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Cyclophosphamide and cancer: golden anniversary

Nature Reviews Clinical Oncology volume 6, pages 638–647 (2009)Cite this article

Abstract

Cyclophosphamide remains one of the most successful and widely utilized antineoplastic drugs. Moreover, it is also a potent immunosuppressive agent and the most commonly used drug in blood and marrow transplantation (BMT). It was initially synthesized to selectively target cancer cells, although the hypothesized mechanism of tumor specificity (activation by cancer cell phosphamidases) transpired to be irrelevant to its activity. Nevertheless, cyclophosphamide's unique metabolism and inactivation by aldehyde dehydrogenase is responsible for its distinct cytotoxic properties. Differential cellular expression of aldehyde dehydrogenase has an effect on the anticancer therapeutic index and immunosuppressive properties of cyclophosphamide. This Review highlights the chemistry, pharmacology, clinical toxic effects and current clinical applications of cyclophosphamide in cancer and autoimmune disorders. We also discuss the development of high-dose cyclophosphamide for BMT and the treatment of autoimmune diseases.

Key Points

  • Cyclophosphamide is an inactive prodrug that requires enzymatic and chemical activation; the resultant nitrogen mustard produces the interstrand and intrastrand DNA crosslinks that account for its cytotoxic properties

  • The major mechanism of cyclophosphamide detoxification involves aldehyde dehydrogenase; cells with high proliferative potential express high levels of aldehyde dehydrogenase and as a consequence are relatively resistant to cyclophosphamide

  • Cyclophosphamide, in combination with other antineoplastic agents, is used for the treatment of various cancers, including breast, lymphoid and pediatric malignancies

  • Cyclophosphamide is also widely used in bone marrow transplantation 'conditioning' and 'mobilization' regimens, and for the treatment of different autoimmune conditions

  • The toxic effects of cyclophosphamide include bone marrow suppression, cardiac and gonadal toxicity, hemorrhagic cystitis and carcinogenesis, with cumulative dose being the principal risk factor

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Figure 1: Formation of aziridinium ion from nitrogen mustard and its DNA alkylating activity.
Figure 2: The metabolic pathway of cyclophosphamide.
Figure 3: Differential sensitivities between hematopoietic stem cells and lymphocytes to cyclophosphamide's cytotoxic effect.

References

  1. Brock, N. & Wilmanns, H. Effect of a cyclic nitrogen mustard-phosphamidester on experimentally induced tumors in rats; chemotherapeutic effect and pharmacological properties of B518 ASTA [German]. Dtsch. Med. Wochenschr. 83, 453–458 (1958).

    Article  CAS  PubMed  Google Scholar 

  2. Gross, R. & Wulf, G. Klinische und experimentelle Erfahrungen mit zyk lischen und nichtzyklischen Phosphamidestern des N-Losl in der Chemotherapie von Tumoren [German]. Strahlentherapie 41, 361–367 (1959).

    Google Scholar 

  3. Friedman, O. M. & Seligman, A. M. Preparation of N-phosphorylated derivatives of bis-P-chloroethylamine. J. Amer. Chem. Soc. 76, 655–658 (1954).

    Article  CAS  Google Scholar 

  4. Arnold, H., Bourseaux, F. & Brock, N. Chemotherapeutic action of a cyclic nitrogen mustard phosphamide ester (B 518-ASTA) in experimental tumours of the rat. Nature 181, 931 (1958).

    Article  CAS  PubMed  Google Scholar 

  5. Dong, Q. et al. A structural basis for a phosphoramide mustard-induced DNA interstrand cross-link at 5'-d(GAC). Proc. Natl Acad. Sci. USA 92, 12170–12174 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Boddy, A. V. & Yule, S. M. Metabolism and pharmacokinetics of oxazaphosphorines. Clin. Pharmacokinet. 38, 291–304 (2000).

    Article  CAS  PubMed  Google Scholar 

  7. Chen, T. L. et al. Nonlinear pharmacokinetics of cyclophosphamide and 4-hydroxycyclophosphamide/aldophosphamide in patients with metastatic breast cancer receiving high-dose chemotherapy followed by autologous bone marrow transplantation. Drug Metab. Dispos. 25, 544–551 (1997).

    CAS  PubMed  Google Scholar 

  8. Silverman, R. B. The Organic Chemistry of Enzyme-catalyzed Reactions (Academic Press, 2002).

    Google Scholar 

  9. Russo, J. E., Hilton, J. & Colvin, O. M. The role of aldehyde dehydrogenase isozymes in cellular resistance to the alkylating agent cyclophosphamide. Prog. Clin. Biol. Res. 290, 65–79 (1989).

    CAS  PubMed  Google Scholar 

  10. Joqueviel, C. et al. Urinary excretion of cyclophosphamide in humans, determined by phosphorus-31 nuclear magnetic resonance spectroscopy. Drug Metab. Dispos. 26, 418–428 (1998).

    CAS  PubMed  Google Scholar 

  11. Duester, G. Genetic dissection of retinoid dehydrogenases. Chem. Biol. Interact. 130–132, 469–480 (2001).

    Article  PubMed  Google Scholar 

  12. Sladek, N. E., Kollander, R., Sreerama, L. & Kiang, D. T. Cellular levels of aldehyde dehydrogenases (ALDH1A1 and ALDH3A1) as predictors of therapeutic responses to cyclophosphamide-based chemotherapy of breast cancer: a retrospective study. Rational individualization of oxazaphosphorine-based cancer chemotherapeutic regimens. Cancer Chemother. Pharmacol. 49, 309–321 (2002).

    Article  CAS  PubMed  Google Scholar 

  13. Jones, R. J. et al. Assessment of aldehyde dehydrogenase in viable cells. Blood 85, 2742–2746 (1995).

    Article  CAS  PubMed  Google Scholar 

  14. Gordon, M. Y., Goldman, J. M. & Gordon-Smith, E. C. 4-Hydroperoxycyclophosphamide inhibits proliferation by human granulocyte-macrophage colony-forming cells (GM-CFC) but spares more primitive progenitor cells. Leuk. Res. 9, 1017–1021 (1985).

    Article  CAS  PubMed  Google Scholar 

  15. Ozer, H., Cowens, J. W., Colvin, M., Nussbaum-Blumenson, A. & Sheedy, D. In vitro effects of 4-hydroperoxycyclophosphamide on human immunoregulatory T subset function. I. Selective effects on lymphocyte function in T–B cell collaboration. J. Exp. Med. 155, 276–290 (1982).

    Article  CAS  PubMed  Google Scholar 

  16. Santos, G. W. et al. The use of cyclophosphamide for clinical marrow transplantation. Transplant. Proc. 4, 559–564 (1972).

    CAS  PubMed  Google Scholar 

  17. Sharkis, S. J., Santos, G. W. & Colvin, M. Elimination of acute myelogenous leukemic cells from marrow and tumor suspensions in the rat with 4-hydroperoxycyclophosphamide. Blood 55, 521–523 (1980).

    Article  CAS  PubMed  Google Scholar 

  18. Jones, R. J. Purging with 4-hydroperoxycyclophosphamide. J. Hematother. 1, 343–348 (1992).

    Article  CAS  PubMed  Google Scholar 

  19. Sladek, N. E. Leukemic cell insensitivity to cyclophosphamide and other oxazaphosphorines mediated by aldehyde dehydrogenase(s). Cancer Treat. Res. 112, 161–175 (2002).

    Article  CAS  PubMed  Google Scholar 

  20. Tanner, B. et al. Glutathione, glutathione S-transferase alpha and pi, and aldehyde dehydrogenase content in relationship to drug resistance in ovarian cancer. Gynecol. Oncol. 65, 54–62 (1997).

    Article  CAS  PubMed  Google Scholar 

  21. Banker, D. E., Groudine, M., Norwood, T. & Appelbaum, F. R. Measurement of spontaneous and therapeutic agent-induced apoptosis with BCL-2 protein expression in acute myeloid leukemia. Blood 89, 243–255 (1997).

    Article  CAS  PubMed  Google Scholar 

  22. Zhang, J., Tian, Q., Chan, S. Y., Duan, W. & Zhou, S. Insights into oxazaphosphorine resistance and possible approaches to its circumvention. Drug Resist. Updat. 8, 271–297 (2005).

    Article  CAS  PubMed  Google Scholar 

  23. Ayash, L. J. et al. Cyclophosphamide pharmacokinetics: correlation with cardiac toxicity and tumor response. J. Clin. Oncol. 10, 995–1000 (1992).

    Article  CAS  PubMed  Google Scholar 

  24. Slattery, J. T. et al. Conditioning regimen-dependent disposition of cyclophosphamide and hydroxycyclophosphamide in human marrow transplantation patients. J. Clin. Oncol. 14, 1484–1494 (1996).

    Article  CAS  PubMed  Google Scholar 

  25. Nieto, Y. et al. Nonpredictable pharmacokinetic behavior of high-dose cyclophosphamide in combination with cisplatin and 1,3-bis(2-chloroethyl)-1-nitrosourea. Clin. Cancer Res. 5, 747–751 (1999).

    CAS  PubMed  Google Scholar 

  26. Anderson, L. W. et al. Cyclophosphamide and 4-hydroxycyclophosphamide/aldophosphamide kinetics in patients receiving high-dose cyclophosphamide chemotherapy. Clin. Cancer Res. 2, 1481–1487 (1996).

    CAS  PubMed  Google Scholar 

  27. Chen, T. L. et al. Nonlinear pharmacokinetics of cyclophosphamide in patients with metastatic breast cancer receiving high-dose chemotherapy followed by autologous bone marrow transplantation. Cancer Res. 55, 810–816 (1995).

    CAS  PubMed  Google Scholar 

  28. Busse, D. et al. Dose escalation of cyclophosphamide in patients with breast cancer: consequences for pharmacokinetics and metabolism. J. Clin. Oncol. 15, 1885–1896 (1997).

    Article  CAS  PubMed  Google Scholar 

  29. Forrester, L. M. et al. Relative expression of cytochrome P450 isoenzymes in human liver and association with the metabolism of drugs and xenobiotics. Biochem. J. 281, 359–368 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Gilbert, C. J. et al. Pharmacokinetic interaction between ondansetron and cyclophosphamide during high-dose chemotherapy for breast cancer. Cancer Chemother. Pharmacol. 42, 497–503 (1998).

    Article  CAS  PubMed  Google Scholar 

  31. Williams, M. L. et al. Enantioselective induction of cyclophosphamide metabolism by phenytoin. Chirality 11, 569–574 (1999).

    Article  CAS  PubMed  Google Scholar 

  32. Deeg, H. J. et al. Marrow graft rejection and veno-occlusive disease of the liver in patients with aplastic anemia conditioned with cyclophosphamide and cyclosporine. Transplantation 42, 497–501 (1986).

    Article  CAS  PubMed  Google Scholar 

  33. Hassan, M. et al. The effect of busulphan on the pharmacokinetics of cyclophosphamide and its 4-hydroxy metabolite: time interval influence on therapeutic efficacy and therapy-related toxicity. Bone Marrow Transplant. 25, 915–924 (2000).

    Article  CAS  PubMed  Google Scholar 

  34. Chang, T. K., Yu, L., Maurel, P. & Waxman, D. J. Enhanced cyclophosphamide and ifosfamide activation in primary human hepatocyte cultures: response to cytochrome P-450 inducers and autoinduction by oxazaphosphorines. Cancer Res. 57, 1946–1954 (1997).

    CAS  PubMed  Google Scholar 

  35. Tosi, P. et al. Safety of autologous hematopoietic stem cell transplantation in patients with multiple myeloma and chronic renal failure. Leukemia 14, 1310–1313 (2000).

    Article  CAS  PubMed  Google Scholar 

  36. Haubitz, M. et al. Cyclophosphamide pharmacokinetics and dose requirements in patients with renal insufficiency. Kidney Int. 61, 1495–1501 (2002).

    Article  CAS  PubMed  Google Scholar 

  37. Brodsky, R. A., Chen, A. R., Brodsky, I. & Jones, R. J. High-dose cyclophosphamide as salvage therapy for severe aplastic anemia. Exp. Hematol. 32, 435–440 (2004).

    Article  CAS  PubMed  Google Scholar 

  38. Dussan, K. B., Magder, L., Brodsky, R. A., Jones, R. J. & Petri, M. High dose cyclophosphamide performs better than monthly dose cyclophosphamide in quality of life measures. Lupus 17, 1079–1085 (2008).

    Article  CAS  PubMed  Google Scholar 

  39. Murdych, T. & Weisdorf, D. J. Serious cardiac complications during bone marrow transplantation at the University of Minnesota, 1977–1997. Bone Marrow Transplant. 28, 283–287 (2001).

    Article  CAS  PubMed  Google Scholar 

  40. Cazin, B. et al. Cardiac complications after bone marrow transplantation. A report on a series of 63 consecutive transplantations. Cancer 57, 2061–2069 (1986).

    Article  CAS  PubMed  Google Scholar 

  41. Hertenstein, B. et al. Cardiac toxicity of bone marrow transplantation: predictive value of cardiologic evaluation before transplant. J. Clin. Oncol. 12, 998–1004 (1994).

    Article  CAS  PubMed  Google Scholar 

  42. Watson, A. R., Rance, C. P. & Bain, J. Long term effects of cyclophosphamide on testicular function. Br. Med. J. (Clin. Res. Ed.) 291, 1457–1460 (1985).

    Article  CAS  Google Scholar 

  43. Boumpas, D. T. et al. Risk for sustained amenorrhea in patients with systemic lupus erythematosus receiving intermittent pulse cyclophosphamide therapy. Ann. Intern. Med. 119, 366–369 (1993).

    Article  CAS  PubMed  Google Scholar 

  44. Sanders, J. E. et al. Ovarian function following marrow transplantation for aplastic anemia or leukemia. J. Clin. Oncol. 6, 813–818 (1988).

    Article  CAS  PubMed  Google Scholar 

  45. Cigni, A. et al. Hormonal strategies for fertility preservation in patients receiving cyclophosphamide to treat glomerulonephritis: a nonrandomized trial and review of the literature. Am. J. Kidney Dis. 52, 887–896 (2008).

    Article  CAS  PubMed  Google Scholar 

  46. Dooley, M. A. & Nair, R. Therapy Insight: preserving fertility in cyclophosphamide-treated patients with rheumatic disease. Nat. Clin. Pract. Rheumatol. 4, 250–257 (2008).

    Article  CAS  PubMed  Google Scholar 

  47. Stillwell, T. J. & Benson, R. C. Jr Cyclophosphamide-induced hemorrhagic cystitis. A review of 100 patients. Cancer 61, 451–457 (1988).

    Article  CAS  PubMed  Google Scholar 

  48. Cox, P. J. Cyclophosphamide cystitis—identification of acrolein as the causative agent. Biochem. Pharmacol. 28, 2045–2049 (1979).

    Article  CAS  PubMed  Google Scholar 

  49. Haselberger, M. B. & Schwinghammer, T. L. Efficacy of mesna for prevention of hemorrhagic cystitis after high-dose cyclophosphamide therapy. Ann. Pharmacother. 29, 918–921 (1995).

    Article  CAS  PubMed  Google Scholar 

  50. Bedi, A. et al. Association of BK virus with failure of prophylaxis against hemorrhagic cystitis following bone marrow transplantation. J. Clin. Oncol. 13, 1103–1109 (1995).

    Article  CAS  PubMed  Google Scholar 

  51. Apperley, J. F. et al. Late-onset hemorrhagic cystitis associated with urinary excretion of polyomaviruses after bone marrow transplantation. Transplantation 43, 108–112 (1987).

    Article  CAS  PubMed  Google Scholar 

  52. Miyamura, K. et al. Adenovirus-induced late onset hemorrhagic cystitis following allogeneic bone marrow transplantation. Bone Marrow Transplant. 2, 109–110 (1987).

    CAS  PubMed  Google Scholar 

  53. Knowles, W. A. Discovery and epidemiology of the human polyomaviruses BK virus (BKV) and JC virus (JCV). Adv. Exp. Med. Biol. 577, 19–45 (2006).

    Article  CAS  PubMed  Google Scholar 

  54. Blume, K. G. et al. Total body irradiation and high-dose etoposide: a new preparatory regimen for bone marrow transplantation in patients with advanced hematologic malignancies. Blood 69, 1015–1020 (1987).

    Article  CAS  PubMed  Google Scholar 

  55. Kondo, M., Kojima, S., Kato, K. & Matsuyama, T. Late-onset hemorrhagic cystitis after hematopoietic stem cell transplantation in children. Bone Marrow Transplant. 22, 995–998 (1998).

    Article  CAS  PubMed  Google Scholar 

  56. Yamamoto, R. et al. Late hemorrhagic cystitis after reduced-intensity hematopoietic stem cell transplantation (RIST). Bone Marrow Transplant. 32, 1089–1095 (2003).

    Article  CAS  PubMed  Google Scholar 

  57. Stillwell, T. J., Benson, R. C. Jr, DeRemee, R. A., McDonald, T. J. & Weiland, L. H. Cyclophosphamide-induced bladder toxicity in Wegener's granulomatosis. Arthritis Rheum. 31, 465–470 (1988).

    Article  CAS  PubMed  Google Scholar 

  58. Kempen, J. H. et al. Long-term risk of malignancy among patients treated with immunosuppressive agents for ocular inflammation: a critical assessment of the evidence. Am. J. Ophthalmol. 146, 802–812 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Vlaovic, P. & Jewett, M. A. Cyclophosphamide-induced bladder cancer. Can. J. Urol. 6, 745–748 (1999).

    PubMed  Google Scholar 

  60. Levine, E. G. & Bloomfield, C. D. Leukemias and myelodysplastic syndromes secondary to drug, radiation, and environmental exposure. Semin. Oncol. 19, 47–84 (1992).

    CAS  PubMed  Google Scholar 

  61. Stone, R. M. Myelodysplastic syndrome after autologous transplantation for lymphoma: the price of progress. Blood 83, 3437–3440 (1994).

    Article  CAS  PubMed  Google Scholar 

  62. Jayachandran, N. V., Chandrasekhara, P. K., Thomas, J., Agrawal, S. & Narsimulu, G. Cyclophosphamide-associated complications: we need to be aware of SIADH and central pontine myelinolysis. Rheumatology (Oxford) 48, 89–90 (2008).

    Article  Google Scholar 

  63. Magrath, I. et al. Adults and children with small non-cleaved-cell lymphoma have a similar excellent outcome when treated with the same chemotherapy regimen. J. Clin. Oncol. 14, 925–934 (1996).

    Article  CAS  PubMed  Google Scholar 

  64. Burkitt, D. Long-term remissions following one and two-dose chemotherapy for African lymphoma. Cancer 20, 756–759 (1967).

    Article  CAS  PubMed  Google Scholar 

  65. Fisher, R. I. et al. Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin's lymphoma. N. Engl. J. Med. 328, 1002–1006 (1993).

    Article  CAS  PubMed  Google Scholar 

  66. Keating, M. J. et al. Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. J. Clin. Oncol. 23, 4079–4088 (2005).

    Article  CAS  PubMed  Google Scholar 

  67. Wierda, W. et al. Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab for relapsed and refractory chronic lymphocytic leukemia. J. Clin. Oncol. 23, 4070–4078 (2005).

    Article  CAS  PubMed  Google Scholar 

  68. Lamanna, N. et al. Pentostatin, cyclophosphamide, and rituximab is an active, well-tolerated regimen for patients with previously treated chronic lymphocytic leukemia. J. Clin. Oncol. 24, 1575–1581 (2006).

    Article  CAS  PubMed  Google Scholar 

  69. Kay, N. E. et al. Cyclophosphamide remains an important component of treatment in CLL patients receiving pentostatin and rituximab based chemoimmunotherapy. Blood 112, 43 (2008).

    Article  Google Scholar 

  70. Gokbuget, N. & Hoelzer, D. Treatment of adult acute lymphoblastic leukemia. Semin. Hematol. 46, 64–75 (2009).

    Article  PubMed  Google Scholar 

  71. Fisher, B. et al. Two months of doxorubicin-cyclophosphamide with and without interval reinduction therapy compared with 6 months of cyclophosphamide, methotrexate, and fluorouracil in positive-node breast cancer patients with tamoxifen-nonresponsive tumors: results from the National Surgical Adjuvant Breast and Bowel Project B-15. J. Clin. Oncol. 8, 1483–1496 (1990).

    Article  CAS  PubMed  Google Scholar 

  72. Fisher, B. et al. Tamoxifen and chemotherapy for axillary node-negative, estrogen receptor-negative breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-23. J. Clin. Oncol. 19, 931–942 (2001).

    Article  CAS  PubMed  Google Scholar 

  73. Mamounas, E. P. et al. Paclitaxel after doxorubicin plus cyclophosphamide as adjuvant chemotherapy for node-positive breast cancer: results from NSABP B-28. J. Clin. Oncol. 23, 3686–3696 (2005).

    Article  CAS  PubMed  Google Scholar 

  74. Jones, S. et al. Extended follow-up and analysis by age of the US Oncology Adjuvant Trial 9735: docetaxel/cyclophosphamide is associated with an overall survival benefit compared to doxorubicin/cyclophoshamide and is well tolerated in women 65 or older [abstract]. San Antonio Breast Cancer Symposium a12 (2007).

  75. Martin, M. et al. Adjuvant docetaxel for node-positive breast cancer. N. Engl. J. Med. 352, 2302–2313 (2005).

    Article  CAS  PubMed  Google Scholar 

  76. McGuire, W. P. et al. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N. Engl. J. Med. 334, 1–6 (1996).

    Article  CAS  PubMed  Google Scholar 

  77. Piccart, M. J. et al. Randomized intergroup trial of cisplatin–paclitaxel versus cisplatin–cyclophosphamide in women with advanced epithelial ovarian cancer: three-year results. J. Natl Cancer Inst. 92, 699–708 (2000).

    Article  CAS  PubMed  Google Scholar 

  78. International Collaborative Ovarian Neoplasm Group. Paclitaxel plus carboplatin versus standard chemotherapy with either single-agent carboplatin or cyclophosphamide, doxorubicin, and cisplatin in women with ovarian cancer: the ICON3 randomised trial. Lancet 360, 505–515 (2002).

  79. Slayton, R. E. et al. Vincristine, dactinomycin, and cyclophosphamide in the treatment of malignant germ cell tumors of the ovary. A Gynecologic Oncology Group Study (a final report). Cancer 56, 243–248 (1985).

    Article  CAS  PubMed  Google Scholar 

  80. Rubie, H. et al. Localised and unresectable neuroblastoma in infants: excellent outcome with primary chemotherapy. Neuroblastoma Study Group, Societe Francaise d'Oncologie Pediatrique. Med. Pediatr. Oncol. 36, 247–250 (2001).

    Article  CAS  PubMed  Google Scholar 

  81. Sandberg, J. S., Owens, A. H. Jr & Santos, G. W. Clinical and pathologic characteristics of graft-versus-host disease produced in cyclophosphamide-treated adult mice. J. Natl Cancer Inst. 46, 151–160 (1971).

    CAS  PubMed  Google Scholar 

  82. Thomas, E. D. et al. Aplastic anaemia treated by marrow transplantation. Lancet 1, 284–289 (1972).

    Article  CAS  PubMed  Google Scholar 

  83. Brodsky, R. A. & Jones, R. J. Aplastic anaemia. Lancet 365, 1647–1656 (2005).

    Article  CAS  PubMed  Google Scholar 

  84. Thomas, E. D. et al. Bone-marrow transplantation (first of two parts). N. Engl. J. Med. 292, 832–843 (1975).

    Article  CAS  PubMed  Google Scholar 

  85. Bensinger, W. I. et al. Transplantation of bone marrow as compared with peripheral-blood cells from HLA-identical relatives in patients with hematologic cancers. N. Engl. J. Med. 344, 175–181 (2001).

    Article  CAS  PubMed  Google Scholar 

  86. Vose, J. M. et al. Autologous transplantation for aggressive non-Hodgkin's lymphoma: results of a randomized trial evaluating graft source and minimal residual disease. J. Clin. Oncol. 20, 2344–2352 (2002).

    Article  PubMed  Google Scholar 

  87. Russell, N. H., McQuaker, G., Stainer, C., Byrne, J. L. & Haynes, A. P. Stem cell mobilisation in lymphoproliferative diseases. Bone Marrow Transplant. 22, 935–940 (1998).

    Article  CAS  PubMed  Google Scholar 

  88. Jayne, D. et al. Autologous stem cell transplantation for systemic lupus erythematosus. Lupus 13, 168–176 (2004).

    Article  PubMed  Google Scholar 

  89. Moore, J. et al. A pilot randomized trial comparing CD34-selected versus unmanipulated hemopoietic stem cell transplantation for severe, refractory rheumatoid arthritis. Arthritis Rheum. 46, 2301–2309 (2002).

    Article  CAS  PubMed  Google Scholar 

  90. Tyndall, A. & Furst, D. E. Adult stem cell treatment of scleroderma. Curr. Opin. Rheumatol. 19, 604–610 (2007).

    Article  PubMed  Google Scholar 

  91. Fassas, A. et al. Hematopoietic stem cell transplantation for multiple sclerosis. A retrospective multicenter study. J. Neurol. 249, 1088–1097 (2002).

    Article  CAS  PubMed  Google Scholar 

  92. Lowenthal, R. M., Cohen, M. L., Atkinson, K. & Biggs, J. C. Apparent cure of rheumatoid arthritis by bone marrow transplantation. J. Rheumatol. 20, 137–140 (1993).

    CAS  PubMed  Google Scholar 

  93. Passweg, J. & Tyndall, A. Autologous stem cell transplantation in autoimmune diseases. Semin. Hematol. 44, 278–285 (2007).

    Article  PubMed  Google Scholar 

  94. Brodsky, R. A. et al. Immunoablative high-dose cyclophosphamide without stem-cell rescue for refractory, severe autoimmune disease. Ann. Intern. Med. 129, 1031–1035 (1998).

    Article  CAS  PubMed  Google Scholar 

  95. Krishnan, C. et al. Reduction of disease activity and disability with high-dose cyclophosphamide in patients with aggressive multiple sclerosis. Arch. Neurol. 65, 1044–1051 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  96. Sensenbrenner, L. L., Steele, A. A. & Santos, G. W. Recovery of hematologic competence without engraftment following attempted bone marrow transplantation for aplastic anemia: report of a case with diffusion chamber studies. Exp. Hematol. 5, 51–58 (1977).

    CAS  PubMed  Google Scholar 

  97. Brodsky, R. A. et al. Durable treatment-free remission after high-dose cyclophosphamide therapy for previously untreated severe aplastic anemia. Ann. Intern. Med. 135, 477–483 (2001).

    Article  CAS  PubMed  Google Scholar 

  98. Korbling, M. et al. 4-Hydroperoxycyclophosphamide: a model for eliminating residual human tumour cells and T-lymphocytes from the bone marrow graft. Br. J. Haematol. 52, 89–96 (1982).

    Article  CAS  PubMed  Google Scholar 

  99. Moyo, V. M. et al. High-dose cyclophosphamide for refractory autoimmune hemolytic anemia. Blood 100, 704–706 (2002).

    Article  CAS  PubMed  Google Scholar 

  100. Petri, M., Jones, R. J. & Brodsky, R. A. High-dose cyclophosphamide without stem cell transplantation in systemic lupus erythematosus. Arthritis Rheum. 48, 166–173 (2003).

    Article  CAS  PubMed  Google Scholar 

  101. Drachman, D. B., Adams, R. N., Hu, R., Jones, R. J. & Brodsky, R. A. Rebooting the immune system with high-dose cyclophosphamide for treatment of refractory myasthenia gravis. Ann. NY Acad. Sci. 1132, 305–314 (2008).

    Article  CAS  PubMed  Google Scholar 

  102. Schwartzman, R. J. et al. High-dose cyclophosphamide in the treatment of multiple sclerosis. CNS Neurosci. Ther. 15, 118–127 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Mayumi, H., Umesue, M. & Nomoto, K. Cyclophosphamide-induced immunological tolerance: an overview. Immunobiology 195, 129–139 (1996).

    Article  CAS  PubMed  Google Scholar 

  104. Luznik, L., Engstrom, L. W., Iannone, R. & Fuchs, E. J. Posttransplantation cyclophosphamide facilitates engraftment of major histocompatibility complex-identical allogeneic marrow in mice conditioned with low-dose total body irradiation. Biol. Blood Marrow Transplant. 8, 131–138 (2002).

    Article  CAS  PubMed  Google Scholar 

  105. Luznik, L. et al. HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol. Blood Marrow Transplant. 14, 641–650 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank Dr. M. J. Higgins for her helpful discussion about the breast cancer section.

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  1. Division of Adult Hematology, Johns Hopkins University, Baltimore, MD, USA

    Ashkan Emadi & Robert A. Brodsky

  2. Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA

    Richard J. Jones

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Under a licensing agreement between Accentia Pharmaceuticals and the Johns Hopkins University, R. A. Brodsky and R. J. Jones are entitled to share royalty received by the University on sales of a method of administering high-dose cyclophosphamide. The study described in this article could impact the value of this method of administering the drug. The terms of this agreement are being managed by the Johns Hopkins University in accordance with its conflict of interest policies. A. Emadi declares no competing interests.

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Emadi, A., Jones, R. & Brodsky, R. Cyclophosphamide and cancer: golden anniversary. Nat Rev Clin Oncol 6, 638–647 (2009). https://doi.org/10.1038/nrclinonc.2009.146

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