WASHINGTON (FRONTLINE MEDICAL NEWS) – Rituximab was superior to azathioprine as maintenance therapy for antineutrophil cytoplasmic antibody–associated vasculitis over long-term follow-up of the MAINRITSAN trial. At 60 months, rituximab significantly improved overall survival and relapse-free survival, compared with azathioprine.

At 60 months, overall survival (OS) rates were 100% for rituximab (Rituxan) versus 93% for azathioprine (P = .045), and relapse-free survival (RFS) rates were 57.9% versus 37.3%, respectively (P = .012).

These long-term maintenance results build on the primary results of MAINRITSAN that were previously published in 2014 ( N Engl J Med. 2014;Nov 6;371[19]:1771-80 ). The primary results showed the superiority of rituximab maintenance therapy versus the then-gold standard azathioprine in maintaining antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV) remission at 28 months following induction therapy with a cyclophosphamide/glucocorticoid regimen.

“Following publication of the primary results, some uncertainties remained as to the duration of remission on rituximab. There is a need for therapy that can prevent relapse over the longer term,” lead author Benjamin Terrier, MD, of the National Referral Center for Rare Systemic Autoimmune Diseases at Cochin Hospital and Paris Descartes University in France, said in his presentation of the long-term follow-up data at the annual meeting of the American College of Rheumatology.

The follow-up results indicate that “over the long term, despite late relapses after the 28-month initial follow-up period, maintenance therapy with rituximab remained significantly superior to azathioprine to maintain remission at 60 months and was associated with better survival,” Dr. Terrier said.

The study included 115 newly diagnosed or relapsing patients with AAV (granulomatosis with polyangiitis, microscopic polyangiitis, or eosinophilic granulomatosis with polyangiitis). Of these, 80% were newly diagnosed. After achieving remission on induction therapy, patients were randomized to rituximab infusion 500 mg on day 1, day 15, and 5.5 months later, then every 6 months for 18 months or to azathioprine for 22 months.

The investigators collected data prospectively on major and minor relapses and adverse events, using a Q-TWIST (Quality Adjusted Time Without Symptoms and Toxicity) analysis to show the trade-off between toxicity and disease activity.

For all relapses, major and minor, rituximab maintained superiority over azathioprine at 60 months. There were 24 events in the rituximab arm: 11 minor relapses and 13 major relapses. There were 36 events in the azathioprine arm: 10 minor relapses, 25 major relapses, and 1 death. Major RFS survival rates were 71.9% versus 49.4%, respectively (P = .003).

“There was an absolute difference of 12 months favoring rituximab for RFS,” Dr. Terrier said.

Serious infections were numerically increased in the rituximab-treated group: 30 compared with 20 in the azathioprine group. Cardiovascular event rates were similar for both groups.

Q-TWIST analysis found significantly longer quality-adjusted time without progression or toxicity in the rituximab arm (P less than .001). The cumulative dose of steroids was comparable between treatment groups.

Six cancers were found in the azathioprine arm (including four skin cancers), compared with two in the rituximab arm.

In the rituximab group, PR3 ANCA positivity or ANCA persistence 12 months after starting rituximab maintenance therapy were associated with higher major relapse rates.

“Combining these two factors allows discerning low relapse rate. Patients negative for ANCA and for PR3 ANCA were at low risk,” Dr. Terrier told the audience. “ANCA monitoring seems to be relevant to guide treatment duration.”

Best rituximab regimen?

A separate study presented at a poster session compared the systemic regimen used in MAINRITSAN (as a control group) versus an experimental regimen of fixed 500-mg rituximab infusions on day 0 post randomization and then every 3 months until month 18, based on ANCA status/titer and/or circulating CD19 B-cell reappearance. The open-label, randomized study included 163 patients with granulomatosis with polyangiitis or microscopic polyangiitis in complete remission after induction therapy with glucocorticoids and cyclophosphamide or rituximab or methotrexate.

At 28 months, the relapse rate was 8% in the control arm and 14% in the experimental arm, a difference that was not statistically significant.

“We found no difference in the primary endpoint of relapse between the two regimens, but the experimental arm received fewer infusions. From this study, we cannot make a strong recommendation for the experimental regimen, but we think it is better, because there is less cumulative exposure to rituximab,” stated lead author Pierre Charles, MD, also of Cochin Hospital.

Both studies were funded by Hoffman-LaRoche. Dr. Terrier and Dr. Charles disclosed financial support from Hoffman-LaRoche.


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