Alkylating Agents

  • Debra A. Goldstein
  • Kara C. LaMattina


The alkylating agents cyclophosphamide and chlorambucil have been utilized in medicine for over 50 years. As our knowledge about the pharmacokinetics of these agents has grown, treatment regimens have evolved. While alkylating agents have been shown to be highly effective in the treatment of ocular inflammation, their use has been limited by the risks of serious side effects including sterility and malignancy. They remain an important tool in the arsenal of treatments, however, particularly in the case of sight-threatening disease.


Alkylating agents Chlorambucil Cyclophosphamide Behçet disease Scleritis Sympathetic ophthalmia Serpiginous choroiditis Malignancy Sterility Premature ovarian failure 


  1. 1.
    Gilman A, Philips FS. The biological actions and therapeutic applications of the B-chloroethyl amines and sulfides. Science. 1946;103(2675):409–15.PubMedCrossRefGoogle Scholar
  2. 2.
    Goodman LS, Brunton LL, Chabner B, Knollmann BC. Goodman & Gilman’s the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill; 2011. xvi, 2084 p.Google Scholar
  3. 3.
    Roda E. Uveitis treated with nitrogen mustard. Am J Ophthalmol. 1952;35(1):114.PubMedCrossRefGoogle Scholar
  4. 4.
    Lacki JK, Schochat T, Sobieska M, Leszczynski P, Wiktorowicz K, Mackiewicz U, et al. Immunological studies in patients with rheumatoid arthritis treated with methotrexate or cyclophosphamide. Z Rheumatol. 1994;53(2):76–82.PubMedGoogle Scholar
  5. 5.
    Fauci AS, Wolff SM, Johnson JS. Effect of cyclophosphamide upon the immune response in Wegener’s granulomatosis. N Engl J Med. 1971;285(27):1493–6.PubMedCrossRefGoogle Scholar
  6. 6.
    Bagley CM Jr, Bostick FW, DeVita VT Jr. Clinical pharmacology of cyclophosphamide. Cancer Res. 1973;33(2):226–33.PubMedGoogle Scholar
  7. 7.
    Katzung BG, Trevor AJ. Basic & clinical pharmacology. New York: McGraw-Hill Education LLC; 2015. Available from: Connect to full text.
  8. 8.
    Dinant HJ, Decker JL, Klippel JH, Balow JE, Plotz PH, Steinberg AD. Alternative modes of cyclophosphamide and azathioprine therapy in lupus nephritis. Ann Intern Med. 1982;96(6 Pt 1):728–36.PubMedCrossRefGoogle Scholar
  9. 9.
    Eiser AR, Grishman E, Dreznin S. Intravenous pulse cyclophosphamide in the treatment of type IV lupus nephritis. Clin Nephrol. 1993;40(3):155–9.PubMedGoogle Scholar
  10. 10.
    Jampol LM, West C, Goldberg MF. Therapy of scleritis with cytotoxic agents. Am J Ophthalmol. 1978;86(2):266–71.PubMedCrossRefGoogle Scholar
  11. 11.
    Jabs DA, Mudun A, Dunn JP, Marsh MJ. Episcleritis and scleritis: clinical features and treatment results. Am J Ophthalmol. 2000;130(4):469–76.PubMedCrossRefGoogle Scholar
  12. 12.
    Pujari SS, Kempen JH, Newcomb CW, Gangaputra S, Daniel E, Suhler EB, et al. Cyclophosphamide for ocular inflammatory diseases. Ophthalmology. 2010;117(2):356–65.PubMedCrossRefGoogle Scholar
  13. 13.
    Durrani K, Papaliodis GN, Foster CS. Pulse IV cyclophosphamide in ocular inflammatory disease: efficacy and short-term safety. Ophthalmology. 2004;111(5):960–5.PubMedCrossRefGoogle Scholar
  14. 14.
    Khan IJ, Barry RJ, Amissah-Arthur KN, Carruthers D, Elamanchi SR, Situnayake D, et al. Ten-year experience of pulsed intravenous cyclophosphamide and methylprednisolone protocol (PICM protocol) in severe ocular inflammatory disease. Br J Ophthalmol. 2013;97(9):1118–22.PubMedCrossRefGoogle Scholar
  15. 15.
    Akpek EK, Jabs DA, Tessler HH, Joondeph BC, Foster CS. Successful treatment of serpiginous choroiditis with alkylating agents. Ophthalmology. 2002;109(8):1506–13.PubMedCrossRefGoogle Scholar
  16. 16.
    Hoffman GS, Kerr GS, Leavitt RY, Hallahan CW, Lebovics RS, Travis WD, et al. Wegener granulomatosis: an analysis of 158 patients. Ann Intern Med. 1992;116(6):488–98.PubMedCrossRefGoogle Scholar
  17. 17.
    Blumenfeld Z, Avivi I, Linn S, Epelbaum R, Ben-Shahar M, Haim N. Prevention of irreversible chemotherapy-induced ovarian damage in young women with lymphoma by a gonadotrophin-releasing hormone agonist in parallel to chemotherapy. Hum Reprod. 1996;11(8):1620–6.PubMedCrossRefGoogle Scholar
  18. 18.
    Blumenfeld Z, Shapiro D, Shteinberg M, Avivi I, Nahir M. Preservation of fertility and ovarian function and minimizing gonadotoxicity in young women with systemic lupus erythematosus treated by chemotherapy. Lupus. 2000;9(6):401–5.PubMedCrossRefGoogle Scholar
  19. 19.
    Koyama H, Wada T, Nishizawa Y, Iwanaga T, Aoki Y. Cyclophosphamide-induced ovarian failure and its therapeutic significance in patients with breast cancer. Cancer. 1977;39(4):1403–9.PubMedCrossRefGoogle Scholar
  20. 20.
    Mok CC, Lau CS, Wong RW. Risk factors for ovarian failure in patients with systemic lupus erythematosus receiving cyclophosphamide therapy. Arthritis Rheum. 1998;41(5):831–7.PubMedCrossRefGoogle Scholar
  21. 21.
    Meistrich ML, Wilson G, Brown BW, da Cunha MF, Lipshultz LI. Impact of cyclophosphamide on long-term reduction in sperm count in men treated with combination chemotherapy for Ewing and soft tissue sarcomas. Cancer. 1992;70(11):2703–12.PubMedCrossRefGoogle Scholar
  22. 22.
    Martin F, Lauwerys B, Lefebvre C, Devogelaer JP, Houssiau FA. Side-effects of intravenous cyclophosphamide pulse therapy. Lupus. 1997;6(3):254–7.PubMedCrossRefGoogle Scholar
  23. 23.
    Radis CD, Kahl LE, Baker GL, Wasko MC, Cash JM, Gallatin A, 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(8):1120–7.PubMedCrossRefGoogle Scholar
  24. 24.
    Kirshon B, Wasserstrum N, Willis R, Herman GE, McCabe ER. Teratogenic effects of first-trimester cyclophosphamide therapy. Obstet Gynecol. 1988;72(3 Pt 2):462–4.PubMedGoogle Scholar
  25. 25.
    Gebhardt DO. The embryo lethal and teratogenic effects of cyclophosphamide on mouse embryos. Teratology. 1970;3(3):273–7.PubMedCrossRefGoogle Scholar
  26. 26.
    McLean A, Newell D, Baker G, Connors T. The metabolism of chlorambucil. Biochem Pharmacol. 1980;29(14):2039–47.PubMedCrossRefGoogle Scholar
  27. 27.
    Palmer RG, Dore CJ, Denman AM. Chlorambucil-induced chromosome damage to human lymphocytes is dose-dependent and cumulative. Lancet. 1984;1(8371):246–9.PubMedCrossRefGoogle Scholar
  28. 28.
    Tessler HH, Jennings T. High-dose short-term chlorambucil for intractable sympathetic ophthalmia and Behcet’s disease. Br J Ophthalmol. 1990;74(6):353–7.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Goldstein DA, Fontanilla FA, Kaul S, Sahin O, Tessler HH. Long-term follow-up of patients treated with short-term high-dose chlorambucil for sight-threatening ocular inflammation. Ophthalmology. 2002;109(2):370–7.PubMedCrossRefGoogle Scholar
  30. 30.
    Patel SS, Dodds EM, Echandi LV, Couto CA, Schlaen A, Tessler HH, et al. Long-term, drug-free remission of sympathetic ophthalmia with high-dose, short-term chlorambucil therapy. Ophthalmology. 2014;121(2):596–602.PubMedCrossRefGoogle Scholar
  31. 31.
    Mamo JG, Azzam SA. Treatment of Behcet’s disease with chlorambucil. Arch Ophthalmol. 1970;84(4):446–50.PubMedCrossRefGoogle Scholar
  32. 32.
    Abdalla MI, el DBN. Long-lasting remission of Behcet’s disease after chlorambucil therapy. Br J Ophthalmol. 1973;57(9):706–11.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Godfrey WA, Epstein WV, O’Connor GR, Kimura SJ, Hogan MJ, Nozik RA. The use of chlorambucil in intractable idiopathic uveitis. Am J Ophthalmol. 1974;78(3):415–28.PubMedCrossRefGoogle Scholar
  34. 34.
    Elliott JH, Ballinger WH. Behcet’s syndrome: treatment with chlorambucil. Trans Am Ophthalmol Soc. 1984;82:264–81.PubMedPubMedCentralGoogle Scholar
  35. 35.
    Miserocchi E, Baltatzis S, Ekong A, Roque M, Foster CS. Efficacy and safety of chlorambucil in intractable noninfectious uveitis: the Massachusetts Eye and Ear Infirmary experience. Ophthalmology. 2002;109(1):137–42.PubMedCrossRefGoogle Scholar
  36. 36.
    Mudun BA, Ergen A, Ipcioglu SU, Burumcek EY, Durlu Y, Arslan MO. Short-term chlorambucil for refractory uveitis in Behcet’s disease. Ocul Immunol Inflamm. 2001;9(4):219–29.PubMedCrossRefGoogle Scholar
  37. 37.
    O’Duffy JD, Robertson DM, Goldstein NP. Chlorambucil in the treatment of uveitis and meningoencephalitis of Behcet’s disease. Am J Med. 1984;76(1):75–84.PubMedCrossRefGoogle Scholar
  38. 38.
    Guesry P, Lenoir G, Broyer M. Gonadal effects of chlorambucil given to prepubertal and pubertal boys for nephrotic syndrome. J Pediatr. 1978;92(2):299–303.PubMedCrossRefGoogle Scholar
  39. 39.
    Reeves BR, Casey G, Harris H, Dinning WJ. Long-term cytogenetic follow-up study of patients with uveitis treated with chlorambucil. Carcinogenesis. 1985;6(11):1615–9.PubMedCrossRefGoogle Scholar
  40. 40.
    Morrison VA, Rai KR, Peterson BL, Kolitz JE, Elias L, Appelbaum FR, et al. Therapy-related myeloid leukemias are observed in patients with chronic lymphocytic leukemia after treatment with fludarabine and chlorambucil: results of an intergroup study, cancer and leukemia group B 9011. J Clin Oncol. 2002;20(18):3878–84.PubMedCrossRefGoogle Scholar
  41. 41.
    Birnbaum AD, Oh F, Sahin O, Little DM, Tessler HH, Goldstein DA. Chlorambucil and malignancy. Ophthalmology. 2010;117(7):1466–e1.PubMedCrossRefGoogle Scholar
  42. 42.
    Shotton D, Monie IW. Possible teratogenic effect of chlorambucil on a human fetus. JAMA. 1963;186:74–5.PubMedCrossRefGoogle Scholar
  43. 43.
    Salder TW, Kochhar DM. Teratogenic effects of chlorambucil on in vivo and in vitro organogenesis in mice. Teratology. 1975;12(1):71–8.PubMedCrossRefGoogle Scholar
  44. 44.
    Murphy ML. A comparison of the teratogenic effects of five polyfunctional alkylating agents on the rat fetus. Pediatrics. 1959;23(1 Part 2):231–44.PubMedGoogle Scholar
  45. 45.
    Diwo E, Gueudry J, Saadoun D, Weschler B, LeHoang P, Bodaghi B. Long-term efficacy of interferon in severe uveitis associated with Behcet disease. Ocul Immunol Inflamm. 2017;25(1):76–84.PubMedCrossRefGoogle Scholar
  46. 46.
    Deuter C, Stubiger N, Zierhut M. Interferon-alpha therapy in noninfectious uveitis. Dev Ophthalmol. 2012;51:90–7.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Debra A. Goldstein
    • 1
  • Kara C. LaMattina
    • 2
  1. 1.Department of OphthalmologyNorthwestern University Feinberg School of MedicineChicagoUSA
  2. 2.Department of OphthalmologyBoston University School of MedicineBostonUSA

Personalised recommendations