Although Danazol and low doses of glucocorticoids could potentially compete for the GR, the possibility of combining Danazol with HDGCs is supported by the example of an 85-year- old female with symptomatic Rai Stage IV CLL and trisomy 12 tumor cells. Fludarabine- and alkylator-based regimens were felt to be contraindicated because of the patient’s congestive heart failure and she was treated with HDGCs (1500 mg Prednisone PO  5 days), 7 but suffered side effects of ﬂuid retention and profound fatigue. On the basis of previous use of Danazol as a steroid-sparing agent in autoimmune disorders, 8 the prednisone dose was lowered to 1000 mg p.o. daily for 4 days and Danazol (200 mg p.o. b.i.d.) was added to the next two treatment cycles. The treatments were better tolerated and the clinical response was maintained and possibly even enhanced (Figure 2d). These observations suggest that Danazol has clinical activity in CLL and can be used safely with HDGCs. Danazol has been prescribed for almost 40 years 3 and has a well-known toxicity proﬁle. It causes virilization in young women with endometriosis, which is not necessarily a problem for older male or post- menopausal female CLL patients. Danazol is otherwise relatively safe but patients must be monitored for thrombosis and lipid and liver abnormalities. 9 Along with its use in autoimmune disorders, 4,8 Danazol is thought to have activity in myelodysplastic syndromes 3 and can prevent interferon-induced thrombocytopenia. 10 Over 2500 papers on Danazol are listed in PubMED but, to our knowledge, its activity in CLL has not been reported before. The mechanism of action of Danazol in CLL is not clear. Blood levels of CD23 were lowered by Danazol in endometriosis, 11 suggesting a direct effect on activated B cells, which are considered the normal counterparts of CLL cells. 12 However, we could not detect an effect of Danazol on CD23 expression by CLL cells in vitro (not shown). Danazol has been reported to decrease the production of inﬂammatory cytokines, including interleukin-6 and tumor necrosis factor-a, which may limit their ability to cause proliferation of CLL cells in vivo. 13 Danazol can also intercalate into cell membranes, 14 which may dysrupt growth-promoting signaling processes and account for a mechanism of action apparently independent of glucocorticoid, estrogen and androgen receptors (Figure 1d). The observations reported in this letter suggest clinical trials to determine whether the anti-CLL effect of Danazol can be exploited to improve the clinical efﬁcacy of HDGCs. Conventional oral doses of Danazol have been reported to achieve erythrocyte membrane levels that approach the mM levels that appear to be needed for cytotoxicity (Figures 1 and 2). Initial clinical studies will focus on determining whether optimal dosing of Danazol in CLL patients can be achieved through the oral route, 7 or whether i.v. administration will be required. CONFLICT OF INTEREST The authors declare no conﬂict of interest. ACKNOWLEDGEMENTS This study was supported by the Canadian Institutes of Health Research (CIHR) and the Leukemia and Lymphoma Society of Canada (to DS) and a QEII-SST graduate scholarship from the University of Toronto (to ST). S Tung 1,2 and DE Spaner 1,2,3,4 1 Division of Molecular and Cellular Biology, Sunnybrook Research Institute, Toronto, Canada; 2 Department of Medical Biophysics, University of Toronto, Toronto, Canada; 3 Sunnybrook Odette Cancer Center, Toronto, Canada and 4 Department of Medicine, University of Toronto, Toronto, Canada E-mail: spanerd@sri.utoronto.ca REFERENCES 1 Gribben JG, O’Brien S. Update on therapy of CLL. J Clin Oncol 2011; 29: 544 - 550. 2 Castro JE, James DF, Sandoval-Sus JD, Jain S, Bole J, Rassenti L et al. Rituximab in combination with high-dose methylprednisolone for the treatment of CLL. Leukemia 2009; 23: 1779 - 1789. 3 Fontana V, Dudkiewicz P, Ahn ER, Horstman L, Ahn YS. 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Danazol and plasma lipoprotein metabolism. Int J Gynaecol Obstet 1995; 50(Suppl 1): S23 - S26. 10 Alvarez G, Go ´ mez-Galicia D, Rodrı ´guez-Fragoso L, Marina V, Dorantes L, Sa ´ nchez- Alema ´n M et al. Danazol improves thrombocytopenia in HCV patients treated with peginterferon and ribavirin. Ann Hepatol 2011; 10: 458 - 468. 11 Matalliotakis I, Neonaki M, Koumantaki Y, Goumenou A, Kyriakou D, Koumantakis E. A randomized comparison of danazol and leuprolide acetate suppression of serum-soluble CD23 levels in endometriosis. Obstet Gynecol 2000; 95: 810 - 813. 12 Tomic J, Lichty B, Spaner DE. Aberrant interferon-signaling is associated with aggressive CLL. Blood 2011; 117: 2668 - 2680. 13 Tanaka T. Danazol regulates the functions of normal human endometrial stromal cell subpopulations by modifying endometrial cytokine networks. Int J Mol Med 2009; 23: 421 - 428. 14 Horstman L, Jy W, Arce M, Ahn YS. 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Phase I and pharmacokinetic study of elacytarabine, a novel 5 0 -elaidic acid derivative of cytarabine, in adults with refractory hematological malignancies Leukemia (2012) 26, 1686--1689; doi:10.1038/leu.2012.1 Cytarabine (ara-C) enters cells primarily as a false substrate through specialized nucleoside transporter proteins, predomi- nantly hENT1 (the human equilibrative nucleoside transporter). 1,2 Reduced hENT1 expression and/or activity is associated with adverse therapeutic outcomes in patients with acute myeloid leukemia (AML) treated with ara-C. 3,4 Elacytarabine (CP-4055) (Figure 1), the lipophilic 5 0 -elaidic acid ester of ara-C, enters cells independently of hENT1 and is active in both ara-C-resistant cell lines 5-7 and animal tumor xenograft models. 8,9 In patients with Accepted article preview online 6 January 2012; advance online publication, 27 January 2012 Letters to the Editor 1686 Leukemia (2012) 1681 - 1729 & 2012 Macmillan Publishers Limited