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Trial backs rituximab for maintenance of ANCA-associated vasculitis remission

Publish date: November 5, 2014

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A first step in determining utility for maintenance therapy

A number of issues need to be considered in interpreting this trial. The doses of rituximab used for remission maintenance were lower than what is often used in patients with other autoimmune diseases treated with rituximab, including rheumatoid arthritis. It has recently been shown that lower doses can be acceptable in those other conditions as well. In this study, that lower dose seemed effective in patients with ANCA-associated vasculitis.
The azathioprine “remission maintenance” dose used in this trial was somewhat lower than is often traditionally used in clinical practice, where 2 mg/kg per day is often utilized for a longer duration than what was used here, which conceivably could have contributed to more flares in the azathioprine group.

Dr. Robert F. Spiera

It is also very important to note that all of these patients were treated with cyclophosphamide as their “remission induction” therapy. Whether these results would be similar in patients treated with rituximab as their remission induction therapy cannot be assumed.

Moreover, it was not demonstrated that rituximab was safer than azathioprine or better tolerated, and the significant cost discrepancies between these two strategies are substantial.

Finally, the primary endpoint of this trial was at 28 months. If we recognize the possibility of even later relapses and a strategy of continued retreatment with rituximab is used, it cannot necessarily be gleaned from this trial what the duration of treatment should be.

However, this study is the first to suggest superiority of rituximab as a remission maintenance therapy over traditional immunosuppressives, including azathioprine (and by extrapolation, methotrexate) in patients with severe ANCA-associated vasculitis.

There are many other possible approaches to dosing and timing of dosing of rituximab in patients with ANCA-associated vasculitis in terms of defining the optimal “remission maintenance” regimen. Ultimately, it also may be that less frequent dosing may be feasible in some patients. In this trial as well as in the previously reported RAVE and RITUXIVAS trials, relapses were infrequent in patients treated with rituximab whose B cells were still depleted, so it may be feasible to use less algorithmic strategies in terms of the timing of retreatment and instead personalize retreatment based on the timing of reconstitution of B cells, particularly in conjunction with rises in ANCA titer. Fine tuning the optimal use of these medications will be defined in further clinical studies, many of which are already ongoing or in planning stages.

Dr. Robert F. Spiera is director of the Vasculitis and Scleroderma Program at the Hospital for Special Surgery in New York. He has received research grants from Roche/Genentech.

FROM THE NEW ENGLAND JOURNAL OF MEDICINE

References

Infusions of rituximab proved superior to the standard of care, daily oral azathioprine, at maintaining remission of ANCA-associated vasculitis in a randomized trial.

At final follow-up after 28 months, the rate of major relapse was 5% for rituximab, compared with 29% for standard azathioprine maintenance. Rates of severe adverse events were similar in the two study groups, Dr. Loic Guillevin of Hôpital Cochin, Paris, and his associates reported in the New England Journal of Medicine.

Despite the decrease in major relapse rate with rituximab and no increase in the rate of severe adverse events, Dr. David Jayne wrote in an editorial accompanying the report that these still remain worrisome, and patients will still require prolonged observation after rituximab withdrawal. The duration of follow-up after the last rituximab dose was short in this study at only 10 months, and previous research indicates that at least half of patients will relapse after a 2-year maintenance course of the drug. Thus, the long-term risk of relapse also requires prolonged patient observation, said Dr. Jayne of the University of Cambridge (England) (N. Engl. J. Med. 2014;371:1839-40).

Dr. Guillevin and his colleagues performed the trial because maintenance of remission is still “a major challenge” in these patients, and serial rituximab infusions have not been thoroughly assessed in prospective studies. They chose to study a relatively low 500-mg dose of the drug. That dose is “lower than that used for induction or maintenance in other conditions, such as rheumatoid arthritis. We opted for this dose because enrolled patients were in remission – that is, already B-cell depleted – and with the aim of limiting the risk of infection,” they wrote.

The study participants were 115 adults who had granulomatosis with polyangiitis (87 patients), microscopic polyangiitis (23 patients), or renal-limited antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (5 patients) and were in complete remission after combined therapy using glucocorticoids plus pulsed cyclophosphamide. They were randomly assigned to receive either the experimental therapy of rituximab infusions at days 0 and 14 and at 6-month intervals for 18 months (57 patients) or the control therapy of azathioprine at 2 mg/kg per day for 12 months, then 1.5 mg/kg per day for 6 months, and finally 1 mg/kg per day for 4 months (58 patients). All patients also further tapered their prednisone dose, which was then kept low at about 5 mg/day for 18 months.

These participants were followed until month 28, which was 10 months after completing rituximab infusions or 6 months after completing oral azathioprine. The primary endpoint of the study – the percentage of patients who experienced a major relapse until the end of follow-up – was 5% for rituximab, which was significantly better than the 29% in the control group (hazard ratio, 6.61; 95% confidence interval, 1.56-27.96; P = .002). The number needed to treat with rituximab rather than azathioprine to avoid a major relapse was only 4, Dr. Guillevin and his associates reported (N. Engl. J. Med. 2014;371:1771-80).

Six patients (11%) who received rituximab and nine (16%) who received azathioprine had minor relapses.

There were no significant differences between the two groups in decreases in total immunoglobulin, IgG, or IgM levels. A total of 25 patients in each group developed at least one severe adverse event. Severe adverse infections developed in 11 patients who received rituximab (19%) and in 8 in the control group (14%). Cancers developed in one patient on rituximab and in two in the control group. There were two patient deaths, both in the control group: one from sepsis and one from pancreatic cancer.

This trial was supported by the French Ministry of Health. Hoffmann-La Roche provided rituximab for the study. Dr. Guillevin reported serving on an advisory board for GlaxoSmithKline and receiving lecture fees from Roche, Actelion, and other companies. His associates reported ties to numerous industry sources. Dr. Jayne reported ties to Sanofi/Genzyme, Roche/Genentech, and other companies.

Trial backs rituximab for maintenance of ANCA-associated vasculitis remission

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