Danazol Therapy for Thrombocytopenia in Patients with Myelodysplastic Syndromes

Abstract

Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal stem cell disorders characterized by ineffective haemopoiesis, resulting in variable degrees of cytopenia and intrinsically carrying the potential of leukaemic transformation. Neither curative nor standard therapy has been available yet for the majority of patients with MDS. Young patients with matched related donors might undergo allogeneic bone marrow transplantation, while high-dose chemotherapy may lead to significant lasting improvement in a limited number of patients with high-risk MDS. Combination of growth factors, like recombinant erythropoietin and recombinant human granulocyte-colony-stimulating factor, or erythropoietin alone, with or without cyclosporine, has shown favourable response rates in subgroups of these patients [1, 2]. Interleukin-3 and interleukin-6 improve platelet count in about one third of patients with MDS but are associated with relatively important side effects [3]. Danazol, a synthetic attenuated androgen, has received special interest due to its initially demonstrated activity in idiopathic thrombocytopenic purpura and autoimmune haemolytic anaemia and some encouraging results from trials in MDS patients with thrombocytopenia [4, 5, 6, 7, 8]. We summarise the results of danazol therapy in 17 patients with MDS and thrombocytopenia and discuss the effect of danazol in this subgroup of MDS patients.Ten male and 7 female patients, with a median age of 69 years (range 37–88 years) were entered into the trial. Eligibility criteria included de novo MDS, platelet count <80 × 109/l and no significant organ disease. According to the French-American British (FAB) criteria, 10 patients were classified as having refractory anaemia (RA), 1 RA with ringed sideroblasts (RARS), 3 RA with excess of blasts (RAEB; 2 with bone marrow blasts <10%) and 3 chronic myelomonocytic leukaemia (CMML). Median time from diagnosis was 11 months (range: 2–82 months). All patients had dysplastic megakaryocytes at diagnosis (mononuclear forms, micromegakaryocytes, immature megakaryocytes) and they had no clinical manifestations of immunological disorder. Cytogenetic analysis was performed in all patients and the platelet suspension immunofluorescence test was used for the detection of platelet antibodies [9].An adequate clinical trial was defined as a daily dose of 600 mg given orally in 3 divided doses. The treatment protocol included an initial dose of 100 mg of danazol given on the first day, after which a dose of 100 mg was added every day till the target daily dose of 600 mg that was usually achieved at the end of the first week of therapy. Patients’ evaluation was carried out after 12 weeks of danazol treatment. A 50% increase of the initial value in platelet count was defined as response to treatment. Criteria for removal from the study included: no response to treatment, toxicity or patient’s refusal to continue treatment. The responders continued to receive danazol till relapse (development of severe thrombocytopenia) or disease progression. Patients’ characteristics are given in table 1.Platelet antibodies were detected in 12/17 MDS patients (70.6%). Seven patients (41.1%) responded to treatment, and have thus achieved a significant increase in platelet counts (from a median value of 40 × 109/l to 122 × 109/l; table 1). Three out of 7 responders reached normal platelet counts; 2 of them had initial platelet counts below 20 × 109/l. Three out of 5 patients with abnormal karyotype and 4/12 with normal cytogenetics responded to therapy. Platelet antibodies were detected in 5/7 responders. Median time of response duration was 11 months (range: 1.5–72). There was no correlation between the severity of thrombocytopenia and response to danazol treatment. Finally, no patient was excluded from the study because of danazol side effects.The study population included a female patient with RAEB and monosomy 7 who had a life-threatening thrombocytopenia (8 × 109/l) and had not responded to previous treatment with corticosteroids and weekly intravenous infusions of vincristine. She was also transfusion dependent because of severe anaemia. Ten weeks after danazol administration, the platelet count reached 100 × 109/l and the haemoglobin levels turned to normal (12.9 g/dl). Six months after the initiation of danazol therapy, she had a normal platelet count (250 × 109/l) and remained in remission for 6 years. A new cytogenetic analysis was carried out after 6 years, confirming the existence of monosomy 7 again. She finally developed acute myeloid leukaemia (AML) that did not respond to standard treatment protocols.Thrombocytopenia in MDS is often one of the major treatment problems in these patients. Combined mechanisms, including dysplastic clonal platelet progenitors and immunological abnormalities, are often involved in the pathogenesis of MDS-related thrombocytopenia. Evidence that danazol administration may be beneficial in MDS with thrombocytopenia has been reported in the literature, but the issue still remains controversial. Buzaid et al. [4]demonstrated a platelet increment in 3/20 MDS patients; however, no clinical benefit was observed, possibly due to the short duration of treatment (4 weeks) in one half of the patients. Stadtmauer et al. [5]showed that danazol could achieve a platelet response rate of 36% in MDS patients with an initial platelet count of >50 × 109/l, while better results have been reported in MDS patients with platelet counts <50 × 109/l treated with 600 mg of danazol [6]. Recently, Chan et al. [7]presented the results of danazol treatment on 29 MDS patients with thrombocytopenia (median platelet count 41 × 109/l), showing a response rate of 76% after 6 weeks and of 72% after 3 months of therapy, independently of the FAB subtype and pretreatment platelet count. However, Chabannon et al. [10]failed to show any positive effect of danazol in MDS patients during long-term follow-up; only 4/76 MDS patients achieved an increase in platelet number. The search for subgroups of patients likely to have a good response was also unsuccessful.The mechanisms whereby danazol improves platelet count in some MDS patients remains unclear. There are indications for either an immunomodulatory or a direct effect on the bone marrow enhancing haemopoiesis [11].Our trial demonstrates that danazol is an effective agent against thrombocytopenia in MDS patients, independently of its severity, FAB subtype, karyotype or detection of antiplatelet antibodies. However, further studies have to be done in order to reveal subgroups of patients with favorable response.