High-Dose Cyclophosphamide Promising for Refractory MS

December 1, 2006

Characterized by a triad of symptoms including inflammation, demyelination, and gliosis, multiple sclerosis (MS) affects approximately 1.1 million persons worldwide.1 The disorder is accompanied by neurologic symptoms that include disturbances of sensation, coordination, and vision along with changes in sexual function, bladder and bowel function, gait, and endurance.

Characterized by a triad of symptoms including inflammation, demyelination, and gliosis, multiple sclerosis (MS) affects approximately 1.1 million persons worldwide.1 The disorder is accompanied by neurologic symptoms that include disturbances of sensation, coordination, and vision along with changes in sexual function, bladder and bowel function, gait, and endurance.2

Current scientific thought about the pathogenesis of MS centers around the idea that any systemic infection may induce the up-regulation of adhesion molecules to the endothelium of the brain and spinal cord. The up-regulated adhesion molecules become a chemotropic attractant to leukocytes, which can then pass through vessel walls and enter the CNS. Lymphocytes recognize myelin antigens and trigger a series of events culminating in the formation of the acute inflammatory demyelinating lesion characteristic of the disorder. The demyelinating lesions attack the myelin sheaths and myelinating cells (oligodendrocytes) mainly in the white matter.

PROGNOSIS POOR

The long-term prognosis for patients with MS is poor. Most patients will develop disabilities because of the disease. In at least half of all patients who relapse, the disease moves into a secondary progressive stage. However, after several years, about 30% of patients with progressive disease become stable, and some may actually show improvement. After entering the secondary progressive stage, about 75% of patients with MS are ambulatory after 5 years, and about 40% remain so after 15 years. Probably the strongest predictor of disease progression is the patient's Expanded Disability Status Scale (EDSS) score into the 3 to 5 range.3 Based on recent advances in the understanding of the underlying pathogenesis of MS, however, available strategies for treatment have widened.4 Some specialists, such as Douglas E. Gladstone, MD, assistant professor of medicine and associate director of Blood and Marrow Stem Cell Transplant at State University of New York, Stony Brook University Medical Center, use aggressive therapy with success.

HIGH-DOSE CYCLOPHOSPHAMIDE

Among the newer approaches to the management of MS is high-dose cyclophosphamide (HDC) therapy, advocated and currently under study by Gladstone. In his experience,5-7 the protocol has resulted in the stabilization, improved function, and improved overall quality of life (QOL) for many patients with severe refractory disease.

The use of HDC in the treatment of patients with MS was predicated on the eradication of B and T lymphocytes, which are considered responsible for the plaque formation, demyelination, and gliosis charac-teristic of MS. At the same time, HDC spares the pluripotent blood stem cells necessary for the reestablishment of essential lymphocyte populations.6-9 "Cyclophosphamide has been used to treat MS in low doses [700 mg/m2 every other month] probably as long as mitoxantrone [Novantrone] has. Cyclophosphamide in high doses for MS [eg, 200 mg/kg over 4 days] has been in use for about 2 years," Gladstone explained.

In discussing an ongoing trial5 that he and colleagues are conducting, Gladstone explained that "patients with either form of MS--relapsing-remitting or progressive--are currently eligible for HDC therapy; however, several criteria must be met before we enroll patients in our study. The criteria include good heart and kidney function. Patients have to demonstrate disease progression despite the use of 2 FDA-approved therapies, and they must have an EDSS score of 3.5 or greater. The primary end point in our study is stabilization of expanded disability status."

"We routinely give patients prophylactic antivirals, antifungals, and antibiotics before they become neutropenic," Gladstone continued, because febrile neutropenia is the most significant adverse effect encountered with HDC therapy. "About half of our patients require more antibiotics during the procedure. We have to keep in mind that we are producing the same toxicities that we see in patients who have leukemia and lymphoma and who are undergoing bone marrow transplantation [BMT]. Starting on day 10, we give all patients granulocyte colony-stimulating factor to decrease the time to absolute neutropenia."

When asked how HDC therapy compares with other approaches to MS, Gladstone explained that in his study, all patients already had disease progression and already had a failed trial of mitoxantrone. "Likewise, almost all patients had been on interferon-beta or combination therapy for several years before being enrolled in our study." In Gladstone's view, HDC is more effective than both mitoxantrone and interferon combination therapy. He added that HDC could be used as salvage therapy when these other treatments fail. "There are no head-to-head studies published yet, but even in a case comparison with monoclonal antibodies combined with interferon, we were able to delay disease progression. In my opinion, HDC compares favorably with the current FDA-approved medi- cations," said Gladstone.

Some investigators who perform autologous BMT for MS also use HDC as an alternative, but "chemotherapy with cyclophosphamide has inherent properties that allow you to use it without BMT," Gladstone continued. "However, the amount of immunosuppression seen with cyclophosphamide is probably very similar to the immunosuppression seen with high doses of chemotherapy used in BMT. Personally, I'm not a big fan of BMT as a therapy for MS," he remarked, adding that European physicians have focused more on autologous BMT for the management of autoimmune diseases.

"The results so far are basically inferior to those obtained with HDC therapy," he said in comment about BMT use among European clinical researchers. "The problem with their approach is that, although they try to purge the offending T lymphocytes, they end up reintroducing the cells into the patient. Moreover, when BMT is given concomitantly with chemotherapy and immunosuppression, many patients do well in the short term but usually relapse or have disease progression by 6 months."

Gladstone conceded that the follow-up time for his study is short. "But beyond 6 months, our results are superior to those obtained using the BMT approach. Our patients have gone way beyond the 6-month mark without any serious problems. This is sort of a milestone in itself. Look at it this way: even if our patients should relapse in 5 years, this is still a pretty good run."

QOL IMPROVED WITH HDC

In discussing specific symptoms that are noticeably improved with HDC therapy, Gladstone was quick to mention that, "some patients in our study had a regression in their EDSS score, clearly manifested by improvements in gait. What's been astounding is that severe dizziness, which many patients with MS have, often dissipates even before they leave the hospital." The reduction in dizziness and improvements in bladder control and gait really have a tremendous impact on the patient's QOL, Gladstone observed. He noted that because of dizziness, many patients lose balance and fall when they close their eyes, for example, to shampoo their hair while showering. With the reduction of dizziness comes reduction in falls and anxiety about doing such things as closing one's eyes. "So, an impressive improvement in the patient's QOL is the reduction in dizziness. These factors are all studied prospectively," said Gladstone.

"We studied the use of HDC retrospectively in other disease states. We had patients and their caregivers fill out questionnaires. In these retrospective studies, from the points of view of both patients and caregivers, there was a general improvement in all aspects of QOL issues. Even when analyzed prospectively, our data demonstrated a definite improvement in all QOL areas. Even when the EDSS score of many patients remained unchanged and no changes were noted during routine physical examination, these patients reported that they felt a general improvement in their QOL status with this treatment."

REFERENCES1. Hauser SL, Goodin DS. Multiple sclerosis and other demyelinating diseases. In: Kasper DL, Fauci AS, Longo DL, et al, eds. Harrison's Principles of Internal Medicine. 16th ed. Vol 2. New York: McGraw-Hill; 2005:2461-2471.
2. Waubant EL, Goodkin DE. Multiple sclerosis. In: Evans RW, Baskin DS, Yatsu FM, eds. Prognosis of Neurological Disorders. 2nd ed. New York: Oxford University Press; 2000:291-311.
3. Coyle P. Multiple sclerosis. In: Gilchrist JM, ed. Prognosis in Neurology. Boston: Butterworth-Heinemann; 1998:183-187.
4. Frohman EM, Racke MK, Raine CS. Multiple sclerosis--the plaque and its pathogenesis. N Engl J Med. 2006;354:942-955.
5. Gladstone DE, Zamkoff KW, Krupp L, et al. High-dose cyclophosphamide for moderate to severe refractory multiple sclerosis. Arch Neurol. 2006;63:E1-E6.
6. Prestrud AA, Gladstone DE. Quality of life after high-dose cyclophosphamide in patients with severe autoimmune diseases. J Eval Clin Pract. 2005;11: 411-416.
7. Gladstone DE, Prestrud AA, Brannagan TH 3rd. High-dose cyclophosphamide results in long-term disease remission with restoration of a normal quality of life in patients with severe refractory chronic inflammatory demyelinating polyneuropathy. J Peripher Nerv Syst. 2005;10:11-16.
8. Gladstone DE, Prestrud AA, Pradhan A, et al. High-dose cyclophosphamide for severe systemic lupus erythematosus. Lupus. 2002;11:405-410.
9. Gladstone DE, Brannagan TH 3rd, Schwartzman RJ, et al. High dose cyclophosphamide for severe refractory myasthenia gravis. J Neurol Neurosurg Psychiatry. 2004;75:789-791.