Cyclosporin A Monotherapy in Young Indian Aplastic Anaemia Patients

Subhash Varma*, Neelam Varma**, Pankaj Malhotra***, Sanjay Singh****, Deepika R Sharma*****

Immunosuppression is the most effective treatment for patients with aplastic anaemia (AA), except for bone marrow transplantation. This may be because immune mediated stem cell suppression appears to be an important pathogenic mechanism is many patients with AA. The mechanism of action of immunosuppressives in AA is unknown. However, they may reverse abnormal immune mediated suppression of hematopoiesis or induce growth and differentiation of marrow stem cells through activation of growth factors or various cytokines. The best results are achieved with antithymocyle globulin and cyclosporin when used with corticosteroids. Few studies have shown that the hematologic response to antithymocyte globulin is poorer in young patients¹. Several studies have shown that cyclosporin A (CyA) could be effective treatment for AA. However, adequate data concerning immunosuppressive therapy, especially the use of CyA in patients of AA are not available from India. We carried out an open labelled prospective evaluation of efficacy and safety of CyA in young patients with AA.

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MATERIAL AND METHOD

Patients of AA (bone marrow proven) attending haematology clinic of Internal Medicine, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh who were not suitable or unable to afford hone marrow transplantation or who were excluded from antithymocyte globulin therapy because of poor response seen in young age were recruited in the study. Written informed consent was taken before enrollment. Fifteen patients were enrolled from July 1998 to Feb 1999. These included 11 males and 4 females. A detailed physical examination was done to rule out any active infection before start of CyA therapy. Baseline investigations included haemogram, liver function tests, renal function tests, HIV, HBsAg and chest x-ray. All patients were followed up once in two weeks and detailed physical examination as outlined in Table 1 was carried out. During each investigation, patients were closely followed regarding occurrence of side effects. Baseline investigations eg, haemoglobin, TLC. platelets, urea, creatinine, SGOT/SGPT and alkaline phosphatase were also monitored once in two weeks, Patients were initially started on CyA 5 mg/kg/day (Panimun Bioral - CyA oral solution USP l00mg/ml - modified) in twice daily dosages. If there was no response in one month, CyA dose was increased to 7.5 mg/kg/day. A response to therapy was considered if there was an increase in baseline haemoglobin, TLC and platelets or decreases in the requirement of blood transfusions as compared to the slate before starting CyA therapy. The blood CyA levels were monitored once in two weeks. Patients were asked to report if they developed any bleeding tendencies, fever or any other side effect immediately to the hospital.

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RESULTS

Out of 15 patients, 3 patients died within 2 weeks of starting CyA because of bleeding complications and septicaemia. Two patients did not report back after one week of starting CyA. Four patients (30.8%) showed response through increase in haemoglobin, TLC, platelets and decrease in blood transfusion requirements. Two additional patients showed partial response through decrease in the number of blood transfusions as compared to pre-CyA therapy state. Four patients did not respond after 12 weeks of therapy and were withdrawn from the study. The mean CyA blood levels were 142.1±85.5 ng/ml as measured by a validated radio immuno assay. There was no significant increase in blood pressure in any patient. The liver function and renal function tests did not show any significant change from the baseline. The most common side effect was gum hyperplasia in two patients (7.7%). CyA was well tolerated among all patients.

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DISCUSSION

AA is a fatal haematologic disorder whose aetiology is not yet clearly defined. The dosage recommendations of CyA in these patients have also not been clearly formalised but it appears than an initial oral CyA dosage of 5 mg/kg/day adjusted according to response and serum creatinine levels is effective. CyA should be continued for at least 3 months and until peripheral red cell counts have stabilised for at least 1 month and then gradually tapered². Eighty four per cent full haematological response in 9-46 months has been reported by Totterman et al³ after using CyA alone or in combination with prednisolone. In severe aplastic anaemia resistant to conventional immunosuppression the response rate is lower but a small proportion (around 15%) may benefit form CyA therapy but longer treatment periods may however be needed to evaluate the role of CyA in AA³. With supportive measures using anabolic steroids and low dose steroids 20-50% patients with severe AA die within 6 months to 1 year after diagnosis ^4,5,6 and only 10-20% survive with persisting haematologic abnormalities. The most definitive therapy has been the use of immunosuppressive agents including antithymocyte globulin, CyA and cyclophosphamide which yield a variable response ranging from 20-80%⁶. There is however no solid basis to understand the effect of CyA but reports of increased release of immune interferon from the mononucleated leucocytes of patients with severe AA and the well known blocking effect of immune interferon by CyA might provide some explanation in the future^7,8. Our CyA response rate of (30.8%) at 5-7.5 mg/ kg, for >12 week treatment in young patients has been useful in reducing the severity of the disease as well as the number of blood transfusions. A low CyA side effect profile indicates that CyA was well tolerated by patients and did not add to the severity of disease.

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CONCLUSION

The efficacy of CyA in the treatment of patients with AA resulted in 30.8% full remittance and 15.8% partial response at 12 weeks of monotherapy.

ACKNOWLEDGMENT

The authors are thankful to Panacea Biotec Ltd., New Delhi for funding the study.

REFERENCES

1. Gluckman E, Esporou Bourdean H, Bamchud A et al. Multicenter randomised study comparing cyclosporine A alone and antithyniocyte globulin with prednisone for treatment of aplastic anemia. Blood 1992; 79(10): 2540-2546.

2. Schrezenmeiere H, Schandler M and Ragavashar A. Cyclosporine A in aplastic anemia - report of a workshop. Annals of Hamatology, 1992: 65:33.

3. Tutterman TH, Hoglund MB, Simonsson B, Almquist D and Killander A. Treatment of pure red-cell aplasia and aplastic anaemia with ciclosporin: Long-term clinical effects. European Journal of Haematology. 1989; 42:126-133.

4. Camitta BM, Thomas ED, Nathan DG et al. Severe aplastic anemia: a prospective study of the effect of early marrow transplantation of mortality. Blood, 1976; 48:63-70.

5. Hinterberger W. Geissler K, Fischer M, Lechner K et al. Aplastic anemia: Assessment of myeloid progenitor cells in the bone marrow and blood provides prognostic information. Acta Haematology, 1985; 73:1-5.

6. Storb R. Aplastic anemia. Journal of Intravenous Nursing, 1997; 20(6): 317-322.

7. Reem GH, Cook LA and Palladino MA. Cyclosporine inhibits interleukin 2 and interferon gamma synthesis by human thymocytes. Transplantation Proceedings, 1983; 15:2387-2389.

8. Zoumbos NC, Gascon P, Djeu J and yound NS. Interferon is a mediator of hematopoetic suppression in aplastic anemia in-vitro and possibly in vivo. Proc Natl Acad Sci (USA), 1985; 82:188-95.

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