Sunday, February 03, 2008

Hematopoeitic stem cell transplantation for multiple sclerosis

Burt RK, Cohen B, Rose J et al. Arch Neurol 2005; 62: 860-864 Neurologic Review.

Authors comment intial attempts by hem-onc specialists used hem-onc protocols targeting SPMS patients. Recent trials from MS specialists with earlier patients are encouraging with less morbidity and mortality and improvement in EDSS. The key factors in success are selecting active patients (active by MRI or clinical criteria), treatment early before progressive disability ensues, and use of safer lymphoablative but not myeloablative HSCT conditioning regimen.

Rationale-- transplant ablates the aberrant disease causing immine cells while transplanted cells regenerate a new and antigen naive immune system.

Animal models -- Theiler murine encephalomyelitis virus (TMEV) in mice is a persistent viral related autoimmune disease, wherease EAE is a relapsing disease like MS. HSCT should be done while still in immune mediated inflammatory process not chronic progressive process.

Mobilizing hematopoietic stem cells (HSC's) from patients with MS-- HSCs are mobilized from peripheral blood from bone marrow with a growth factor such as granulocyte colony stimulating factor or chemotherapy (cyclophosphamide). GCF's can induce worsening of MS sometimes irreversibly and thus are prevented by administering steroids or cyclophosphamide. Ex vivo, lymphoctes and monocytes are purged and stem cells are selected, sometimes with monoclonal antibodies.

Conditioning regimen-- again the goal is lymphoablation not myeloablation. Myeloablative agents anyways will kill stem cells. Total body iradiation has the potential of causing neural stem cell apoptosis. Non myeloablative regiments include fludaribine, cyclophosphamide, Campath 1h, antithymocyte globulin. Fever induced pseudoexacerbations due to conduction blocks in marginally functional demyelinated axons should be avoided. The goals are 1) dose escale agents that work as conventional therapy 2) maximize immune suppression without myeloablation 3) avoid conditioning agents that injure disease affected and damaged CNS tissue 4) minimize the risk of fever 6) design justifiable regimens.

First generation protocols-- were extremely effective on MRI but not clinically due to late stage patients selected. tHERE WERE ALSO TREATMENT RELATED DEATHS.

Second generation therapies: the rationale for autologous HSCT is that MS is an environmentally caused disease, not a genetic stem cell defect. Nonmyeloablative treatments would presume to be more safe, following which HSC are infused to shorten period of cytopenias. Ruled OUT are etoposide, total body irradiation, busulfan, melphalan, and carmustine. Instead, cyclophosphamide and Campath 1H are used. Criteria are active disease despite treatment and EDSS 2.5-6.0, or higher if they have rapid deterioration and activity on MRI. A German protocol uses cyclophosphamide and rabbit antithymocyte globulin. At Northwestern, a regimen of cyclophosphamide and Campath 1H is used. More than half do not requrie a blood transfusion.

Comment-- to my knowledge this therapy is cash on the barrelhead, which has given some serious MS researchers pause in suggesting it.

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