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    You are here : Home » MS Research News » Drugs » Cyclophosphamide

    Cyclophosphamide

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    Treatment of RRMS with high dose cyclophosphamide induction

    CyclophosphamideBackground: Previous studies have described stabilization of aggressive multiple sclerosis (MS) with one-time induction therapy with high-dose cyclophosphamide (HiCy). The long-term benefit of this stabilization followed by conventional therapy has not been explored.

    Objective: The objective of this study was to evaluate the safety and clinical outcomes following treatment of relapsing-remitting MS with HiCy induction therapy followed by glatiramer acetate maintenance.

    Methods: A retrospective review of a closely followed population of thirty two MS patients treated with HiCy (200mg/kg intravenous infusion over 4 days) followed by maintenance with glatiramer acetate was performed.

    Results: Annualized relapse rate was reduced from 1.37 in the 2 years prior to treatment to 0.27 over a mean post-treatment follow-up period of 14 months (range 0.5-33.8). The projected probability of relapse-free survival at 2 years was 0.64 (95% CI 0.37-0.82). The projected probability of Expanded Disability Status Scale (EDSS) progression-free survival at 2 years was 0.77 (95% CI 0.43-0.92). The mean number of gadolinium-enhanced lesions was reduced from 0.86 (SD 1.6) at baseline to 0 at 12 months and 0.08 (SD 0.28) at 15-24 months. A total of 55% of patients had no evidence of disease activity in follow-up. Infectious complications occurred in 47% with no long-term morbidity and no deaths.

    Conclusions: Induction therapy with HiCy followed by long-term maintenance with glatiramer acetate is well tolerated in patients with MS, and appears to be efficacious in reducing the risk of relapse, disability progression, and new MRI lesions.

    Summary: Recent developments, including the development and licencing of Nataluzimab and Fingolimod have increased the therapeutic avenues available for patients with relapsing remitting multiple sclerosis who continue to get severe relapses despite treatment with the first line disease modifying drugs of interferon beta or glatiramer acetate. However, both Nataluzimab and Fingolimod have side effects which require discontinuation, including infusion reactions, liver function abnormalities and thyroid abnormalities for Nataluzimab, and symptomatic bradycardia, severe headaches and flu like symptoms for Fingolimod, and for these reasons a proportion of patients will not be able to have either treatment. For these patients it is important to have alternative treatments to attempt to prevent relapse associated disability.

    In this study the authors performed a retrospective analysis of 40 patients treated with high dose cyclophosphamide for relapsing remitting multiple sclerosis at John Hopkins. These patients were treated according to a standardised protocol and had detailed and standardised radiological and clinical follow up with MRI, assessment of relapse number and EDSS assessment every 3 months for 2 years.

    This is the largest and most detailed retrospective review to date of the use of cyclophosphamide in patients with relapsing remitting MS. All but one patient had been prescribed disease modifying drugs prior to cyclophosphamide without good clinical effect, and the patients had a median of 2 relapses in the prior 2 years. Cyclophosphamide treatment followed by glatiramer acetate lead to a reduction in annualised relapse rate, and significant reduction in number of gadolinium enhancing lesions at 3 and 12 months. Side effects were however common with 84% of patient experiencing nausea and vomiting and 47% experiencing infections. Whilst an important addition to the therapeutic literature this was not a clinical trial as there was no comparator arm.

    Authors: Harrison DM, Gladstone DE, Hammond E, Cheng J, Jones RJ, Brodsky RA, Kerr D, McArthur JC, Kaplin A.

    Source: Multiple Sclerosis 2011, August 24 & Pubmed PMID: 21865410 (01/09/11)

    High-dose cyclophosphamide shows promise for aggressive multiple sclerosis

    Cyclophosphamide

    High-dose cyclophosphamide, aimed at immune system ablation, is a safe and well-tolerated treatment for aggressive multiple sclerosis that can markedly reduce disease activity and disability, according to the results of a small, open-label trial.

    In an earlier study of 13 patients with severe refractory multiple sclerosis, treatment with high-dose cyclophosphamide followed by granulocyte colony-stimulating factor often stabilized or improved disability. The current study investigated the safety and efficacy of this treatment further by examining clinical and radiologic features not previously studied and by including a longer follow-up period.

    As reported in the August issue of the Archives of Neurology, Dr. Douglas A. Kerr and colleagues focused on the safety and tolerability of high-dose cyclophosphamide in nine patients (20 to 47 years of age) with aggressive relapsing-remitting multiple sclerosis. Clinical and radiologic efficacy endpoints were secondary outcomes.

    Eight of the patients were unresponsive to conventional therapy and one patient was treatment naive. Cyclophosphamide was given at a dose of 50 mg/kg/day intravenously for four days. Granulocyte colony-stimulating factor was then started six days later, given at a dose of five micrograms/kg/day until the absolute neutrophil count was over one billion cells/L for two consecutive days.

    During a mean follow-up period of 23 months, none of the patients died and there were no unexpected adverse events, Dr. Kerr, from Johns Hopkins University School of Medicine in Baltimore, and co-researchers report. As anticipated, all of the patients developed total or near-total pancytopenia, but hematopoietic recovery was achieved ten to 17 days later with the use of granulocyte colony-stimulating factor.

    High-dose cyclophosphamide therapy resulted in significant reductions in the Expanded Disability Status Scale score (39.4 per cent) and in the average number of gadolinium-enhancing lesions on MRI (81.4 per cent).

    Due to disease flare-ups, two patients required treatment with other immunomodulatory therapies during the study, the authors note.

    "This immunoablative regimen of cyclophosphamide for patients with aggressive multiple sclerosis is worthy of further study and may be an alternative to bone marrow transplantation," the team concludes.

    Source: Medicexchange.com © 2008 Medicexchange PLC (13/08/08)

    Cyclophosphamide promising against multiple sclerosis
    Treatment with an immune-suppressing drug may help people with the incurable disease multiple sclerosis, researchers say.

    Their small study showed that treatment with high doses of cyclophosphamide, a generic cancer drug that has been around for half a century, cut the level of disability in MS patients, improved their physical functioning and reduced the number of brain lesions related to the condition.

    Nine patients were tracked for two years after getting the drug. Five of them had no signs of disease activity, and the other four showed dramatic improvement, said Dr. Douglas Kerr of Johns Hopkins University in Baltimore.

    The patients were able to recover physical functions that had been lost to the disease, Kerr said.

    Existing drugs tend at best to slow the deterioration in MS patients and typically need to be given again and again.

    "Every other therapy that's out there and, as far as I'm aware, every other therapy that's on any drug company's drawing board, is designed to hold the disease at bay for as long as you take the drug," said Kerr, whose study was published in the journal Archives of Neurology.

    "This is one in which you give it once to hopefully reset the immune system back to a naive state so it's no longer attacking the brain and spinal cord. And so that, I think, makes it quite different and quite exciting," Kerr added.

    The nine patients in the study were given large doses of cyclophosphamide intravenously for four consecutive days in a bid to "reboot" the immune system -- and then no more of it.

    REDUCING DISABILITY

    The patients in the study had relapsing-remitting MS, the most typical form of it in which patients have periods of symptoms followed by periods of remission with no symptoms.

    Kerr said the findings could herald a significant advance in the treatment of MS. He said the researchers aim to begin a large, multi-center clinical trial of the approach next year.

    Multiple sclerosis is thought to be an autoimmune disease in which a person's immune system mistakenly attacks parts of the body as if they were foreign.

    In MS, the body attacks the myelin sheath, the fatty material that surrounds and protects nerve cells. This causes interference in the messages between the brain and body, triggering vision problems, muscle weakness, difficulty with coordination and balance and thinking and memory problems.

    Kerr said the nine patients were the "worst of the worse," with eight of them failing all other treatments and the ninth having had no previous treatment.

    After two years, the patients experienced an average 40 percent reduction in disability and an 87 percent improvement in tests measuring physical and mental function, the researchers said. Brain imaging also showed a decrease in the average number of brain lesions from 6.5 to 1.2 lesions.

    Kerr said cyclophosphamide has been used with mixed results in the past in MS treatment. Monthly infusions at a much lower dose worked modestly at best, he said. The drug also has been used alongside others in conjunction with bone marrow transplant treatment, he added.

    There is one other immunosuppressant drug used for MS.

    The U.S. Food and Drug Administration in 2000 approved the cancer drug Novantrone, also known as mitoxantrone, for MS treatment. It is marketed by OSI Pharmaceuticals Inc.

    Source: Yahoo! News © 2008 Yahoo! Inc (10/06/08)

    Short-Term Exposure to Cyclophosphamide Reduces Long-Term Brain Atrophy in Refractory Relapsing-Remitting Multiple Sclerosis
    Short-term exposure to the potent immunosuppressive effects of cyclophosphamide can prevent brain atrophy in patients with relapsing-remitting multiple sclerosis (RRMS) who are not responding to interferon beta (IFNbeta) or glatiramer acetate treatment, according to a comparative study presented at the 23rd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

    Chemotherapy, including cyclophosphamide, is an option for patients who continue to progress or to have relapses on conventional disease modifying treatments. However, there are concerns that long-term intense immunosuppression might cause an accelerated rate of atrophy in the brain, said Jai Parumal, MD, Multiple Sclerosis Fellow, Multiple Sclerosis Clinical Research Centre, Department of Neurology, Wayne State University School of Medicine, Detroit.

    Recent data have shown dramatic loss of brain volume in patients given short intense immunosuppression and immunoablation. However, it remains unclear whether short-term exposure to cyclophosphamide can minimize this long-term loss of brain volume, and thus reduce the consequent clinical disability.

    Dr. Parumal and colleagues conducted a study of patients with confirmed RRMS who had failed therapy with IFNbeta or glatiramer acetate, defined as at least one relapse in the previous year and an accumulation of neurological disability.

    The 31 patients in the cyclophosphamide treatment group had a mean age of 36.4 years and 42% were male. The 41 patients in the control group had a mean age of 34.6 years and 39% were male. The control group patients had received either IFNbeta or glatiramer acetate with monthly steroids for 6 to 12 months and had declined treatment with cyclophosphamide.

    Both group had RRMS confirmed by magnetic resonance imaging (MRI) at baseline.

    Twelve healthy volunteers were also enrolled and underwent MRI imaging to confirm the reproducibility of the imaging technique.

    Baseline disease characteristics across these two groups were similar for (respectively): disease duration, 8.6, 8.9 years; prior 1-year relapse rate, 2.3, 2.1; and mean expanded disability status scale (EDSS), 5.1, 4.9.

    Cyclophosphamide was administered at a dose of 1,000 mg/m2 IV monthly, for 6 months for almost all cases, with the cyclophosphamide dose adjusted to achieve a 2-week postcyclophosphamide white blood cell nadir of 2,000 to 2,500.

    Brain MRI for the treatment and nontreatment groups were (respectively): mean T2W lesion volumes, 21.8, 20.9 mL; mean T1W lesion volumes, 2.1, 2.5 mL; mean number of T1W Gd-enhancing lesions, 2.9, 2.9; patients with Gd-enhancing lesions, 76%, 71%; and mean brain volume, 1,497.5, 1,512.2 mL. No significant differences were found between these two treatment groups at baseline.

    Brain volumes were measured at baseline and approximately 3 years later using an identical protocol and the fully automated structural imaging evaluation using normalization of atrophy (SIENA) technique, and once compared with the baseline measures, they were expressed as percentage brain volume changes.

    Using SIENA, cross-sectional normalized brain volume showed a significantly greater decrease for patients not treated with cyclophosphamide over that for cyclophosphamide-treated patients (-2.7% vs -1.3%, respectively; P =.001). These changes represented annualized brain atrophy rates of 0.90 and 0.43 mL/year, respectively, despite continuous treatment with disease modifying therapies during this period.

    This short-term treatment with relatively low doses of cyclophosphamide thus produced a significant reduction in brain atrophy over that of patients not treated with cyclophosphamide.

    Dr. Parumal stressed, "It is not only that short-term treatment with immunosuppression did not accelerate brain atrophy, which was a concern, but it turned out to be beneficial in fact, compared to patients who were not treated with [cyclophosphamide]."

    He indicated the need for further studies with long-term follow-up of brain atrophy in patients undergoing similar immunosuppressive treatment.

    Source: Presentation title: Short-Term Exposure to Cyclophosphamide Is Effective in Reducing Long-Term Brain Atrophy in Refractory Relapsing-Remitting Multiple Sclerosis. Abstract P810 (23/10/07)

    MS treatment 'a miracle'
    Rocky Point woman undergoes high-dose regimen at Stony Brook.

    Linda Jacobellis had multiple sclerosis, a disease for which there is no cure, for 16 years. Now, she announces, "I no longer have MS." She ascribes her cure, in part, to "a miracle from my mother in heaven." But mostly she credits her recovery to a breakthrough regimen of high-dose chemotherapy at Stony Brook University Hospital.

    Doctor Douglas Gladstone, assistant professor of hematology/oncology at Stony Brook, doesn't discount help from above. But he used eight pages in the August edition of the Journal of the American Medical Association's "Archives of Neurology" to describe how his new high-dose chemotherapy treatment has changed MS. Jacobellis's life and the lives of 12 other MS patients who hadn't responded to other treatments.

    He's also considerably more circumspect claiming a "cure" for the disease. He describes Mr. Jacobellis's condition in professional terms as "prolonged remission." He relates her current status to cancer patients who have no indication of that disease for five or more years. He notes this new treatment regimen is, "Once in a lifetime. These people should never need another MS medication again."

    People with MS have bodies running amok. Their autoimmune system, which is supposed to protect against invading disease, turns against its own central nervous system, according to the Multiple Sclerosis Society's website. White blood cells attack the covering of nerve fibres in the brain, spinal cord and optic nerves. They strip the covering, myelin, from these nerve fibres, leaving scar tissue known as sclerosis, and disrupt the ability of nerves to conduct electrical impulses to and from the brain.

    MS symptoms, which can vary from person to person, are terrible. They include: bladder and bowel dysfunction; memory and attention disorders; depression; fatigue; difficulty walking and other balance or coordination problems; pain and vision difficulties, including blindness. Some people can also be afflicted with hearing loss, seizures, speech disorders, and tremors.

    There is no cure. Until now, available medication only slows the underlying course of the disease.

    For 11 years Ms. Jacobellis suffered from relapsing-remitting MS. She had flare-ups followed by recovery periods. But since 2001 her condition worsened to progressive MS. Her disease wasn't remitting. She was getting steadily sicker.

    Her greatest fear: "I thought I'd be a burden." She was afraid she would be wheelchair bound, unable to feed herself, and most important, unable to be part of Andrew, her grandson's, life.

    After an MRI of her brain "looked terrible," she related how her neurologist referred her to Dr. Gladstone for treatment. Dr. Gladstone, according to Ms. Jacobellis, suggested she not undertake the course of medication recommended by the neurologist, but instead, "Go for the gusto. Meaning she consider enrolling, if she qualified, in his new treatment study. He was using high-dose chemo to essentially kill off the infected autoimmune system and then replace it with a new, healthy one.

    She knew the dangers of taking part in an experimental treatment, but her fear of being further ravaged by the disease outweighed her fear of the treatment going bad.

    She said making the decision was "not tough at all. I prayed I qualified."

    She did.

    Dr. Gladstone and his associates administered a massive, four-day course of the cancer treatment "cyclophosphamide," which killed off all the white blood cells (lymphocytes) as well as "turning off" the rest of her autoimmune system.

    She then spent the next two weeks at Stony Brook in a sterile environment while her body healed itself, replacing her white bloods cells and turning the autoimmune system back on.

    The result? Ms. Jacobellis reported, "My last MRI showed no new lesions; no new enhancements, and no new activity. I no longer have the MS virus in my body; Dr. Gladstone killed every last T cell in my body. I no longer have MS."

    Dr. Gladstone was less effusive but no less encouraged by the results of his study. His paper describes his goal, which was to "stop the disease progression rather than induce disease regression." In other words, the objective wasn't to get patients back to a pre-disease condition, but just to stop the disease from getting any worse.

    For most people, not getting any sicker wouldn't be much of a victory. For MS patients, arresting the progression of the disease is almost beyond hope.

    The results were better than expected. In the neutral, scientific language of medical research Dr. Gladstone wrote, "After treatment, no patient met study criteria for disease progression. Further 5 (42%) of patients showed a decrease of 1 or greater in their EDSS scores."

    For the layman: all of the patients got better. Some got a whole lot better.

    Not everyone is as excited by the news as Ms. Jacobellis. MS Society spokesman Dr. Nicholas Larocca characterised the study results as "interesting."

    He went on to say that, "It was a small study. Very successful, but one we would want to be repeated with a larger group."

    When asked why the MS Society wasn't broadcasting the results as bigger news, he said, "Many things go into this. The use of the high-dose chemotherapy drug Cyclophosphamide has been around a long time and there are lots of different protocols. I can't speak to the extent that this is a unique protocol."

    He also pointed out that there was no "control group," a scientific protocol that matches an equal number of patients who do not receive the medicine with those who are being treated. He said without control groups the results assume that people would not have gotten better anyway.

    Research oncologists, such as Dr. Gladstone, never use control groups, asking what sort of person with a fatal disease would enroll in a drug trial where there's a fifty/fifty chance of getting a placebo? (A placebo is medicine that looks like the real thing but has no effect on the patient.)

    When pressed Dr. Larocca conceded, "In all likelihood this (the results) were not of a spontaneous character." (Meaning the patients got better because of the treatment.)

    Ms. Jacobellis, 52, doesn't seem to be very concerned about the MS Society's reaction. Her main concern, she says, is others with multiple sclerosis. She talks with and e-mails hundreds of MS patients and her message is as simple as it is dramatic, "Hang in there! Help is on the way."

    She continued, "If they can stop my illness at this point, help for you is right around the corner."

    Dr. Gladstone is continuing his trials.

    Source: The North Shore Sun © 2006 Times-Review Newspapers(02/10/06)

    An unlikely MS therapy
    Multiple sclerosis responds to high doses of chemotherapy in local study, improving health of five subjects.

    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 hospitalised 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."

    Source: Newsday.com Copyright Newsday Inc.(15/08/06)

    © Multiple Sclerosis Resource Centre

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