Immunosuppressive Therapy

IS therapy remains the most important primary treatment modality for the major portion of patients affected by this disease. The most common IS regimens combine equine ATG (at 40 mg/kg/day for 4 days) with cyclosporine A (CsA) (12-15 mg/kg in a divided dose b.i.d.) given for at least 3 months, but usually for 6 months (Figure 41.6). Steroids are usually added to counteract the serum sickness intrinsic to ATG therapy. Rabbit ATG (3.5 mg/kg/d X 5d) is likely as effective as horse ATG, but its efficacy has not been compared in a randomized trial.77 The response rate to horse ATG ranges from 70 to 80%, with a 5-year survival of 80-90%.12'78-81 ATG appears to be superior to CsA,82,83 and the combination of ATG and CsA provides better results than ATG alone or CsA alone.8485 Intense immunosuppression with ATG/CsA has also been administered with good success in elderly patients.86 The addition of granulocyte colony-stimulating factor (G-CSF) may improve neu-tropenia, but does not increase survival.87 Patients who respond have excellent survival, while those who are refractory have less favorable survival, with counts at 3 months post-ATG therapy having a good correlation with long-term prognosis. Most patients who are destined to respond do so by that time, and subsequent improvement may occur in additional one fourth of patients. Newer IS regimens may employ other agents, such as mycofenolate mofetil and, in the context of CsA toxicity, Dacluzimab Zenapax [anti-IL-2 receptor (CD25) monoclonal antibody], but the efficacy of these agents is not known. Refractory patients may be retreated with multiple courses of ATG. Repeated ATG may result in salvage of a significant proportion of patients. In one study of patients refractory to horse ATG, rabbit ATG resulted in a 50% response rate and excellent long-term survival.77 No good prognostic factors are available with regard to the response to ATG, with the exception of the presence of HLA-DR15 alleles and the PNH clone, both of which correlate with good responsiveness to immunosuppression.88

High-dose cyclophosphamide has been advocated as an effective first-line therapy alternative to ATG.89 High response rates were reported to be associated with prevention of relapse, and also with clonal disease. However, prolonged cytopenia has resulted in an excessive toxicity related to neutropenic complications in a randomized trial between ATG/CsA and cyclophos-phamide/CsA, resulting in a termination of the study.9091 Long-term follow-up of patients treated with cyclophosphamide showed that relapse and clonal disease can occur after this type of therapy.9192 It seems that high-dose cyclophosphamide does not constitute advancement over ATG/CsA, and should be used only in selected cases or in the context of clinical trials.

OTHER THERAPIES Hematopoietic growth factors

Hematopoietic growth factors should not be used in the primary setting. Some patients will show an improvement of neutropenia with G-CSF, but severe

Figure 41.6 Results of immunosuppression and stem cell transplantation in aplastic anemia. (a) Allogeneic stem cell transplantation. Data are presented from individual hospital series in peer-reviewed publications from 1991 to 1997. The shaded area represents the 5-year probability of survival (with the same confidence intervals) of patients reported to the International Bone Marrow Transplant Registry (IBMTR) during this period. (b) The continuing influence of age on survival, as reflected in IBMTR data. (c) Comparative probability of survival after immunosup-pression and stem cell transplantation. The data are for patients reported to the Working Party on Severe Aplastic Anemia of The European Group for Blood and Marrow Transplantation in the 1980s and 1990s. CSA = cyclosporine; FHCRC = Fred Hutchinson Cancer Research Center; MTX = methotrexate; UCLA = University of California, Los Angeles (Adapted with permission from Ref. 9)

neutropenia due to a typical AA is mostly refractory. In combination with an ATG/CsA regimen, G-CSF can improve neutropenia (neutrophil response), and response to this therapy constitutes an early positive prognostic factor with respect to future response.87 However, no survival advantage has been reported.87 Dose escalation does not appear to be beneficial.93

Anabolic steroids

Anabolic steroids have been widely used as therapy of AA, prior to the advent of IS therapy.9495 Currently, androgens are mostly used as a salvage therapy for refractory patients. Historically, response rates to androgens were clearly observed, and were reported to be 30-60%. The androgens in current use include oxymethylone and danazol. Danazol has a relatively low virilizing potential.

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