American Journal of Hematology 26:83-87 (1987)

Cyclosporin A for the Treatment of Aplastic Anemia Refractory To Antithymocyte Globulin Ronald Bridges, Graham Pineo, and Walter Blahey

Department of Medicine, Calgary General Hospital and University of Calgary, Alberta, Canada

Antithymocyte globulin (ATG) is an established form of therapy for severe aplastic anemia (SAA). However, in patients who do not respond to this treatment and who are not candidates for bone marrow transplantation few successful therapeutic alter- natives exist. We report two such patients who have shown a therapeutic response to Cyclosporin A (CSA) (Sandimmune, Sandoz). Case 1, a 15 year old male, and Case 2, a 34 year old female, were diagnosed as having SAA in September 1984 and May 1984 respectively. Treatment with high dose Methylprednisolone (MPN) and ATG in Case 1 and MPN, ATG and Oxymetholone in Case 2 for ten days was ineffective in both cases. Case 1 developed anaphylaxis with both repeat ATG and ALG (antilym- phoblast globulin), and Case 2 failed to respond to repeat ATG. Both required frequent packed cells and platelet transfusions.

At five and six months respectively following completion of ATG therapy, CSA was started at 10 mglkglday in divided doses orally. Renal and liver functions and CSA blood levels were followed, Within six weeks both patients exhibited a hemato- logic response and were no longer transfusion dependent. On maintenance therapy of 4 mg/kg/day (Case 1) and four months after discontinuing CSA (Case 2) the hemato- logic values are as follows: hemoglobin 160 and 130 g/L, absolute granulocyte count 3100 and 1640 X 109/L, and platelets 132 and 84 X 109/L respectively. Side effects included hypertrichosis, gingival hyperplasia and mild reversible nephrotoxicity . CSA appears to represent an effective form of therapy for patients with SAA refractory to ATG .

Key words: aplastic anemia, immune mechanisms, immunosuppressive therapy

INTRODUCTION

Aplastic anemia is a potentially fatal hematopoietic disorder of uncertain etiol- ogy. Immune mechanisms have been shown to play a role in the pathogenesis of some cases of severe aplastic anemia (SAA) [l-31. As a result, immunosuppressive agents such as corticosteroids, cyclophosphamide, antithymocyte globulin (ATG), and anti- lymphocyte globulin (ALG) have been employed in the treatment of this disorder [4- 71. Where it is feasible, bone marrow transplantation is considered the treatment of choice with the second alternative being ATG [ 11. However, in patients who are not candidates for bone marrow transplantation or who do not respond to ATG, few therapeutic alternatives exist. Recent reports have indicated a favorable response of

Received for publication December 5 , 1986; accepted March 23, 1987. Address reprint requests to G.F. Pineo, MD, Department of Medicine, Calgary General Hospital, 841 Centre Avenue E, Calgary, Alberta, T2E OAl, Canada

0 1987 Alan R. Liss, Inc.

84

some patients with SAA to the potent immunosuppressive agent cyclosporin A (CSA) [8-121. We report two such patients who have shown a therapeutic response to CSA.

Case Report: Bridges, Pineo, and Blahey

I , ,

CASE REPORTS Case 1

A 15-year-old male was admitted to the Calgary General Hospital in October 1984 with a 2-month history of anorexia, weight loss, progressive dyspnea, bleeding gums, and blurred vision. He had previously been well with no history of a recent viral infection nor exposure to drugs or toxins. Physical examination revealed few purpuric lesions and bilateral retinal hemorrhages but no other abnormalities. Hema- tologic examination revealed hemoglobin, 40 g/L; white blood count, 2.1 x 109/L; absolute granulocyte count (AGC), 1.2 x 109/L; and platelets, 12 x 109/L. Bone marrow aspiration and biopsy confirmed the presence of SAA.

As illustrated in Figure 1, frequent transfusions were required. The rapid development of isoimmunization resulted in the need for single-donor human leuko- cyte antigen (HLA)-matched platelets within 2 weeks of diagnosis. Treatment with high-dose methylprednisolone (MPN) and ATG (Atgam, Upjohn) was initiated as previously described [6]. Oxymetholone was not given as hepatic enzymes were elevated at the time. Ten weeks following ATG treatment the patient was considered refractory. A second course of ATG was undertaken. However, during administration of the first drug infusion, he became febrile with associated urticaria, tachycardia, and bronchospasm indicative of an anaphylactic reaction. This was relieved by discontinuing the ATG and giving antihistamines. Four weeks later Minnesota anti-

Time f rom Diagnosis (months)

Fig. 1. Case I . Hemoglobin, 0- 0 ; absolute granulocyte count, x-x; and platelet count - - - - from time of diagnosis of SAA. Platelet counts less than 10 X 109/L were not deter-

mined. Transfusions and treatment modalities utilized were indicated. I indicates the time of a severe upper respiratory tract infection and previous gingival surgery.

Case Report: Cyclosporin A and Aplastic Anemia 85

lymphoblast globulin (MALG) was obtained. Test dose administration of MALG resulted in a similar anaphylactic reaction and the drug was discontinued.

In March 1985, 5 95 months following diagnosis, treatment was commenced with cyclosporin A (Sandimmune, Sandoz) at 10 mg/kg/day in divided oral doses. CSA blood levels as well as renal and hepatic function tests were followed carefully. Within 2 months of initiating treatment with CSA, no further transfusions were required. Thereafter, the maintenance CSA dosage was reduced to 4 mg/kg/day. During treatment with CSA he exhibited significant side effects to the drug including gingival hyperplasia requiring surgery, hypertrichosis, and mild reversible nephrotox- icity. These adverse effects were minimized with a reduction of CSA dosage without any change in the hematologic response.

Case 2 A 34-year-old female was admitted to the Calgary General Hospital in June

1984 with a 2-month history of fatigue, lethargy, easy bruising, and menorrhagia. There was no history of recent viral infection and no exposure to drugs or toxins. Examination revealed petechiae over the lower limbs. Hematological investigations included hemoglobin, 100 g/L; white blood count, 2.3 X 109/L; AGC, 0.3 X 109/L; and platelets, 10 X 109L. Bone marrow aspiration and biopsy confirmed the presence of SAA.

Treatment was undertaken with ATG (Atgam, Upjohn), high-dose MPN, and oxymetholone [6] (Fig. 2). Frequent transfusions were required. Four months after completion of the ATG no hematologic benefit was observed and a second course of ATG and high-dose MPN was initiated. Oxymetholone was withheld. Again there was no hematologic improvement and the patient remained transfusion dependent.

Tlme from Diagnosis (mOnth8l

Fig. 2. Case 2. Hemoglobin, 0-0; absolute granulocyte count, x-x; and platelet count, - - - - from time of diagnosis of SAA. Platelet counts less than 10 X 109/L were not deter-

mined. Transfusions and treatment modalities utilized were indicated. i indicates the occurrence of severe menorrhagia.

86 Case Report: Bridges, Pineo, and Blahey

In May 1985, CSA (Sandimmune, Sandoz) was started in an oral dosage of 10 mg/kg/day in divided doses. Blood levels of CSA as well as renal and hepatic function tests were monitored. The CSA dosage was decreased by 1-2 mg/kg/day every 2-4 weeks to a maintenance dose of 2 mg/kg/day. Two months after starting CSA, she developed severe menorrhagia requiring transfusion of packed cells and platelets. This bleeding stopped and she required no further blood products. Although she experienced no adverse side effects of CSA, she elected to discontinue the drug in April 1986. Hematologic change has not been observed to date (February 1987).

DISCUSSION

Evidence that immunologic mechanisms are involved in the pathogenesis of some cases of SAA exists in the form of clinical and in vitro investigations 11-31. The immunosuppressive therapy most widely used at present in the treatment of SAA is ATG, which has produced remissions in 40-60% of such patients [1,6]. However, in individuals with SAA who are not candidates for bone marrow transplantation and who do not respond to ATG, few therapeutic options exist. In the two patients reported here and in previous reports, CSA has been shown to have a therapeutic effect in the treatment of SAA despite resistance to previously administered immu- nosuppressive agents [9-121. In some cases CSA combined with MPN and oxymeth- olone has been effective where CSA alone has been ineffective [8]. The combination of CSA and ALS was no more effective than CSA alone 181.

Both of our patients exhibited a hematologic response within 10 weeks of starting CSA. This is longer than the response time noted in previous reports 19-11]. The hematologic responses in our patients were observed 6 and 8 months, respec- tively, after completion of ATG therapy. Patients showing a therapeutic response to ATG usually do so within 3 months of commencing therapy 161. Thus, it is unlikely that the observed responses represented a late response to ATG, although this cannot be completely excluded. Furthermore, it is possible that our patients experienced spontaneous remissions of the disorder.

Cyclosporin A is a potent immunosuppressive agent that selectively inhibits lympholune production by T helper cells 1131. As a result cyctoxic T cell differentia- tion is inhibited and a favorable environment is created for T suppressor cell prolif- eration [13]. The dosage of CSA employed was empiric, based on previous reports and the drug dosage utilized in previous organ transplantation studies [ 10,11,13]. At present the exact dose necessary to maintain an immunosuppressive action while minimizing adverse side effects is not known in this setting. As observed in previous trials, CSA does exhibit a range of potentially serious side effects including hypertri- chosis, hypertension, gingival hyperplasia, tremor, hepatic and renal dysfunction 1 131. The risk of developing a malignant lymphoproliferative disorder while taking CSA alone appears to be negligible [ 131. In the treatment of SAA, ATG and ALG usually have a prolonged effect [6,7]. The effect of withdrawing CSA is not known at present. Our second patient will be observed closely for evidence of relapse so that further treatment can be initiated.

Favorable responses to CSA in patients with SAA are reported here and in previous publications [9-121. However, these are only case reports utilizing small numbers of patients and a more extensive study using CSA in SAA is required to hl ly determine its therapeutic benefit. This prompts us to recommend a randomized

Case Report: Cyclosporin A and Aplastic Anemia 87

crossover trial comparing CSA with ATG, MPN, and oxymetholone in patients with SAA who are not candidates for bone marrow transplantation.

SUMMARY

Bone marrow transplantation and ATG are established forms of therapy for SAA. In patients who are not candidates for bone marrow transplantation or who fail to respond to two cycles of ATG, few therapeutic alternatives exist. We report two patients with SAA who failed to respond to ATG but who experienced a striking and sustained response to CSA persisting 16 months in one case and 12 months in the other. The latter patient has since discontinued CSA with no adverse effects. The only significant side effects were gingival hyperplasia, hypertrichosis, and mild nephrotoxicity, which resolved with a reduction in drug dosage. Cyclosporin A, a potent immunosuppressive agent, appears to represent an effective form of therapy for patients with SAA who are refractory to ATG.

ACKNOWLEDGMENTS

The authors wish to express their thanks to Dr. John Klassen, University of Calgary, for CSA blood level determinations; to Sandoz (Canada) for providing the CSA; and to Dr. Richard Condie, University of Minnesota, for providing the antilym- phoblast Globulin.

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