General toxicity of cyclophosphamide in rheumatic diseases
- Megan B Clowse, MD, MPH
Megan B Clowse, MD, MPH
- Assistant Professor of Medicine
- Duke University Medical Center
- Division of Rheumatology and Immunology
- 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
- 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) is an alkylating agent that was introduced into clinical practice as a chemotherapeutic agent but has also been used to treat a number of systemic autoimmune diseases. It is generally used in cases of life- or organ-threatening rheumatic diseases, such as antineutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitis or systemic lupus erythematosus (SLE) with renal or central nervous system involvement.
CYC is also associated with a variety of toxicities which should lead clinicians to consider less toxic alternative medications whenever possible. While much of our knowledge about the toxicity of CYC has been extrapolated from its use in oncology, there are important differences in dosing and duration of treatment when used to treat rheumatic diseases.
This topic will provide an overview of the mechanism of action and major toxicities associated with CYC use for the treatment of systemic rheumatic diseases. General principles of the use of CYC for rheumatic diseases as well as the pharmacology of the drug are discussed separately. (See "General principles of the use of cyclophosphamide in rheumatic diseases".)
MECHANISM OF ACTION
Alkylating agents exert their biologic activity via covalent binding and crosslinking of a variety of macromolecules including DNA, RNA, and proteins. DNA crosslinking, probably the most important biologic action of these drugs, impairs DNA replication and transcription, ultimately leading either to cell death or to altered cellular function .
The degree of inhibition of immune function is dependent upon the dose and duration of therapy. Alkylating agents are cytotoxic. Absolute lymphopenia is frequently seen following their administration, with reductions in the number of B cells and T cells of both CD4+ and CD8+ types [2,3]. The ratio of circulating T cells and B cells may also be affected .
- Hall AG, Tilby MJ. Mechanisms of action of, and modes of resistance to, alkylating agents used in the treatment of haematological malignancies. Blood Rev 1992; 6:163.
- Clements PJ, Yu DT, Levy J, et al. Effects of cyclophosphamide on B- and T-lymphocytes in rheumatoid arthritis. Arthritis Rheum 1974; 17:347.
- 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.
- Cupps TR, Edgar LC, Fauci AS. Suppression of human B lymphocyte function by cyclophosphamide. J Immunol 1982; 128:2453.
- Contreras G, Pardo V, Leclercq B, et al. Sequential therapies for proliferative lupus nephritis. N Engl J Med 2004; 350:971.
- Jayne D, Rasmussen N, Andrassy K, et al. A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies. N Engl J Med 2003; 349:36.
- Ekhart C, Rodenhuis S, Smits PH, et al. Relations between polymorphisms in drug-metabolising enzymes and toxicity of chemotherapy with cyclophosphamide, thiotepa and carboplatin. Pharmacogenet Genomics 2008; 18:1009.
- Takada K, Arefayene M, Desta Z, et al. Cytochrome P450 pharmacogenetics as a predictor of toxicity and clinical response to pulse cyclophosphamide in lupus nephritis. Arthritis Rheum 2004; 50:2202.
- Mok CC, Ying KY, Ng WL, et al. Long-term outcome of diffuse proliferative lupus glomerulonephritis treated with cyclophosphamide. Am J Med 2006; 119:355.e25.
- de Groot K, Harper L, Jayne DR, et al. Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized trial. Ann Intern Med 2009; 150:670.
- Hoffman GS, Kerr GS, Leavitt RY, et al. Wegener granulomatosis: an analysis of 158 patients. Ann Intern Med 1992; 116:488.
- de Groot K, Adu D, Savage CO, EUVAS (European vasculitis study group). The value of pulse cyclophosphamide in ANCA-associated vasculitis: meta-analysis and critical review. Nephrol Dial Transplant 2001; 16:2018.
- Gourley MF, Austin HA 3rd, Scott D, et al. Methylprednisolone and cyclophosphamide, alone or in combination, in patients with lupus nephritis. A randomized, controlled trial. Ann Intern Med 1996; 125:549.
- 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.
- Huynh-Do U, Gantenbein H, Binswanger U. Pneumocystis carinii pneumonia during immunosuppressive therapy for antineutrophil cytoplasmic autoantibody-positive vasculitis. Arch Intern Med 1995; 155:872.
- Jarrousse B, Guillevin L, Bindi P, et al. Increased risk of Pneumocystis carinii pneumonia in patients with Wegener's granulomatosis. Clin Exp Rheumatol 1993; 11:615.
- Pryor BD, Bologna SG, Kahl LE. Risk factors for serious infection during treatment with cyclophosphamide and high-dose corticosteroids for systemic lupus erythematosus. Arthritis Rheum 1996; 39:1475.
- Austin HA 3rd, Klippel JH, Balow JE, et al. Therapy of lupus nephritis. Controlled trial of prednisone and cytotoxic drugs. N Engl J Med 1986; 314:614.
- Vernovsky I, Dellaripa PF. Pneumocystis carinii pneumonia prophylaxis in patients with rheumatic diseases undergoing immunosuppressive therapy: prealence and associated features. J Clin Rheumatol 2000; 6:94.
- Wung PK, Holbrook JT, Hoffman GS, et al. Herpes zoster in immunocompromised patients: incidence, timing, and risk factors. Am J Med 2005; 118:1416.
- 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.
- 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.
- Rivkees SA, Crawford JD. The relationship of gonadal activity and chemotherapy-induced gonadal damage. JAMA 1988; 259:2123.
- Watson AR, Taylor J, Rance CP, Bain J. Gonadal function in women treated with cyclophosphamide for childhood nephrotic syndrome: a long-term follow-up study. Fertil Steril 1986; 46:331.
- Wang CL, Wang F, Bosco JJ. Ovarian failure in oral cyclophosphamide treatment for systemic lupus erythematosus. Lupus 1995; 4:11.
- Huong DL, Amoura Z, Duhaut P, et al. Risk of ovarian failure and fertility after intravenous cyclophosphamide. A study in 84 patients. J Rheumatol 2002; 29:2571.
- Clowse ME, Copland SC, Hsieh TC, et al. Ovarian reserve diminished by oral cyclophosphamide therapy for granulomatosis with polyangiitis (Wegener's). Arthritis Care Res (Hoboken) 2011; 63:1777.
- Ramsey-Goldman R, Mientus JM, Kutzer JE, et al. Pregnancy outcome in women with systemic lupus erythematosus treated with immunosuppressive drugs. J Rheumatol 1993; 20:1152.
- Alarfaj AS, Khalil N. Fertility, ovarian failure, and pregnancy outcome in SLE patients treated with intravenous cyclophosphamide in Saudi Arabia. Clin Rheumatol 2014; 33:1731.
- Watson AR, Rance CP, Bain J. Long term effects of cyclophosphamide on testicular function. Br Med J (Clin Res Ed) 1985; 291:1457.
- Guesry P, Lenoir G, Broyer M. Gonadal effects of chlorambucil given to prepubertal and pubertal boys for nephrotic syndrome. J Pediatr 1978; 92:299.
- Fukutani K, Ishida H, Shinohara M, et al. Suppression of spermatogenesis in patients with Behçet's disease treated with cyclophosphamide and colchicine. Fertil Steril 1981; 36:76.
- Bogdanović R, Banićević M, Cvorić A. Testicular function following cyclophosphamide treatment for childhood nephrotic syndrome: long-term follow-up study. Pediatr Nephrol 1990; 4:451.
- Hoorweg-Nijman JJ, Delemarre-van de Waal HA, de Waal FC, Behrendt H. Cyclophosphamide-induced disturbance of gonadotropin secretion manifesting testicular damage. Acta Endocrinol (Copenh) 1992; 126:143.
- Kirshon B, Wasserstrum N, Willis R, et al. Teratogenic effects of first-trimester cyclophosphamide therapy. Obstet Gynecol 1988; 72:462.
- Murray CL, Reichert JA, Anderson J, Twiggs LB. Multimodal cancer therapy for breast cancer in the first trimester of pregnancy. A case report. JAMA 1984; 252:2607.
- Wiebe VJ, Sipila PE. Pharmacology of antineoplastic agents in pregnancy. Crit Rev Oncol Hematol 1994; 16:75.
- Clowse ME, Magder L, Petri M. Cyclophosphamide for lupus during pregnancy. Lupus 2005; 14:593.
- Enns GM, Roeder E, Chan RT, et al. Apparent cyclophosphamide (cytoxan) embryopathy: a distinct phenotype? Am J Med Genet 1999; 86:237.
- Vaux KK, Kahole NC, Jones KL. Cyclophosphamide, methotrexate, and cytarabine embropathy: is apoptosis the common pathway? Birth Defects Res A Clin Mol Teratol 2003; 67:403.
- Paladini D, Vassallo M, D'Armiento MR, et al. Prenatal detection of multiple fetal anomalies following inadvertent exposure to cyclophosphamide in the first trimester of pregnancy. Birth Defects Res A Clin Mol Teratol 2004; 70:99.
- Paskulin GA, Gazzola Zen PR, de Camargo Pinto LL, et al. Combined chemotherapy and teratogenicity. Birth Defects Res A Clin Mol Teratol 2005; 73:634.
- Zemlickis D, Lishner M, Erlich R, Koren G. Teratogenicity and carcinogenicity in a twin exposed in utero to cyclophosphamide. Teratog Carcinog Mutagen 1993; 13:139.
- Berry DL, Theriault RL, Holmes FA, et al. Management of breast cancer during pregnancy using a standardized protocol. J Clin Oncol 1999; 17:855.
- Kart Köseoglu H, Yücel AE, Künefeci G, et al. Cyclophosphamide therapy in a serious case of lupus nephritis during pregnancy. Lupus 2001; 10:818.
- Trasler JM, Hales BF, Robaire B. Paternal cyclophosphamide treatment of rats causes fetal loss and malformations without affecting male fertility. Nature 1985; 316:144.
- Tolchin SF, Winkelstein A, Rodnan GP, et al. Chromosome abnormalities from cyclophosphamide therapy in rheumatoid arthritis and progressive systemic sclerosis (scleroderma). Arthritis Rheum 1974; 17:375.
- Russell JA, Powles RL, Oliver RT. Conception and congenital abnormalities after chemotherapy of acute myelogenous leukaemia in two men. Br Med J 1976; 1:1508.
- Lohrmann HP. The problem of permanent bone marrow damage after cytotoxic drug treatment. Oncology 1984; 41:180.
- Vasquez S, Kavanaugh AF, Schneider NR, et al. Acute nonlymphocytic leukemia after treatment of systemic lupus erythematosus with immunosuppressive agents. J Rheumatol 1992; 19:1625.
- Radis CD, Kahl LE, Baker GL, et al. Effects of cyclophosphamide on the development of malignancy and on long-term survival of patients with rheumatoid arthritis. A 20-year followup study. Arthritis Rheum 1995; 38:1120.
- Bernatsky S, Clarke AE, Suissa S. Hematologic malignant neoplasms after drug exposure in rheumatoid arthritis. Arch Intern Med 2008; 168:378.
- Reinhold-Keller E, Beuge N, Latza U, et al. An interdisciplinary approach to the care of patients with Wegener's granulomatosis: long-term outcome in 155 patients. Arthritis Rheum 2000; 43:1021.
- 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.
- Talar-Williams C, Hijazi YM, Walther MM, et al. Cyclophosphamide-induced cystitis and bladder cancer in patients with Wegener granulomatosis. Ann Intern Med 1996; 124:477.
- Stillwell TJ, Benson RC Jr, DeRemee RA, et al. Cyclophosphamide-induced bladder toxicity in Wegener's granulomatosis. Arthritis Rheum 1988; 31:465.
- Bedi A, Miller CB, Hanson JL, et al. Association of BK virus with failure of prophylaxis against hemorrhagic cystitis following bone marrow transplantation. J Clin Oncol 1995; 13:1103.
- Gupta N, Lawrence RM, Nguyen C, Modica RF. Review article: BK virus in systemic lupus erythematosus. Pediatr Rheumatol Online J 2015; 13:34.
- Umeda M, Ichinose K, Okada A, et al. A rare case of hemorrhagic cystitis complicated with thrombocytopenia and hemophagocytic syndrome associated with BK virus, under immunosuppressive treatment of systemic lupus erythematosus. Mod Rheumatol 2016; 26:467.
- Baker GL, Kahl LE, Zee BC, et al. Malignancy following treatment of rheumatoid arthritis with cyclophosphamide. Long-term case-control follow-up study. Am J Med 1987; 83:1.
- Fernandes ET, Manivel JC, Reddy PK, Ercole CJ. Cyclophosphamide associated bladder cancer--a highly aggressive disease: analysis of 12 cases. J Urol 1996; 156:1931.
- Bressler RB, Huston DP. Water intoxication following moderate-dose intravenous cyclophosphamide. Arch Intern Med 1985; 145:548.
- Salido M, Macarron P, Hernández-García C, et al. Water intoxication induced by low-dose cyclophosphamide in two patients with systemic lupus erythematosus. Lupus 2003; 12:636.
- Spital A, Ristow S. Cyclophosphamide induced water intoxication in a woman with Sjögren's syndrome. J Rheumatol 1997; 24:2473.
- Lee YC, Park JS, Lee CH, et al. Hyponatraemia induced by low-dose intravenous pulse cyclophosphamide. Nephrol Dial Transplant 2010; 25:1520.
- Singh G, Fries JF, Williams CA, et al. Toxicity profiles of disease modifying antirheumatic drugs in rheumatoid arthritis. J Rheumatol 1991; 18:188.
- Subramaniam SR, Cader RA, Mohd R, et al. Low-dose cyclophosphamide-induced acute hepatotoxicity. Am J Case Rep 2013; 14:345.
- Garas G, Crawford GP, Cain M. Anaphylactic reaction to intravenous cyclophosphamide. Aust N Z J Med 1995; 25:59.