Danazol therapy for the anemia of myelofibrosis: assessment of efficacy with current criteria of response and long-term results

Abstract

The efficacy of danazol was assessed in 50 patients with myelofibrosis and anemia using the recently revised criteria of the International Working Group for Myelofibrosis Research and Treatment. According to them, anemia response (clinical improvement) is defined as transfusion cessation in transfusion-dependent patients or an Hb increase >2 g/dl in patients without transfusion requirements, both maintained for at least 12 weeks. Median follow-up from danazol start was 36 months (interquartile range [IQR] 19.2-58.8). Anemia response was achieved in 15 patients (30 %), including 5 of the 27 with transfusion dependency (18.5 %) and 10 of the 23 without transfusion requirements (43.5 %). Median time to response was 5 months (IQR 4-7) and median duration of the response 14 months (IQR 10-21). Among responder patients, 5 discontinued therapy due to toxicity or personal decision and 1 died from spleen rupture while being in response. A trend for worse response was seen in transfusion-dependent patients (p = 0.055). A platelet increase >50 × 10(9)/l was observed in 3 of 13 thrombocytopenic patients, all of whom had moderate thrombocytopenia. Toxicity was usually moderate, leading to treatment withdrawal in only 4 patients. Danazol is effective in 30 % of patients with anemia-associated myelofibrosis. The responses are less frequent in patients with transfusion dependency.

Inflammatory functional iron deficiency common in myelofibrosis, contributes to anaemia and impairs quality of life. From the Nordic MPN study Group

“…MF has the most severe symptom burden of the MPNs, and anaemia is an important reason for the fatigue, which is the most common and pronounced symptom of MF patients . The anaemia can be treated with erythropoiesis‐stimulating agents, cortisone, androgens or thalidomide plus cortisone, but the response rate varies and anaemia treatment is still an unmet need in this disease …”

Development of hepatocellular carcinoma after long-term immunosuppressive therapy including danazol in a dog

“…However, such reports are limited in veterinary medicine [12, 18], and hence, its utility remains unclear. In humans, danazol has been shown to have adverse effects, such as reversible liver damage and virilization [4, 5]. Although a causal relationship has not been conclusively established, some patients have developed hepatocellular carcinoma (HCC) after the administration of danazol [3, 6, 7, 15, 19, 22].…”

“…More importantly, there have been several reports of human patients developing HCC after administration of danazol [3, 6, 7, 15, 19, 22]. Although the effect of danazol on the liver is not completely clear even in humans, danazol is known to adversely affect liver enzymes, such as ALT and ALP, by elevating their levels [4, 5]. In addition, hepatocellular adenomas and focal nodular hyperplasia induced by danazol have been reported in humans [2]; chronic injury to the hepatic cells may induce these abnormalities.…”

Primary myelofibrosis: current therapeutic options

“…Anemia is a frequent manifestation of PMF 19 that might be caused by different interacting factors, such as bone marrow insufficiency (fibrosis), hypersplenism, bleeding, iron deficiency, vitamin B12 or folate deficiency, or autoimmune hemolysis 20, 21. Moreover, specific PMF treatment with cytoreductive drugs (HU) 17 and JAK1/2 inhibitors 22 can lead to, or increase, anemia in these patients.…”

“…Danazol, a semisynthetic attenuated androgen that has fewer side effects, results in an anemia response rate of 30–57% depending on the adopted response criteria 21, 23, 24. In a cohort of 50 patients with PMF, Cervantes et al 21 described a 30% response rate [defined by transfusion cessation in transfusion-dependent patients or an increase in hemoglobin (Hb) >2 g/dL in patients without transfusion requirements], with a median duration of anemia response of 14 months. Androgens should not be used in patients with prostatic symptoms, prostate cancer or moderate to advanced hepatic disease.…”