What is the role of cyclophosphamide in the treatment of granulomatosis with polyangiitis (GPA)?

Updated: Oct 09, 2019
  • Author: Christopher L Tracy, MD; Chief Editor: Herbert S Diamond, MD  more...
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Generalized or severe disease generally requires aggressive therapy. Since introduced by Fauci et al in the 1970s, oral cyclophosphamide in combination with high-dose glucocorticoids (ie, prednisone 1mg/kg/day) has been the criterion standard for induction of remission in AAV.

Eventually, intravenous cyclophosphamide was investigated as an alternative to oral cyclophosphamide in an effort to decrease treatment-associated toxicities, and, while the emphasis has been placed on optimizing treatment by minimizing exposure to cyclophosphamide and seeking alternative comparable therapies, the combination of cyclophosphamide (intravenous or oral) and glucocorticoids remained the recommended therapy for induction of remission in generalized/severe GPA for years. [4]

In 2011, however, the US Food and Drug Administration (FDA) approved the use of rituximab (a monoclonal antibody that targets B cells), in combination with glucocorticoids, as an alternative to cyclophosphamide for induction of remission in AAV (GPA and microscopic polyangiitis).

Cyclophosphamide can be given either by a daily oral route or intermittent intravenous route in combination with high-dose glucocorticoids. The recommended daily oral dose of cyclophosphamide is 2 mg/kg/day (not to exceed 200 mg/day). Pulsed (intravenous) cyclophosphamide (15 mg/kg every 2 weeks for the first 3 pulses, then every 3 weeks for the next 3-6 pulses) is an alternative to daily oral cyclophosphamide; it results in less cumulative exposure to cyclophosphamide and, therefore, theoretically causes fewer adverse effects.

Pulsed cyclophosphamide has been shown to be as effective as daily oral cyclophosphamide in inducing remission. [58] A study found, however, that there was a trend toward higher relapse rates with pulsed cyclophosphamide later in the maintenance phase of treatment. Nonetheless, this study was not intended to detect a difference between the 2 groups; more studies are needed. [4, 58]

Cyclophosphamide doses are reduced as needed for renal function and age. Cyclophosphamide therapy is usually continued until significant disease improvement or remission occurs, typically 3-6 months. The patient is then transitioned to a less toxic medication for maintenance of remission. Cyclophosphamide toxicity manifests as hemorrhagic cystitis (in 15-43% of cases after oral treatment), bladder cancer (30-fold increased incidence as compared with controls), increased risk of other malignancies, cytopenias, infertility, and opportunistic infections, typically occurring during cyclophosphamide-induced leukopenia.

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