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Posted: Mon Oct 02, 2006 11:05 am Post subject: Cyclophosphamide
This is a story of a couple of months ago, but is doing the rounds again. It's something cheery for a Monday.
Ian
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 tremours.
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."
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."
Arch Neurol. Published online August 14, 2006.
Learning Objectives for This Educational Activity
Upon completion of this activity, participants will be able to:
* Identify hematopoietic effects of high-dose cyclophosphamide in MS patients.
* Describe disease progression associated with use of high-dose cyclophosphamide in MS patients resistant to 2 or more disease-modifying treatments.
Clinical Context
MS is the most common immune-mediated inflammatory and demyelinating disorder of the nervous system and has no cure. According to the current authors, 50% of patients will require ambulatory aids 15 years after disease onset, and therapy is aimed at preventing relapse and slowing long-term disability. Currently, the only FDA-approved chemotherapy for MS is mitoxantrone, which is associated with neutropenia, amenorrhea in women, heart failure, cardiac dysfunction, and rarely, acute myeloid leukemia. However, high-dose cyclophosphamide is a chemotherapy option for severe, refractory, immune-mediated illnesses, and it acts by eradicating B and T cells responsible for disease while sparing the pluripotent blood stem cells.
The current trial is a descriptive cohort study examining the effect of a single intervention with intravenous high-dose cyclophosphamide in MS patients with moderate to severe disease refractory to at least 2 disease-modifying treatments for a 2-year follow-up period. The goal was to sustain and prevent deterioration rather than to induce remission.
Study Highlights
* Included for analysis were 12 patients who met the McDonald International Panel Diagnostic Criteria for MS who had an EDSS of 3.5 or higher with active disease despite a minimum of 2 FDA-approved disease-modifying therapies.
* Patients with relapsing-remitting treatment failure had at least 2 or more relapses in the prior year.
* Patients with secondary progressive disease had objective neurologic deterioration within the past year.
* All therapies, except steroids, were stopped within 3 weeks of the study, and patients had normal renal and cardiac function.
* Patients received 200 mg/kg of cyclophosphamide intravenous based on adjusted ideal body weight for 4 days.
* Hemorrhagic cystitis prophylaxis was composed of forced diuresis and mesna.
* All patients received antibacterial antifungal and antiviral drugs for prophylaxis.
* Irradiated blood product transfusions maintained hemoglobin levels at more than 8.5 g/dL and platelet count higher than 10 x 109/L.
* Patients with febrile neutropenia received broad spectrum antimicrobials.
* Baseline evaluation included EDSS score, brain magnetic resonance imaging (MRI), and neuro-ophthalmologic assessment.
* Evaluations were repeated every 6 months for 2 years.
* Quality of life was measured using the Short Form 36 in 10 patients.
* Median age was 41 years, median baseline EDSS score was 6.5, and 54% had secondary progressive MS.
* 54% previously had received mitoxantrone, 85% had received therapy within 90 days of the first dose of cyclophosphamide, and all patients had experienced neurologic deterioration within 1 year of the high-dose cyclophosphamide despite at least 2 disease-modifying treatments.
* Median follow-up was 15 months.
* Patients experienced absolute neutropenia for a median of 9 days, received a median of 1.0 unit of packed red cells, and a median of 1.0 single-unit donor platelet infusion.
* 46% experienced febrile neutropenia. Nausea was common and controlled with antiemetics, and serum chemistry abnormalities were transient. No patient experienced long-term morbidity or required rehospitalization after discharge.
* 42% of patients met criteria for a sustained response with a decrease of 1.0 points or more on the EDSS score. No patient showed sustained worsening (EDSS increase of more than 1.0 point).
* 75% of patient showed improved bladder function after treatment.
* 50% had complete improvement in bladder and bowel function scores.
* All patients had abnormal baseline MRI results consistent with MS, and 82% had 15 or more lesions.
* During follow-up, no patients had an increase in number of lesions.
* At baseline, 18% of patients had one enhancing lesion, and all resolved after high-dose cyclophosphamide treatment.
* Visual acuity in 2 patients was normal at baseline and remained normal at 2 years.
* 44% of 9 patients improved by 2 or more lines on the Snellen eye chart examination, with only 1 patient improving from 20/50 to 20/20 vision.
* Color perception improved in 5 (50%) of 10 patients.
* 7 patients with Short Form 36 follow-up at 1 year improved in their mean mental and physical scores.
* At last follow-up, 10 patients improved in 8 measured components of the Short Form 36, including role physical, general health, vitality, and social functioning.
* 88% of 8 patients reported fatigue reduction.
Pearls for Practice
* In MS patients receiving a single intervention of high-dose cyclophosphamide, hematopoietic effects of neutropenia, anemia, and thrombocytopenia are transient and reversible.
* High-dose cyclophosphamide given to MS patients refractory to at least 2 disease-modifying drugs is associated with disease stabilization, improved quality of life, and visual and bladder function at 2 years. _________________ Dunmann.
Joined: May 04, 2006 Posts: 3456 Location: Mid-Michigan
Posted: Mon Oct 02, 2006 3:09 pm Post subject:
That's what I like to hear! Thanks for the links Ian and dunmann.
While I like Tovaxin due to it's seemingly high effaciacy and low risk of side effects and I continue to hope that my wife does get into the IIb clinical trial of Tovaxin, it seems that if you have to be periodically retreated it isn't "killing" the disease and must be allowing MS to progress in at least some small way.
It remains to be seen how long Cyclophosphamide keeps MS away but even if it's only for the 10 years they have treated patients out to, that is a huge step in the right direction.
I agree with the researcher about the clinical trials.....when you have something with a known safety profile which seems 100% effective, double blind placebo trials are a waste of time.
I noticed in the first link that either the writer or researchers seem to think that there is such a thing as regression of MS as if MS the disease and the disability the disease has caused is one and the same. MS (or any other disease) has two speeds, stop and forward. MS has no reverse/regression gear although there is a separate issue of regression of symptoms and disability which depend on the body's ability to heal itself once the disease has been slowed/stopped.
I don't like Cyclophosphamide's side effects but I like it's one time regimine and I like it's seeming 100% effaciacy.
Joined: May 04, 2006 Posts: 295 Location: Calgary, AB, Canada
Posted: Mon Oct 02, 2006 3:41 pm Post subject:
Wow...I was waiting for this one. I wonder if this one will be better than the one in Canada where they get rid of the immune system and then give stem cells. That one has had deaths but I wonder which one will be better at stopping the disease long term. This is really good news.
I also wonder why they interview the MS society all the time. They always say the samething. I guess that is the only thing they can say at this point but it's just so very annoying. "The results look interesting." I could have said that myself. Why don't studies like this move faster? How is the MS society involved in this very "interesting" finding?
NN
Last edited by sh8un on Mon Oct 02, 2006 6:20 pm; edited 1 time in total
Joined: May 04, 2006 Posts: 3456 Location: Mid-Michigan
Posted: Mon Oct 02, 2006 5:38 pm Post subject:
sh8un wrote:
I wonder if this one will be better than the one in Canada where they get rid of the immune system and then give stem cells. That one has had deaths but I wonder which one will be better at stopping the disease. Why don't studies like this move faster? How is the MS society involved in this very "interesting" finding?
NN
Hi Neda,
The answer to your question regarding stem cell transplant vs high dose cyclophosphamide, at least according to the researcher.
Quote:
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.
I THINK the reason that stem cell transplantation is so much more dangerous is that extremely high doses of chemo are used to kill the bone marrow, which leaves you without an immune system (as high dose cyclophosphamide does) but also leaves the patient having to wait for the stem cells to rejuvinate the bone marrow before it can rejuvinate the immune system.
School was a long way back (1973) but I think that the marrow creates ALL of your blood cells so it seems that the long recovery would also have to involve transfusions, which seems especially dangerous when you don't have a working immune system.
On the other hand, from what I can tell it seems that cyclophosphamide specifically targets the white blood cells and spares the bone marrow, which produces the red and white cells. All in all, dangerous but a LOT less dangerous than stem cell transplantation.
How cyclophosphamide stops the production of the self reactive aspect is something I don't know but would like to.
It might seem humorous but what has always given me the heebie jeebies regarding stem cell transplantation is after your marrow has been sufficiently killed off and you are at your most vulnerable moment, what if they find that the fridge had gone on the blink, or if they drop the bottle of your stem cells or if they mislable the bottle or a million other mistakes that have been made over the years in labs?
Joined: Jul 28, 2005 Posts: 1334 Location: Sydney, Australia
Posted: Tue Oct 03, 2006 2:42 am Post subject:
Lyon wrote:
... but I think that the marrow creates ALL of your blood cells ....
... from what I can tell it seems that cyclophosphamide specifically targets the white blood cells and spares the bone marrow, which produces the red and white cells ...
How cyclophosphamide stops the production of the self reactive aspect is something I don't know but would like to.
A theory i read a little while ago.
http://www.thisisms.com/ftopicp-18919-.html#18919
The theory being, T-cells generated by cell division (homeostatic expansion) are more likely to be auto-reactive.
Joined: May 04, 2006 Posts: 3456 Location: Mid-Michigan
Posted: Tue Oct 03, 2006 5:26 pm Post subject:
CureOrBust wrote:
A theory i read a little while ago.
http://www.thisisms.com/ftopicp-18919-.html#18919
The theory being, T-cells generated by cell division (homeostatic expansion) are more likely to be auto-reactive.
Hi Cure,
White blood cells multiply by cell division.
Homeostatic expansion is the recognition by the body that more cells are needed and the call to the cells to divide more rapidly and to live longer in order to meet that need.
From what I could tell from the summary they were saying that it's been realized from Campath treatment that homeostatic expansion fails in MS patients.
I think the summary is saying specifically that after MS patients were given Campath (which effectively kills T cells)
Quote:
T-cells are a type of white blood cell (leukocyte) that belongs to a division of the immune system called the acquired immune system. This is the part of the immune system that learns to combat invading bacteria and viruses (pathogens) through exposure to them. The leukocytes that belong to the acquired immune system are called lymphocytes and have receptors on their surface that recognise broken down protein fragments, called antigens, by binding with them.
researchers have noticed that the participants T cell count doesn't return to normal as quickly as it should, due to the failure of homeostatic expansion.
From what I can tell, the hope for Campath is that even with the seeming failure of homeostatic expansion and slower T cell rejuvination, when the T cells do return it will be without the myelin reactiveness. The Campath results so far seem to back that up.
Like all these other new treatments, I'd really like to know a lot more about them.
We got a call Today and my wife (and I) have an appointment Friday regarding the IIb Tovaxin trial. It's the initial appointment to draw blood in order to determine if they can isolate myelin reactive T cells so cross your fingers!
Sounds like participants here in Michigan are going to start being treated in November or December.
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