Danazol Treatment for Thrombocytopenia in Lower-Risk Myelodysplastic Syndromes: A Pilot Real Life Experience

Background: Severe thrombocytopenia is an uncommon event in patients (pts) with lower-risk MDS, but it may significantly affect the prognosis. No specific pharmacological approaches other than hypometilating agents (not licensed in Europe in lower-risk MDS), able to improve platelet count in this setting, are currently available. Trials testing efficacy and safety of Eltrombopag are ongoing (Oliva 2017). Few data were reported about danazol, an attenuated androgen, that seems to have also some effectiveness in this still unmet need (Wattel 1994; Chan 2002).

Aims: To assess the efficacy and safety of danazol in improving the platelet count in low risk MDS pts with severe thrombocytopenia.

Methods: We retrospectively reviewed 35 thrombocytopenic MDS pts treated with danazol. The initial and maximal dose was 600 mg/day for all pts, modulated according to response and toxicity. The response was evaluated according to IWG response criteria (Cheson 2006). The outcome was strictly observed every 3 months (mo) up to the 12th mo, and the platelets average number in each observation moment was described. The time to response, the response rate and the enduring of response were also recorded.

Results: Of the 35 pts, according to 2016 WHO classification, 4 pts were MDS-ULD; 19 were MDS-MLD (3 of them with medullar hypocellularity), 7 were MDS-EB1 and 5 were affected by MDS/MPN. At baseline the platelet count was lower than 20x10^3/mL in 11 pts, the median was 23x10^3/mL . At starting time of danazol therapy the IPSS-R cytogenetic class of risk was very low in 2 cases, low in 28 cases, intermediate in 3 cases and very high in 1 case. Cytogenetic was not available in one patient. In the 30 MDS pts, the IPSS-R was "very low" in 1 patient, "low" in 16, "intermediate" in 7, "high" in 4 and "very high" in 1. In 1 case it was not evaluable due to the lack of cytogenetics. Two pts were not included in the analysis because they were treated for less than 3 mo (in 1 case danazol was withdraw to permit the beginning of another therapy and in 1 case due to death for other neoplastic disease). The response rate was 63,6% (21 responders on 33 evaluable). Median time to response was 3.5 mo (range 0.3 - 12.4 mo); the average response time was 5.09 mo. In the first year of treatment, the platelet count (evaluated at baseline, 3, 6, 9 and 12 mo) changed in a significant way (F test after repeated measures ANOVA: p < 0.001 as shown in Figure 1). Pairwise comparisons of platelet count according to Bonferroni showed a significant difference for baseline vs. 3 mo (p = 0.0013), baseline vs 6 mo (p = 0.0255), baseline vs 9 mo (p = 0.0047) and baseline vs 12 mo (p = 0.0014); however, no significant differences (p ≥ 0.05) in counts were seen for all the further pairwise comparisons at 3, 6, 9 and 12 mo. The median and average duration of the response for the entire population were respectively 12,5 and 32,5 mo. Only 6 of the 21 responders (28%) lost the response (the median and average duration of response were respectively 5.8 and 12.9 mo). Within the 21 responders, the median progression free survival was not reached after 24 mo. The probability to maintain the response after 50 mo was assessed at 58.2% (C.I. 24.1% to 81.4% - Figure 2). The overall survival showed a significant difference (logrank test: p = 0.0064) between responders and non-responders (Figure 3). Adverse events recorded were as follows: moderate (grade 1 and 2) increase in transaminases in 4 cases (with reduction of danazol to 400 mg/day); 1 case of severe but reversible liver toxicity (grade 3) (with subsequently drug suspension); severe (grade 3) but reversible renal failure in 1 case (the drug was stopped); moderate (grade 1 and 2) increasing of serum creatinine in 6 case (with reduction of danazol to 400 mg/day in 2 of these); reversible cutaneous rash in 3 cases; amenorrhea in 1 case (the only fertile woman in the series); weight loss and loss of appetite in 1 case, weight gain in 1 case.

Conclusion: Even if the mechanism of action of danazol in pts with MDS is unclear, this series confirms its efficacy to improve platelet count in the most of MDS pts with severe thrombocytopenia. The response was often clinically significant. It may not be immediate but seems to be reachable after 3-6 mo of treatment. A responsive patient has a good probability to maintain a long-lasting response. The toxicity profile of this drug is acceptable. Waiting for more effective options, danazol may be a good therapeutic option for these pts.

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