We have described our retrospective multicenter experience with cyclophosphamide in the management of children with severe MS. Cyclophosphamide therapy was associated with improvement in relapse-related neurologic deficits when administered acutely and with marked reduction in relapses and stabilization of EDSS scores in the majority of children receiving induction or maintenance therapy.
Childhood-onset MS is relatively rare and available literature on therapy is limited to retrospective studies of first-line disease-modifying treatments.20–22
Although no standardized approach to the definition of treatment success, or failure, exists, there is a cohort of children who will continue to worsen on first-line treatment. Indeed, defining and identifying treatment failure has been a difficult task in the adult MS population, and a multitude of definitions have been used. The presence of continued relapses and formation of new MRI lesions despite therapy are generally considered indicators of refractory disease. Other important indicators of refractory disease, particularly for the consideration of cyclophosphamide treatment, are the presence of poor recovery from relapses and disease progression in the absence of relapses. In the majority of the cases we described, children experienced either poor recovery from relapses or progressive disease, as evidenced by increased EDSS scores in the year prior to cyclophosphamide initiation.
In our cohort, cyclophosphamide treatment reduced relapse rate and stabilized disability scores in the majority of patients. New gadolinium-enhancing and T2 MRI lesions were present even in the first year following cyclophosphamide initiation, suggesting that the onset of therapeutic effect may be delayed and incomplete. Although beyond the scope of this study, quantitative lesion analyses are required to determine the extent of cyclophosphamide effects on MRI parameters in children. We observed that over 50% of patients with over 1 year of follow-up after the cessation of therapy continued to experience frequent relapses and required additional second-line treatments, suggesting that cyclophosphamide treatment did not induce a permanent suppression of the inflammatory process in this cohort of pediatric MS patients. Our results may differ from observations in adults1
because of the selection of a particularly active pediatric MS population, or may be due to key differences in the immunologic response in children compared to adults, a hypothesis which requires further exploration.
Forty-one percent of children treated with cyclophosphamide were non-Caucasian in ethnicity. Several studies examining the effect of race on MS-associated disability in the adult population have demonstrated increased levels of disability in African American patients.24–26
We have reported on the more diverse ancestry of pediatric MS cohorts, relative to adult-onset MS populations,14,27
raising the possibility that ethnicity may influence disease severity, either defined by the early onset of MS, or by an aggressive disease course. Larger, multinational studies are required to validate this observation.
Cyclophosphamide therapy was associated with several adverse events in our cohort, the most significant being the development of bladder carcinoma. Risk of bladder carcinoma has been linked to cumulative cyclophosphamide dosage of 100 g or more.28
Long-term follow-up of patients treated with cyclophosphamide demonstrated an increased risk of bladder carcinoma as long as 17 years post-treatment,29
necessitating lifelong surveillance in exposed patients. Use of Mesna during the treatment period may help to reduce the incidence of hemorrhagic cystitis and bladder cancer. The risk of secondary lymphoma or leukemia and other malignancies are also a concern for children exposed to cyclophosphamide, and these risks may be partially dependent on the total cumulative dose.29
Concomitant steroid administration improves tolerability, but increases the risk of osteoporosis, which was a significant finding in our cohort.
Risk of infertility is an important consideration, and must be balanced with potential benefits of treatment. A study in childhood cancer survivors found that cyclophosphamide exposure between the ages of 13 and 20 years was an independent risk factor for acute ovarian failure.30
In females, postpubertal exposure seems to pose a higher risk to fertility than prepubertal exposure.31,32
Analyses of cyclophosphamide use in adults suggest that female infertility may be associated with cumulative dose received and patient age.33,34
GnRH agonists such as leuprolide acetate have been shown to reduce the risk of premature ovarian failure,35
and should be considered at the time of treatment initiation. Studies from the pediatric oncology literature suggest that cyclophosphamide administered both before and after puberty pose risks to male fertility in later life.36,37
Sperm cryopreservation should be considered in postpubertal males.
Although our retrospective study provides important information regarding the safety profile of cyclophosphamide in pediatric MS, we recommend that a prospective, multicenter study of cyclophosphamide in patients with refractory disease be considered to better define treatment outcomes. In our study, 15 of 17 patients experienced two or more relapses in the year prior to cyclophosphamide initiation, and therefore, these criteria may be used as a guideline to define refractory disease. Of the two cases that did not fit this definition, patient 3 had sequential MRIs with new lesions, and patient 17 progressed by 0.5 EDSS points to a pretreatment EDSS of 7 in the 9 months prior to cyclophosphamide initiation, and also demonstrated new lesion activity on MRI. Future clinical trials may consider a treatment length of 6–12 months, and response should be evaluated at 6-month intervals, clinically and by MRI, to follow potential clinically silent lesion accrual. Cumulative lifetime dose should be limited to 80 g to minimize side effects. Our results suggest that for patients undergoing a severe relapse unresponsive to corticosteroids, IVIg, or plasma exchange, an induction course of cyclophosphamide may be considered; however, prospective studies are required to definitively determine efficacy.
Our study did not examine use of cyclophosphamide in monophasic pediatric demyelinating diseases, and we cannot comment on a role for cyclophosphamide in children with disorders such as acute disseminated encephalomyelitis. Efficacy of cyclophosphamide treatment has been reported in children with severe transverse myelitis.38
The recent availability or imminent availability of novel immunomodulatory and immunosuppressive agents, such as natalizumab, rituximab, daclizumab, alemtuzumab, and cladribine provide potential future avenues for children requiring more intensive MS therapy. However, the risk of progressive multifocal leukoencephalopathy, severe infections, melanoma, and other malignancies is a major concern, particularly in the context of an immature immune system or in a population of patients experiencing primary exposures to viral infections, such as the JC virus. These risks must be compared to those experienced by children and adults exposed to cyclophosphamide, particularly the risks of bladder cancer and secondary malignancies as well as infertility.
While cyclophosphamide remains a second-line agent in the care of children with MS, it may have an important role in the treatment of some of the most severely affected children. Further studies will be needed to determine its efficacy and safety profile compared to emerging second- and third-line therapies. Multinational collaboration to define safety, treatment response, and failure of both conventional and second-line agents, as well as to develop standardized treatment algorithms for children with MS, would be invaluable.