|Preliminary Results Show Beneficial Effects of Imatinib in Scleroderma|
|Wednesday, 14 April 2010 12:45|
Imatinib (Gleevec), a drug that has significantly improved survival in chronic myelogenous leukemia and gastrointestinal stromal tumor, is showing beneficial effects on skin and lung manifestations in patients with diffuse cutaneous scleroderma. Interim results of a preliminary trial were reported at the American College of Rheumatology (ACR) 2009.
Imatinib was tolerable for most patients with dose adjustments and management of adverse effects, researchers announced. These promising preliminary results in scleroderma need to be replicated in a phase 3 randomized controlled trial of longer duration, said lead author Jessica Gordon, MD, from the Hospital for Special Surgery in New York City.
The phase 2a single-center single-group open-label clinical trial involved 30 patients with diffuse scleroderma; 20 had the disease for less than 4 years and 10 had it for 4 years or more. Imatinib 400 mg/day was given for 12 months, and patients were evaluated 15 months after the initiation of treatment. About one quarter of the patients had received no previous therapy; the other three quarters were taking multiple antirheumatic drugs.
Mean age was 48.4 years, 80% were women, 74% were Caucasian, 13% were African American, and 13% were Hispanic. Efficacy data were available at 3 and 6 months for 26 patients, at 9 months for 21 patients, and at 12 months for 17 patients. Safety data were available for all patients who took at least 1 dose of the study drug. Of the 340 adverse events reported, 177 were possibly related to imatinib. Thirty six infections occurred, and 7 required hospitalization. There were 24 serious adverse events — 1 possibly related to imatinib and 14 occurring in 1 patient who dropped out of the study. That patient had received multiple antirheumatic drugs prior to imatinib, Dr. Gordon noted.
Edema occurred in 80% of patients, nausea in 73%, myalgia in 63%, and fatigue in 37%. Eighty-three percent of patients required dose adjustments for muscle-related problems (37%), fluid retention (30%), fatigue (13%), and nausea (13%). The median dose of imatinib was 350 mg. At 12 months, in 17 evaluable patients, the mean improvement in Modified Rodnan Skin Score (MRSS) was 7.1 points, reflecting a reduction in skin thickening. The change in average MRSS became more pronounced over time. Skin biopsy showed reduced sclerosis and increased interstitial space. Pulmonary function tests showed a 7.8% improvement in forced vital capacity after 12 months of treatment and an 8.8% improvement in diffusion capacity.
"Imatinib stabilized pulmonary parameters in patients with and without interstitial lung disease," Dr. Gordon said. A smaller proof-of-concept study of 10 patients with active diffuse scleroderma was also reported at ACR 2009. That study failed to show improvement in skin thickening with imatinib and found that patients had difficulty tolerating the drug. Lead author Janet Pope, MD, from St. Joseph's Health Care in London, Ontario, said imatinib was unlikely to be a feasible treatment for early active diffuse scleroderma.
What to Make of Conflicting Results
A scleroderma specialist put these 2 preliminary studies into perspective for Medscape Rheumatology. Monique Hinchcliff, MD, from the Scleroderma Program at Northwestern University School of Medicine in Chicago, Illinois, said: "The effect on skin thickening reported by Gordon et al. is an important finding. Pope et al. found that imatinib 600 mg/day was not well tolerated in patients with diffuse scleroderma and that there was no reduction in skin thickening in patients taking the drug.
Despite these findings, patient- and physician-reported outcomes were the same or improved in 6 patients in the second study. "Some patients felt better on the drug despite the side effects and lack of skin improvement," she explained. "The take-home message from these preliminary studies is that imatinib may be a drug for some people with scleroderma — probably a subset of patients, perhaps with early disease. We need to identify subgroups prospectively that are imatinib responders. Also, we need a bigger study with proper controls powered to show a significant difference between groups," she stated.
Source: American College of Rheumatology (ACR) 2009: Abstract 606 and 608. Presented October 18, 2009; Medscape Medical News