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Bone marrow transplants appear to stop MS attacks
Idea is to 'reboot' immune system, but risky treatment not for everyone

By Kylie Taggart

OTTAWA - Three years ago, six patients with rapidly progressing multiple sclerosis were on the path to the inevitable: severe disability. But since receiving an autologous bone marrow transplant, they have had no further attacks of their MS.

These exciting preliminary results are from a bone marrow transplantation study being carried out in Ottawa, Toronto and Montreal. Full study results are expected to answer questions about the underlying cause of multiple sclerosis, and possibly lead the way for a new treatment for specific cases of MS.

Led by neurologist Dr. Mark Freedman and bone marrow transplant physician Dr. Harold Atkins at the Ottawa Hospital, the study will involve 32 patients with rapidly progressing MS. Eight patients will serve as controls and 28 will receive an autologous bone marrow transplant following the ablation of their immune system using chemotherapy. The study is funded for six years by the MS Society Scientific Research Foundation, which has asked the researchers to stagger enrolment to ensure safety as the study progresses. Eleven transplants have been carried out to date.

The idea behind "rebooting the immune system" of MS patients came from cases of MS patients who contracted leukemia. After receiving bone marrow transplants for the leukemia, their MS symptoms improved.

The first large-scale attempts at bone marrow transplants as a treatment for MS were carried out in Greece. Others researchers have followed suit, with about 125 MS patients having undergone variations of the procedure worldwide.

It is a serious procedure for a serious disease. Once recruited, patients have bone marrow removed from their pelvis. This is then frozen and stored as a safety measure. To obtain the hemato-poeitic stem cells, first a single, large dose of chemotherapy is given. This is followed by the drug G-CSF, which prompts bone marrow to produce more white blood cells. The stem cells are collected about 11 days later and are purified at the Canadian Blood Services Laboratory in Ottawa.

Patients are then given busulphan, cyclophosphamide and anti-thymocyte globulin to abolish their existing immune system. Once this is accomplished, the hematopoeitic stem cells are transplanted into the patient.

Patients are in hospital for about three weeks. Side-effects include those common to aggressive chemotherapy: nausea, fatigue, vomiting, diarrhea, dry mouth, hair loss and back pain.

Other researchers have used a less intense regimen, only to have the disease return.

"You can make the side-effects less by giving less intense chemotherapy, but then you run the risk of not completely destroying the immune system," Dr. Atkins, a physician-scientist at the Ottawa Hospital, explained in an interview.

There has been a casualty: One patient, a 40-year-old man, died of hepatic insufficiency two months after receiving the transplant, a direct result of the highly toxic agents used to wipe out the immune system. The autopsy results from this patient will help researchers understand what happens after a transplant.

"There are risks to this procedure, and it is not for everybody. But there is promise," Dr. Atkins said.

The initial results are hopeful indeed. Of the six patients who will be three years post-transplant come spring, none has shown any clinical evidence of further disease activity, Dr. Freedman, director of the multiple sclerosis research clinic at the Ottawa Hospital, said in an interview.

Their immune systems seem to be working fine as well.

"None of them have got any serious infections or have trouble handling colds," Dr. Atkins said.

Cell counts are low, but mostly within the normal range. Also, there was some initial concern that G-CSF might incite new disease activity, but this did not occur.

Preliminary results from imaging also show the transplants are having some effect on the disease. MRI scans show a complete absence of enhancing lesions following the transplants, indicating little or no new inflammation in the brain.

The overall burden of disease as seen on T2-weighted MRI studies was also steadily reduced.

Although there are only preliminary data available on brain atrophy, it also appears to have slowed in the patients with transplants, Dr. Freedman said.

Dr. Douglas Arnold and graduate student Jacqueline Chen at the Montreal Neurological Institute used the MRI technique called magnetization transfer ratio to image areas of the brain that are remyelinating, and to separate them from areas of the brain that are demyelinating. Prior to transplant, the ratio of demyelinating areas to remyelinating areas was very high in the five patients studied.

"Following the transplant study the ratio dropped dramatically. There was very little demyelination, but there was also very little remyelination. It looks like we've stopped the process of demyelination," said Dr. Freedman.

But while the results thus far are promising, it's difficult to say whether this will lead to a new treatment.

"I don't want to sell this as a cure for MS. This is a very serious treatment for a very serious form of MS. There are other things to go through before one would even consider this as a possible treatment." Dr. Freedman said.

However, with more study, Drs. Atkins and Freedman hope to discover what part of the procedure is affecting the disease process and is most responsible for the remission.

"Maybe we don't have to do transplants to see the benefit. Maybe there's something else we can do." Dr. Atkins said.

Another exciting aspect of this study is that it will help clarify the underlying cause of MS.

"In reality we don't know for sure that MS is an autoimmune disease. There are still people who believe it is a virus and other people who believe it is in the genes. So, if it is truly in the genes and doesn't matter what environment you're in and what exposure you have, changing the entire immune system and rebooting it will do nothing," Dr. Freedman said.

"If we can show that we've been able to remove and have completely ablated any trace of immunological memory, and I think we're able to do that, and the disease comes back, it can't possibly be an acquired defect. It has got to be genes. End of story. So, it is really testing the autoimmune hypothesis," he said.

Recruitment continues for the study. Dr. Freedman said it has been more difficult getting patients for the control group. All the patients who qualify for the study want to get the transplant, he said. Two patients are even moving to Ottawa for a year from B.C. to participate in the trial.

The study also involves MS clinics at St. Michael's Hospital in Toronto and the Montreal Neurological Institute in Montreal. The bone marrow transplant unit at the Royal Victoria Hospital in Montreal is also participating.

Copyright 2003 The Medical Post. All rights reserved.

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