Rituximab at fixed regimen better for long-term remission: Study
Comparison of 18 months of fixed vs. tailored dosing and azathioprine
An 18-month fixed-schedule maintenance regimen of rituximab is better at keeping ANCA-associated vasculitis (AAV) in remission for up to seven years than azathioprine or a rituximab regimen tailored to an individual, according to pooled data from the Phase 3 MAINRITSAN program.
Doubling the length of this fixed-schedule regimen did not further lower patients’ relapse rates over those years, suggesting that “extending RTX [rituximab] from 18 to 36 months should probably only be considered in patients at high risk of relapse, as it does not appear to prevent long-term relapses,” the researchers wrote.
Findings were described in the study “Rituximab as maintenance therapy for ANCA-associated vasculitides: pooled analysis and long-term outcome of 277 patients included in the MAINRITSAN trials,” published in Annals of the Rheumatic Diseases.
MAINRITSAN trials tested rituximab at various dosing regimens
AAV is caused by self-reactive antibodies called ANCAs that lead to inflammation and damage to small blood vessels. As a result, disease symptoms can occur anywhere in the body.
Rituximab, marketed as Rituxan in the U.S., MabThera in Europe, and available as biosimilars, is an antibody AAV treatment that works to reduce the number of B-cells, immune cells that produces antibodies, including those thought to drive this disease.
It is approved for granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), the two most common types of AAV, both as an induction therapy (to bring the disease into remission) and maintenance therapy (to keep the disease in remission).
The Phase 3 Maintenance of Remission using Rituximab in Systemic ANCA-associated Vasculitis (MAINRITSAN) trials tested several rituximab maintenance regimens in AAV patients.
Data from MAINRITSAN (NCT00748644) covered 114 patients and showed that fixed-schedule infusions of 500 mg of rituximab outperformed the immunosuppressant azathioprine, both given over 18 months (about 1.5 years), at keeping AAV in remission for up to five years. The fixed rituximab regimen involved infusions on days zero and 14 and at six, 12, and 18 months, while azathioprine was given daily.
These findings supported rituximab’s U.S. approval for GPA and MPA as a maintenance treatment.
The MAINRITSAN 2 study (NCT01731561), which involved 162 GPA and MPA patients, showed that an individually tailored rituximab regimen — where patients would receive a new rituximab infusion if the number of B-cells or ANCAs increased — did not perform better than the fixed regimen.
In MAINRITSAN 3 (NCT02433522), involving 97 patients in remission at the end of MAINRITSAN 2, an additional four rituximab infusions given over 18 months reduced the risk of relapse or death by 7.5 times relative to a placebo, supporting that prolonging rituximab treatment could benefit patients at high risk of relapse.
“However, the optimal RTX schedule and duration remain unknown, and long-term follow-up of these trials is needed to clarify the long-term risk of relapse, the long-term safety of RTX and thus, the most accurate maintenance strategy,” the researchers, almost all in France, wrote.
Data covered 277 patients, most given rituximab on fixed or tailored schedules
To find which regimen may be best for keeping AAV in remission, they pooled data covering 277 patients who participated in the MAINRITSAN trials. This represented “the largest [group] of AAV patients treated with RTX maintenance therapy in [appropriately controlled] trials to date,” the team wrote.
Most patients were newly diagnosed with AAV (70.8%) and tested positive for ANCAs (81.9%). Nearly three-quarters (73.6%) had GPA, 68 (24.5%) had MPA, and five (1.8%) had renal-limited vasculitis, where inflammation and damage are limited to the kidneys.
A total of 58 patients were treated for 18 months with azathioprine, 97 were given 18 months of a fixed rituximab regimen, and 40 were on a tailored rituximab regimen for 18 months. Among those given an additional 18 months of a fixed rituximab regimen in MAINRITSAN 3, 41 previously were on a fixed schedule and 42 on a tailored schedule of rituximab.
Patients were followed for a median of 73 months, or about six years.
The main goal was time to a first major relapse, defined as disease reappearance or worsening with a Birmingham Vasculitis Activity Score greater than zero — indicating disease activity — and involvement of at least one major organ or a life-threatening manifestation, or both.
A total of 134 patients experienced at least one relapse, for a total of 195 relapses, 102 of which were major. Time to a major relapse was a median 11 months shorter for patients on azathioprine than for those on rituximab (25 vs. 36 months), regardless of the regimen.
After 84 months (about seven years), 49% of azathioprine-treated patients, 70% of those given the 18-month fixed rituximab regimen, 49% of those on the tailored regimen, 83% of patients on a fixed 36-month regimen, and 74% of those on tailored followed by fixed 36-month regimen had no major relapses.
18-month fixed regimen lowered risk of major relapse by 66% vs. tailored one
By that time, the 18-month fixed rituximab regimen significantly reduced the risk of a major relapse by 62% compared with azathioprine, and by 66% relative to the tailored rituximab regimen.
Prolonging the fixed-schedule regimen for another 18 months was not linked to a significantly lower risk of a major or overall relapse compared with an initial 18-month duration.
In terms of safety, azathioprine treatment associated with the highest chance of adverse events, while both azathioprine and the tailored rituximab regimen were linked to the highest rates of serious infections.
A seven-year survival rate was lowest for patients on the 18-month tailored regimen and those who then received an additional 18 months of fixed regimen (85%), and highest for the 18-month fixed regimen group (94%).
“This pooled and long-term analysis of the 277 patients enrolled in the three MAINRITSAN trials shows that the 84-month sustained remission rate in patients with AAV is higher with the 18-month fixed RTX regimen,” the researchers wrote.
They noted that little benefit was seen with extending 18 months of fixed-schedule treatment to 36 months, expect possibly for “patients at high risk of relapse.”
“However, as this study was underpowered to make this comparison, further prospective studies [those following patients over time] are needed to determine the potential long-term benefits of extending treatment in these patients,” the scientists added.
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