High-dose immunosuppressive therapy and autologous peripheral blood stem cell transplantation for severe multiple sclerosis

Abstract

There were 26 patients 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 (range, 5.0-8.0). HDIT consisted of total body irradiation, cyclophosphamide, and antithymocyte globulin (ATG) and was followed by transplantation of autologous, granulocyte colony-stimulating factor (G-CSF)-mobilized CD34-selected stem cells. Regimen-related toxicities were mild. Because of bladder dysfunction, there were 8 infectious events of the lower urinary tract. One patient died from Epstein-Barr virus (EBV)-related posttransplantation lymphoproliferative disorder (PTLD) associated with a change from horse-derived to rabbit-derived ATG in the HDIT regimen. An engraftment syndrome characterized by noninfectious fever with or without rash developed in 13 of the first 18 patients and was associated in some cases with transient worsening of neurologic symptoms. There were 2 significant adverse neurologic events that occurred, including a flare of MS during mobilization and an episode of irreversible neurologic deterioration after HDIT associated with fever. With a median follow-up of 24 (range, 3-36) months, the Kaplan-Meier estimate of progression (>/= 1.0 point EDSS) at 3 years was 27%. Of 12 patients who had oligoclonal bands in the cerebrospinal fluid at baseline, 9 had persistence after HDIT. After HDIT, 4 patients developed new enhancing lesions on magnetic resonance imaging of the brain. 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 3 study is planned to fully assess efficacy.

Figure 1. Survival and progression after HDIT

Estimated survival was 91% and treatment failure was 27% at 3 years. Tick marks represent censored observations.

Figure 2. Neurologic status after HDIT: change in EDSS

Distribution of the changes in EDSS scores compared with baseline at 3, 12, and 24 months after HDIT.

Figure 3. Neurologic status after HDIT: change in Scripps score

Dot plot of the changes in Scripps score compared with baseline at 1, 3, 6, 12, and 24 months. There was no change evident in the mean Scripps score 2 years after HDIT. Center bar indicates the mean of the changes in Scripps score. Top and bottom bars are the 95% confidence limits.

Figure 4. Recovery of lymphocyte subsets

Median subset counts in the patients before transplantation (prior to G-CSF mobilization, arbitrarily displayed as day −30) and approximately on days 7, 30, 80, 180, 365, and 730. Error bars denote the 10^th to 90^th percentiles. Reference values are indicated by the solid thick lines that represent the 10^th to 90^th percentiles and the broken thin lines that represent the medians of 104 healthy adults. The numbers of patients studied were 22 before transplantation, 23 on day 7, 22 on day 30, 20 on day 80, 19 on day 180, 13 on day 365, and 3 on day 730.