Anemia due to marrow failure

In severe aplastic anemia, a major study of 110 patients compared HLA-identical marrow transplantation with oral, intramuscular or no androgen therapy (Camitta et al. 1979). This showed a major survival advantage (70% vs. 35% six month survival) for 47 patients having HLA-identical bone marrow transplantation compared with 63 patients in whom no donor was available who were randomised to oral (oxymetholone 3-5 mg/kg/day), intramuscular (nandrolone decanoate 3-5 mg/kg/wk)ornoandrogen therapy (Camitta etal. 1979). The latter three groups did not differ in survival, a finding consistent with another small randomised study that showed no survival benefit due to androgen therapy (50-100 mg nandrolone phenylpropionate weekly) compared with placebo vehicle injections (Branda et al. 1977).

In standard non-transplantation treatment for aplastic anemia, a randomised cross-over study of 44 patients concluded that anti-thymocyte globulin (ATG) was superior to androgen therapy (nandrolone decanoate 5 mg/kg/wk). This conclusion was, however, flawed as half the patients had failed prior androgen therapy, thus constituting an entry bias against androgen therapy (Young etal. 1988). Coupled with ATG, androgen therapy appears to offer morbidity but not mortality benefit in aplastic anemia. A randomised, controlled multi-centre study of the

European Bone Marrow Transplantation in Severe Aplastic Anaemia Study Group of 134 patients with newly diagnosed severe aplastic anemia receiving standard therapy (including ATG and methylprednisolone) demonstrated an improvement in transfusion independence due to treatment with oxymetholone (2 mg/kg/day) compared with placebo (Bacigalupo et al. 1993). However there was no overall benefit in survival that was determined principally by the severity of disease based on leucocyte count. These findings confirmed the benefit of androgen therapy on transfusion independence but not survival from two smaller randomised placebo-controlled studies involving 61 patients using oral methenolone acetate (2-3 mg/kg/day) (Kaltwasser etal. 1988; Li Bock etal. 1976) but contradict another randomised placebo-controlled study which found no benefit from androgen therapy (fluoxymesterone 25 mg/m2/day or oxymetholone 4 mg/kg/day) over placebo in 53 patients (Champlin et al. 1985). None of these studies reported survival benefits or formally evaluated quality of life and all frequently observed female virilisation.

An important pair of studies attempted to define the optimal dosage and type of androgen therapy for aplastic anemia (French Cooperative Group for the Study of Aplastic and Refractory Anaemias 1986). In the first study, 110 patients were randomised into four groups according to androgen (norethandrolone, fluoxymesterone) anddose (high 1 mg/kg/d,low 0.2 mg/kg/d). Survival was mainly influenced by disease severity but, in less severe cases, high-dose androgen therapy significantly improved survival over low-dose androgen therapy. Despite randomisation, there were imbalances between treatment groups with respect to disease severity and age that undermine the interpretability of the findings. In the second study, 125 patients were randomised to four different androgens - norethandrolone, stanozolol, flu-oxymesterone (all at 1 mg/kg/day) or testosterone undecanoate (1.7 mg/kg/day). The fluoxymesterone treatment group had the best and stanozolol the worst survival with norethandrolone and testosterone undecanoate being equivalent and intermediate in efficacy. Once again, however, the treatment groups were unbalanced with respect to disease severity and age. Hence the reported benefit limited to the less severe and older (>30 yr) cases remains dubious. The superiority of any specific androgen remains to be unequivocally demonstrated with particular difficulty in comparing effective doses of different androgens.

The French Cooperative Study Group also reported a series of cohort studies examining the efficacy of androgen therapy in patients with aplastic anemia. Their initial cohort randomised 352 men and women to treatment with meth-androstenolone (1 mg/kg/day), oxymetholone (2.5 mg/kg/day), methenolone acetate (2.5 mg/kg/day) or norethandrolone (1 mg/kg/day). The methandro-stenolone group had the best, whereas oxymetholone and methenolone groups exhibited equally the worst two-year survival from randomisation (Cooperative

Group for the Study of Aplastic and Refractory Anaemias 1979). However, treatment groups were unbalanced for disease severity, the principal determinant of survival. Despite post-hoc stratified analyses, it remains ultimately difficult to conclude whether underlying disease prognosis or drug effects explained the differences in group survival. In a follow-up study from the same cohort who survived at least two years from initial randomisation, 137 patients were re-randomised to rapid (3 month) or slow (20 month) withdrawal of their original androgen therapy. The slow withdrawal group had a higher rate of maintained remission consistent with androgen therapy having maintained a clinical benefit, presumably via maintenance of hemoglobin levels, but no survival data were reported (Najean and Joint Group forthe Study of Aplastic and Refractory Anaemias 1981).

Overall, androgen therapy does not improve survival in aplastic anemia but provides a morbidity benefit by maintaining hemoglobin and transfusion independence, although the improved quality of life has not been quantified. In severe aplastic anemia, bone marrow transplantation from an HLA-identical sibling (if feasible) is the preferred treatment and superior to androgen therapy. Androgen therapy may be useful in less severe aplastic anemia for which bone marrow transplantation is not available or justified. However, the relative merits of androgen therapy compared with HLA non-identical bone marrow transplantation or in the presence of failing or failed bone marrow transplantation have not been clearly defined. Although it is prudent to avoid injectable androgens in a population that may be thrombocytopenic, the preponderant use of oral 17a-alkylated androgens in aplastic anemia appears unjustified when non-hepatotoxic oral androgens such as 1-methyl androgens (methenolone, mesterolone) and testosterone undecanoate appear to be equally effective.

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