MONTREAL – The immunosuppressant mycophenolate mofetil worked as effectively as cyclophosphamide for treating scleroderma-related interstitial lung disease while being better tolerated and causing fewer adverse effects in a multicenter, head-to-head comparison with 142 randomized patients.
“The findings support the increasingly common clinical practice of prescribing MMF [mycophenolate mofetil] for this disease,” said Dr. Donald P. Tashkin at the annual meeting of the American College of Chest Physicians.
Mitchel L. Zoler/Frontline Medical News
Dr. Donald P. Tashkin
Another limitation of cyclophosphamide is that it is usually not used for more than 1 year because of concerns that longer use substantially increases a patient’s risk for developing malignancy. That’s another reason why there is a “strong need for longer and safer immunosuppressive treatment with a drug like MMF,” said Dr. Tashkin, a pulmonologist at the University of California, Los Angeles.
When used in this trial on patients with scleroderma, as defined by the American College of Rheumatology and with a baseline forced vital capacity of no more than 80% of predicted, “MMF was effective at reducing the rate of decline in vital capacity, improving symptoms such as dyspnea – the cardinal symptom of interstitial lung disease, and reducing lung fibrosis seen on CT scans, and MMF was better tolerated” than cyclophosphamide, Dr. Tashkin said in an interview. Cyclophosphamide treatment in this new trial “was associated with more toxicity, especially hematologic toxicity, an was not nearly as well tolerated, with more patients withdrawing because of side effects or a perceived lack of benefit.”
“Cyclophosphamide has a lot of side effects. MMF is just now coming into increased use. I think we’ll see it being used more for first-line treatment because the side effects with cyclophosphamide are so bad,” commented Dr. Thomas Fuhrman, chief of anesthesiology at the Bay Pines (Fla.) VA Healthcare System.
Dr. Thomas Fuhrman
Dr. Tashkin and his associates conceived the Scleroderma Lung Study II (SLSII) as a follow-up to the first SLS run about a decade ago that compared cyclosphosphamide against placebo for controlling progression of interstitial lung disease in scleroderma patients. The results from the first SLS trial established cyclosphosphamide as a treatment that could preserve forced vital capacity percent predicted in patients with scleroderma-induced interstitial lung disease (N Engl J Med. 2006 Jun 22;354[25]:2655-666).
For the new study they enrolled patients who averaged 52 years old, with an average scleroderma duration of almost 3 years. Their average percent predicted forced vital capacity was 67%, and their baseline dyspnea index was 7.1.
Patients received either a target oral MMF dosage of 1.5 g b.i.d. for 2 years, or a target cyclophosphamide dosage of 2 mg/kg/day for up to 1 year, followed by a year of placebo. Cyclophosphamide treatment was capped at 1 year to protect against causing malignancy. Among the 73 patients randomized to the cyclophosphamide arm, 58 had data available after 12 months with 48 patients continuing on cyclophosphamide, and 53 had data available out to 2 years, with 37 patients remaining on their assigned regimen. Among 69 patients randomized to MMF 58 had data available after 12 months with 53 continuing on MMF, and 53 patients had data available through 24 months with 49 remaining on their MMF regimen.
After 24 months, the average percent predicted forced vital capacity, the study’s primary endpoint, had increased by 3.3% among patients on MMF and 3.0% among those in the cyclophosphamide arm in an intention-to-treat analysis, a nonsignificant difference. After 24 months 72% of patients in the MMF arm and 65% in the cyclophosphamide arm had a positive change, compared with baseline, in their percent predicted forced vital capacity, Dr. Tashkin reported.
MMF also showed a superior overall safety profile. Patients on cyclophosphamide had a significantly increased rate of withdrawal from the study medication. Drug discontinuations occurred in 36 of the cyclophosphamide patients and in 20 of those on MMF. Serious adverse events attributable to study medication occurred in eight patients on cyclophosphamide and three patients on MMF. The most frequent protocol-defined adverse event was leukopenia, which occurred in 30 patients on cyclophosphamide and four patients on MMF.
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