Cell cycling stress in the monocyte line as a risk factor for progression of the aplastic anaemia/paroxysmal nocturnal haemoglobinuria syndrome to myelodysplastic syndrome

Severe aplastic anaemia (SAA) causes permanent stem cell damage from which patients do not recover after treatment with antilymphocyte globulin (ALG). To produce peripheral blood values compatible with life, the few remaining stem and precursor cells are put under stress. We defined a 'stress factor ' (Sf) for various haematopoietic lines as the ratio of the corresponding p eripheral blood (PB) value to the total colony number in short-term bone ma rrow cultures from 86 patients with different outcomes. Both values are exp ressed as percentage of normal, hence SF averages 1 in normal steady-state haematopoiesis. SF was elevated in all patients, from 2-to 40-fold, with wi de variations in different patient groups and striking differences between haematopoietic lineages. In long-term disease-free survivors after ALG (gro up 1) the mean total colony count was 19 % of normal, with a significantly higher proportion of erythroid burst-forming units compared to normal. They had ineffective erythropoiesis with haemoglobin (Hb) values below, and ret iculocyte counts above normal; platelet counts were 67% of normal. In contr ast, monocyte counts were in the high normal range, resulting in a high SF (18.7 +/- 1.9) for monocytes. In patients who developed paroxysmal nocturna l haemoglobinuria (PNH) after ALG (group 2), ineffective erythropoiesis, re flecting haemolysis, was more pronounced and they had striking relative mon ocytosis, resulting in a significantly higher SF for monocytes (33.7 +/- 5. 7) compared with group 1 (p < 0.0001). High monocyte counts most likely ref lect the relative resistance of nucleated cells to complement, compared wit h red cells and platelets. Patients who developed myelodysplastic syndrome (MDS) or acute myeloid leukaemia (AML) after ALG, with or without PNH (grou p 3), had the highest SF for monocytes (39 +/- 10). They also had neutrophi l counts in the upper range, or above normal, resulting in a high SF for ne utrophils: 32 +/- 19. In patients with persisting or relapsing-remitting pa ncytopenia without a clinically detectable clonal disorder (group 4), all v alues were strikingly similar to those of the PNH group. In patients who ac hieved normal PB values after uncomplicated bone marrow transplantation (gr oup 5), the SF averaged 3, but they also had ineffective erythropoiesis and mild relative monocytosis, a possible sign of occult PNH. We conclude that all patients after treatment of SAA have ineffective erythropoiesis and re lative monocytosis, and that these abnormalities probably reflect PNH. We s uggest that the resulting high SF for the leukocyte - particularly the mono cyte line - predisposes to the development of MDS/AML. We discuss how these results may provide some of the missing pieces in the puzzle of SAA/PNH. C opyright (C) 2000 S. Karger AG, Basel.