Here's some more info about the study.
High-Dose Cyclophosphamide Effective in Refractory Multiple Sclerosis CME
News Author: Caroline Cassels
CME Author: Désirée Lie, MD, MSEd
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.
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.
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.
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.
* 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.