Mycophenolate mofetil plus glucocorticoids boosts response in immune thrombocytopenia
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Adding mycophenolate mofetil to a glucocorticoid in first-line treatment for immune thrombocytopenia improves response and decreases the risk for refractory or relapsed disease, according to data.
However, writing in The New England Journal of Medicine, the researchers cautioned that the addition of mycophenolate mofetil may lead to a “somewhat decreased quality of life.”
“First-line immune thrombocytopenia treatment is unsatisfactory but has remained unchanged for decades,” Charlotte A. Bradbury, MD, PhD, of the Bristol Hematology and Oncology Center, University Hospitals Bristol, in the United Kingdom, and colleagues wrote. “Although a small number of studies have tested alternative approaches, a safe, effective, and durable first-line strategy has not been conclusively identified. Therefore, high-dose glucocorticoids continue to be the recommended treatment.”
“Mycophenolate mofetil is widely used in the United Kingdom as a second-line treatment for immune thrombocytopenia and is less expensive than many alternative treatments,” they added. “Although no data from randomized, controlled trials have been published, evidence from retrospective data indicates that mycophenolate mofetil is effective (with response rates of 50% to 80%), although platelet response typically takes 4 to 6 weeks.”
To analyze whether mycophenolate mofetil added to glucocorticoid is more effective as first-line treatment than glucocorticoid alone in patients with immune thrombocytopenia, Bradbury and colleagues conducted the multicenter, open-label, randomized, controlled FLIGHT trial. A total of 120 participants older than 16 years with a primary or secondary diagnosis of immune thrombocytopenia were assigned to receive either glucocorticoid monotherapy or a combination regimen with glucocorticoid and mycophenolate mofetil.
The primary efficacy outcome was treatment failure, defined as a platelet count of less than 30×109 per liter and the start of a second-line treatment, all assessed in a time-to-event analysis. Secondary outcomes included response rates, side effects, bleeding, patient-reported quality-of-life measures and serious adverse events. Follow-up lasted for up to 2 years after the initiation of the trial therapy.
According to the researchers, the mycophenolate mofetil group demonstrated fewer treatment failures — 13 out of 59 participants, or 22% — compared with the monotherapy group — 27 out of 61 participants, or 44% (HR = 0.41; 95% CI, 0.21-0.8). The mycophenolate mofetil group also demonstrated greater response, with 91.5% of patients having platelet counts greater than 100×109 per liter, compared with 63.9% in the glucocorticoid-only cohort (P < .001).
In addition, the researchers found no evidence of a difference between the two groups regarding the occurrence of bleeding, rescue treatments or side effects, including infection. However, participants in the mycophenolate mofetil group did report worse quality-of-life outcomes, regarding physical function and fatigue, than those who received glucocorticoids only.
“As compared with a glucocorticoid-only regimen, treatment with mycophenolate mofetil combined with a glucocorticoid was an effective first-line treatment option, with greater response and less risk of treatment failure and with durable responses over an average of 18 months of follow-up,” Bradbury and colleagues wrote. “Because more than half the patients receiving a glucocorticoid-only regimen had not required second-line treatment during follow-up and because mycophenolate mofetil use may be associated with more fatigue, further research is needed to clarify the role of mycophenolate mofetil in immune thrombocytopenia treatment pathways.”
“For example, mycophenolate mofetil could be used in patients for whom laboratory and clinical markers suggest that a glucocorticoid-only regimen would be expected to fail,” they added. “Early use of mycophenolate mofetil may also be particularly valuable for patients in whom early disease control with avoidance of relapse is a priority, either from the patient’s perspective or on clinical grounds, such as when severe bleeding or additional bleeding risk factors (eg, the patient is receiving anticoagulation or antiplatelet therapy) are present.”
Perspective
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David A. McLain, MD, MACR, FACP, FRCP
Mycophenolic acid (MPA) was first isolated as a fermentation product of Penicillium stoloniferum cultures by Italian scientist Bartolomeo Gozio in 1896. It had antibacterial, antiviral, antifungal, antitumor and immunosuppressive properties. MPA was reformulated as mycophenolate mofetil (MMF) as a “prodrug” because it had enhanced bioavailability, better efficacy, and fewer GI side effects. In 1995, the FDA approved MMF for the prevention of renal, cardiac, and hepatic allograft rejection.
Mycophenolate sodium is also available as an enteric-coated formulation (Myfortic, Novartis). Mycophenolate inhibits production of guanosine nucleotides through inhibition of inosine-5′-monophosphate dehydrogenase (IMPDH). Normally, lymphocyte activation increases IMPDH levels tenfold. T and B lymphocytes are uniquely dependent on the de novo synthesis of guanosine nucleotides, unlike other cell types, which are able to utilize a salvage synthesis pathway. MMF is therefore considered relatively lymphocyte selective compared to other purine antagonists such as azathioprine.
MMF also inhibits the recruitment of leukocytes into foci of inflammation by decreasing lymphocyte and monocyte adhesion to endothelial cells. MMF has been used off-label for lupus nephritis, vasculitis, scleroderma, bullous disorders, immune glomerulonephritis, acute and chronic graft-versus-host disease, prevention of GVH disease, lung transplants, myasthenia gravis, psoriasis, noninfectious uveitis, pulmonary fibrosis, sarcoidosis, multiple sclerosis, Crohn’s disease and others.
This article provides evidence for yet another disease amenable to MMF, although off-label use has been common in rheumatology for years for various diseases. This is a problem for Medicare Part D coverage as Part D plans are prohibited from covering off-label uses unless the indication is supported by one of the Medicare-approved compendia. The ACR was able to add scleroderma to the compendia so that MMF is now covered for Part D plans. To suggest a specific drug/disease pair for future advocacy efforts or with questions, contact practice@rheumatology.org.
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