Clinical heterogeneity in chronic myeloid leukaemia reflecting biological diversity in normal persons

The molecular basis of chronic myeloid leukaemia (CML) is well defined and highly consistent, yet prognosis varies considerably. This could reflect the biological diversity occurring in normal populations. We used a colony replating assay to measure the proliferative capacity of progenitor cells from 211 CML patients and 86 normal persons. Results were expressed as the frequency distributions of the proliferation index (PI) for individual cases. Normal PI values varied among individuals but were reproducible in individuals. The PIs for CML patients were moderately but significantly greater (P = 0.004) than normal values, consistent with increased progenitor cell proliferation in CML. Exposure of CML progenitor cells to the Abl-kinase inhibitor imatinib shifted their PI towards the normal range, implicating p210BCR-ABL. as a cause of the increased PI. The PIs of CML patients were higher than those of their human leucocyte antigen (HLA)-matched siblings PI (P = 0.003) and patient PI increased exponentially with sibling PI (r = 0.77; P = 0.001), but not with the PI values of HLA-matched unrelated individuals (P = 0.66). Finally, patients with high-risk prognostic scores (according to the Sokal or Hasford systems) had a significantly higher PI than those with low risk scores (P = 0.01 and 0.03 respectively). We conclude that heterogeneity in the CML patient population is analogous to the constitutional diversity in normal subjects.