Postgrad Med J: first published as 10.1136/pgmj.66.780.827 on 1 October 1990. Downloaded from Postgrad Med J (1990) 66, 827 - 830 © The Fellowship of Postgraduate Medicine, 1990 Danazol in non-splenectomized patients with refractory idiopathic thrombocytopenic purpura D.Z. Edelmann'2, B. Knobel23, I. Virag' and D. Meytes"'3 Departments of 'Hematology and 2Medicine 'B', The Edith Wolfson Medical Center, Holon 58100, and 3The Sackler Faculty ofMedicine, Tel-Aviv University, Israel

Summary: Seven non-splenectomized patients with chronic refractory idiopathic thrombocytopenic purpura were treated with danazol 800 mgdaily. All were failures and four were refractory to all additional previous therapy. Five patients benefited from danazol and in two sustained normal plateletcounts, for over 44 and 51 months, were observed. We conclude that danazol is useful for long term management of otherwise refractory idiopathic thrombocytopenic purpura. The advantage of danazol over splenectomy as a first line treatment in failure is suggested.

Introduction Thrombocytopenia in most patients with idio- decline in platelet counts and bleeding. The addi- pathic thrombocytopenic purpura (ITP) responds tion ofimmunosuppressive therapy in five patients to ."-3 Splenectomy is considered the treat- failed to raise platelet counts. ment of choice in steroid failures,",4'5 followed by All patients were treated with a fixed dose of immunosuppressive therapy when needed.'"2 danazol (Danocrine®, Winthrop) 800 mg daily for by copyright. Danazol, a derivative of ethinyl , is a at least 3 months. Evaluation of response was synthetic attenuated with reduced mas- scaled as follows: 'excellent' - when platelet count culinizing capacity, initially formulated for the rose to 100 x 109/1 or more and remained there for treatment of .2'3'6-8 Favourable at least 2 months with continued therapy; 'good' - a results of danazol therapy in refractory ITP were sustained increase to 50-100 x 109/l; 'transient' - first described by Ahn et al. in 1983.6 In the few when the rise was to more than 50 x 109/l and reports published since, the authors were almost lasted less than 2 months; 'poor' - when platelet equally divided between those who achieved counts did not rise over 20 x 109/1. similar results8-"0 and those who failed to show a significant response.3"T Since splenectomy may http://pmj.bmj.com/ have operative and in particular considerable post- Results operative complications, we considered it worth- while to examine the effect of danazol in patients Results of treatment with danazol are presented in with ITP, prior to splenectomy. Table II. Five ofthe seven patients improved under danazol. Three had 'excellent', one 'good' and one a 'transient' response. Two of the excellent re-

Materials and methods sponders (Nos 1, 3) have maintained their platelet on September 25, 2021 by guest. Protected counts above 100 x 109/1 for 44 and 51 months, Seven patients with chronic refractory ITP, who with danazol being the only treatment. In patient refused splenectomy, were studied. Patients' data No. 1 the discontinuation of danazol was and treatment regimen before danazol are present- associated with a significant reduction of platelet ed in Table I. Six were steroid failures and in one counts, while readministration was repeatedly fol- steroids were contraindicated. In five patients a lowed by a rise to normal values. In patient No. 7 daily dose of (60-150 mg), during at after 3 months of treatment with an excellent least 6 weeks, failed to raise platelet counts to response the dose of danazol was reduced and adequate levels. In one patient (No. 5) although a platelet count declined to 30 x 109/1. This value was transient response, up to 142 x 109/1 platelets, was higher than the one previously observed with noted, steroid withdrawal was associated with a prednisone and azathioprine combined. Synergis- tic effect of prednisone and danazol was noted in the good responder (No. 6), in whom prednisone Correspondence: D. Meytes, M.D. was reduced from 30 mg daily prior to danazol Accepted: 9 May 1990 therapy to 10 mg when the two drugs were given Postgrad Med J: first published as 10.1136/pgmj.66.780.827 on 1 October 1990. Downloaded from 828 D.Z. EDELMANN et al.

Table I Patients' data and treatment regimens prior to danazol therapy Duration of ITP prior Age to danazol Previous treatment Patient (yrs) Sex (months) Steroids vincristine colchicine azathioprine 1 62 F 235 + - - - 2 84 M 180 + - - - 3 72 F 49 + - - - 4 55 F 38 + + - + 5 61 M 13 + + + + 6 55 M 4 + + + 7 62 F 12 + - - +

Table II Results of danazol therapy in idiopathic thrombocytopenic purpura Platelet count (x 109/1) Duration of Before On danazol follow up Patient danazol for I month maximal value (months) Responset 1 50 92 137 44 Excellent 2 18 6 7.2 9 Poor 3 16 25 122 51 Excellent 4 23 55 55 50 Transient 5 11 16 16 8.5 Poor 6* 9 65 65 40 Good 7 15 114 209 15 Excellent by copyright. 'Patient stopped danazol because of side effects; tsee text for explanation.

simultaneously. In this patient there was a 7-fold Danazol for refractory ITP was first introduced elevation in platelet count. This patient was the in 1983 by Ahn et al. with encouraging results.6 only one who suffered from side effects ofdanazol. Fifteen out of 22 patients (68%) were improved He had headache and nausea which caused cessa- and in 11 (50%) sustained normal platelet counts tion of treatment. One patient exhibited a 'tran- for 2-3 months were recorded. These results sient' response though danazol was continued. seemed especially promising, as danazol has been http://pmj.bmj.com/ Maximal response was seen within one month of utilized for the management of many non- treatment in three of the five responders. No haematological disorders in the last 15 years with- response was noted in two patients. out significant side effects.2 6-8'1-'4 The mechanism of danazol activity in ITP is not clear. Animal experiments suggest that it reduces antibody secre- Discussion tion by enhancing the function ofsuppressor cells,2 but the study ofthe effect ofdanazol on the level of The potential therapeutic modalities available for antiplatelet antibodies in patients with auto- on September 25, 2021 by guest. Protected patients with ITP who do not respond to steroids immune thrombocytopenia has yielded conflicting are far from being satisfactory. results.'5 Danazol also suppresses macrophage Immunosuppressive drugs such as vinca activity2 and may mediate its clinical effect at least alkaloids, cyclophosphamide and azathioprine in part by decreasing the number of available Fc have been shown to produce a rise in platelet counts (IgG) receptors on human monocytes.'6 It appears in some patients. However, side effects, mainly to be an effective immune modulator which in- bone marrow suppression and sterility, together creases T helper/inducer cells in patients with with the short lived effect ofvinca alkaloids and the autoimmune thrombocytopenia.'7 carcinogenic potential of cyclophosphamide and The results of clinical studies following the first azathioprine are major disadvantages. Splenec- report6 are inconsistent (Table III). In two, a tomy, besides having operative and post-operative beneficial effect was seen: in one,8 all three patients hazards does not benefit all patients. High dose demonstrated various degrees of response; in the intravenous immunoglobulin IgG is very expensive other,9 7 out of 14 patients (50%) responded and 5 and only of temporary effect. had a sustained complete remission. Postgrad Med J: first published as 10.1136/pgmj.66.780.827 on 1 October 1990. Downloaded from DANAZOL IN NON-SPLENECTOMIZED PATIENTS 829

Table III Data from published studies using danazol for the treatment of idiopathic thrombocytopenic purpura No. of Results' Danazol splenectomized no. of benefited dosage patients/total no. patients/total Author mg/day ofpatients no. ofpatients Ahn6 400-800 15/22 Favourable 15/22 Mcvery3 600 6/10 Non-favourable 3/10 Heyd8 800 3/3t Favourable 3/3 Buelli9 600 6/14 Favourable 7/14 Almagro'° 400-800 t Non-favourable 2/9 'Favourable - 50% or more response rate; non-favourable - 30% or less response rate. tOne patient underwent splenectomy after secondary danazol failure. ;No data on the number of patients who underwent splenectomy before danazol.

In contrast, in two other studies results were ated with systemic 'erythematosus'5 and in all much less encouraging. In one study only one out 6 patients thrombocytopenia resolved within 6 of 10 patients had a sustained increase in platelet weeks of the addition of danazol treatment to the counts and two others had transient response; in previously existing medications. For two of the the second,'° only one single patient out of 9 patients had failed, for one patient showed long-term normalization ofplatelet counts glucocorticoids and azathioprine had failed, for while in another a transient response was noted. another and had failed glucocorticoids splenectomy by copyright. The reason for the different results is not clear. and for the remaining two patients glucocorticoids, Whether different patient populations or splenectomy and azathioprine had been unhelpful. differences in danazol dosage, which was not The effectiveness of danazol in steroid resistant uniform for all patients reported, cause the dis- patients on the one hand and its safety on the other, crepant results, cannot be determined. Our data, raises the possibility that this drug should be although based on a small group ofpatients, are in considered among the first line therapeutic accordance with those ofAhn et al.6 and also show modalities available for the treatment of ITP. Its various degrees of improvement in 5/7 of the introduction before splenectomy and/or immuno- patients. Moreover, in all previous studies the suppressives may be not infrequently associated of the were with favourable majority patients splenectomized. results and might save splenec- http://pmj.bmj.com/ Clinical experience with danazol in non- tomy in many patients. The optimal doses for splenectomized patients has been very limited so induction of response and for its maintenance, as far. well as the duration of therapy remain to be Danazol was found useful in the treatment of determined in future controlled studies in a larger refractory autoimmune thrombocytopenia associ- group of ITP patients.

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