Cyclophosphamide (brand names, Cytoxan and Neosar) is a chemotherapy being investigated as a treatment of interstitial lung disease (ILD), a potential complication of scleroderma. In ILD, lung tissue and spaces around the air sacs, called the interstitium, become inflamed and damaged. This can be caused by an overactive immune system as in the case of scleroderma.

Cyclophosphamide is approved by the U.S. Food and Drug Administration (FDA) to treat several types of cancer and specific types of kidney disease in children.

How cyclophosphamide works

Cyclophosphamide belongs to a group of medications called alkylating agents that work by binding to DNA, blocking it from being “read” so to prevent protein synthesis. Cells that cannot synthesize proteins die — a benefit when cells are cancerous.

Cyclophosphamide can also suppress the activity of immune system cells, which in the case of autoimmune diseases, such as scleroderma, can lead to lower levels of damaging autoantibodies — proteins that mistakenly attack the body’s own tissues — and help to lessen inflammation.

Clinical trials for scleroderma-related ILD

A Phase 3 clinical trial (NCT00004563) evaluated the efficacy and safety of cyclophosphamide versus placebo in slowing or preventing the progression of symptomatic pulmonary disease in 158 patients with systemic scleroderma.

Its primary endpoint, or measure, was the change in forced vital capacity (the amount of air which can be forcibly exhaled after taking the deepest breath possible) at the end of 12 months of treatment. Secondary endpoints included quality of life, activity, dyspnea indices that rate the severity of breathing difficulties, and carbon monoxide diffusing capacity or the ability of the lungs to transfer gas from inhaled air to the blood.

Trial results, which were published in The New England Journal of Medicine, showed a “significant but modest” beneficial effect of treatment on lung function, shortness of breath, skin thickening, and health-related quality of life. But two-year follow-up data, published in the American Journal of Respiratory and Critical Care Medicine, found most improvements were no longer evident at 24 months post-treatment, except for sustained effect on dyspnea or shortness of breath.

A Phase 2 trial (NCT00883129) compared cyclophosphamide’s effectiveness  to that of CellCept (mycophenolate mofetil) for two years, with the primary outcome being changes in forced vital capacity. At the study’s end, researchers verified that both treatments showed significant improvements in lung function, but CellCept being better tolerated and associated with longer-lasting benefits. These results were published in The Lancet Respiratory Medicine journal.

A prospective Phase 3 clinical trial (NCT01570764) underway in France is evaluating the efficacy of cyclophosphamide in combination with prednisone in treating systemic scleroderma-related ILD. About 40 patients are randomized into two groups: one a treatment arm and the other given placebo. The study’s outcome measures o include forced vital capacity, quality of life, shortness of breath, and changes in the six minute walk test (6MWT). The study  is expected to conclude in October 2018.

Other details

The most common side events associated with cyclophosphamide use are general weakness, stomach discomfort or pain, diarrhea, nausea or vomiting, and lower immune cell counts.

Cyclophosphamide is available as an injection, an infusion, or as an oral treatment.

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