Over the past 15 years, intravenous cyclophosphamide (Cytoxan) has been demonstrated to be a safe and effective therapy for childhood systemic lupus erythematosus (SLE). Its use has been associated with both improved survival and an improved quality of life for children with diffuse proliferative glomerulonephritis (DPGN) and other life-threatening manifestations of SLE[1],[2],[3],[4]. Before the routine use of intravenous cyclophosphamide, the prognosis for children with continuing active renal disease was extremely poor[5]. The adult experience compiled by the National Institutes of Health suggests that the intermediate-term improvement in survival for children with SLE receiving cyclophosphamide will be associated with dramatic long-term improvement as well. Our long-term follow-up data indicate that children experience a better quality of life because the use of intravenous cyclophosphamide provides dramatic relief of the symptoms of SLE while sparing them the many serious long-term side effects of corticosteroids.
HSS Protocol
At Hospital for Special Surgery, children with SLE complicated by DPGN are now routinely entered into a protocol calling for the use of monthly intravenous cyclophosphamide for seven months, followed by every three month cyclophosphamide for a total of thirty six months (17 doses). The standard regimen consists of the monthly intravenous infusion of 500 to 1000 mg/m2. In comparison with daily oral therapy, the immunosuppressive effects of this single large dose appear to be greater, but its toxicity appears to be less[6],[7]. The initial dosage of cyclophosphamide should be 750 mg/m2 in patients free of significant renal or hepatic compromise and 500 mg/m2 (or less) if significant compromise is present. The dose is progressively adjusted upward to the maximum dose of 1 gm/m2 in increments of 250 mg/m2.
There must be careful monitoring of the white blood cell nadir 10 to 14 days following cyclophosphamide administration. If the patient experiences a white blood cell nadir of less than 2000 total white blood cells/mm3 or less than 1000 granulocytes/mm3, the dosage should be reduced by 125 mg/m2. In small children, even though the calculated surface area may indicate a higher dosage, the dosage of cyclophosphamide should not exceed 40 mg/kg because of potential cardiotoxicity.
Once a child has completed six months of therapy, continued administration of intravenous cyclophosphamide at three month intervals for a total of thirty-six months appears to offer optimal benefit. Several centers have attempted to shorten the duration of therapy, but they have experienced an unacceptable level of recurrent disease activity. Following the completion of this protocol, most children have remained well off cyclophosphamide. A small number have required repeat treatment with cyclophosphamide (for three months) because of disease flares occurring 6 to 24 months following cessation of the original treatment course[3],[4]. In contrast to the few children who have flared after completing this regimen, a substantial proportion of children who were withdrawn from cyclophosphamide after a shorter duration of therapy have flared[8].
Methylprednisolone for Low WBC
In reviewing our earliest results, it was apparent that a significant number of patients were dropped from the study because they became leukopenic during the first few months of intravenous cyclophosphamide therapy and further doses were withheld. Since many of these patients ultimately went on to renal failure with active disease, it was clear that a better approach was needed.
At this time, children admitted for intravenous cyclophosphamide who are found to have total WBC less than 4000 or absolute neutrophil counts less than 2,500 are given intravenous methylprednisolone (30 mg/kg up to a maximum of 1 gram). Interestingly their WBC is usually lower the next day. They then receive a second dose of intravenous methylprednisolone and almost invariably their WBC rises to 6,000 or 7,000. This demonstrates that the patient can mount a WBC response, and I have not had any patient develop profound neutropenia or septic complications when I then gave them cyclophosphamide. If the patient does not respond to three doses of methylprednisolone 24 hours apart, I would not give cyclophosphamide. That has only happened to me once. That patient was discharged on a higher daily dose of prednisone and ultimately responded with an increased WBC. This regimen has the advantage of giving additional methylprednisolone therapy to children with active disease manifested by continuing leukopenia. Don't forget to observe for the usual complications of bolus methylprednisolone therapy, including hypertension, hypotension, and pancreatitis.
Side Effects
Nausea, vomiting, alopecia, and moderate degrees of myelosuppression, are common side effects of intravenous cyclophosphamide. Infection during the period of immunosuppression with the risk of sepsis and death remains an ever-present concern, but can be minimized by careful inpatient observation during the 12 hours before and 24 hours after administering the cyclophosphamide. The more worrisome complications of sterility, pulmonary fibrosis, hemorrhagic cystitis, and secondary oncogenesis have not been reported in childhood. However, they remain potential complications. Male children with SLE appear to be at risk of infertility whether or not they are treated with cyclophosphamide[9],[10],[11],[12],[13],[14],[15].
Outpatient administration of intravenous cyclophosphamide is utilized by some centers. However, it is impossible to assure adequate hydration and appropriate electrolyte status for a child who has received a "central acting" emetic without parenteral fluids. Hospitalization allows assured hydration with careful monitoring of blood pressure and electrolyte status coupled with superior control of emesis using intravenous anti-emetic agents and the administration of MESNA[16]. In addition, we have recognized children with occult infections because they became febrile in the hospital during the night prior to planned administration of cyclophosphamide. In our hands, hospitalization clearly results in both reduced toxicity and improved patient compliance.
Outcomes
Children with diffuse proliferative glomerulonephritis (even if complicated by nephrotic syndrome) generally respond well to intravenous cyclophosphamide, as do children with membranoproliferative glomerulonephritis. However, in children with "pure" membranous nephritis, response has been less satisfactory.16 Cyclosporine or other agents may ultimately prove superior therapy for this group[17],[18],[19].
Children with significant renal compromise for a prolonged period prior to the initiation of therapy may continue to deteriorate during the initial six months of cyclophosphamide therapy. The risks of continued treatment with cyclophosphamide probably outweigh the potential benefits for these patients. Similarly, if significant chronicity without activity is found on the initial renal biopsy, cyclophosphamide therapy is unlikely to succeed.
Some children with aggressive SLE do not tolerate the transition to every three month intravenous cyclophosphamide therapy. Many of these children can be controlled by an additional three months of monthly therapy. However, a few children continue to experience disease flares whenever the interval between cyclophosphamide doses is extended. Combinations of multiple immunosuppressive agents (e.g. cyclophosphamide and methotrexate) have been useful for these children with good success[20].
Intermittent intravenous cyclophosphamide also has been used successfully in corticosteroid resistant lupus cerebritis, recurrent digital infarction, and pneumonitis. Because the use of intravenous cyclophosphamide for childhood SLE is associated with prompt disease control it allows minimization of the total dose of corticosteroids the children received. Evidence suggests that this has a major impact on improving both the quality and duration of life for children with SLE.
posted 11/14/2002