Wednesday, December 16, 2009

Can Immune System Transplants Halt-MS?

This posting information on this page is now becoming rather dated; the information here regarding treatment data is from the very early phase II studies. If you have come to this blog for the first time I suggest starting at the following page-link first. I think you will find what you are looking for here:

Today Judy and I had an easy day. Didn't do too much, although I did buy an extra respirator filter mask for my stay in the hospital when I can walk around. Don't want to catch any killer germs from the environment that will sicken me while walking the hallways.

I thought I'd take this quiet time opportunity to share a brief, but important general medical article regarding this specific immuno-ablation treatment that I will be receiving here in Heidelberg. It is a report by Dr. Bowen (principal researcher of the HALT-MS clinical trial) on the specifics of the HALT-MS phase II study protocol. Following the first article is a preliminary one-year follow up report regarding the early study results (fantastically good data, in my opinion). Keep in mind that I have an EDSS of 3.5. . . .

Can Immune System Transplants Halt-MS?

Neurology Reveiws, vol 14, No 8, August, 2006
Immunomodulating treatments are currently the only established forms of therapy for multiple sclerosis (MS), but by and large these treatments have been only partly effective for most patients. Based on the results of experimental models and on clinical observations in patients with malignancy and patients with MS, hematopoietic stem cell transplantation was proposed for the treatment of autoimmune diseases and has been shown in several clinical trials to be at least moderately effective in patients with MS. A newer strategy—high-dose immunosuppression (also known as immunoablation) plus autologous transplantation, which involves the complete eradication and reconstitution of the patient’s bone marrow—has shown promise in early studies and is now being investigated in ongoing phase II trials.

Autologous hematopoietic stem cell transplantation was first studied [in the US] as a treatment for MS in the late 1990s [and in the early 1990's in Europe]. Results have been analyzed in both single-center and multicenter trials and collectively in a retrospective study by the European Group for Blood and Marrow Transplantation (EBMT) retrospective study. Of the 85 patients with MS in the EBMT database, 74% were found to be progression-free at three years from transplantation, a percentage that is fairly consistent with all transplant studies in MS reported to date.

Because of the different clinical forms of MS treated, as well as the wide range of immunoablative regimens used in these studies, however, observers have recommended caution in interpreting these results. It may be that the benefit of the procedure was derived from an effect earlier in the disease or that patients with the relapsing-remitting form of the disease respond better to this aggressive form of treatment. The downside to the approach is that there is significant morbidity, with an overall death rate of 7% for this group of patients, according to James Bowen, MD, a principal investigator of the ongoing High-Dose Immunosuppression and Autologous Transplantation for Multiple Sclerosis (HALT MS) study.

"The question is, if we are destroying these people’s bone marrow and then replacing it, why don’t we have a 100% success rate instead of a 75% success rate?" he said at the 20th Annual Meeting of the Consortium of Multiple Sclerosis Centers. "There could be three explanations. One is that MS may not be an autoimmune disease; we may be limiting the inflammation, but there may be apoptosis going on under the radar that we are not addressing with this treatment. Another is that oddly enough, we may not be aggressive enough, and we may need to be more immunosuppressive and throw out the remaining B cells in order to have more success.

"The third explanation may be that it may be too late—the damage is already done, and so many of the T cells are destined to go ahead and die over the coming three years—and that we should be treating patients earlier." Dr. Bowen is Medical Director of the Evergreen Healthcare MS Center in Kirkland, Washington.


"If we treat people with high-dose immunosuppression, like they do with bone marrow transplants [eg, in cancer patients], what happens?" Dr. Bowen asked. "The short-term effects are that you wipe out the entire bone marrow, but parts of it quickly recover." Specifically, the red blood cells, leukocytes, and platelets recover within 14 to 21 days, and lymphocyte counts recover within three months. Long-term effects include changes in lymphocyte subtypes, he elaborated.

Immunosuppression results in a decreased CD4/CD8 ratio, preferential loss of naïve CD4+ cells, and a profound depletion of B cells, immunoglobulin M (IgM), and IgA. There is less of an effect on memory CD4+ cells, and modest decreases are seen in IgG. Natural killer cells remain relatively resistant, normalizing almost immediately. Total B-cell counts become normal within one to three months, often with overshoot. The CD8+ cells, which become normal within three to six months, can also overshoot. The subset of CD8+CD28 suppressor cells can take more than one year to recover. The CD4+ cells undergo prolonged loss, which is enhanced with older patients.

Dr. Bowen ticked off a list of immunosuppressive treatments, including cyclophosphamide, methotrexate, azathioprine, and rituximab. "These are some of the standard immunosuppressive drugs," he said. "There is some evidence that these do work, but we want them to work better."

He then reviewed several published studies involving autologous stem cell transplants. In a phase I/II study conducted at Northwestern University, Chicago, that was published in 2003, Burt and colleagues investigated intense immune-suppressive therapy and autologous hematopoietic stem cell support in 21 patients with rapidly progressive MS. Outcomes could be stratified largely by the patients’ Expanded Disability Status Scale (EDSS) score. Of the nine patients with a pretransplantation EDSS score of 6.0 or less, none had neurologic progression that increased their disability by 1.0 or greater, while eight of the 12 patients with pretransplantation scores greater than 6.0 showed worsening by at least a 1-point increase—representing gradual neurologic deterioration. Two of these patients died from complications of progressive disease, at 13 and 18 months following treatment. The investigators concluded that intense immune suppression using a total body irradiation–based regimen and hematopoietic stem cell transplantation is not effective for patients with progressive disease and high pretransplantation EDSS scores.

In another study published in 2003, Nash and colleagues—including Dr. Bowen—at the Fred Hutchinson Cancer Research Center in Seattle, conducted a pilot study of high-dose immunosuppressive therapy in 26 patients with severe MS (median baseline EDSS score, 7.0). Immunosuppressive therapy consisted of total body irradiation, cyclophosphamide, and antithymocyte globulin, and it was followed by autologous transplantation. Although regimen-related toxicities were mild, patients experienced a number of adverse events or complications, and one died from Epstein-Barr virus–related posttransplantation lymphoproliferative disorder. However, 14 of the remaining 25 patients were stable at two years, and the estimate of survival at three years was 91%. Given that the study population was a heterogeneous high-risk group, investigators were able to modify their initial approaches to reduce treatment risks and used the clinical issues identified here in the planning of a phase III study aimed at fully assessing efficacy.
Several European studies, including trials conducted in Barcelona; Thessaloniki, Greece; and by the Italian GITMO-Neuro Intergroup, all achieved similar results, Dr. Bowen noted.


Dr. Bowen touched briefly on allogeneic stem cell therapy. "It turns out that this is the only method known that can completely eliminate the immune system," Dr. Bowen observed, adding that mortality with this procedure is high.

However, he and his colleagues at the Hutchinson Center were encouraged by the overall outcomes that occurred when seven European patients with cancer and MS were brought to Seattle for allogeneic stem cell therapy. After the transplant, oligoclonal bands were detected in the cerebrospinal fluid of only one patient. Five of the patients ultimately survived.


In the HALT MS study, which is being supported by the NIH, investigators are seeking to determine whether intensive suppression of the immune system using chemotherapeutic drugs, along with infusion of an autologous hematopoietic stem cell graft, will stop disease activity in patients with poor-prognosis MS as measured by clinical indicators and imaging studies. A pilot study involving 19 patients with MS demonstrated that all but one of the patients stabilized or showed clinical improvement following high-dose chemotherapy, with MRI detecting a new lesion in only one patient 4.5 years after treatment.

In this follow-up study, patients will be given prednisone and granulocyte colony-stimulating factor to mobilize CD34+ hematopoietic stem cells from the bone marrow into the peripheral blood, where the cells will be collected by leukapheresis. A minimum of seven days after the collection of their autologous graft, patients will be hospitalized and receive high-dose chemotherapy consisting of carmustine, etoposide, cytarabine, and melphalan, then thymoglobulin, followed by transplantation of the autologous hematopoietic stem cell graft. The primary end point is time to treatment failure within five years following the transplant, and the anticipated total enrollment is 30.

A second ongoing trial sponsored by the NIH involves MS patients with poor prognosis based on the rate of progression and refractoriness to the approved treatments, interferon-beta and glatiramer acetate. Participants are being treated with immune ablation using cyclophosphamide and the antibody Campath 1, followed by reconstitution with autologous peripheral blood stem cells, or high-dose cyclophosphamide treatment without stem cell rescue. Last follow-up and data entry closure were expected to take place in the spring of 2006.

With respect to HALT MS, Dr. Bowen is optimistic that this strategy of high-dose immunosuppression plus autologous transplantation will prove to be successful. But even if it does fail in many patients, he hopes that the trial will demonstrate why immunoablation failed.
"High-dose immunosuppression probably slows MS in the critical group of patients who have this disease and are doing poorly," he concluded. "They have 75% stability going out three years. The transplant morbidity is markedly reduced with the current protocol. It may be that true immunoablative therapy might be more successful than what we’re doing now, but that will be on the future horizon."


May, 2008, Denver, Colorado

Background: High-dose immunosuppressive therapy and autologous hematopoietic stem cell transplantation (HDIT/AHSCT) may induce sustained remission in patients with autoimmune disease and is being tested as rescue therapy for MS. In a previous clinical trial of HDIT/AHSCT for advanced progressive-type MS (median EDSS 7.0), the estimated progression rate was 37% at 6 years. Since degenerative changes may contribute to loss of neurological function in progressive MS, HDIT/AHSCT in relapsing-remitting MS is currently being studied in a NIH-sponsored clinical trial (HALT MS).

Case Presentation: 27 y/o female with RRMS for 8 years who continued to relapse on IFN-beta 1b, IFN-beta 1a, glatiramer acetate, methotrexate and mitoxantrone. In the 12 months prior to enrollment, she had 5 relapses and there were as many as 24 enhancing lesions on a single MRI. At baseline, the EDSS was 5.5 and she had 13 enhancing lesions. The most recent follow-up EDSS was 4.5. The patient is one year post transplantation now and has not experienced further relapses, progression of disease nor developed new or enhancing MRI lesions. No unexpected or severe toxicity with HDIT/AHSCT was experienced. Neutrophil and platelet counts recovered by days 11 and 12 respectively.

Discussion: This phase II study is being conducted in RRMS (EDSS 3.0-5.5 with ≥2 relapses on treatment and ≥1.0 EDSS worsening over past year) using HDIT/AHSCT with high-dose chemotherapy (BEAM), antithymocyte globulin and T-cell-depletion of hematopoietic cell grafts by CD34-selection. 25 patients with an intended 5-year follow-up will be enrolled. To date, 5 patients have enrolled in the trial.

Conclusions: HALT MS is the first clinical trial of HDIT/AHSCT in RRMS patients poorly responsive to conventional treatment. Thus far, patients have tolerated the treatment well and early results suggest some neurological improvement as illustrated by this one year follow-up of the first-transplanted patient.

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