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High-Dose Cyclophosphamide for Treatment of Aplastic Anemia
- Robert A. Brodsky, MD; and
- Richard J. Jones, MD
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IN RESPONSE:
Over 15 years ago, a prospective, controlled study by Speck and colleagues suggested that antilymphocyte globulin was superior to allogeneic bone marrow transplantation for aplastic anemia (1). Initially embraced by many, the conclusions of this study have not stood the test of time, and bone marrow transplantation is now the preferred treatment for patients with matched siblings.
The randomized, controlled trial can be limited by the details of study design and execution. The NIH trial reported 6-month data on just 13 patients treated with cyclophosphamide and cyclosporine and just 12 patients treated with ATG and cyclosporine. The study accrued less than 20% of its planned enrollment and was terminated although neither rules for stopping nor primary or secondary end points were ever met. In addition, in contrast to our study, the NIH started cyclosporine concomitantly with cyclophosphamide and continued it for 6 months. The concomitant use of cyclosporine with cyclophosphamide may increase toxicity (2); furthermore, cyclosporine blocks the induction of tolerance, a potential mechanism of action for cyclophosphamide (3).
We found that high-dose cyclophosphamide alone leads to durable treatment-free remissions in most patients with aplastic anemia (4). Six patients from our initial trial (4) have remained in complete remission for more than 14 years, two for more than 20 years. The reported relapse rate for patients treated with ATG and cyclosporine in an earlier NIH series (5) was 50% at 5 years and 87% at 7 years. As we detailed in our report, all three deaths in our patients occurred among the nine who had very severe aplastic anemia. Such patients had an early mortality rate of 28% while taking ATG and cyclosporine in the NIH series. The survival rate in our patients is now 88.9% with no relapses, myelodysplasia, or PNH. All of the patients in our recent study are regularly screened for PNH or myelodysplasia. It is true that most patients with aplastic anemia harbor small PNH populations before treatment. We are monitoring these minute populations with highly sensitive assays, and so far they have regressed or remained stable.
Although the jury is still out on the role of high-dose cyclophosphamide in aplastic anemia, we hope the NIH group does not believe that the results of a small trial combining cyclosporine with cyclophosphamide and having only short follow-up should halt further study on this promising treatment approach. Over 15 years ago, because of the high rate of late complications (relapse and secondary clonal disorders) in patients with aplastic anemia who received antilymphocyte globulin, Speck and colleagues recommended continued study of bone marrow transplantation.
Robert A. Brodsky, MD
Richard J. Jones, MD
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Baltimore, MD 21231
The Editors welcome submissions for possible publication in the Letters section. Authors of letters should:
•Include no more than 300 words of text, three authors, and five references
•Type with double-spacing
•Send three copies of the letter, an authors' form signed by all authors, and a cover letter describing any conflicts of interest related to the contents of the letter.
Letters commenting on an Annals article will be considered if they are received within 6 weeks of the time the article was published. Only some of the letters received can be published. Published letters are edited and may be shortened; tables and figures are included only selectively. Authors will be notified that the letter has been received. If the letter is selected for publication, the author will be notified about 3 weeks before the publication date. Unpublished letters cannot be returned.
Annals welcomes electronically submitted letters.
- Copyright ©2004 by the American College of Physicians
