Danazol As First-Line Therapy for Myelodysplastic Syndromes

Introduction: Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematological disorders characterized by ineffective hematopoiesis and variable degrees of peripheral cytopenias. Neither curative nor standard therapy has been available yet for the majority of patients with MDS. Patients with available matched donor may undergo an allogeneic bone marrow transplant with a potential cure rate 30-50%. Danazol is a synthetic anabolic steroid with properties similar to corticosteroids, such as inhibition of interleukin-1 and TNF-α production. Also, has demonstrated activity in immune cytopenias and aplastic anemia but its efficacy in MDS has shown contradictory results. Recently there has been increasing interest in telomere dysfunction in hematological diseases. Short telomeres are the major prognostic risk factor for clonal evolution to myelodysplasia and acute leukemia. Danazol not only prevents telomere loss, but a mean increase occurs with improvement observed early during the course of hormone therapy. In our center with poor access to new strategies and therapies the use of danazol remains as an attractive option for patients with MDS because of its low cost. In this study we aim to document the clinical evolution of patients diagnosed with MDS treated with danazol as first-line therapy in our institution.

Methods: We include patients diagnosed with MDS according to WHO criteria treated with danazol between 2005 and 2015. Response was defined as one or more of the following criteria: a rise in the platelet count >25 x 10⁹/I, an increase in hemoglobin >2 g/dl or disappearance of a previous requirement for red blood cell transfusion, or an increase in neutrophil count >0.5 x 109/L. All patients received packed red blood cell and platelet transfusions according to physician criteria. Patients were given intravenous or oral antibiotics as needed as prophylaxis. Criteria for stop danazol included: no response to treatment, toxicity or patient's refusal to continue treatment. Blood counts were preformed at least 1-month intervals for the first 4 months. We compared those who responded versus no responders using the Student's t test or Mann-Whitney U test as corresponded.

Results: Forty-two patients with MDS were treated with danazol. Median follow-up was 12 months (range 3-75). Median dose used was 400 mg (range 100-600) orally in two divided doses. Mean duration of treatment for all patients was 6 months (range 3-72 months). The distribution by WHO subtypes included 26 refractory cytopenia with multilineage dysplasia (RCMD) (62%), 6 patients with refractory cytopenia with unilineage dysplasia (RCUD), 6 refractory anemia with excess blasts (RAEB), 2 refractory anemia with ring sideroblasts (RARS) and 1 MDS associated with isolated del(5q). Twenty-four (60%) patients presented clinical response. Response for patients with anemia was 23.8% (10/24), increase in absolute neutrophil count occurred in 36.8% (7/19), and 60% (24/40) presented an increase in platelet count. Time to initial response was 2 months (range, 1-8) while time to better response of 3 month (range, 1-8). Response was not associated to any MDS classification or administrated dose. Toxicity was mild and danazol was not discontinued in any patient. Side effects included three patients with gastrointestinal symptoms, and 4 patients reported weight gain. Median overall survival was 24 months (CI95% 5.1-42). Fifteen patients died (35.7%). Five patients progressed to AML.

Conclusion: Different agents have been used in MDS. However, for the majority of patients with MDS no curative treatment exists. In conclusion our data suggest that Danazol may be effective in MDS with minimal toxicity, especially in patients with thrombocytopenia. Response was independent of severity, WHO classification and administrated dose.

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Clinical characteristics of responders versus non-responders

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Clinical characteristics of responders versus non-responders

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