Stem Cell Transplantation in Patients With MS in the HALT Trial
George H. Kraft, MD, MS––Director, Western MS Center, Alvord Professor of MS Research, University of Washington, Seattle, WA; Annette Wundes, MD––Western MS Center, Assistant Professor of Neurology, University of Washington, Seattle, WA; Richard Nash, MD––Fred Hutchinson Cancer Research Center, Seattle, WA.
The Fred Hutchinson Cancer Research Center (FHCRC) in Seattle, Washington has been a leading force in advancing stem cell transplantation for cancer and other, mostly auto-immune, diseases. Stem cell transplantation has been investigated as a possible treatment for multiple sclerosis (MS) for some years now. The Western MS Center at the University of Washington works closely together with the FHCRC, and this article is an update on our current investigations.
What is Stem Cell Transplantation?
The term “stem cell transplantation” can refer to either the transfer of fetal stem cells to a diseased patient or the manipulation of a person’s own stem cells as part of a treatment regimen. For treatment of MS, it is the latter type of transplantation that is used. With such treatment a person’s immune system is purposely wiped out by high-dose chemotherapy and possibly other means, such as radiation. This intensive course of chemotherapy also destroys most blood cells and the bone marrow, where blood cells are formed.The person then requires rebuilding a new blood and immune system, which is done by infusion of blood “stem cells” (cells that have the capacity to generate new blood and immune cells after they find their way to the bone marrow). These stem cells can either be the person’s own stem cells collected prior to the high dose chemotherapy (‘autologous’= from same individual) or stem cells from a matched donor (‘allogeneic’ = from same species, but different individual).
Stem cells cannot easily be collected from the blood, as they usually reside in the bone marrow. In the past, stem cells could only be harvested by repeated, painful aspirations of bone marrow from the hip bone or the breast bone (hence the term ‘bone marrow transplantation’). The procedure needed to be done under anesthesia. Now, we can give a drug (called G-CSF) to increase the number of stem cells circulating in the blood, and stem cells can be collected by a procedure similar to dialysis. This is much more pleasant for the donor, and no anesthesia is required.
Once stem cells are given to a patient, they repopulate the bone marrow and restart building all the cell types found in the blood (Figure 1), a process called “engraftment”. If someone receives cells previously collected from her/himself (‘autologous’), the body readily accepts its own cells. However, if stem cells of a matched donor are being given (‘allogeneic’), they are still different enough (not a perfect match) that the body will recognize the tissue as “foreign.” As a result, immunosuppressive medications are generally required for the rest of the person’s life.
Figure 1.Five steps in performing HDIT/HSCT for MS. For the patients treated with this technique from 1998-2001, irradiation of the blood-forming bone marrow was done along with high-dose chemotherapy and ATG. In the current HALT-MS protocol, only high dose chemotherapy mixture called “BEAM” and anti-thymocyte globulin (ATG) are used.
What is an Auto-immune Disease?
All immune-mediated diseases have in common an attack on an organ or body tissue by misdirected immune cells or their antibodies. Examples are attacks on the skin (scleroderma), joints (juvenile rheumatoid arthritis), and other organs (systemic lupus erythematosus). In MS, the attacked tissue is the brain and spinal cord. Although poorly understood, it appears that people with MS are not born with a misdirected immune system, but rather that environmental factors encountered during childhood trigger this abnormal immune response, which manifests as MS later in life.
Why is Stem Cell Transplantation Being Looked at in MS?
We believe that MS is caused by the exposure to unknown environmental factors during childhood in a genetically-predisposed person. Later in life, other stimuli trigger the misdirected immune system to produce MS attacks. It was speculated that strong immunosuppressive treatments would “knock out” a person’s attacking immune cells, and that a new immune system that was not “programmed” to attack the nervous system could then be transplanted into the patient. The concept of the treatment of MS by stem cell transplantation in the trial proposed by Dr. Sullivan, a pioneer in this area working at the FHCRC, was straightforward: knock out the existing immune system using a combination of irradiation, high-dose chemotherapy, and other drugs, and then replace the immune system using stem cells collected from the same person prior to immunosuppression. After transplantation, the individual would effectively have a “new” immune system that would not attack nerves in the brain and spinal cord.
What is the Experience of Stem cell Transplantation in MS?
We started treating patients with MS with this technique in 1998, and continued to do so through April, 2001. We used the newer stem cell peripheral collection technique, which was faster and less painful. Twenty-six patients with MS were treated with this method, and continue to be followed today. They had different types of MS (i.e., relapsing-remitting, secondary progressive, and primary progressive). All had severe disease that had not responded to standard MS therapy. (Nash, et al. 2003).
Simultaneously, scientists in Europe were performing similar investigational treatments on patients with MS using various protocols to achieve complete immunosuppression. They were also finding benefit for patients with MS who had failed conventional therapy. (Saccardi, et al., 2005; Fassas & Kimiskidis, 2004).
Since initiating the first stem cell transplantation trials for MS, analysis of the reconstituted cell types has been found to change the balance of cell types. It appeared that not only were the cells that were programmed to attack the nervous system eliminated, but the cell that regenerated tended to be of a different mix; more “protective” cells appear to have been produced, and the cells appear to have less “attack mode” bias. As time proceeds and patients continue to be studied for more years after their transplants, it will be interesting to observe what happens to this balance of cell types. Might it be possible that stem cell transplantation does more than just eliminate the cells that attack the central nervous system? Might it be that the entire blood cell repertoire is remodeled into one that is more biased toward health than destruction?
Thus far, about 400 patients with MS worldwide have been treated with stem cell transplantation. Experience from the North American and European research indicates the pattern of patients with MS who have responded best. These characteristics are summarized in the Table 1.
As a result of this world-wide experience, we are currently engaged in a National Institutes of Health (NIH)-sponsored study called HALT-MS (High-dose immunosuppression and autologous stem cell transplantation for poor prognosis multiple sclerosis). This study uses a refined protocol for immunosuppression based on the international experience in MS. Its purpose is to confirm whether high dose immunosuppression followed by autologous stem cell transplantation can induce a sustained MS remission and prevent further neurologic degeneration in selected patients with MS who have the active relapsing form of the disease that is not responding sufficiently to standard treatment. The lead center in this study is the FHCRC/UWMC (MS evaluations and transplant); partner centers are the Ohio State University (MS evaluations and transplant), Baylor College of Medicine (MS evaluations), and the M.D. Anderson Cancer Centerin Houston (transplant).
At the American Academy of Neurology (AAN) meeting in 2008 Chicago, Illinois the HALT-MS group presented early results of the first three patients entered in this study. (Kraft, et al. 2008). Patient 1 was a 27 year-old woman with an eight-year history of relapsing MS, who continued having relapses despite treatment with five different MS drugs, including chemotherapy (Novantrone®). She had had five relapses in the year before stem cell transplantation. At the time of entry to the program, her gait was limited and she had 13 enhancing brain lesions on MRI (meaning that dye leaks into the brain tissue during MRI, indicating active inflammation at that time). After her transplant, she received no further MS medications, yet her neurologic function has improved.
Patient 2 was a 25 year-old woman with relapsing MS for 4 years who had responded poorly to Copaxone® and corticosteroids. Before stem cell transplantation, she had four enhancing brain lesions and some gait impairment. She received no further MS medications, and 3 months post-transplant her neurologic status had significantly improved.
Patient 3 was a 46 year-old woman with relapsing MS for 10 years, who had relapsed on Copaxone® and Novantrone®. She too had an enhancing lesion. Two months post-transplant, her neurologic function was stable.
Since then, we have transplanted six more patients, and six more have met eligibility and are pre-transplant. Data on these patients will be presented at scientific meetings later this year.
Those of us involved in these studies believe that, in addition to stopping MS attacks in patients who are not responding to available treatment options, another important outcome is to gather more data as to whether this treatment will protect against the degeneration of axons (nerve fibers) seen in MS. We know that disability is caused by the degeneration of nerve cells in the brain and spinal cord, and it is suspected that multiple attacks of MS damage these nerve cells. But, is there also an independent degeneration of nerve cells? Or does degeneration occur only as a secondary response to the repeated attacks? We are increasingly optimistic that stem cell transplantation suppresses the inflammatory attacks that cause demyelination. Will this also prevent axonal degeneration? These question have yet to be answered.
It important to understand that all aggressive therapies hold risk, and that is true for hematopoetic stem cell transplantation. In 2002 the European Group for Blood and Marrow Transplantation (EBMT) published the results of their study of 85 subjects treated. There were seven deaths in that study, five due to toxicity and infectious complications, two with neurological deterioration. The risk of death of any cause at 3 years was 10% (Fassas & Kimiskidis, 2002). This group of patients had failed standard therapy and had severe disability.
Looking Ahead: What Does the Future Hold?
The current study—HALT-MS—is still open for new participants. We are actively recruiting severe, refractory relapsing MS patients who have failed conventional therapy. The definition of “severe” is two or more relapses in 18 months or one relapse plus several enhancing or new T2 lesions on MRI. In addition, eligible patients will have lost neurologic function (least 1 point of so-called EDSS) over the same period.
Interested physicians or patients should consult the HALT-MS Web site (www.halt-ms.org) for updated information on specifics of the inclusion and exclusion criteria, as. well as contact information; the lead HALT-MS study nurse, Bernie McLaughlin, RN (206) 667-4916; or Dr. Kraft (firstname.lastname@example.org).
Fassas A. S., Passweg J. R., Anagnostopoulos, A., Kaziz, A., Kozak, T., Havrdova, E. et al. (2002). Hematopoietic Stem Cell Transplantation for Multiple Sclerosis: A Retrospective Multicenter Study. Journal of Neurology, 249, 1088-1097
Fassas, A., & Kimiskidis, V. K. (2004). Autologous hemopoietic stem cell transplantation in the treatment of multiple sclerosis: Rational and clinical experience. Journal of Neurological Sciences, 223(1), 53-8.
Kraft, G. H., Bowen, J., Openshaw, H., Forman, S. J., Frohman, E., Griffith, L. M., et al. (2008). Phase II Clinical Trial (Halt MS: Immune Tolerance Network) of High Dose Immunosuppressive Therapy (HDIT) and Autologous Hematopoetic Stem Cell Transplantation (AHSCT) for Active Relapsing-Remitting (RR) Multiple Sclerosis (MS): Early Results. Neurology, 70 (Suppl 1), A95.
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Nash, R. A., Bowen, J. D., McSweeney, P. A., Pavletic, S. Z., Maravilla, K. R., Park, M. S., et al. (2003). High-dose immunosuppressive therapy and autologous peripheral blood stem cell transplantation for severe multiple sclerosis. Blood, 102(7), 2364-72.
Saccardi, R., Mancardi, G. L., Solari, A., Bosi, A., Bruzzi, P., Di Bartolomeo, P., et al. (2005). Autologous HSCT for severe progressive multiple sclerosis in a multicenter trial: Impact on disease activity and quality of life. Blood, 105(6), 2601-7.