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ABSTRACT & COMMENTARY
Synopsis: High-dose cyclophosphamide has been shown to be effective treatment for severe aplastic anemia. In this report, such treatment was compared with the more conventional approach of antithymocyte globulin. The trial was terminated after three patients in the cyclophosphamide group died within three months of treatment. Thus, although there are theoretical advantages for treatment with high-dose cyclophosphamide in this disorder, these advantages are unlikely to outweigh the increased life-threatening toxicity of such an approach. For the time being, ATG with cyclosporin remains the standard of care for aplastic anemia patients who are not candidates for bone marrow transplantation.
Source: Tisdale JF, et al. Lancet 2000;356:1554-1559.
High-dose cyclophosphamide has been proposed as an effective therapy for aplastic anemia, with a response rate similar to that with regimens containing antithymocyte globulin (ATG), but with more durable remissions and reduced clonal hematological complications.1,2 These early reports of such treatment have been encouraging, but no direct comparison with ATG-based regimens has been available. Tisdale and colleagues from the National Heart, Lung, and Blood Institute (NHLBI, NIH) performed a phase III, prospective, randomized trial to compare response rates to immunosuppression with either high-dose cyclophosphamide plus cyclosporin or conventional immunosuppression with ATG plus cyclosporin in previously untreated patients with severe aplastic anemia.
Thirty-one patients were enrolled in this study; 15 were assigned cyclophosphamide (1h intravenous infusion of 50 mg/kg daily for 4 days) and 16 were assigned ATG (40 mg/kg daily for 4 days). Both groups also received cyclosporin, initially at 12 mg/kg daily with adjustment to maintain concentrations at 200-400 ug/L, for six months. The primary end point was hematological response (no longer meeting the criteria for severe aplastic anemia and becoming transfusion independent). Analyses were by intention to treat. Secondary endpoints were overall survival, event-free survival, response duration, and evolution to paroxysmal nocturnal hemoglobinuria, myelodysplasia or acute leukemia.
The trial was terminated after three early deaths in the cyclophosphamide group. Median follow-up was 21.9 months for the 31 that were enrolled, and all of these patients had completed their initial immunosuppressive treatment. There was excessive morbidity in the cyclophosphamide group (invasive fungal infections in 4 patients vs none in the ATG group) and three early deaths within the first three months (vs none in the ATG group). There was no significant difference at six months after treatment in the overall response rates among evaluable patients (6/13 [46%] cyclophosphamide vs 9/12 [75%] ATG).
Tisdale et al suggest that cyclophosphamide is a dangerous choice for initial treatment of severe aplastic anemia. However, long-term analysis of these treated patients may demonstrate that remission duration or overall survival will be better for those that have survived the initial treatment with cyclophosphamide. Still, the use of high-dose cyclophosphamide in this setting remains to be established.
COMMENT by William B. Ershler, MD
The majority of patients with acquired aplastic anemia may be effectively treated with immunosuppressive therapy and ATG with cyclosporin has produced significant responses in the majority of cases. However, ATG-induced responses have generally been incomplete and relapses are not uncommon. Nevertheless, although incomplete, the responses most frequently result in freedom from transfusions and definitely in prolonged survival.3 This stated, the promise of high-dose cyclophosphamide as an alternative was a more robust remission, perhaps even cure and the hopeful expectation that relapses would be less common and long-term clonal disorders, such as paroxysmal nocturnal hemoglobinuria, myelodysplasia, and leukemia would occur less frequently. These findings are unlikely to be demonstrated in the current study because the high level of early toxicity, including death in three of 16 treated patients, forced the early termination of the recruitment phase. Thus, even if these outcomes of the high-dose cyclophosphamide treatment actually occur, it is unlikely there will be a sufficient number of patients in the present trial to establish this with statistical significance.
The use of high-dose cyclophosphamide is unlikely to become the standard of care for severe aplastic anemia. For younger patients with appropriately matched allogeneic bone marrow donors, transplantation remains an appropriate choice. For others, immunosuppression with ATG and cyclosporin is likely to remain the standard of care. New, more selective immunosuppressive approaches are also under development and will soon be in clinical trial. Hopefully, the promises of the early cyclophosphamide trials will be realized with one or several of these new potent immunopharmacological agents.
1. Brodsky RA, et al. Blood 1996;87:491-494.
2. Brodsky RA, et al. Blood 1999;94:674.
3. Young NS, et al. Blood 1995;85:3367-3377.