Autologous Hematopoietic Stem Cell Transplantation for Refractory Multiple Sclerosis

• Autologous haemopoietic stem cell transplantation (Procedure): Immuno-ablation and autologous CD34 selected hematopoietic stem cell transplantation (HSCT). Stem cell mobilization with cyclophosphamide 2g/m2 and filgrastim 10 ug/kg/d x 5 day. Stem cell collection with cobe cpectra stem cell purification with Miltenyi CliniMACS Stem cell transplant conditioning with busulphan 3.2 mg/kg ; fludarabine 30mg/m2 or cladribine 10mg ；cytarabine 1-2g/m2 or idarubicin 8mg/m2；cyclophosphamide 40mg/kg followed by CD34 selected autologous hematopoietic stem cell transplant.

Primary outcomes

• 3 year MS activity free survival [3 year follow-up post transplant]: The events for the primary outcome are: clinical relapse, appearance of a new or Gd-enhancing lesion on MRI, or sustained progression of EDSS score.

Secondary outcomes

• Time to MS treatment failure [3 years]: Disease activity and disability will be assessed with clinical relapse, appearance of a new or Gd-enhancing lesion on MRI, or sustained progression of EDSS score and quality of life.
• Transplant related morbidity [3 years]: Rate of transplant related events.
• Transplant related mortality [3 years]: Rate of transplant related death.
• Immune reconstitution following transplant [3 years]: Rate of immune reconstitution following transplant.
• Hematopoietic reconstitution following transplant [3 years]: Rate of hematopoietic reconstitution following transplant.
• Imaging changes associated with the disease activity [3 years]: Imaging changes include: new or enlarging T2-weighted lesion count and new T1-weighted lesion count at all scans after baseline; T2-weighted lesion volume; Gd-enhanced lesion count and volume; and total volume of non-enhancing T1-weighted lesions on all MRI scans.

Sex: All, ages: 18 Years to 60 Years

Inclusion Criteria:

1. Age 18-60 years;
2. Diagnosed multiple sclerosis with relapses or progression and sustained accumulated impairment by a neurologist expert in the field;
3. EDSS score of 3-6 (including 3 and 6);
4. EDSS cerebellar functional score ≥ 3 or EDSS pyramidal functional score ≥3；
5. Evidence of current disease activity;
6. If a patient has previously received a cytotoxic agent (mitoxantrone, cyclophosphamide etc.) they must have normal bone marrow morphology and cytogenetics before being considered eligible for this study ;
7. No evidence of hepatic inflammation or fibrosis;

Exclusion Criteria:

1. Patients with evidence of myelodysplasia or other non-autoimmune cytopenia;
2. Patients having received a cytotoxic agent within one month of enrolling in this study;
3. Patient with any active or chronic infection (herpes simplex virus, varicella-zoster virus, cytomegalovirus, EB virus, human immunodeficiency virus, hepatitis virus, syphilis, etc.);
4. Patients having received a cytotoxic agent within one month of enrolling in this study;
5. Patients with a malignant tumor currently or within the last 5 years;
6. Patients with cardiac, renal, pulmonary, hepatic or other organ impairment;
7. Patients whose life expectancy is severely limited by another conditions;
8. Pregnancy or risk of pregnancy;
9. Patients unable to give written informed consent in accordance with research ethics board guidelines.

• Qiang Liu, M.D.,Ph.D, Principal investigator, Tianjin Medical University General Hospital