Findings from MAINRITSAN3 trial ’convincing,’ but AEs are an issue

An extra 18 months of rituximab (Rituxan) therapy was linked with lower rates of relapse in patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV) versus standard maintenance therapy, according to the French Vasculitis Study Group.

In the three-center MAINRITSAN3 trial, relapse-free survival (RFS) estimates at month 28 were 96% (95% CI 91%-100%) in the rituximab group and 74% (95% CI 63%-88%) in the placebo group, for an absolute difference of 22% (95% CI 9%-36%), and with a hazard ratio of 7.5 (95% CI 1.67-33.7, P=0.008), reported Loïc Guillevin, MD, of the Hôpital Cochin at Paris Descartes University, and co-authors.

Also at 28 months, major RFS estimates were 100% (95% CI 93% to 100%) in the rituximab group versus 87% (95% CI 78% to 97%, (P=0.009) in the placebo group, they wrote in the Annals of Internal Medicine.

However, at least one serious adverse event (AE) developed in 24% of patients in the rituximab group versus 30% in the placebo group. And more patients in the rituximab experienced infectious serious AEs (12% versus 9%) including septic shock, urinary tract infection, and pneumonia.

AAV “is a serious, life-threatening illness in which there is inflammation of the blood vessels in the body,” according to an AnnalsPatient Summary.” While treatment to remission with glucocorticoids and rituximab has proven successful, AAV relapses are still a problem even after maintenance therapy.

“The authors make a convincing argument that long-term rituximab should be the standard of care for ANCA-associated vasculitis,” noted Gary S. Hoffman, MD, MS, of the Cleveland Clinic, in an editorial accompanying the study.

But given the incidence of serious AEs, a time schedule for what constitutes appropriate “long-term treatment” must be determined, even in a patient population in relatively good shape (in remission; no need for high-dose corticosteroids; rituximab-tolerant), he cautioned.

Hoffman drew particular attention to patients who are at lower risk for relapse, asking “what are the risk-benefit properties of preemptive rituximab treatment versus cautious monitoring for and treatment of early signs of relapse?”

He pointed out that nearly three-fourths of the MAINRITSAN3 control group experienced extended periods of remission after stopping rituximab, while others relapsed within 6 to 12 months after ending treatment.

“Given that ANCA metrics and B-cell reconstitution are not reliable predictors of imminent relapse, what other surrogate markers might guide preemptive treatment?” Hoffman wrote.

The 2014 MAINRITSAN trial demonstrated the superiority of rituximab over azathioprine in maintaining remission and influenced AAV treatment consensus guidelines. The MAINRITSAN2 trial showed no statistically significant difference in AAV relapse rates with individually tailored and fixed-schedule rituximab regimens.

For inclusion in MAINRITSAN3, all patients had to have successfully completed MAINRITSAN2 without any major relapses and be in complete remission, the authors explained.

The third trial’s patient population (mean age 63.9 years; 35% women) consisted of 68 people with granulomatosis with polyangiitis (GPA) and 29 with microscopic polyangiitis (MPA). Among them, 59% had newly diagnosed AAV and 41% had relapsing disease. All patients achieved complete remission after completing an 18-month maintenance regimen. Patients received rituximab or placebo infusion every 6 months for 18 months for a total of four infusions.

The trial’s primary endpoint was RFS at month 28, with relapse defined as “new or reappearing symptoms or worsening disease, with a Birmingham Vasculitis Activity Score [BVAS, version 3] greater than 0,” Guillevin’s group wrote. “Complete remission was defined as a [BVAS] of 0 (score range, 0 to 63, with higher scores indicating more active disease).”

The authors pointed out that patients in MAINRITSAN2 who experienced a minor relapse that was successfully treated only with an increased glucocorticoid dose were eligible for MAINRITSAN3.

Patients started with pre-medication (IV methylprednisolone, dexchlorpheniramine, and acetaminophen) before all rituximab and placebo infusions. They then received an IV 500-mg fixed dose of rituximab (n=50) or placebo (n=47) at randomization and at months 6, 12, and 18.

For the patients who were still getting low-dose prednisone at randomization, the latter was tapered, then stopped or maintained at 5 mg/d, based on the site investigator’s judgment. Finally, pneumocystis jirovecii pneumonia prophylaxis was recommended for all patients, either as daily sulfamethoxazole-trimethoprim or monthly pentamidine aerosolizations.

The authors reported that major RFS was 100% (95% CI 93%-100%) in the rituximab group versus 87% (95% CI 78%-97%) in the placebo group (P=0.009). Half a dozen patients in the latter group had major relapses consisting of three cases of renal flares and three cases of pulmonary flares. All of these patients received a new induction regimen with high-dose glucocorticoids and rituximab, and all subsequently achieved remission. A single patient had permanently impaired renal function but did not require extrarenal dialysis.

Mean Vasculitis Damage Index scores were 2.2 for the rituximab group at inclusion and at month 28, and 1.6 and 1.7, respectively, for the placebo group. Guillevin and co-authors found that the two groups did not differ significantly at the end of the trial for 0.00 difference in mean change from baseline (95% CI 0.12-0.11, P=0.95).

The authors also found that at month 28 30% of the patients in the rituximab group had ANCA positivity versus 56% in the placebo group (P=0.057). “Of note, the ANCA evolution pattern of negative at inclusion but becoming positive’ seemed to be associated with AAV flares: It was observed in 50% of patients who had a relapse versus 15% of those who did not,” they stated.

Additionally, one patient with persistent ANCA negativity had a relapse. No patients with ANCA and CD19+ B-cell negativity had a relapse. In the placebo group, 40% with PR3 ANCA positivity had a relapse versus 12% with MPO ANCA positivity. The authors cautioned that biological parameters were assayed at each participating center.

Other study limitations included the potential risk of selection bias based on results in MAINRITSAN2. Also, “recruitment to MAINRITSAN3 was difficult, because to be eligible, patients must have completed MAINRITSAN2 and been willing to participate in this new randomized trial, possibly receiving the placebo, with a visit every 3 months,” the authors noted.

Guillevin’s group highlighted some take-home messages from the trial:

  • Rituximab should be the new gold standard to maintain remission.
  • A 500-mg dose per infusion is sufficient.
  • Treatment should be prolonged.
  • An individually tailored regimen is feasible.
  1. An additional 18 months of rituximab (Rituxan) infusions was associated with lower rates of relapse compared with standard maintenance therapy in patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV).

  2. At least one serious adverse event (AE) developed in 24% of patients in the rituximab group versus 30% in the placebo group, and more patients in the rituximab had serious AEs, including septic shock, urinary tract infection, and pneumonia.

Shalmali Pal, Contributing Writer, BreakingMED™

The study was funded by the French Ministry of Health and Hoffmann-La Roche, as well as supported by Assistance Publique Hôpitaux de Paris. Hoffmann-La Roche provided rituximab for the study.

Guillevin reported TKTK

Hoffman disclosed no relationships relevant to the contents of this paper.

Cat ID: 914

Topic ID: 74,914,730,914,192,925