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VBCR - April 2013, Volume 2, No 2 - Drug Update

Rituximab (Rituxan) is the most recent and the only treatment approved by the US Food and Drug Administration (FDA) for antineu­trophil cytoplasmic autoantibody (ANCA)-associated vasculitis, but there is still a role for cyclophosphamide in these diseases, especially in patients with more severe forms, according to several researchers.

Traditional immunosuppressive drugs have improved treatment outcomes for patients with ANCA-associated vasculitis, but the development of biologic agents and a better understanding of the pathogenesis of the disease have contributed to the discovery of rituximab as an effective alternative to the immunosuppressive drug cyclophosphamide.

“This is an exciting period in which we now have 2 options for remission induction for severe GPA [granulomatosis with polyangiitis] and MPA [microscopic polyangiitis],” said Carol Langford, MD, MHS, FACP, Director of the Center for Vasculitis Care and Research, Cleveland Clinic, OH.

Targeting B-Cells Enhances Remission
B lymphocytes have been a target in GPA since cyclophosphamide demonstrated a profound effect on suppressing B-lymphocyte function in patients with the disease, said Ulrich Specks, MD, Professor of Medicine, Mayo Clinic, Rochester, MN. The activity and extent of GPA is directly linked to the frequency of activated peripheral blood B lymphocytes.

Rituximab was approved by the FDA in 2011 for the treatment of patients with GPA or MPA based on the results of the Ri­tuximab for ANCA-Associated Vasculitis (RAVE) study. The study included 197 patients with active, severe GPA or MPA who were randomized to rituximab 375 mg/m2 once weekly for 4 weeks or to oral cyclophosphamide 2 mg/kg daily for 3 to 6 months.

The primary end point was the percentage of patients who achieved clinical remission, defined as a Birmingham Vasculitis Activity Score for Wegener’s granulomatosis of 0 and complete tapering of the prednisone dose at 6 months. In the rituximab group, 64% of the patients achieved the primary end point compared with 53% of the patients in the cyclophosphamide group, which met the criterion for noninferiority, said Dr Specks.

“RAVE demonstrated that rituximab is a proven alternative to cyclophosphamide for induction of remis­sion in patients with severe ANCA- associated vasculitis, which is of particular importance for patients who have a severe disease flare
that requires treatment, and for patients who want to preserve their fertility,” because infertility is a potential side effect of cyclophosphamide, Dr Specks said.

Sustained remission was also equivalent between rituximab and cyclophosphamide in a second randomized controlled trial known as RITUXVAS, an open-label study of 44 patients who were randomized in a 3:1 ratio to rituximab plus 2 infusions of cyclophosphamide or to intravenous (IV) cyclophosphamide for 6 months followed by oral azathioprine. All of the patients were newly diagnosed with ANCA-associated vasculitis at entry; all had severe renal disease; all were, on average, 10 years older than the patients enrolled in the RAVE study; and 25% had received a plasma exchange immediately before randomization.

The primary end point of RITUXVAS, sustained remission at 12 months, was achieved by 76% of the rituximab group versus 82% of the cyclophosphamide group on an intent-to-treat analysis. The RITUXVAS trial demonstrated that over 12 months, a single course of ri­tuximab achieved the same results as a 6-month course of cyclophosphamide followed by azathioprine.
Remission maintenance was again shown to be similar between the 2 strategies in an analysis of the 18-month follow-up of RAVE partici­pants.

Cyclophosphamide Still an Option in Some Cases
Cyclophosphamide is a much better-understood agent now than it was nearly 40 years ago. It continues to have a role in inducing remission in patients with GPA and MPA, particularly in patients who have severe forms of these diseases, Dr Langford explained.
The additional learning experience with cyclophosphamide has led to improved patient outcomes and improved strategies to reduce its side effects. In a German cohort of 445 patients who were observed for 4 decades, mortality rates declined over time, as a result, in part, to the improved use of cy­­­clophosphamide.

Toxicity Profile
The toxicity profile of these agents involves not only acute toxicities, such as infection, bone marrow suppression, and cystitis, “but also long-term complications, including infertility for both men and women, myelodysplasia that can lead to lymphoma and leukemia, and the potential for bladder cancer,” Dr Langford pointed out.

The risk of bladder cancer with cyclophosphamide use is related to the total dose and the duration of the exposure, with a 5% risk at 10 years from the first cyclophosphamide dose, to a 15% risk at 16 years from the first dose.

Improved Treatment
Better use of cyclophosphamide has evolved, Dr Langford said. Strategies by the treatment of ANCA-associated vasculitis is now considered in 2 phases—the induction of remission, followed by maintenance. Azathioprine maintenance after 3 to 6 months of cyclophosphamide therapy maintains remission without increasing the relapse rate. Methotrexate maintenance is similarly as effective as azathioprine in maintaining remission.

Other strategies include limiting the duration of exposure from 3 to 4 months, avoiding its use in nonsevere disease, and using it as prophylaxis for Pneumocystis, as well as for urothelial protection.

Careful Monitoring Recommended
The time to remission is equivalent between intermittent IV dosing and daily oral cyclophosphamide at a median of 3 months; however, intermittent therapy is associated with a higher rate of relapse.

Patients who receive daily therapy, however, have a higher rate of leukopenia, leading to the recommendation that the complete blood count should be monitored every 1 to 2 weeks for the duration of daily therapy.

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