Outpatient Hematopoietic Grafting in Patients With Multiple Sclerosis Employing Autologous Non-cryopreserved Peripheral Blood Stem Cells: A Feasibility Study

Multiple sclerosis (MS) is a chronic, inflammatory, debilitating disease that causes destruction of central nervous system (CNS) myelin, with varying degrees of axonal damage. It mainly affects young adults and is twice as common in women as in men (1). Studies published from the 1990s brought animal models and theoretical considerations of hematopoietic stem cell transplantation (HSCT) being useful in the prevention and treatment of autoimmune diseases, with clinical responses in some patients, suggesting that high-dose chemotherapy followed by HSCT rescue could "reset" the immunological changes through the control of autoreactive clones, followed by immunological tolerance after immune reconstitution (2); this led to the conclusion that HSCT may be a viable therapeutic option for MS (1-6). Autologous HSCT have been done in patients with MS since 1996 and more than 700 HSCTs have been performed around the world (1-6). Most patients have been treated in small trials or in multicenter studies. In retrospective analyzes, a progression-free survival of more than five years after transplant has been observed, the neurological outcomes being considerably more favorable in patients with the relapsing-remitting type and/or those who showed an inflammatory pattern in magnetic resonance imaging (MRI) during the pre-transplant screening. Reports of good results, particularly in the aggressive forms of MS reinforce the effectiveness HSCT in MS patients with prominent inflammatory activity. The risk of transplant related mortality in HSCT for MS was conventionally considered very high but has declined since 2001 to 1.3% (2-6), this probably being the result of the changes in the conditioning regimens, thus reducing toxicity. Recent data, with more than 700 autologous transplants for MS in Europe, showed an overall survival of 92% in five years and a progression-free survival of 46%, the main cause of mortality and morbidity being the recurrence of the autoimmune disease (2-6). The consensus provides an indication of HSCT in patients with progressive MS unresponsive to conventional therapy and Expanded Disability Status Scale (EDSS) (1) between 3.0 and 6.0. The forms of the disease that might benefit from transplantation are: relapsing remitting, primary or secondary progressive, and the "malignant" form, provided there is evidence of inflammatory activity at the time of transplant indication.

Since 1993 our group has engaged in practicing HSCT using novel methods to both decrease the toxicity of the procedures and diminish costs (7-14); we have done over 400 HSCT for different diseases such as acute leukemia, chronic leukemia, aplastic anemia, myeloma, lymphoma, myelodysplasia and autoimmune diseases, including MS. Within the subset of autologous HSCT, the salient features of our method is that we conduct them on an outpatient basis (8-9, 15-16) and we avoid freezing and thawing the hematopoietic cells in order to both increase viability of hematopoietic cells in the graft and to reduce costs (8-9, 15-16) and we always employ peripheral blood stem cells (PBSC). All these changes have turned the practice of autografting in our hands in an affordable procedure which can be offered to individuals living in underprivileged circumstances such as those prevailing in developing countries (17). Having gained experience autografting hematological malignancies (8-9, 15) we aim to engage in a program of grafting non-cryopreserved autologous hematopoietic stem cells in patients with MS, employing a modification of the autografting conditioning regimen used in malignant diseases.

Material and methods

1. Patients:

Patients with MS refered to our center for a HSCT will be prospectively entered in the study. Individuals with a relapsing-remitting (RRMS) course, secondary progressive (SPMS) or primary progressive (PPMS). Patients should have a Karnofsky performance status (18) above 70% and a EDSS score (1) of 6 or below. The study has been approved by the Ethics Committee of the Clinic Ruiz and all patients sign a consent form after being fully informed about procedure an possible complications. 2. Peripheral blood stem cell mobilization and apheresis: