General principles of the use of cyclophosphamide in rheumatic diseases
- W. Joseph McCune, MD, MACR
W. Joseph McCune, MD, MACR
- Michael H and Marcia S Klein Professor of Rheumatic Diseases
- Associate Chief, Division of Rheumatology
- Director, Lupus Program
- University of Michigan
- Megan B Clowse, MD, MPH
Megan B Clowse, MD, MPH
- Assistant Professor of Medicine
- Duke University Medical Center
- Division of Rheumatology and Immunology
- Section Editor
- Daniel E Furst, MD
Daniel E Furst, MD
- Section Editor — Treatment Issues in Rheumatology
- Clinical professor, University of Washington, Seattle
- Clinical professor, University of Florence, Florence, Italy
- Professor of Rheumatology, University of California in Los Angeles (Emeritus)
- Director of Research, Pacific Arthritis Associates
Cyclophosphamide (CYC), an alkylating agent, is one of the most potent immunosuppressive therapies available. It has been used extensively to treat severe manifestations of a variety of autoimmune and inflammatory diseases. Examples include organ-threatening manifestations of rheumatic diseases such as systemic lupus erythematosus (SLE), granulomatosis with polyangiitis (GPA; Wegener’s), microscopic polyangiitis (MPA), polyarteritis nodosa, eosinophilic granulomatosis with polyangiitis (EGPA; Churg-Strauss syndrome), Behçet’s syndrome, primary angiitis of the central nervous system, and isolated vasculitic neuropathy.
It is a prodrug that is converted to its active form in the liver and, to a lesser extent, in other organs. It can be administered either orally or intravenously. Oral administration usually corresponds to daily dosing and intravenous use to intermittent dosing (eg, every two to four weeks), but some exceptions exist. For example, extremely ill patients who are unable to ingest medications orally may receive daily doses of CYC via the intravenous route at the same doses they would otherwise receive orally.
Although very effective, CYC has the potential for devastating toxicity both in the short and long term (even after the medication has been stopped). Concerns about such drug toxicity, especially malignancy, have restricted its use to patients with the most severe disease. Newer, short-term protocols using significantly reduced cumulative doses of CYC have reduced, but not eliminated, associated risks.
Two major aims govern the use of CYC:
●Prompt control of the underlying disease, to limit the extent and severity of damage
- Wiernik PH, Duncan JH. Cyclophosphamide in human milk. Lancet 1971; 1:912.
- Regan MJ, Hellmann DB, Stone JH. Treatment of Wegener's granulomatosis. Rheum Dis Clin North Am 2001; 27:863.
- Haubitz M, Bohnenstengel F, Brunkhorst R, et al. Cyclophosphamide pharmacokinetics and dose requirements in patients with renal insufficiency. Kidney Int 2002; 61:1495.
- Koren G, Carey N, Gagnon R, et al. Cancer chemotherapy and pregnancy. J Obstet Gynaecol Can 2013; 35:263.
- de Jonge ME, Huitema AD, Rodenhuis S, Beijnen JH. Clinical pharmacokinetics of cyclophosphamide. Clin Pharmacokinet 2005; 44:1135.
- Donelli MG, Bartosek I, Guaitani A, et al. Importance of pharmacokinetic studies on cyclophosphamide (NSC-26271) in understanding its cytotoxic effect. Cancer Treat Rep 1976; 60:395.
- Bingham S, Emery P. Renal toxicity of antirheumatic drugs. In: Rheumatology and the Kidney, Adu D, Emery P, Madaio M (Eds), Oxford University Press, 2001. p.445.
- Koseoglu V, Chiang J, Chan KW. Acquired pseudocholinesterase deficiency after high-dose cyclophosphamide. Bone Marrow Transplant 1999; 24:1367.
- Vigouroux D, Voltaire L. [Prolonged neuromuscular block induced by mivacurium in a patient treated with cyclophosphamide]. Ann Fr Anesth Reanim 1995; 14:508.
- Walker IR, Zapf PW, Mackay IR. Cyclophosphamide, cholinesterase and anaesthesia. Aust N Z J Med 1972; 2:247.
- Allopurinol and cytotoxic drugs. Interaction in relation to bone marrow depression. Boston Collaborative Drug Surveillance Program. JAMA 1974; 227:1036.
- Witten J, Frederiksen PL, Mouridsen HT. The pharmacokinetics of cyclophosphamide in man after treatment with allopurinol. Acta Pharmacol Toxicol (Copenh) 1980; 46:392.
- Stolbach L, Begg C, Bennett JM, et al. Evaluation of bone marrow toxic reaction in patients treated with allopurinol. JAMA 1982; 247:334.
- Balow JE, Austin HA 3rd, Tsokos GC, et al. NIH conference. Lupus nephritis. Ann Intern Med 1987; 106:79.
- Boumpas DT, Austin HA 3rd, Vaughan EM, et al. Risk for sustained amenorrhea in patients with systemic lupus erythematosus receiving intermittent pulse cyclophosphamide therapy. Ann Intern Med 1993; 119:366.
- Koyama H, Wada T, Nishizawa Y, et al. Cyclophosphamide-induced ovarian failure and its therapeutic significance in patients with breast cancer. Cancer 1977; 39:1403.
- Houssiau FA, Vasconcelos C, D'Cruz D, et al. Immunosuppressive therapy in lupus nephritis: the Euro-Lupus Nephritis Trial, a randomized trial of low-dose versus high-dose intravenous cyclophosphamide. Arthritis Rheum 2002; 46:2121.
- Tam LS, Chan PK, Ho SC, et al. Risk factors for squamous intraepithelial lesions in systemic lupus erythematosus: a prospective cohort study. Arthritis Care Res (Hoboken) 2011; 63:269.
- Zard E, Arnaud L, Mathian A, et al. Increased risk of high grade cervical squamous intraepithelial lesions in systemic lupus erythematosus: A meta-analysis of the literature. Autoimmun Rev 2014; 13:730.
- Ognenovski VM, Marder W, Somers EC, et al. Increased incidence of cervical intraepithelial neoplasia in women with systemic lupus erythematosus treated with intravenous cyclophosphamide. J Rheumatol 2004; 31:1763.
- Stern A, Green H, Paul M, et al. Prophylaxis for Pneumocystis pneumonia (PCP) in non-HIV immunocompromised patients. Cochrane Database Syst Rev 2014; :CD005590.
- Sakurai M, Saijo N, Shinkai T, et al. The protective effect of 2-mercapto-ethane sulfonate (MESNA) on hemorrhagic cystitis induced by high-dose ifosfamide treatment tested by a randomized crossover trial. Jpn J Clin Oncol 1986; 16:153.
- Fukuoka M, Negoro S, Masuda N, et al. Placebo-controlled double-blind comparative study on the preventive efficacy of mesna against ifosfamide-induced urinary disorders. J Cancer Res Clin Oncol 1991; 117:473.
- Vose JM, Reed EC, Pippert GC, et al. Mesna compared with continuous bladder irrigation as uroprotection during high-dose chemotherapy and transplantation: a randomized trial. J Clin Oncol 1993; 11:1306.
- Monach PA, Arnold LM, Merkel PA. Incidence and prevention of bladder toxicity from cyclophosphamide in the treatment of rheumatic diseases: a data-driven review. Arthritis Rheum 2010; 62:9.
- Payne H, Adamson A, Bahl A, et al. Chemical- and radiation-induced haemorrhagic cystitis: current treatments and challenges. BJU Int 2013; 112:885.
- Yilmaz N, Emmungil H, Gucenmez S, et al. Incidence of Cyclophosphamide-induced Urotoxicity and Protective Effect of Mesna in Rheumatic Diseases. J Rheumatol 2015; 42:1661.
- Zonzits E, Aberer W, Tappeiner G. Drug eruptions from mesna. After cyclophosphamide treatment of patients with systemic lupus erythematosus and dermatomyositis. Arch Dermatol 1992; 128:80.
- Knysak DJ, McLean JA, Solomon WR, et al. Immediate hypersensitivity reaction to cyclophosphamide. Arthritis Rheum 1994; 37:1101.
- Griggs JJ, Mangu PB, Anderson H, et al. Appropriate chemotherapy dosing for obese adult patients with cancer: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol 2012; 30:1553.
- McCune WJ, Golbus J, Zeldes W, et al. Clinical and immunologic effects of monthly administration of intravenous cyclophosphamide in severe systemic lupus erythematosus. N Engl J Med 1988; 318:1423.
- Aronoff GR, Bennett WM, Berns JS, et al. Drug Prescribing in Renal Failure: Dosing Guidelines for Adults and Children, 5th, American College of Physicians, Philadelphia 2007. p.97.
- Boumpas DT, Austin HA 3rd, Vaughn EM, et al. Controlled trial of pulse methylprednisolone versus two regimens of pulse cyclophosphamide in severe lupus nephritis. Lancet 1992; 340:741.
- Lidsky MD, Sharp JT, Billings S. Double-blind study of cyclophosphamide in rheumatoid arthritis. Arthritis Rheum 1973; 16:148.
- Stofer-Vogel B, Cerny T, Borner M, Lauterburg BH. Oral bioavailability of mesna tablets. Cancer Chemother Pharmacol 1993; 32:78.
- Inadequate contraception
- Active infection
- Prior history of hemorrhagic cystitis
- PRETREATMENT EVALUATION
- Drug interactions
- - Infertility risk
- - Contraception
- Laboratory and clinical testing
- Prophylaxis for Pneumocystis jirovecii pneumonia infection
- Prevention of drug-induced cystitis
- Immunization requirements
- INTERMITTENT (PULSE) CYCLOPHOSPHAMIDE
- Drug dose of intermittent CYC
- Administration of intermittent CYC
- Monitoring of intermittent CYC
- DAILY ORAL CYCLOPHOSPHAMIDE
- Drug dose for oral CYC
- Administration of oral CYC
- Monitoring of oral CYC dosing
- CYCLOPHOSPHAMIDE IN THE INTENSIVE CARE UNIT
- SUMMARY AND RECOMMENDATIONS