Fewer Mycophenolate Adverse Events in Scleroderma Lung Study

Kate Johnson

November 02, 2015

MONTREAL — Mycophenolate mofetil can be substituted for cyclophosphamide for the immunosuppressive treatment of scleroderma-related interstitial lung disease, and might even be safer, according to results from the Scleroderma Lung Study II.

"These findings support the increasingly common clinical practice of prescribing mycophenolate mofetil for this disease," said investigator Donald Tashkin, MD, from the School of Medicine at the University of California, Los Angeles.

He described the limited treatment options currently available for patients with scleroderma-related interstitial lung and presented the study results here at CHEST 2015.

The first Scleroderma Lung Study showed that cyclophosphamide significantly improved lung capacity "to a modest extent," as reported by Medscape Medical News. However, "the benefits were done at 2 years, with significant toxicities and an increased risk of malignancy with treatment beyond 1 year," he reported.

The hypothesis of the Scleroderma Lung Study II was that mycophenolate would be less toxic and more effective than cyclophosphamide.

These findings support the increasingly common clinical practice of prescribing mycophenolate mofetil for this disease.

Dr Tashkin and his colleagues randomly assigned 69 patients to mycophenolate titrated up to a dose of 3 g in divided doses for 2 years and 73 patients to cyclophosphamide titrated up to 2 mg/kg for a year followed by a year of placebo.

Mean disease duration was 2.6 years and mean age of the participants was 52 years; 41% of the patients had limited scleroderma and 59% had diffuse scleroderma.

"Most of the patients improved, with no difference between the treatment arms," Dr Tashkin reported.

Forced Vital Capacity

Forced vital capacity — the primary end point — was significantly better at 24 months in both the cyclophosphamide and mycophenolate groups (2.86 and 2.17, respectively).

The only difference in secondary outcomes was the decrease in single-breath diffusing capacity for carbon monoxide between the cyclophosphamide and mycophenolate groups (2.14 vs 0.40).

Significantly more patients withdrew from treatment in the cyclophosphamide group than in the mycophenolate group during the 24-month treatment phase, and time to treatment failure or withdrawal favored mycophenolate mofetil (log-rank test, P = .019).

Table. Scleroderma Lung Study II Reasons for Treatment Discontinuation

Reason Cyclophosphamide, n (%) Mycophenolate Mofetil, n (%)
Adverse event 15 (41.7) 7 (35.0)
Patient request 9 (25.0) 8 (40.0)
Noncompliance 6 (16.7) 3 (15.0)
Loss to follow-up 2 (5.6) 1 (5.0)
Death 2 (5.6) 1 (5.0)
Treatment failure 2 (5.6) 0 (0.0)


The rate of serious adverse events was similar in the two treatment groups, except there were more serious events related to the study drug in the cyclophosphamide than the mycophenolate group (8 vs 1), and leukopenia and thrombocytopenia were more common in the cyclophosphamide group (P < .05).

Overall, there were 16 deaths: 11 in the cyclophosphamide group and five in the mycophenolate group. The morbidity and mortality committee concluded that almost all deaths were probably related to underlying scleroderma, mostly respiratory failure, said Dr Tashkin.

"Both agents appear to have comparable efficacy, but mycophenolate mofetil was better tolerated, with significantly fewer treatment failures and premature withdrawals, and fewer adverse events," he said.

"The data are interesting," said Marco Matucci-Cerinic, MD, PhD, from the University of Florence in Italy. "They suggest not only that cyclophosphamide and mycophenolate mofetil are almost equal, but also that mycophenolate mofetil can be used as a maintenance therapy for longer periods, while cyclophosphamide is limited and cannot go over a certain dosage."

However, he told Medscape Medical News, he has problems with the overlap of diffuse and limited disease in the study.

"Consider that the diffuse disease is an aggressive subset, while the limited disease is subchronic; therefore, they behave completely differently," he explained. "I would be very happy to see the results split into two populations to really have the profile of both drugs in the aggressive subset. This would be likely the best achievement of the study."

"In fact, what we really need in scleroderma is to have a therapy of induction, to obtain remission, and then a therapy of maintenance," Dr Matucci-Cerinic explained.

"Cyclophosphamide is an induction therapy for the diffuse subset when it is used intravenously, but not orally, and the same goes for mycophenolate mofetil. I hope you can understand the real problem that we are left with despite the results of the study. In the European Union, we have abandoned oral cyclophosphamide and use only intravenous for diffuse disease, while mycophenolate mofetil is mainly used for maintenance in diffuse and limited disease."

This study was funded by the National Heart, Lung, and Blood Institute and Hoffmann-La Roche. Dr Tashkin and Dr Matucci-Cerinic have disclosed no relevant financial relationships.

CHEST 2015: American College of Chest Physicians Meeting. Presented October 27, 2015.


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