CML patients treated with interferon or bone marrow transplant can enter long-term cytogenetic remissions. Surprisingly, only a portion of these patients will eventually relapse. Because CML patients carry a cancer- specific marker--the t(9;22) resulting in an aberrant BCR-ABL gene and protein--the detection of very low levels of minimal residual disease is now possible with the use of FISH and PCR-based technologies. However, the clinical relevance of minimal residual disease is unclear because of the heterogeneity of outcome in these patients. For instance, bone marrow transplant recipients and interferon-treated patients may show evidence of residual BCR-ABL- positive cells or eve of cytogenetic positivity without clinical relapse. Conversely, we have also observed a PCR-negative CML patient who relapsed within several months. We therefore propose to undertake a systematic analysis of CML patients in cytogenetic remission after treatment with the transplant, interferon, or chemotherapy programs (outlined in this P01) to determine (i) if low levels of residual disease detected by PCR or FISH in bone marrow are accounted for by the presence of BCR-ABL message in cells capable of dividing and forming colonies; (ii) if the study of the percentage of PCR-positive colonies adds relevance to the PCR assay and can help determine which patients with minimal residual disease will relapse; and (iii) if differential expression of the BCR-ABL message and p210/BCR-ABL in hematopoietic cells at different stages of maturation (obtained by cell separation techniques and by stage-specific colony assays) exists. These experiments will be performed in various categories of patients such as those after allograft who are PCR-positive or FISH-positive and relapse as opposed to those who do not relapse. Our results will be compared to those obtained from experiments with interphase vs metaphase FISH in an attempt to understand the clinically different subsets of patients with minimal residual disease and to elucidate the mechanisms by which small numbers of Ph+ cells remain without the occurrence of relapse.
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