Could aplastic anaemia be considered a pre-pre-leukaemic disorder?

Clinical evidence for a link between aplastic anaemia, paroxysmal nocturnal haemoglobinuria (PNH) and hypoplastic leukaemia is provided by studies of clonal disorders, which may be a complication of congenital or acquired aplastic anaemia. Fanconi's anaemia is the most common congenital disorder and leukaemia occurs in at least 10% of cases. In acquired aplastic anaemia, a high incidence of myelodysplastic syndrome (MDS) was noted in patients with aplastic anaemia, seemingly cured of their aplasia by antilymphocyte globulins (ALG). In a recent survey, the 10-year cumulative incidence rates were 9.6% for MDS, 6.6% for acute leukaemia (115-fold higher than in the general population). Biological evidence is provided by bone marrow morphology, as a certain degree of dysmyelopoiesis is not unusual in aplastic anaemia. Cytogenetic analyses in aplastic anaemia are scarce, but data have shown clonal cytogenetic abnormalities at diagnosis in otherwise typical aplastic anaemia. Recently, flow cytometry to assess the glycosyl-phosphatidylinositol (GPI) molecule defect in PNH has demonstrated that a significant proportion of patients with otherwise typical aplastic anaemia have, in fact, a GPI defect due to alterations within the PIG-A gene. Finally, aplastic anaemia patients were recently reported to have molecular evidence of clonal haematopoiesis; this must now be discussed in light of recent clonality studies in normal individuals. The clinical and biological evidence for a link between aplastic anaemia, PNH and hypoplastic leukaemia allows the generation of a model of aplastic anaemia as a possible pre-pre-leukaemic disorder.