Rituximab and Cyclophosphamide: A Tale of Two Treatments

Posted by Rena Xu • July 14th, 2010

This week, the Journal publishes two research reports comparing the efficacy of rituximab to cyclophosphamide for treating anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, a serious autoimmune disorder in which blood vessel walls are attacked by antibodies that target neutrophil cytoplasmic antigens.

Cyclophosphamide, an alkylating agent with potent immunosuppressive activity, has been the mainstay of therapy for ANCA-associated vasculitis. Cyclophosphamide is usually effective but has a range of severe side effects, including leukopenia, thrombocytopenia, hemorrhagic cystitis, infections, and later, cancer and infertility. These adverse events have provided a powerful incentive to identify a similarly effective but safer alternative to replace cyclophosphamide in long-term treatment regimens.

This week’s research reports ask whether rituximab might be such an alternative. Rituximab is a B-cell-depleting anti-CD20 monoclonal antibody, currently approved by the FDA for treating non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, and rheumatoid arthritis.

The Rituxivas trial, reported by Jones et al., investigated whether patients newly diagnosed with ANCA-associated vasculitis had a better treatment response and fewer severe adverse events with a rituximab-based regimen as compared with a cyclophosphamide-based regimen. The authors’ hope was “that a rituximab-based regimen might be more effective and safer.” Instead, they observed that rituximab was not superior to cyclophosphamide in treating ANCA-associated renal vasculitis. The two regimens produced similarly high remission rates; unfortunately, they also had similarly high rates of adverse events.

The Rave trial, reported by Stone et al., chose disease remission at six months as the primary endpoint and suggested that rituximab was not inferior to cyclophosphamide for remission induction. In fact, the authors concluded that rituximab might work better than cyclophosphamide among patients with relapsing disease. Still, there was no real difference observed in the rates of adverse events between patients on rituximab and patients on cyclophosphamide. Dr. Ronald Falk and Dr. J. Charles Jennette of the University of North Carolina Kidney Center pointed out in an accompanying editorial that this finding is somewhat troublesome, considering that the trial used oral cyclophosphamide instead of the generally less-toxic intravenous form.

These two trials had a few important differences in design. First, they differed in whether the patients assigned to the rituximab treatment group also received cyclophosphamide: they did in the Rituxivas trial, but not in the Rave trial. Second, the trials differed in the length of follow up; the Rituxivas trial reported data on sustained remission for 12 months, whereas the Rave trial only reported to 6 months.

Taken together, the studies are noteworthy for their complementary perspectives on the use of rituximab, a relatively new therapy about which there still isn’t much literature. Of the Journal’s decision to publish the reports, NEJM deputy editor Dr. Julie Ingelfinger stated, “These papers represent important contributions to the clinical understanding about a disease associated with high morbidity and mortality. They offer potentially useful insight into whether – and under what circumstances – rituximab should be used.”

At the same time, many physicians will want more answers. The editorial by Dr. Falk and Dr. Jennette stated, “The unanswered question is whether anti-B cell therapy will importantly alter the immunopathogenetic process, permitting the cessation or diminution in remission maintenance therapy.”

Do you currently use rituximab in your clinical practice? Do the findings reported in these studies surprise you? Will they influence your treatment choices going forward?

One Response to “Rituximab and Cyclophosphamide: A Tale of Two Treatments”

  1. As a nephrologist, I thought that Rituximab might have answered the calling of being benign in many of the diseases we treat. These trials both showed that the adverse events in the rituximab arms were very similar to the non rituximab arms. But I believe this is mainly due to the net immunosuppresion they received in that arm. The rituximab arms also got cyclophosphamide. This combination might lead to more infections as your net immunosuppresion is at the highest rate.
    Besides, the benefit we thought rituximab might offer in terms of attacking the B “effector” cells might be limited due to its effect perhaps on B “regulatory” cells as well and inhibiting B regulatory function as well.

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