(Abstract) High-dose cyclophosphamide for ...MS

 
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PostPosted: Mon Aug 14, 2006 1:52 pm    Post subject: (Abstract) High-dose cyclophosphamide for ...MS Reply with quote

From JAMA Archives of Neurology:
Quote:



High-Dose Cyclophosphamide for Moderate to Severe Refractory Multiple Sclerosis

Douglas E. Gladstone, MD; Kenneth W. Zamkoff, MD; Lauren Krupp, MD; Robert Peyster, MD; Patrick Sibony, MD; Christopher Christodoulou, PhD; Emily Locher, RN; Patricia K. Coyle, MD


Arch Neurol. 2006;63:(doi:10.1001/archneur.63.10.noc60076).

Background High-dose cyclophosphamide is active in immune-mediated illnesses.

Objective To describe the effects of high-dose cyclophosphamide on severe refractory multiple sclerosis.

Design, Setting, and Patients Patients with multiple sclerosis with an Expanded Disability Status Scale (EDSS) score of 3.5 or higher after 2 or more Food and Drug Administration–approved disease-modifying therapy regimens were evaluated.

Interventions Patients received 200 mg/kg of cyclophosphamide over 4 days.

Main Outcome Measures Patients had brain magnetic resonance imaging and neuro-ophthalmologic evaluations every 6 months and quarterly EDSS and quality-of-life evaluations for 2 years.

Results Twelve patients were evaluated for clinical response (median follow-up, 15.0 months; follow-up range, 6-24 months). During follow-up, no patients increased their baseline EDSS scores by more than 1.0. Five patients decreased their EDSS scores by 1.0 or more (EDSS score decrease range, 1.0-5.0). No patient had a new lesion on brain magnetic resonance imaging. No patient showed any enhancing lesions. Patients reported improvement in all of the quality-of-life parameters measured.

Neurologic improvement involved changes in gait, bladder control, and visual function. Treatment response was seen regardless of the baseline presence or absence of contrast lesion activity. Patient quality-of-life improvement occurred independently of EDSS score changes.

In this small group of patients with treatment-refractory multiple sclerosis, high-dose cyclophosphamide was associated with minimal morbidity and improved clinical outcomes.

Conclusions
High-dose cyclophosphamide treatment in patients with severe refractory multiple sclerosis can result in disease stabilization, improved functionality, and improved quality of life. Further studies are necessary to determine the most appropriate patients for this treatment.

Published online August 14, 2006 (doi:10.1001/archneur.63.10.noc60076).


Author Affiliations: Departments of Medicine (Drs Gladstone and Zamkoff and Ms Locher), Neurology (Drs Krupp, Christodoulou, and Coyle), Radiology (Dr Peyster), and Ophthalmology (Dr Sibony), State University of New York at Stony Brook.














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PostPosted: Wed Aug 16, 2006 6:52 pm    Post subject: More on this.... Reply with quote

from Newday.com, August 15, 2006:
Quote:

An unlikely MS therapy

Multiple sclerosis responds to high doses of chemotherapy in local study, improving health of five subjects

BY JAMIE TALAN
Newsday Staff Writer

August 15, 2006

High doses of a cancer drug have given multiple sclerosis patient Maureen Kearney her kick-boxing life back.

An oncologist at Stony Brook University Hospital has been using high doses of the chemotherapy drug cyclophosphamide to treat multiple sclerosis. Kearney's symptoms, which left her in a wheelchair or using canes, have virtually disappeared.

"I was so tired of living my life," said Kearney. The 28-year-old woman was diagnosed with multiple sclerosis at 21. Her condition progressed quickly. What started with numbness and tingling in her left hand soon turned into complete numbness on her entire left side. On good days, the Farmingdale woman got around with a cane. Six months after her diagnosis she went on Betaseron, a standard treatment for multiple sclerosis, and gradually regained some strength. She started walking again, finished a master's degree and started teaching.

But every five months a new attack would wipe her out, sending her back into the wheelchair. Last year she was hospitalized four times. The Betaseron seemed to just stop working.

By the time Stony Brook's Dr. Douglas Gladstone met the young woman, she was blind in her left eye, had blurred vision in her right and was shaking and moving slowly with the help of a walker.

Gladstone enrolled a dozen patients into the experimental drug trial with cyclophosphamide, a powerful drug used to treat leukemia and lymphoma. It wipes out the body's immune system, which is exactly why Gladstone suspected it would work in multiple sclerosis. In the disease process, T-cells of the immune system attack the myelin sheath, the insulation around the nerve cells.

The patients enrolled in this study accepted the risks of the chemotherapy, which temporarily leaves them open to any number of infections. The odds of death are one in 100.

"I was willing to face this risk rather than facing a wheelchair in my near future," said Linda Jacobellis, a 54-year-old mother from Rocky Point.

She'd had MS for 16 years when she heard about the experiment. Her condition had progressed to where she had to hold the wall as she walked or she would topple over. Fatigue, also common to the condition, was unrelenting. "Things were looking bad," she said.

The medicine was infused into patients two hours a day for four days. They stayed in the hospital an additional two weeks. And because it wiped out their immune systems, they lived in a sterile environment with little access to the outside world.

"I got back brand new T-cells with no disease," said Jacobellis. "I am so much better, and so happy that no one will have to take care of me. There is no more walking holding the wall. I am stronger. I still have to watch my balance, but it's given me my life back."

Kearney feels the same way. The treatment alleviated her tremors, returned her sight and gave her back her balance. "Today, I can stand with my two feet together, even balance on one foot. I kick-box. I went skiing for the first time in five years. This is the type of life I now lead."

Neither woman has taken any other multiple sclerosis medicines since their infusions.

Results of the study were published this week in the Archives of Neurology.

Gladstone, an assistant professor in the department of medicine, said he has seen similar results with other autoimmune diseases, including lupus.

The multiple sclerosis patients were followed from six to 24 months. No one got worse, and five people actually got better, he said.

While he is happy with the results, "it is not ready for prime time yet," he said. "I'm an oncologist, and I treat multiple sclerosis as aggressively as I do cancer. ... These patients have a miserable quality of life. This helps."


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PostPosted: Mon Aug 28, 2006 1:48 pm    Post subject: More on this Reply with quote

From Medscape Medical News, 8/28/06:

Quote:


High-Dose Cyclophosphamide Effective in Refractory Multiple Sclerosis

News Author: Caroline Cassels
CME Author: Désirée Lie, MD, MSEd


Release Date: August 25, 2006

August 25, 2006 — High-dose cyclophosphamide — a chemotherapeutic agent originally used to treat cancer — may offer patients with moderate to severe refractory multiple sclerosis (MS) a viable treatment option, according to researchers.

"Our study shows high dose cyclophosphamide makes it possible to silence MS in the most severely affected patients who are resistant to traditional treatment and that this effect appears to be durable," Douglas Gladstone, MD, of State University of New York at Stony Brook, told Medscape.

Their report is published online in the August 14 Early Release issue of the Archives of Neurology.

Previous studies by Dr. Gladstone and others have shown high-dose cyclophosphamide decreases disease activity and improves quality of life in numerous immune-mediated illnesses, including chronic inflammatory demyelinating polyneuropathy, myasthenia gravis, systemic lupus erythematosus, and aplastic anemia.

This notable track record in the treatment of other autoimmune diseases prompted Dr. Gladstone and his colleagues to test it in MS patients.

Unexpected Result

The study included 13 patients who had expanded disability status scores (EDSS) of 3.5 or higher, with a median score of 6.5. In addition, patients' quality of life was also assessed.

Despite the fact that all subjects were receiving a minimum of 2 FDA-approved disease-modifying therapies, they all had active disease. In addition, they had all failed treatment, which was defined as 2 or more relapses within the previous year.

"Half of these patients had disease progression even after large doses of mitoxantrone. In addition, almost all of them were on interferon and steroids and they were still experiencing disease progression. This population was so ill our expectations were that we would only be able to achieve the primary goal of stopping disease progression in one-third of the patients," said Dr. Gladstone.

With the exception of steroids, patients stopped all therapies 3 weeks before initiation of high-dose cyclophosphamide. They were then hospitalized and received a 4-day infusion of 200 mg/kg of cyclophosphamide.

However, Dr. Gladstone and his team were surprised to find that not only did high-dose cyclophosphamide prevent disease progression in all of the patients, but almost half of them experienced a marked improvement in their EDSS scores — a result that Dr. Gladstone said was "completely unexpected."

But, he cautioned, this does not indicate that high-dose cyclophosphamide causes disease regression. A more plausible explanation, Dr. Gladstone said, is that the ability of the drug to stop disease progression allows patients to access the full physical potential that they retain.

Furthermore, the investigators report, patients experienced a marked improvement in their quality of life, although this was not limited to those who experienced decreases in the EDSS scores. In addition, the majority of patients experienced a clinically significant reduction in fatigue severity scale scores.

Durable Effect?

While the durability of the treatment is still unknown, at 15-months follow-up, all of the patients met study criteria for disease stabilization, and none met criteria for disease progression. In addition, Dr. Gladstone said, treatment with high-dose cyclophosphamide in previous studies of other autoimmune diseases has been extremely durable.

"Our follow-up times in some of our earlier studies have been as long as 10 years and in those patients, cyclophosphamide had an impressive sustained effect and there's really no reason to think MS would be any different. So we believe there's a good chance that this could be durable for many of our patients," he said.

High-dose cyclophosphamide was extremely well tolerated among all patients, Dr. Gladstone added.

"When we first launched this study there was concern by the FDA that cyclophosphamide would produce a new toxicity profile in MS patients, but this did not bear out. It has exactly the same profile as in other patient groups."

Nevertheless, Dr. Gladstone said, the adverse effect profile of the drug is not benign and carries with it the risk for infection: transient dilated cardiomyopathy and bladder complications as well as more minor and transient adverse effects, including hair loss, mild nausea, and loose stools.

However, he added, based on these results, high-dose cyclophosphamide appears to be a superior treatment of MS compared with current research looking at the use of hematopoietic stem cell transplantation where results have been disappointing largely due to the need for much higher doses of chemotherapy and other forms of immunosuppression.

Dr. Gladstone and colleagues are continuing to enroll patients in their study, which he said, will help them better determine the most appropriate patients for high-dose cyclophosphamide therapy.

"At this point we just don't know who are the best candidates for this treatment. My hunch is that people with MS who are at an earlier stage in their disease will fare better, but that remains to be shown."















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PostPosted: Mon Oct 09, 2006 2:28 pm    Post subject: Reply with quote

Here is an abstract appearing in the October 2006 Archives of Neurology:

Quote:
Vol. 63 No. 10, October 2006

High-Dose Cyclophosphamide for Moderate to Severe Refractory Multiple Sclerosis

Douglas E. Gladstone, MD; Kenneth W. Zamkoff, MD; Lauren Krupp, MD; Robert Peyster, MD; Patrick Sibony, MD; Christopher Christodoulou, PhD; Emily Locher, RN; Patricia K. Coyle, MD


Arch Neurol. 2006;63:1388-1393. Published online August 14, 2006 (doi:10.1001/archneur.63.10.noc60076)

Background High-dose cyclophosphamide is active in immune-mediated illnesses.

Objective To describe the effects of high-dose cyclophosphamide on severe refractory multiple sclerosis.

Design, Setting, and Patients Patients with multiple sclerosis with an Expanded Disability Status Scale (EDSS) score of 3.5 or higher after 2 or more Food and Drug Administration–approved disease-modifying therapy regimens were evaluated.

Interventions
Patients received 200 mg/kg of cyclophosphamide over 4 days.

Main Outcome Measures Patients had brain magnetic resonance imaging and neuro-ophthalmologic evaluations every 6 months and quarterly EDSS and quality-of-life evaluations for 2 years.

Results Twelve patients were evaluated for clinical response (median follow-up, 15.0 months; follow-up range, 6-24 months). During follow-up, no patients increased their baseline EDSS scores by more than 1.0. Five patients decreased their EDSS scores by 1.0 or more (EDSS score decrease range, 1.0-5.0). Two of 11 patients had a single enhancing lesion at baseline; these lesions resolved after high-dose cyclophosphamide treatment. At 12 months, 1 patient showed 1 new enhancing lesion without a corresponding high-intensity T2-weighted or fluid-attenuated inversion recovery signal.

Patients reported improvement in all of the quality-of-life parameters measured. Neurologic improvement involved changes in gait, bladder control, and visual function. Treatment response was seen regardless of the baseline presence or absence of contrast lesion activity. Patient quality-of-life improvement occurred independently of EDSS score changes. In this small group of patients with treatment-refractory multiple sclerosis, high-dose cyclophosphamide was associated with minimal morbidity and improved clinical outcomes.


Conclusions[/b] High-dose cyclophosphamide treatment in patients with severe refractory multiple sclerosis can result in disease stabilization, improved functionality, and improved quality of life. Further studies are necessary to determine the most appropriate patients for this treatment.



Author Affiliations: Departments of Medicine (Drs Gladstone and Zamkoff and Ms Locher), Neurology (Drs Krupp, Christodoulou, and Coyle), Radiology (Dr Peyster), and Ophthalmology (Dr Sibony), State University of New York at Stony Brook.

http://tinyurl.com/fel85

This is an updated version of the authors' previous abstract (above).
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