Danazol Treatment for Paroxysmal Nocturnal Hemoglobinuria

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1 Case Report Danazol Treatment for Paroxysmal Nocturnal Hemoglobinuria Masahiro MURAKAWA,Tsunefumi SHIBUYA, Mine HARADA, Takashi OKAMURA, Yoshinobu ASANO, Hideki OKAMURA and Yoshiyuki NlHO Danazol was administered to two patients with paroxysmal nocturnal hemoglobinuria (PNH) with a dramatic effect on the hematological findings. The patients, 31- and 41-year-old females, were initially diagnosed as having aplastic anemia, and were initially treated with anabolic steroid and immunosuppressive therapy, respectively. Sugar water and Hamtests turned positive at the start of danazol therapy in the former patient and after two months in the latter patient. This drug produced a dramatic improvement in the hemoglobin level and the platelet count and showedfew side effects in the patients. A possible mechanismof action of danazol for PNHis briefly discussed. Key words: Hemolytic anemia, Aplastic anemia, Hematopoiesis, Therapy Danazol, a synthetic androgen with a reduced virilizing effect, is administered for the treatment of endometriosis. Ahn et al (1) introduced this drug as an effective agent for the treatment of immune thrombocytopenic purpura (ITP), and it has also been reported to be useful in the treatment of autoimmune hemolytic anemia (AIHA) even when corticosteroids were ineffective (2). Furthermore, many reports have described the effects of this agent in patients with aplastic anemia (AA) (3), pure red cell aplasia (PRCA) (4) and myelodysplastic syndrome (MDS) (5, 6). Paroxysmal nocturnal hemoglobinuria (PNH) is a primary disorder of bone marrow hemopoietic cells characterized by an unusual susceptibility to the hemolytic action of complement (7, 8). Pancytopenia and intravascular hemolysis followed by hemoglobinuria and subsequent renal damage in the course are sometimes difficult to control. Therapeutic trials of corticosteroids and anabolic steroids for PNHhave not always been satisfactory (9). Although the administration of danazol has been reported to be effective (10), the usefulness of this therapy has not been established. Recently, we experienced two cases of PNHin which danazol produced a dramatic effect for the recovery from severe anemia. Danazol also had fewer side effects such as virilization and skin complications than anabolic steroids and gave encouraging results. We herein report two cases of PNHsuccessfully treated with danazol. CASE REPORT Case 1 (I.G.) A 31-year-old Japanese womanwas admitted to a local hospital on July 23, 1988, because of headache and transient left hemiparesis. At the age of 27, dysfunctional genital bleeding had developed and she was diagnosed to have aplastic anemia (AA) on the basis of hematological and bone marrow findings at a local hospital. Fluoxymesterone and prednisolone the patient (PSL) had produced some effects, but had refused treatment with anabolic steroids and had been given blood transfusions alone. From the First Department of Internal Medicine, Faculty of Medicine, Kyushu University, Fukuoka Received for publication August 14, 1989; Accepted for publication June 5, 1990 Reprint requests should be addressed to Tsunefumi Shibuya, MD,First Department of Internal Medicine, Faculty of Medicine, Kyushu University, Maidashi, Higashi-ku, Fukuoka 812, Japan 417

2 Murakawa et al At admission to a local hospital, Hb was 6.0 g/dl, RBC 1.63xlO12/l, Ht 19.7%, MCV 121 fl, MCH 36.8 pg, MCHC30.5% and PNH was diagnosed on the basis of positive sugar water and Hamtests. She was transfused with 7 units of washed red blood cells for two days, and then was referred to our department for further examination and for control of the disease on August 8, At admission to our department, hematological findings just after transfusion were as follows (Table 1); Hb 7.7 g/dl, RBC 2.21x1012/l, Ht 24.0%, MCV 109 fl, MCH 34.8 pg, MCHC32.1%, reticulocytes 2.3%, WBC 1.9x 109/l and platelets 38 x 109/l. Sugar water and Hamtests were positive. Serum haptoglobin level was less than 10 mg/dl. Bone marrow aspiration showed a nucleated cell count (NCC) of 15 x 199/1 with 26.0% erythroid series, and bone marrow biopsy also showed highly hypoplastic marrow. Danazol, at a dose of 400 mg/day, was started on August 13, and she was discharged and followed up in our outpatient clinic. In October 1988, the dose of danazol was reduced to 200 mg/day because of amenorrhea and appearance of facial acne. The hemoglobin level gradually increased from November 1988 (Fig. 1). On May 9, 1989, hematological findings were as follows; Hb 15.0 g/dl, RBC 4.51X1012/l, Ht 47.1%, MCV 104 fl, MCH 33.3 pg, MCHC 31.8%, reticulocytes 1.9%, WBC 2.7xlO9/l, and platelets 61x 109/L NCC of the bone marrow was 321 x 109/l with 36% erythroid series. In addition, the serum haptoglobin level recovered to 103 mg/dl. The remission has thereafter been maintained for more than 12 months with a dose of only 100 mg/day of danazol. Liver function did not deteriorate during the course. Case 2 (S.T.) A 41-year-old Japanese woman visited a physician on March 8, 1988, complaining of palpita- Table 1. Laboratory findings of patient 1 at admission. Peripheral Blood Blood Chemistry WBC 1 9x lo9/l T.bil. 0.7 mg/dl St. 3% LDH 526 IU/1 Seg. 51% BUN 9 mg/dl Mo. 4% Creat. 0.7 mg/dl Lym. 42% Iron 99 ^g/ml RBC 2.21 x lo12/l TIBC 253 /ug/m\ Hb 7.7 g/dl Ferritin 67.8 ng/ml Hct 24.0% Haptoglobin < 10 mg/dl Reticulocyte 2. 3 % Platelet 38 x l09/l Serology Sugar water test (+ ) CRP (-) Ham test (+) CH50 41 CH50-U C3 74 mg/dl Bone Marrow C4 31 mg/dl NCC 15 X 10V1 Coombs test (-) M/E ratio 0.68 Cold agglutinin test (-) Macro-Poly. 2.0% Macro-Orth. 1.2% Urine Examination Norm-Poly. 18.4% Occult blood (-) Norm-Orth. 4.4% Protein (-) Neu-Myelo. 3. 6% Urobilinogen (N) Neu-Meta. 2.0% Hemoglobin (-) Neu-Stab. 4.4% Casts (-) Neu-Seg. 7.6% Hemosiderin (-) Monocyte 1.2% Lymphocyte 55.2% Stool Examination Megakaryocyte (-) Occult blood (-) K aryotype 46XX Eggs (-) 418

3 Danazol for PNH I.G. PNH m 400mg s- Jul. Aug. Sep. Oct. Nov. Dec. Jan. Feb. Mar. '88 '89 Fig. 1. Clinical course of patient 1. Arrows show RBCtransfusions. tion. Severe pancytopenia was found and she was referred to our hospital immediately. On admission, hematological findings revealed marked pancytopenia (Table 2); Hb 4.1 g/dl, RBC 1.05X 1012/l, Ht ll.2%, MCV 106 fl, MCH 39 pg, MCHC 36.6%, reticulocytes 2.6%, WBC 2.6x 109/l and platelets 22 x 109/l. Bone marrow aspiration showed a NCC of 43 x 109/l with 24% erythroid series, and bone marrow biopsy also showed markedly decreased hemopoiesis. Neither sugar water test nor Hamtest was positive at this time. She was diagnosed as having AAand two courses of pulse-therapy with methylprednisolone were administered without effect. On May 14, 1988, administration of cyclosporin A (Cy-A) at a dose of 280 mg/day was started. The frequency of blood transfusions was decreased thereafter and the leukocyte and platelet counts increased. On September 6, 1988, Cy-A was stopped for economic reasons and danazol at a dose of 400 mg/day was started. In two weeks, the hemoglobin level started to rise with a dramatic increase of reticulocytes to more than 10.0% in the peripheral blood. On November 15, 1988, hematological findings were as follows; Hb 9.1 g/dl, RBC 2.39xlO12/l, Ht 29.0%, MCV 121 fl, MCH 38.1 pg, MCHC 31.4%, reticulocytes 9.6%, WBC 3.1xl09/l, and platelets 58x l09/l. NCC of the marrow increased up to 431 x lo9/l with 60.8% erythroid series. At this time, both sugar water and Hamtests turned positive. Thereafter, the Hb level reached a plateau level of approximately 8 g/dl and the platelet count was then maintained at approximately 50 X 109/l, as shown in Fig. 2. All symptoms due to pancytopenia were alleviated, although facial acne and amenorrhea appeared after two months. Liver function was not affected by the agent. DISCUSSION Danazol is well knownto be effective in some patients with chronic ITP who have failed to respond to prednisolone (PSL), immunosuppressants and splenectomy (1 1-15). The mechanisms of the effect of danazol for ITP have been explained in terms of enhancement of thrombopoiesis (15), suppression of anti-platelet auto-antibody production (16, 17), and impairment of clearance of immunoglobulin-bound platelets by macrophages (18). A clinical trial of danazol for the treatment of autoimmune hemolytic anemia (AIHA) with an evaluable effect was reported by Ahn et al (2). In that study, the reduction of the dose of corticosteroids became possible with concomitant administration of danazol. It was speculated that danazol worked by blocking the binding of IgG and C3 to erythrocytes. With respect to the effect of danazol for AAand 419

4 .--\ \/ U 1 ^.-# 400mg Murakawa et al Table 2. Laboratory findings of patient 2 at admission. Peripheral Blood Blood Chemistry WBC 2.6x lo9/l T.bil. 1.4 mg/dl St. 1% D.bil. 0.2 mg/dl Seg. 56% LDH 593 IU/1 Mo. Lym. 2% 41% BUN Creat mg/dl mg/dl RBC Hb 1.05 x l012/l 4.1 g/dl Iron TIBC /ig/ml ptg/m\ Hct 1 1.2% Haptoglobin <10 mg/dl Reticulocyte 2. 6% Platelet 22 x lo9/l Serology Sugar water Ham test test (-) (-) CRP CH50 37 (-) CH50-U C3 66 mg/dl Bone Marrow C4 26 mg/dl NCC 43 x 109/l Coombs test (-) M/E ratio 2.02 Cold agglutinin test (-) Proerythroblast 0.4% Macro-Poly. 0.4% Urine Examination Norm-Baso. 3.2% Occult blood (-) Norm-Poly. 12.8% Protein (-) Norm-Orth. 7. 2% Urobilinogen (N) Myeroblast 0. 8% Casts (-) Neu-Promyelo. 2. 8% Hemosiderin (-) Neu-Myelo % Neu-Meta. 8.4% Stool Examination Neu-Stab. 5.2% Occult blood (-) Neu-Seg % Eggs (-) Eo-Meta. 0.4% Eo-Seg. 0.8% Monocyte 0.8% Lymphocyte 25. 2% Plasma cell 1.6% Megakaryocyte 6.25 x 106/l K aryotype 46XX S.T. A.A. --PNH Hb (g/dl)10 9 Platelets xio9/i)' li U IIU iiii il iiu "V./à"- Mar. Apr. May Jun. Jul. Aug. Sep. Oct. Nov. Dec. Jan. Feb. Mar. 88 '89 Fig. 2. Clinical course of patient 2. Small arrows show RBCtransfusions and large arrows show platelet transfusions. 420

5 Danazol for PNH MDS,in which a decrease of hemopoietic stem cells or ineffective hemopoiesis is thought to be the main cause of pancytopenia, only a few papers have been reported (3, 5, 6). Danazol may act as a direct stimulator of hemopoiesis in such cases, in the same way as anabolic hormones (19). On the other hand, MDSis sometimes accompanied by immunethrombocytopenia or hemolysis (5) and hence it is probable that danazol exerts its beneficial effect through mechanisms similar to those in ITP and AIHA. The present two cases indicate the usefulness of danazol for the treatment of PNH, as has been previously cells with reported increased (10). PNH is susceptibility a disorder of blood to complementmediated lysis, and the PNH cells presumably arise from a clonal mutation of a hemopoietic This fact has been demonstrated by stem cell. the single glucose-6-phosphate dehydrogenase (G-6-PD) isoenzyme in patients who were heterozygous at G-6-PDlocus (20). The two cases reported here showed marked bone marrow hypoplasia and negative results in Ham and sugar water tests initially, and thus a diagnosis of AA was made at presentation. In patient 1, PNHappeared to occur in the course of AA, as many patients with PNH have a prior history of AA(21). In patient 2, danazol was initially administered for the treatment of AA, and subsequently PNHdeveloped. It is not surprising that PNHshould arise from a defective clone in the marrowof AA.As the bone marrowbecame hyperplastic and the Hamtest turned positive with danazol treatment, it is probable that the agent accelerated the proliferation of an abnormal clone with increased susceptibility to complement. It is also probable, however, that not only overproduction of hemopoietic cells but also suppression of their complement- and macrophage-mediated lysis may have produced the subsequent increase of blood cells in the peripheral blood. Further studies to define the clinical effects of danazol on PHN clones, and particularly on the immune system, are therefore necessary. REFERENCES 1) Ahn YS, Harrington WJ, Simon SR, Mylvaganam R, Pall LM, So AG. Danazol for the treatment of idiopathic thrombocytopenia purpura. N Engl J Med 308: 1396, Ahn YS, Harrington WJ, Mylvaganam R, Ayub J, Pall LM. Danazol therapy for autoimmune hemolytic anemia. Ann Int Med 102: 298, Nakamura K, Yoshimitsu K, Ootsuka H, Nakano H, Nagata Y. Long-term danazol treatment for an adolescent girl with aplastic anemia. Asia-Oceania J Obst Gynecol 12: 365, Lippman SM, Durie BGM, Garewal HS, Giordano G, Greenberg BR. Efficacy of danazol in pure red cell aplasia. Am J Hematol 23: 373, Cines DB, Cassileth PA, Kiss JE. Danazol therapy myelodysplasia. Ann Int Med 103: 58, in Kornberg A, Yona R, Iuklea S, Kaufman S. Danazol and myelodysplastic syndrome(letter). Ann Int Med 104: 446, Rosse WF, Dacie JV. Immunelysis of normal human and paroxysmal nocturnal hemoglobinuria (PNH) red blood cells. J Clin Invest 45: 736, Aster RH, Enright E. A platelet and granulocyte membrane defect in paroxysmal nocturnal hemoglobinuria; usefulness for the detection of platelet antibodies. J Clin Invest 48: 1199, Firkin F, Goldberg H, Firkin BG. Glucocorticoid management of paroxysmal nocturnal hemoglobinuria. Aust Ann Med 17: 127, Harrington WJ, Ahn YS, Cohen JJ, Ayub J, Pall LM. Treatment of paroxysmal nocturnal hemoglobinuria with danazol. Blood (Abstr.) 64: 86a, McVerry BA, Auger M, Bellingham AJ. The use of danazol in the management of chronic immune thrombocytopenic purpura. Br J Haematol 61: 145, Mazzucconi MG, Francesconi M, Falcione E, et al. Danazol therapy in refractory chronic immune thrombocytopenic purpura. Acta Haematol 77: 45, West SG, Johnson SC. Danazol for the treatment of refractory autoimmunethrombocytopeniain systemic lupus erythematosus. Ann Int Med 108: 703, Dan K, Nomura T. Evaluation of the danazol therapy in chronic refractory idiopathic thrombocytopenic purpura. Jpn J Clin Hematol 27: 1705, 1986 (in Japanese). Suzuki H, KojimaT, Sano M, Saito H, Kawamoto M. Effects of danazol on idiopathic thrombocytopenic purpura. Jpn J Clin Hematol 26: 709, 1985 (in Japanese). Michakski JP, McCombs CC, Roubinian JR, Talal N. Effect of androgen therapy on survival and suppressor cell activity in aged NZB/NZWFl hybrid mice. Clin Exp Immunol 52: 229, Agnello V, Pariser K, Gell J, Gelfand J, Nuran R, Turksoy RN. Preliminary observation on danazol therapy of systemic lupus erythematosus: Effects on DNAantibodies, thrombocytopenia and complement. J Rheumatol 10: 682, Schreiber AD, Chien P, Tomaski A, Cines DB. Effect of danazol in immunethrombocytopenic purpura. N Engl J Med 316: 503,

6 Murakawa et al Kennedy BJ, Gilberstein S. Increased erythropoiesis induced by androgenic-hormone therapy. N Engl J Med 256: 719, Oni SB, Osunkoga BO, Luzzato L. Paroxysmal nocturnal hemoglobinuria. Evidence for monoclonal origin of abnormal red cells. Blood 36: 145, ) Lewis SM, Dacie JV. The aplastic anaemia-paroxysmal nocturnal haemoglobinuria syndrome. Br J Haematol 13: 236,