Late Clonal Complications in Severe Aplastic Anemia

One hundred and seventy patients with severe aplastic anemia (SAA) were treated in Basel, from 1976 to 1992. Forty one underwent bone marrow transplantation (BMT) and 129 antilymphocyte globulin (ALG) therapy. As of January 1, 1993, 99 of the 170 patients are alive (58% ± 7%) and the probability to be alive at 15 years is 54% ± 4%. Until now, 29 patients have developed a clonal complication. All occurred within the ALG group. Nine patients developed a myelodysplastic syndrome (MDS), 16 patients paroxysmal nocturnal hemoglobinuria (PNH) and 4 patients both, PNH and MDS. The cumulative risk of developing a clonal complication after ALG-therapy is 42% ± 13% at 15 years; for MDS this risk is 26% ± 8% and for PNH 25% ± 5%. The development of a clonal disease directly affects long term prognosis. The survival of the patients with stable disease is 81% ± 10% and 36% ± 13% for those with clonal evolution (p = 0.001). The most important risk factor is the type of treatment. In contrast to patients treated with ALG, none of the patients treated with BMT developed MDS or PNH (p < 0.001). No other clinical parameter, such as age, sex, etiology of SAA, severity of the disease and splenectomy correlate with an increased risk of developing this complication. In contrast, morphological parameters at the time of diagnosis, during bone marrow regeneration and at remission are indications in this respect. Patients with high reticulocyte and granulocyte counts, an increased erythrocyte volume (MCV) and more dys-erythropoiesis in the bone marrow at the time of diagnosis as well as a lower hemoglobin with an increased proportion of erythroblasts at remission are at risk for late PNH after ALG-therapy. The presence of ring sideroblasts and atypical monocytes in the bone marrow during regeneration as well as a persistent increase of MCV, a higher proportion fetal hemoglobin, lower granulocyte counts in the peripheral blood and dysmegakaryopoiesis in remission are predictive for a late MDS. Cytogenetic analyses were reevaluated in the 13 patients with secondary MDS. Before ALG-therapy 12 of the 13 patients had a normal karyotype while at transformation with MDS 5 of the 13 patients presented a clonal chromosomal abnormality. Two additional patients had non clonal abnormalities. Thus, long term observation of patients with aplastic anemia clearly demonstrates that the incidence of late clonal evolution after treatment with ALG is much higher than previously suspected. Routine morphologic follow-up examination of blood and bone marrow can detect patients at risk for this late hematological complication after immunosuppressive therapy.