Dr. Langford said that she personally feels more comfortable using cyclophosphamide in patients excluded from the RAVE trial—that is, those with rapidly progressive glomerulonephritis with creatinine of more than 4.0 mg/dL and those with alveolar hemorrhage requiring mechanical ventilation.
Other Potential Indications for Cyclophosphamide
Drs. Langford and Specks agreed that cyclophosphamide has a primary role for treatment in patients with adverse events specific to rituximab or those who fail rituximab, which, according to Dr. Specks, is quite rare.
Dr. Langford also emphasized that she thinks patients with newly diagnosed severe disease who do not have an absolute contraindication to cyclophosphamide should be given cyclophosphamide as an option. For these patients, she suggested that both agents offer a benefit–risk profile that will appeal differently to different patients.
She noted that one advantage of cyclophosphamide is its established efficacy over 40 years of experience. “We understand this agent very well and can provide patients with detailed information regarding its efficacy, its toxicity, and strategies as to how to optimally use it,” she said, emphasizing that dosing strategies are available to minimize or prevent the known side effects that can affect fertility in men and women, blood counts, and cause bladder toxicity. For example, she said that these side effects can be reduced or prevented by limiting the duration of treatment to three to four months but no more than six consecutive months.
Some patients, she said, will feel more comfortable receiving cyclophosphamide based on this extensive body of experience, while other patients will prefer the overall side-effect profile of rituximab despite some unanswered questions, such as the long-term treatment-related toxicities as well as the diverse infectious consequences of immunosuppression.
She emphasized that time is needed to understand the full picture of rituximab. “Our experience with cyclophosphamide taught us that toxicities can take time to develop and recognize and that refinement of how to optimally use the agent also requires longer term experience and investigation,” she cautioned.
Dr. Specks also highlighted the need for caution when using rituximab because it is an immunosuppressive agent, but emphasized that the overall infection risk seems similar to that of carefully monitored cyclophosphamide treatment followed by azathiprine. He also said that rituximab has no long-term risks to fertility or known long-term malignancy risk, but emphasized that the RAVE trial was not designed to address these issues.
Mary Beth Nierengarten is a freelance medical journalist based in St. Paul, Minn.
