Severe aplastic anemia can be treated with either bone marrow transplantation (BMT) or immunosuppressive therapy (IST). A retrospective review of patients with severe aplastic anemia treated with both of these modalities was conducted. Fifteen BMT and 16 IST patients were available for analysis, and follow-up of 22 and 15 years was available for the BMT and IST groups, respectively. Median survival was limited to 4.3 months in BMT patients vs. 135.2 months in IST patients, despite the older median age of the latter (22 vs. 55 years). Actuarial survival at 1 and 5 years was 87% and 78% for the IST patients and 40% and 33% for the BMT patients. Hematologic response rates, as defined by achievement of transfusion independence, were similar for the two groups. Long-term responses and survival are possible with antithymocyte globulin/cyclosporin A.
Severe aplastic anemia (SAA) is an uncommon and serious disorder characterized by pancytopenia, hypocellular bone marrow, and a high mortality rate.1 Before the development of effective treatment modalities, more than 50% of patients died within 6 months of presentation.2 Dramatic improvements in the outcome of patients with SAA have been realized during the last three decades, largely because of the success of allogeneic bone marrow transplantation (BMT).3 Experience gained by the most active centers suggests that BMT results in long-term survival rates of 68% to 80%.4-7 Although these accomplishments are noteworthy, BMT may not be appropriate for the majority of patients with SAA because of advanced patient age or the lack of suitable marrow donors.
Immunosuppressive therapy (IST) is another option for patients with SAA who are not candidates for BMT. Commonly used regimens have included antithymocyte globulin (ATG) or antilymphocyte globulin alone or in combination with other agents, such as steroids, cyclosporin A (CyA), or androgens.4,5,8,9 Two randomized trials have firmly established the role of combining ATG or antilymphocyte globulin with CyA in the treatment of moderate or severe aplastic anemia.10,11 Large retrospective series that have compared BMT and IST included IST patients who were treated heterogeneously, and in the majority of instances, they did not receive combinations of ATG and CyA.4,5 A description of a large number of patients from the European Group for Blood and Marrow Transplantation did not specify the proportion of patients who received ATG and CyA.7 Our group of SAA patients treated with IST is unique because they have received IST with ATG and CyA since 1985.
We conducted a retrospective review of SAA patients treated at the Kansas University Medical Center with either BMT or IST. Our objectives were to describe and compare survival and response rates between the two groups and to record any treatment-related toxicities. Our initial experience with IST consisting of ATG/CyA and BMT for aplastic anemia patients has been reported previously.12,13
BMT and intensive IST with ATG and CyA are widely recognized effective treatments for SAA.4,5,8,9 The decision to pursue one treatment or the other is largely dependent on the availability of a suitable HLA-matched donor and the age of the patient. In SAA, adults older than 40 years tend to have significantly poorer survival after allogeneic BMT.7
In the present study, SAA patients treated primarily with IST had improved survival over patients treated with BMT. This was true even though the BMT group was significantly younger than the IST group. The dissimilar survival outcomes between the two groups may relate to the high treatment-related mortality in our BMT patients, many of whom were transplanted at a time when higher-resolution HLA DNA typing and adequate GVHD prophylaxis were not available. Moreover, our BMT group was composed of high-risk patients, three of whom were critically ill with fulminant fungal and bacterial infections (requiring ventilatory support) at the time of transplantation, and two other patients were older than 50 years.
Shortcomings of our investigation are certainly its retrospective nature and the small number of patients. Because this was a retrospective study conducted over a number of years, both the BMT and IST groups were given the preparatory and supportive drugs in a heterogeneous fashion. This alone could affect our results considerably.
The majority of our IST patients (14 of 16) were treated with a longer duration of ATG, which ranged from 12 to 14 days. 13 This longer course of lower-dose ATG was relatively well tolerated by our patients, and significant features of significant serum sickness did not occur. The total amount of ATG administered at 15 mg/kg/day for 12 days is only slightly more than when administered at 40 mg/kg/day for 4 days (180 vs. 160 mg). Even though a 4-day treatment course has been rigorously tested and proven to be of benefit,14 a longer course of ATG using lower daily doses may be better tolerated by those patients with lower cardiac reserve and less tolerance for large volume loads. ATG given for a longer duration at lower doses has been shown to be as affective as shorter courses given at higher doses.15
Our IST patients required long-term administration of CyA for the maintenance of blood counts after ATG infusion. The optimal duration of CyA administration has not been defined. Bacigalupo et al. noted that prolonged CyA is required for optimal control of blood counts.7 In 100 SAA patients treated with ATG, CyA, prednisolone, and granulocyte colony-stimulating factor, the actuarial probability of discontinuing CyA was 38% at 5 years.
In our patients, not including the two early deaths, the median duration of CyA administration was 738 days. Our practice is to maintain CyA at therapeutic levels and then taper it slowly after patients have achieved their best-- sustained response. In our experience, increasing the dose of CyA can result in additional improvements in blood counts if a decline in blood counts is noted upon an initial attempted taper. Prolonged administration of CyA raises concerns about other important side effects, including hypertension, renal disease, and the formation of de novo malignancies such as lymphoproliferative disorders.16 In the majority of our patients, dose reductions of CyA had been achieved within 12 months of its initiation.
In our experience, older patients with SAA treated with IST had at least equivalent long-term survival than younger patients treated with BMT. However, the survival of our SAA patients undergoing BMT was inferior to more recent outcomes reported from other centers.4,5,7 Because of the inferior outcomes seen in our transplanted patients, and the fact that our study was conducted retrospectively, we cannot draw firm conclusions from our comparative analysis. However, we can conclude that long-term quality responses and survival are possible using intensive IST with ATG and CyA.
Because a significant number of patients do not have suitable HIA-matched donors and are beyond the age limit for undergoing transplantation, IST is the only therapeutic modality to which appropriate responsiveness may occur. Prolonged administration and titration of CyA is required for optimal control of blood counts. Growth factors such as granulocyte colony-stimulating factor used in combination with ATG, CyA, and steroids seem to improve hematologic response rates in patients with SAA.9,17 If superior survival rates are demonstrated by adding growth factors to IST in randomized trials, then the use of granulocyte colonystimulating factor in combination with ATG, CyA, and steroids may become the next standard by which hematopoietic stem cell transplantation results will be compared.
The authors are grateful to Diana Phillips for her assistance in preparing this manuscript.
1. Young NS, Alter BP: Aplastic Anemia Acquired and Inherited, p 12. Philadelphia, PA, Saunders, 1994.
2. Hinterberger-Fischer M, Hinterberger W, Hockern P, et al: Treatment of severe aplastic anemia with combined immunosuppression (antithymocyte globulin and high-dose methylprednisolone). Acta Haematol 1986; 76: 196-201.
3. Camilla BM, Thomas ED, Nathan DG, et al: Severe aplastic anemia: a prospective study of the effect of early marrow transplantation on acute mortality. Blood 1976: 48: 63-70.
4. Paquette RL, Tebyani N, Frane M, et al: Long-term outcome of aplastic anemia in adults treated with antithymocyte globulin: comparison with bone marrow transplantation. Blood 1995; 85: 283-90.
5. Doney K, Leisnering W, Storb R, Appelbaum FR, Primary treatment of acquired aplastic anemia: outcomes with bone marrow transplantation and immunosuppressive therapy. Ann Intern Med 1997: 126: 107-15.
6. Deeg HJ, Leisenring W, Storb R, et al: Long-term outcome after marrow transplantation for severe aplastic anemia. Blood 1998; 91: 3637-45.
7. Bacigalupo A, Brand R, Oneto R, et al: Treatment of acquired severe aplastic anemia: bone marrow transplantation compared with immunosuppressive therapy. The European Group for Blood and Marrow Transplantation experience. Semin Hematol 2000; 37: 69-78.
8. Tichelli A, Socie G, Henry-Amar M, et al: Effectiveness of immunosuppressive therapy in older patients with aplastic anemia. Ann Intern Med 1999; 130: 193-201.
9. Bacigalupo A, Bruno B, Saracco P, et al: Antilymphocyte globulin, cyclosporin, prednisolone, and granulocyte colony-stimulating factor for severe aplastic anemia: an update of the GITMO/EBMT study on 100 patients. Blood 2000; 95: 1931-4.
10. Frickhofen N, Joachim P, Kaltwasser JP, et al: Treatment of aplastic anemia with antilymphocyte globulin and methylprednisolone with or without cyclosporine. N Engl J Med 1991; 324: 1297-1304.
11. Marsh J, Schrezenmeier H, Marin P. et al: Prospective randomized muticenter study comparing cyclosporin alone versus the combination of antithymocyte globulin and cyclosporin for treatment of patients with nonsevere aplastic anemia: a report from the European Blood and Marrow Transplant (EBMT) Severe Aplastic Anaemia Working Party. Blood 1999; 93: 2191-5.
12. Goldman B, Amare M, Skikne BS: Aplastic anemia: the role of bone marrow transplantation. J Kans Med Soc 1980; 81: 137-9.
13. Doolittle GC, Bodensteiner DC, Skikne BS, Amare A: Therapy of aplastic anemia with sequential antithymocyte globulin and cyclosporin. Am J Hematol 1991; 36: 144-6.
14. Rosenfeld SJ, Kimball J, Vining D, Young NS: Intensive immunosuppression with antithymocyte globulin and cyclosporine as treatment for severe acquired aplastic anemia. Blood 1995; 85: 3058-65.
15. Young N, Griffith P, Brittain E, et al: A multicenter trial of antithymocyte globulin in aplastic anemia and related diseases. Blood 1988; 72: 1861-9.
16. Shell AG, Disney AS, Mathew TH, Livingston BRR Keogh AM: Lymphoma incidence, cyclosporine, and the evolution and major impact of malignancy following organ transplantation. Transplant Proc 1997; 29: 825-7.
17. Gluckman E, Rokicka-Milewska R, Gordon-Smith EC, et al: Results of a randomized study of glycosylated rHuG-CSF lenograstim in severe aplastic anemia. Blood 1998; 92(suppl 1): 376a.
Guarantor: CDR Robert J. Ellis, MC USNR
Contributors: Qamar Kahn, MD*; CDR Robert J. Ellis, MC USNR*; Barry S. Skikne, MD*; Mathew S. Mayo, PhD^; John W. Allgood, MD^^; David M. Bodensteiner, MD*; Delva Deauna-Limayo, MD*; James D. Cook, MD*
*Division of Hematology and Bone Marrow Transplantation, ^Director of Biostatistics, Kansas Cancer Institute, and ^^Department of Radiation Oncology, Kansas University Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160.
This manuscript was received for review in April 2001 and was accepted for publication in December 2001.
Reprint & Copyright (c) by Association of Military Surgeons of U.S., 2002.
Copyright Association of Military Surgeons of the United States Jul 2002
Provided by ProQuest Information and Learning Company. All rights Reserved