To the Editor:
We report a patient with aplastic anemia (AA) who exhibited cytogenetic abnormalities at presentation, but who recovered hematologically with disappearance of cytogenetic abnormalities after cyclosporine (CyA) therapy.
A 55-year-old woman presented to our hospital in September 1995 with breathlessness on exertion of 1-month duration. She was pale, and petechiae were observed on her skin. A hemogram revealed severe pancytopenia with hemoglobin (Hb) 3.8 g/dL, granulocyte count 0.35 × 109/L, platelet count 13 × 109/L, and reticulocyte count 11 × 109/L. Serum lactate dehydrogenase, bilirubin, and haptoglobin were within normal range. Bone marrow examination showed a severely hypocellular marrow with depression of all three hematopoietic cell lines, and no dysplastic features. The same findings were obtained on trephine biopsy. Magnetic resonance imaging of the lumbar spine revealed homogeneously fatty marrow. Therefore, the diagnosis of AA was made. Oral CyA therapy at a daily dose of 350 mg in combination with 300 μg/m2 of filgrastim for 4 weeks and pulse therapy with methylprednisolone was started in September 1995. There was a gradual response of all three cell lines, and she became completely independent of blood transfusions about 1 year later. CyA was then carefully tapered to 100 mg twice daily. As of September 1997, she is maintaining Hb > 8 g/dL, granulocyte count > 1.0 × 109/L, and platelet count > 50 × 109/L. Bone marrow examination performed in March 1997 showed a nearly normocellular marrow and no dysplastic features other than a few binucleated erythroblasts. Cytogenetic analyses of bone marrow cells were serially performed. As summarized in Table1, on analyses performed in September 1995 (initial presentation), October 1995, and January 1996 (4 months after initiation of treatment), cytogenetic abnormalities chiefly involving the short arm of chromosome 1 (1p) were detected in 30% to 37.5% of metaphases analyzed. However, since 5 months after initiation of treatment, no cytogenetic abnormalities were detected in four analyses performed.
Immunosuppressive therapies such as antithymocyte globulin and CyA have been used successfully to treat AA,1,2 and immune-mediated suppression of hematopoiesis has therefore been considered the most important mechanism responsible for bone marrow failure in AA.3 However, recent studies have shown that long-time survivors of AA after immunosuppressive therapy are at high risk of developing myelodysplastic syndrome (MDS) and acute myelogenous leukemia, in which clonal cytogenetic abnormalities commonly are present.4 This suggests that clonal abnormalities of stem cells also play a role in the pathophysiology of AA. Although cytogenetic abnormalities have infrequently been reported in patients with AA at presentation, Applebaum et al5 reported that seven of 176 patients with AA had clonal cytogenetic abnormalities at presentation, and that 2 of these 7 cases evolved into MDS. Interestingly, in the present case, chromosomal abnormalities detected at presentation disappeared after initiation of immunosuppressive therapy with CyA. Although it is unclear whether these cytogenetic abnormalities were chiefly responsible for bone marrow failure in the present case, our findings suggest that both immunological mechanisms and clonal hematopoietic abnormalities may play roles in the pathogenesis of AA.
