Predominantly BCR-ABL negative myeloid precursors in interferon-alpha treated chronic myelogenous leukemia: a follow-up study of peripheral blood colony-forming cells with fluorescence in situ hybridization

The mechanism and target cell of the life-prolonging effect of interferon-a lpha (IFN-alpha) in chronic myelogenous leukemia (CML) are controversial. W e studied the influence of IFN-alpha treatment on the frequency of malignan t hematopoietic precursor cells in the peripheral blood (PB) of CML patient s during the course of the disease. PB 10-day colony-forming cells (PB-CFCs ) were assessed with regard to their quantity, lineage distribution, and BC R-ABL status, as determined by fluorescence in situ hybridization (FISH). P B-CFC numbers were determined in 39 patients (29 in the chronic phase, 6 in an advanced stage, and 4 with progression to an advanced stage during foll ow-up). Thirty-one patients were evaluated either once or several times to determine the BCR-ABL status of the colonies. BCR-ABL negative PB-CFCs were detectable at diagnosis in 5 of 11 patients. A major reduction of BCR-ABL positive colonies to < 25% of PB-CFCs was observed in 10/13 determinable IF N-<alpha> treated patients in early and late chronic phases, indicating a h igh proportion of BCR-ABL negativity at the clonogenic cell level. In contr ast, only 3 of these patients had a cytogenetic response of <25% Philadelph ia chromosome (Ph-1)-positive metaphases in bone marrow cytogenetics. Treat ment with IFN-<alpha> and/or hydroxyurea (HU) during chronic phase was acco mpanied by a reduction of PB-CFCs to subnormal levels (median 24 CFCs/ml) c ompared to controls (median 207 CFCs/ml), untreated patients in chronic pha se (median 25,979 CFCs/ml), and patients with advanced disease (median 6,04 7 CFCs/ml). In blast crisis (6 patients), all colonies tested were BCR-ABL positive. Our results show that IFN-alpha treatment leads to a marked reduc tion of malignant myeloid precursor cells in the PB of CML patients, which exceeds the degree of cytogenetic remission. This offers an explanation for the good therapeutic efficacy and even life-prolonging effect of IFN-alpha , which is also observed in cytogenetic non-responders.