Proliferative activity of leukaemic blasts and cytosine arabinoside pharmacodynamics are associated with cytogenetically defined prognostic subgroupsin acute myeloid leukaemia

The biological mechanisms responsible for the association of specific karyo types with prognosis in acute myeloid leukaemia (AML) remain largely unclea r. A prospective study was performed to evaluate how far cytogenetically de fined prognostic subgroups of AML differ in their proliferative activity as a potential mechanism for differential sensitivities to S-phase-specific i nduction chemotherapy comprising cytosine arabinoside (AraC). One hundred a nd eighty-seven patients with de novo AML were included in the study; 25 pa tients with a favourable [inv(16), t(8;21), t(15;17)] karyotype, 99 with a normal karyotype, 29 with an unfavourable karyotype (-5, 5q-, -7, 7q-, comp lex aberrations) and 34 with cytogenetic aberrations of unknown prognostic significance (all others). The favourable group demonstrated the highest ex vivo proliferative activity (PA) (3.41 pmol/10(5) cells), significantly (P = 0.02) exceeding the unfavourable group with the lowest PA (0.72) and the group with a normal karyotype (1.06) or with karyotype of unknown signific ance (1.05) that both demonstrated an intermediate PA. Samples with a high PA (> median of the whole group) were more likely to produce interleukin 3, granulocyte macrophage colony-stimulating factor (GM-CSF), granulocyte CSF (G-CSF) (56%, 43% and 50%) than cells with a low PA (33%, 36% and 36%; n.s .), The effect of priming by exogenous GM-CSF or G-CSF was significantly mo re pronounced in samples with a low PA than in rapidly proliferating sample s (P < 0.01). For the whole group, a high PA was closely associated with an increased incorporation of AraC triphosphate (AraCTP) into the DNA (P < 0. 0001). Clinically, a high PA was associated with a better complete remissio n (CR) rate in the normal (95% versus 62%) and the unfavourable group (75% versus 33%). The significant differences in proliferative activity between cytogenetic subgroups of AML are associated with increased cytosine arabino side pharmacodynamics and constitute one potential mechanism for the differ ent response of cytogenetic subgroups to AraC-based induction therapy.