Efficacy and Safety of Danazol in Patients with Myelodysplastic Syndromes or Myelodysplastic/Myeloproliferative Neoplasms: A Multicenter Observational Study

Thrombocytopenia affects about two thirds of patients with myelodysplastic syndromes (MDS) and treatment is not standardized. Immunosuppressants, such as corticosteroids, cyclosporin or anti-thymocyte globulin show some efficacy, particularly in hypocellular cases, and eltrombopag was associated with a 47% PLT response. The androgen danazol may be beneficial in this setting given its anabolizing and immunomodulatory properties. In this observational multicenter study, 59 patients with MDS (53) or MDS/myeloproliferative neoplasms (MDS/MPN; 5 chronic myelomonocytic leukemia, CMML, 1 unclassified) treated with off-label danazol at 6 centers in Northern Italy were retrospectively evaluated. Response was assessed at 3-month intervals according to IWG 2018 criteria. Adverse events were registered according to CTCAE version 5. A two-tailed Fisher's exact test was used to calculate p values for differences in dichotomous variables, whereas Student's t test was used for continuous variables. Log Rank Mantel-Cox test was used for survival analysis. As shown in Table 1, patients were mainly males with a median age of 69 years (27-87), and were equally distributed between very low/low IPSS-R risk score (47%), and intermediate/higher risk (53%). Twenty percent (9/44 evaluable) of patients had a hypocellular bone marrow (<25% cellularity), and 26% (11/42) had WHO grade 2 fibrosis. All patients were thrombocytopenic (median 21 x 103/μL, range 2 - 98), 52% were anemic (median Hb 11.1 g/dL, 6.9 - 15.7), and 25% had received at least 1 red blood cell transfusion in the 8 weeks before danazol initiation. Danazol was administered for a median of 11.3 months (0.6 - 149.5) at a meandaily dose of 450 mg (range 125 - 600). Concomitant treatments were corticosteroids (34%), recombinant erythropoietin (rEPO 7%), and corticosteroids plus rEPO (3%). PLT response was obtained in 54% of evaluable patients (30/56) after a median of 3.3 months (1.3 - 24.6) from treatment start. Response was slightly higher in patients with greater baseline PLT levels (mean baseline PLT count 25 vs 19 x 103/mcL for responders vs non-responders, respectively, p 0.07), grade 0-1 fibrosis (64% response vs 27% in those with grade 2, p 0.07) and concomitant use of steroids (77% vs 45% response, p 0.06). Erythroid improvement was obtained in 7/16 (44%) patients after a median of 6.8 months (2.5 - 16.8), independently from concomitant rEPO or steroid administration. After a median of 17.2 months from initial PLT response, 78% of patients maintained it, whereas 22% relapsed. AEs occurred in 68% of cases, mainly grade 1-2, including creatinine increase (44%; 5% grade 3), transaminitis (36%), mood disorders (7%), and others. AEs required dose reduction in 11 (19%) and interruption in 4 (7%) of patients. Twenty-eight patients died during the follow up. PLT-responders had a significantly lower mortality rate compared to non-responders (10/27, 37%, vs 16/23, 70; p = 0.02) and a longer overall survival (p < 0.001, figure 1). In colcusion, danazol induced PLT response in more than half of MDS patients and erythroid improvement in 44%, including non-responders to steroids and cyclosporin, and independently of marrow cellularity. PLT response was significantly associated with a higher overall survival further suggesting a clinical impact on patient outcome. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal