The majority of patients diagnosed with aplastic anemia are treated with immunosuppressive therapy (IST) because they either lack a compatible sibling donor or are too old for hematopoietic stem cell transplant. Approximately two thirds of patients successfully respond to IST with horse anti-thymocyte globulin (h-ATG) and cyclosporine. Despite various efforts to improve IST results, horse ATG plus cyclosporine is still the regimen with better outcomes and is thus the standard treatment. Treatment limitations remain in up to one-third of patients who fail IST, but also one-third of responders will eventually relapse and 15% may evolve to MDS or AML at long-term.
One attempt to improve IST results is cyclophosphamide. It was first used in high dose (200 mg/kg) as an alternative to h-ATG/cyclosporine at Johns Hopkins Hospital in the 1990’s, rendering equivalent responses, but with fewer relapses or MDS progression. Nevertheless, in a randomized study conducted at the NIH in 1998, excess toxicity and death from fungal infections were observed in the patients treated with cyclophosphamide at the same high dose and the study was prematurely terminated. More recently, a lower “moderate” dose of cyclophosphamide (120mg/kg) was attempted in a study from China showing good responses and also less toxicity and cost.
With this scenario, the NIH conducted a new study treating 22 patients with aplastic anemia with “moderate” dose cyclophosphamide plus cyclosporine. The results of this present study showed that only 9 patients (41%) responded after 6 months (lower than the historic two-third response observed with h-ATG plus cyclosporine. Infectious events were serious and frequent, despite intensive antimicrobial prophylaxis, and progression to MDS at one year was detected in 22% of patients.
Although cyclophosphamide may appear an attractive choice to treat patients with aplastic anemia due to its low cost, prospective controlled studies showed that it produces lower response in comparison to h-ATG/cyclosporine and does not reduce relapse or MDS evolution, regardless of high or “moderate” doses. Cyclophosphamide toxicity is substantial and not avoided by antimicrobial prophylaxis.
In conclusion, to date h-ATG/cyclosporine appears to be the most adequate option to treat patients with aplastic anemia without a suitable donor for transplant.