Cml patients with advanced phase disease retain clonogenic progenitor cells which are responsive to interferon alfa and STI571 in vitro

We investigated if progenitor cells from CML patients with accelerating/transformed (AP) disease differ from chronic phase (CP) cells in their sensitivities to interferon(IFN)-α and STI571. We used a colony replating assay which measures the self-renewal capacity of clonogenic cells (CFU-GM). The results are expressed as the area-under-the-curve (AUC) of the cumulative distribution obtained by plotting the numbers of secondary colonies produced by replating individual primary colonies. The AUC for CP-CML CFU-GM is significantly greater than that for normal marrow CFU-GM (79.6–5.0 (mean–sem), n=90 vs 63–4.4, n=63; p=0.029, t test). CP CFU-GM exposed to pharmacological concentrations of IFN-α (50U/ml) or STI571 (0.1μM) exhibit a reduced AUC (respectively 63–5% and 52–7% of control level; n=33 and 30) but normal CFU-GM show an increase. Moreover, responses to IFN-α and STI571 are closely correlated in samples from individual CP patients (r=0.74). The AUC for CFU-GM from 16 patients with AP disease was increased compared with CP results (114–3.1; p=0.001). It was reduced to 52–7% of control levels by IFN-α and 41–6% by STI571. These results were not significantly different from the corresponding values for CP-CML cells (p=0.4 and 0.6). Finally, the in vitro responses to IFN-α and STI571 of progenitor cells from patients with AP disease were related to one another (r=0.6). Thus: (1) CML patients retain progenitor cells with similar kinetic properties and responses to IFN-α and STI571 throughout the course of their disease; (2) clinical resistance to IFN-α may not be intrinsic to progenitors (3) IFN-α and STI571 may be effective treatment of at least selected AP-CML patients.