High-Dose Cyclophosphamide in MS
High-Dose Cyclophosphamide in MS
Abstract & Commentary
By Gregg L. Caporaso, MD, PhD, Assistant Professor of Neurology and Neuroscience, Weill Cornell Medical College. Dr. Caporaso reports no financial relationship relevant to this field of study.
Synopsis: A single, high-dose treatment of cyclophosphamide stabilized or improved function in multiple sclerosis patients with moderate to severe disease that did not respond to prior trials of immunomodulatory or immunosuppressive drugs.
Source: Gladstone DE, et al. High-dose cyclophosphamide for moderate to severe refractory multiple sclerosis. Arch Neurol. 2006; 63:1388-1393.
Gladstone and colleagues evaluated the efficacy of high-dose cyclophosphamide (HDC) treatment in 13 patients with moderate to severe relapsing-remitting (RRMS) or secondary progressive multiple sclerosis (SPMS). All patients in the study had had at least 2 relapses or suffered neurological deterioration during the previous year. In addition, all patients had been treated earlier with corticosteroids and interferon (IFN)-beta. Eleven patients also received a second IFN-beta formulation, glatiramer acetate (GA), IVIg, mitoxantrone, and/or another immunosuppressive therapy during the course of their disease. Except for steroids, these other therapies were stopped at least 3 weeks before the study began.
The patients received a total of 200 mg/kg of cyclophosphamide over 4 days. They also received mesna and forced diuresis to help prevent hemorrhagic cystitis as well as prophylaxis against bacterial, viral, and fungal infections. On day 10, patients began receiving granulocyte colony-stimulating factor (filgrastim) until their neutrophil counts reached 1000/mm3. Blood or platelets were transfused at predetermined thresholds. Patients had repeated neurological, neuro-ophthalmic, and MRI examinations over 2 years.
Six patients had RRMS and 7 had SPMS. Their ages ranged from 26 to 52 years (median 41) and disease duration from 3.1 to 29 years (median 6.5). All but one subject was female. The level of disability on the Expanded Disability Status Scale (EDSS) for patients at study entry ranged from 4.0 (ie, relatively severe disability, but still fully ambulatory) to 8.0 (ie, retains most self-care functions, but largely restricted to bed or wheelchair). Patients were followed for 6 to 24 months (median 15). Of the 12 patients that could be evaluated clinically, 5 experienced at least a 1.0-point improvement on the EDSS, one had a 0.5-point improvement, 5 remained stable, and one worsened by 0.5 point. The results on the individual functional subscores that make up the EDSS were more variable, with most patients experiencing improvement in 2 or more functions and worsening in one or more. Of note, all patients had bladder dysfunction prior to treatment and 75% experienced improvement with HDC, with 50% experiencing a complete resolution of symptoms.
There were no significant changes in the number of T2-weighted lesions on brain MRI with treatment. Only 2 patients had gadolinium-enhancing lesions prior to treatment and only one developed an enhancing lesion after HDC. Visual acuity improved by 2 or more lines on the Snellen eye chart in 44% of patients. All patients reported an improvement in their quality of life and 88% reported a reduction in fatigue.
Patients tolerated the treatment well. On average, the subjects developed absolute neutropenia for 9 days and received one unit of packed red cells and one unit of platelets during treatment. Half the patients had neutropenic fever and most experienced nausea, but no long-term morbidity was observed.
Commentary
Since its first use in a patient with multiple sclerosis (MS) 40 years ago, more than 30 clinical studies have examined the effects of cyclophosphamide on the disease. Upon review, Weiner and Cohen concluded that cyclophosphamide appears to be most effective in "cases of worsening MS that have an inflammatory component as evidenced by relapses and/or gadolinium-enhancing lesions on MRI or in patients in earlier stages of disease where inflammation predominates."1 Consistent with this conclusion, the best responses to HDC (changes in EDSS scores from 5.5 to 2.0 and from 6.0 to 1.0) were seen in patients who had the shortest disease durations in the study (3.1 and 5.8 years, respectively), had 2–3 relapses in the previous year, and who had received no other treatments other than steroids and IFN-beta.
With traditional protocols, most treating neurologists administer cyclophosphamide at doses of 800-1000 mg/m2 on a monthly or bimonthly basis for one to 2 years. This dose translates to 1.2–1.75 g/dose of cyclophosphamide for the average female patient. In contrast, the HDC in the present study would represent 11–13 g for a 55–65 kg woman. The HDC used by Gladstone et al is believed to eliminate the T cells and B cells that contribute to autoimmune diseases while sparing hematopoietic stem cells. As a consequence, the patients in this study required prolonged hospitalization, antimicrobials, and, in most cases, supportive transfusions of blood components while erythrocytes, white blood cells, and platelets were reconstituted. These considerations, as well as the toxic effects of cyclophosphamide, which include alopecia, infertility, and hemorrhagic cystitis, would thus limit the high-dose regimen to a selected subgroup of patients.
The design of this study makes it difficult to evaluate the efficacy of HDC compared to conventional cyclophosphamide protocols or to mitoxantrone, the only cytotoxic drug approved by the FDA for patients with worsening RRMS or SPMS. Post-treatment data were only provided for one patient who had previously received cyclophosphamide, and she demonstrated no change in EDSS score after HDC. Seven patients in the study had previously received mitoxantrone, but all had received submaximal doses. Nevertheless, this group of patients had stable or improved EDSS scores for a median of 16.5 months. It would be interesting to study HDC head-to-head with conventional cyclophosphamide protocols or mitoxantrone in patients with worsening RRMS or SPMS who have already been treated with IFN-beta or GA.
In addition, a longer-term study should address the duration of the effects of HDC. Worldwide experience in over a hundred patients who have received autologous hematopoietic stem cell transplants (HSCT) for MS (some of whom were treated with HDC combined with another cytotoxic therapy) indicates that MS disease activity can resume after a few years in up to 40% of cases, despite this extreme treatment protocol. Indeed, even in the present study, there was MRI evidence of recurrent disease after HDC in one patient. Approximately 5% mortality has been observed with HSCT; therefore, it will be important to assess the risk of HDC in a larger cohort. A longer post-treatment observation period is also required with these patients before the long-term benefits of HDC can be determined.
Reference:
1. Weiner HL, Cohen JA. Treatment of multiple sclerosis with cyclophosphamide: critical review of clinical and immunologic effects. Multiple Sclerosis. 2002;8:142-154.
A single, high-dose treatment of cyclophosphamide stabilized or improved function in multiple sclerosis patients with moderate to severe disease that did not respond to prior trials of immunomodulatory or immunosuppressive drugs.Subscribe Now for Access
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