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Keywords:

  • myelofibrosis with myeloid metaplasia;
  • therapy;
  • androgens;
  • danazol

Summary

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Discussion
  6. References

Androgens are considered the treatment of choice for the anaemia of myelofibrosis with myeloid metaplasia (MMM). Good results have been reported in a few patients treated with danazol, a synthetic attenuated androgen. The long-term efficacy and tolerability of danazol as treatment for the anaemia of MMM was evaluated in 30 patients, who received 600 mg/d, with progressive tapering to the minimum effective dose in the responders after 6 months. Complete response (CR) was defined as transfusion cessation with normal Hb and partial response (PR) as an Hb increase ≥1·5 g/dl with transfusion-independent Hb values >10 g/dl maintained for at least 8 weeks. Median follow-up was 20·5 months (range: 3·5–58 months). Response was achieved in 11 patients (37%), including eight CRs and three PRs. Median time to response was 5 months (range: 1–9 months). Four patients stopped responding at 6–24 months, two responders discontinued treatment because of toxicity, and five maintained response at 3·5–42 months. Pretreatment variables associated with response were lack of transfusion requirement (P= 0·001) and higher Hb at treatment start (P= 0·02). Toxicity was usually moderate, leading to treatment withdrawal in only two cases. Danazol is effective and well tolerated in a substantial proportion of MMM patients with anaemia.

Myelofibrosis with myeloid metaplasia (MMM) is a chronic myeloproliferative disorder characterized by bone marrow fibrosis and extramedullary haematopoiesis, with the fibrosis being a reactive phenomenon to the neoplastic proliferation of a pluripotent haemopoietic stem cell (Jacobson et al, 1978). Anaemia is one of the main clinical problems for MMM patients, as many present with anaemic symptoms and virtually all develop severe anaemia during evolution of the disease (Reilly, 1998). For many years, androgens have been considered as the treatment of choice for the anaemia of MMM (Kennedy, 1962; Silver et al, 1964; Hast et al, 1978; Besa et al, 1982; Brubaker et al, 1982). However, the results are mostly based on old reports that generally included only small numbers of patients. In this regard, good results have been reported with the use of danazol, a synthetic attenuated androgen that can also correct the thrombocytopenia in some cases, but the experience of such therapy is limited to a few patients whose follow-up is short (Chabannon et al, 1990; Levy et al, 1996; Cervantes et al, 2000). As novel treatment modalities, such as thalidomide and other newer drugs, are currently being evaluated in MMM (Barosi et al, 2001; Cortes et al, 2003; Giles et al, 2003; Mesa et al, 2003), accurate information is required regarding the results of conventional therapies for MMM, such as danazol, so that comparisons can be made with the newer treatments for this disease.

The primary aim of the present study was to evaluate the long-term efficacy and tolerability of danazol in the treatment of the anaemia of MMM and to analyse the variables associated with a favourable response to such therapy.

Patients and methods

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Discussion
  6. References

Patients and diagnostic criteria

Between November 1995 and August 2004, 33 patients with MMM who were either transfusion-dependent or had a Hb value ≤10·0 g/dl received danazol as treatment for the anaemia. The results in the first seven patients were the subject of a previous publication (Cervantes et al, 2000). Although the study was retrospective, the criteria for danazol therapy were homogeneous and patients were consecutively recruited during most of the study period. There were two main criteria for danazol treatment institution. The first one was anaemia without concurrent causes (for instance, iron deficiency or autoimmune haemolysis) in the absence of hyperproliferative features of MMM (leucocytosis, marked thrombocytosis, massive splenomegaly or constitutional symptoms). In addition, those patients with the hyperproliferative form of MMM, had danazol added to cytolytic therapy in case that the latter did not improve the anaemia or provoked a fall in the Hb values. With regard to the choice between danazol and human recombinant erythropoietin (rHuEPO), during the first 8 years of the study the rule was to give danazol first. In the final year, based on our results on rHuEPO treatment for the anaemia of MMM (Cervantes et al, 2004), rHuEPO was the first-choice in patients with inadequate Epo levels, with danazol being given in case of failure to respond to rHuEPO. This approach was taken in only two patients.

The diagnosis of MMM was based on the criteria established by the Italian Consensus Conference on Diagnostic Criteria for Myelofibrosis with Myeloid Metaplasia (Barosi et al, 1999). Bone marrow histology was evaluated according to the criteria of Lennert et al (1975), in which three MMM subtypes are considered: myelofibrosis with increased haemopoietic cellularity and reticulin fibrosis (MF/C), myelofibrosis with reticulin and collagen fibrosis but no new bone formation (MF/O−) and decreased haemopoietic cellularity, marked reticulin and collagen fibrosis and osteosclerosis (MF/O+). The karyotype of bone marrow or unstimulated peripheral blood cells was analysed whenever assessable metaphases could be obtained.

Treatment schedule, criteria of response and toxicity assessment

Patients were scheduled to receive danazol orally at an initial dose of 600 mg/d (or 800 mg/d in patients with a body weight >80 kg), unless toxicity developed. After the initial 6-month period, responders had a dose reduction to 400 mg/d for an additional 6 months, which was then gradually tapered down to the minimum dose necessary to maintain the response. In patients not showing any sign of response at 6 months, therapy was discontinued.

A complete response (CR) was defined as the cessation of transfusion requirements with Hb >11 g/dl and a partial response (PR) as an increase in the Hb ≥1·5 g/dl with transfusion independence and Hb values >10 g/dl maintained for at least 8 weeks. The favourable responses included both CR and PR patients. The remaining situations were considered as treatment failures. During the initial phase of therapy, patients were monitored on a monthly basis. Thereafter, the timing of the monitoring was adjusted, depending on the response in each individual patient. The general policy was to transfuse packed RBCs when the Hb levels dropped below 8·0 g/dl or the anaemia was overtly symptomatic.

During the treatment period, in addition to the standard haematological parameters, liver function tests were monitored on a monthly basis and patients were assessed for the possible development of hepatic tumours by ultrasonography every 6–12 months. In men, systematic screening for prostate tumours was also performed. Other possible adverse effects were recorded.

Statistical methods

The capacity of several pretreatment variables to predict a favourable response to danazol was analysed using the chi-squared test and the Student's t-test.

Results

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Discussion
  6. References

During the study period, no patient who was potentially eligible for danazol therapy was excluded because of concurrent liver disease or prostatic benign adenoma; drug treatment was not avoided in young females. As a result of early death (from pneumonia, heart failure and complication of chronic lung disease, respectively), three patients received the treatment for <2 months and could not be evaluated for response. The main characteristics at the start of treatment of the 30 assessable patients are summarized in Table I. Sixteen patients had received one or more therapies prior to danazol, including hydroxyurea (nine patients), anagrelide (five patients), rHuEPO, prednisone and splenectomy (two cases each), and interferon alpha and ciclosporin A (one case each); danazol was the first-choice treatment in the remaining 14 patients. As previously mentioned, danazol was not instituted at the same time as other therapies in any patient. In seven patients MMM followed a previous diagnosis of essential thrombocythaemia and one had postpolycythaemic myelofibrosis. Distribution of histological subtypes was as follows: MF/C phase, 17 patients, MF/O− phase, nine patients, and MF/O+ phase, four patients. Assessable metaphases could be obtained in only 11 patients; cytogenetical abnormalities were observed in four cases (trisomy 8, del 7q, t (2;11), and derivative 8, one case each).

Table I.  Main clinico-haematological features at the start of danazol treatment in 30 patients with myelofibrosis with myeloid metaplasia.
Feature 
  1. *Median (range); M, male; F, female.

  2. †Below costal margin.

Age (years)*64 (25–84)
Gender (M/F)19/11
Time lapse diagnosis-treatment (months)*5·3 (0–160)
Spleen size (cm)†
 <548%
 5–1044%
 >108%
Transfusion requirement (yes/no)18/12
Hb (g/dl)*8·6 (5·9–10)
 <8·547%
 <9·063%
Reticulocytes (×109/l)*64 (9–213)
WBC count (×109/l)*5·3 (0·8–14·9)
Platelet count (×109/l)*207 (14–1250)

For the 30 assessable patients, the median follow-up from the start of danazol treatment was 20·5 months (range: 3·5–58 months). A favourable response was achieved in 11 patients (37%), including eight CRs (27%) and three PRs. Table II shows the main characteristics of responding patients. Four of the 11 responders received concomitant therapy during danazol treatment (hydroxyurea, two cases; anagrelide, one patient; hydroxyurea plus anagrelide, one case). The median time to response was 5 months (range: 1–9). Three patients showed the first signs of response between 1 and 3 months from treatment start and eight between 3 and 6 months. In two patients with PR at 6 months, the response improved to CR at months 7 and 9 of treatment respectively. One of two patients with previous failure to rHuEPO treatment responded to danazol. Pretreatment variables that were significantly associated with a favourable response to danazol were lack of transfusion requirement (P= 0·001) and higher Hb at treatment start (P= 0·02), whereas leucocyte and reticulocyte counts had borderline significance (Table III). Although there was no threshold for the Hb with regard to the achievement of a response, eight of the 11 responders had a Hb level between 9 and 10 g/dl at start of treatment. No influence on the response could be demonstrated for previous splenectomy or spleen size. On the contrary, one of the four patients with a cytogenetic abnormality (trisomy 8) responded to treatment. Normalization of the platelet counts was observed in two of seven patients with thrombocytopenia, which was moderate in both cases.

Table II.  Main characteristics of the 11 patients with myelofibrosis with myeloid metaplasia and anaemia who had a favourable response to danazol treatment.
Patient no.Age/sexPrevious therapyPretreatmentPost-treatmentTime to response (months)Response duration (months)Treatment duration (months)
Hb (g/dl)Platelets (×109/l)Hb (g/dl)Platelets (×109/l)
  1. *Plus splenectomy; HU, hydroxyurea; Agl, anagrelide; Epo, rHuEPO.

  2. †Treatment stopped because of toxicity while the patient in response.

 179/MNone5·91261221161117
 225/FNone9·26512·585331+34+
 362/MHU*6·18613213612†18
 453/FNone1022312·3280442+46+
 557/FHU, Agl9·856311·24625 2† 7
 669/MHU106711·993510+15+
 779/FNone9·721311·84564 610
 860/FHU, Epo9·618511·13605 6+11+
 959/FAgl9·227310·72126 922
1051/MHU9·411810·91729 3·5+12·5+
1184/MNone8·724310·434612425
Table III.  Univariate study of the pretreatment variables associated with a favourable response to danazol therapy in 30 patients with myelofibrosis with myeloid metaplasia.
VariableP-value
  1. NS, not significant.

Lack of transfusion requirements0·001
Higher Hb value0·02
Higher WBC count0·08
Higher reticulocyte count0·09
Lapse time diagnosis-treatmentNS
AgeNS
SexNS
Spleen sizeNS
Platelet countNS

Four patients stopped responding at 6–24 months, in two of the complete responders the drug had to be definitively stopped because of toxicity, and the remaining five patients (among them, four complete responders) continued to maintain the response between 3·5 and 42 months of achievement. In the responders, maintenance danazol dose was 200 mg/d. Six of the 12 patients that switched from danazol to rHuEPO because of therapeutic failure or toxicity achieved a favourable response to the latter treatment.

Danazol was usually well tolerated. The most frequent toxicity consisted of a moderate increase in the liver enzymes during the first months of treatment, which was registered in eight patients (<100 IU/l, five cases; 100–200 IU/l, two cases; >200 IU/l, one case) and improved following a reduction in the danazol dose to 400 mg/d. Headache and a mild increase in the muscle mass were occasionally observed. Only two patients experienced severe side effects leading to definitive withdrawal of treatment (cholestatic hepatitis and prostate adenocarcinoma, one case each). No case of peliosis hepatis or liver cell adenoma was registered during the study.

Discussion

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Discussion
  6. References

Anaemia is the most important clinical manifestation of MMM. Its origin is multifactorial, with contributing factors including ineffective haematopoiesis, decreased bone marrow reserve, hypersplenism, immune haemolysis, myelosuppression secondary to cytolytic therapy, bleeding and occasionally iron, folic acid or vitamin B12 deficiency (Reilly, 1998). Once treatable causes are ruled out, androgen therapy has been traditionally considered as the choice treatment. The efficacy of testosterone in the anaemia of MMM was first shown in the 1960s (Kennedy, 1962; Silver et al, 1964). Androgens, such as nandrolone, fluoxymesterolone, methandrostenolone and oxymetholone, have been reported to improve the anaemia of MMM in 30–60% of cases (Hast et al, 1978; Besa et al, 1982; Brubaker et al, 1982), with abnormal karyotype and severely compromised marrow haemopoiesis being associated with low chance of achieving a response (Besa et al, 1982). However, the reports on androgen treatment of the anaemia of MMM are scarce; they include a few patients whose follow-up were usually short, and were published more than two decades ago.

Similar results to those obtained with conventional androgens have been reported with danazol, a synthetic attenuated androgen that has proved useful in other haematological disorders, such as idiopathic thrombocytopenic purpura (Ahn et al, 1983), autoimmune haemolytic anaemia (Ahn et al, 1985) and the myelodysplastic syndromes (Stadtmauer et al, 1991). However, the experience with this therapy in the anaemia of MMM is restricted to isolated case reports (Chabannon et al, 1990; Levy et al, 1996) and our preliminary series of seven patients (Cervantes et al, 2000).

In the present series, including 30 patients treated in recent years with a long follow-up, responses to danazol approached 40%, with three quarters of them being complete. It must be noted that stringent response criteria were employed, as a PR was considered as an Hb increase >1·5 g/dl with transfusion-independent Hb values higher than 10 g/dl maintained for a minimum of 8 weeks, whereas in other studies (Cervantes et al, 2000; Hasselbalch et al, 2002) reductions in the transfusion requirements lasting for only 4 weeks were also considered as PRs.

Several aspects of the present study deserve comment. Firstly, danazol was given at a dose of 600–800 mg/d and treatment was maintained for at least 6 months, unless toxicity developed. However, we do not know whether similar results would have been obtained using lower danazol doses. Secondly, median time to response was 5 months, with eight of the 11 responses being observed between 3 and 6 months of starting treatment. On the contrary, after a progressive reduction, the minimum necessary dose to maintain the response was 200 mg/d. In this sense, the loss of response in the two patients in whom danazol was discontinued because of toxicity indicates the need for maintenance therapy.

Pretreatment variables associated with response to danazol were lack of transfusion requirement and higher Hb concentration at treatment start. Of note, borderline significance was also observed for higher leucocyte and reticulocyte counts. The mechanism of action of danazol is not well known. It has been hypothesized that, in addition to stimulating the bone marrow, it might improve the cytopenias by decreasing the number of the Fcγ receptors (Stadtmauer et al, 1991). Based on the results from the present study, it could be speculated that the higher the haemopoietic reserve, the higher the possibility of response. Finally, the favourable responses were durable in half of the cases, especially in patients who achieved a CR.

We recently reported a 45% response rate to rHuEPO treatment in the anaemia of MMM, with inadequate erythropoietin levels being the best predictor of response (Cervantes et al, 2004). In this regard, the lack of cross-resistance between danazol and rHuEPO in the present study is noteworthy. Indeed, one patient who failed to respond to rHuEPO responded to danazol, whereas six of the 12 patients that switched from danazol to rHuEPO, because of failure or toxicity, responded to this latter treatment. These observations should be taken into account when deciding therapy for patients with MMM and anaemia.

Danazol therapy was usually well tolerated. The most frequent toxicity consisted of a moderate increase in the liver enzymes, registered during the first months of treatment in some patients and usually improving after a dose reduction to 400 mg/d. Only two patients experienced severe side effects (cholestatic hepatitis and prostate adenocarcinoma respectively) leading to definitive treatment withdrawal. These complications, although infrequent, indicate the mandatory monitoring of liver function and periodic imaging surveillance to detect possible liver tumours during therapy, whereas systematic screening for prostate cancer must be carried out in men.

In conclusion, danazol, administered for a sufficient period time, was effective and well tolerated in a substantial proportion of MMM patients with anaemia. The present results can be used for historical comparison and indicate the need for a randomized, prospective, multicentric study comparing danazol with the newer strategies for the treatment of MMM.

References

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Discussion
  6. References
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