median follow-up of 24 (3-36) months, the Kaplan-Meier estimate of progression ( 1.0 points EDSS) at 3 years was 27%. Of 12 patients who had oligoclonal bands in the cerebrospinal fluid at baseline, 9 had persistence after HDIT. Four patients developed new enhancing lesions on magnetic resonance imaging of the brain after HDIT. The estimate of survival at 3 years was 91%. Important clinical issues in the use of HDIT and stem cell transplantation for MS were identified; however, modifications of the initial approaches appear to reduce treatment risks. This was a heterogeneous high-risk group, and a phase III study is planned to fully assess efficacy.
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