To the Editor:
We read with great interest the European trial of cyclosporine alone versus antithymocyte globulin (ATG) and cyclosporin together for the treatment of patients with nonsevere aplastic anemia.1
The results are very interesting and suggest that combined therapy is superior to single therapy. However, we are concerned with the differing age groups of patients who received combination therapy compared with those who received cyclosporine alone. Patients who received combination therapy had a median age of 29, with range of 1 to 67 years; those who received cyclosporine alone had a median age of 35, with range of 17 to 84 years. Thus, the median age of patients in the combined therapy group was significantly lower than that in the single-therapy group (P = .04), but also only the combined therapy group had pediatric patients. This has two important possible ramifications for interpretation of the study. First, it may have masked differences in the therapy providing a bias toward combined therapy. Second, it is possible that the natural history, course prognosis, and treatment of children may be different from that of adults when analyzed separately.
There is no national or international database for reporting data on children or adults with moderate or mild aplastic anemia, nor are there very good diagnostic criteria in terms of bone marrow cellularity and growth characteristics of bone marrow cells. Definitions based on peripheral counts may fail to distinguish between pathogenically different diseases.
Despite meager databases, several single institutional studies on the outcome of acquired, moderate aplastic anemia in children have been published.2-5 Based on these studies, children with moderate aplastic anemia do well: approximately half recover on their own, and many others respond to supportive care and/or minimal immunosuppression. For example, of 14 children treated for acquired, moderate aplastic anemia at St Judes’ Children’s Research Hospital during 1978 to 1991, approximately half underwent spontaneous recovery; 3 received no therapy, 4 supportive care only, and 5 progressed to severe disease and needed bone marrow transplantation.2 All patients were alive and well 7 to 10 years later. Similarly good results with approximately 50% spontaneous recovery rates were reported by other investigators.3-5 Results have been better in more recent years, paralleling the improvements in supportive care and the rapid increase of growth factors that may be of benefit to patients with moderate disease involving one or more lines of progenitor cells.
With these thoughts in mind, we wonder whether the authors could address differences in response rates of younger versus older subjects, and whether these differences may have played a role in the overall better response of patients randomized to ATG plus cyclosporin.
We agree with the authors’ conclusion that further studies using less aggressive therapy than combined ATG + cyclosporine are indicated. In addition to ATG alone, other therapies should include the various growth factors including granulocyte-macrophage colony-stimulating factor (GM-CSF), G-CSF, interleukin-3 (IL-3), and IL-6,6all of which have been reported to have beneficial effects in severe aplastic anemia and other bone marrow failure states; these effects may be even better in patients with moderate disease.
Response
We note the comments of Reddy and colleagues concerning a difference in age between the 2 groups of patients in our series. Unfortunately, there is an error in the published manuscript. The age for patients treated with the combination of antithymocyte globulin (ATG) and cyclosporin (CSA) is 35 years (median), with a range of 7 to 84, and not 17 to 84 as originally published. There is a difference in age between the 2 groups as we reported (P = .04). In the group treated with ATG and CSA, there were 8 children (age ≤18 years), of whom 6 had a complete response; 1 had a partial response and 1 was a nonresponder. In contrast, of 10 children treated with CSA alone, there were only 3 complete responders and 7 showed no response (P = .04). Therefore, there was a predominance of younger patients randomized to treatment with CSA alone in our study, and the response to CSA alone among this age group was inferior to the combination of ATG and CSA.
There have been few prospective randomized studies using immunosuppressive therapy (IST) in children with aplastic anemia (AA). A recent update from the European Blood and Marrow Transplant (EBMT) Group has reported an improvement in survival after IST for children with severe AA over the last 3 decades, with survival increasing from 33% in cases treated before 1980, 60% for those treated between 1980 and 1989, and 70% for those treated after 1990.1-1 A similar trend is seen in adult patients and the improvement may reflect the use of CSA with ATG, the use of multiple courses of ATG, as well as improved supportive care.1-2
We agree that future prospective trials of children, as well as adults, with nonsevere AA are indicated. However, we are concerned about the use of hematopoietic growth factors alone in the treatment of children with AA, as this may delay IST.1-3 Finally, we agree that spontaneous recovery may occur in AA, but this has to be balanced against the risk of progression of the disease to severe AA. In our study there was a higher rate of progression in patients treated with CSA alone as compared with more intensive immunosuppression with the combination of ATG and CSA.
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