Changing response of clonogenic myeloid leukemia blasts to granulocyte-macrophage colony-stimulating factor (GM-CSF) during anti-leukemic therapy--a case report on the basis of a clinical phase II trial.
In a clinical phase II trial GM-CSF was applied to 23 patients with acute leukemias carrying a high risk of early death because of old age or advanced disease. Concomitant laboratory investigations included the analysis of colony assays for normal granulopoietic progenitors (CFU-GM) and leukemic CFU-L with and without the addition of GM-CSF, as well as DNA measurements by flow cytometry (FCM) for the detection of DNA-aneuploidies. The present analysis is focused on one particular patient with acute myeloid leukemia (AML) in whom the detection of a DNA aneuploidy provided the readily accessible means to monitor the response of leukemic blasts to induction chemotherapy and subsequent GM-CSF treatment in vivo complementing the colony assay analyses performed in vitro. Prior to therapy 60% of cells revealed a DNA aneuploidy with a DNA index of 1.26 and in-vitro exposure of leukemic bone marrow blasts to GM-CSF (100 U/ml) enhanced the growth of CFU-L and CFU-GM with a significantly higher stimulatory index for CFU-L (1:19 versus 1:5.5). Three days after the completion of two cycles of induction therapy with thioguanine, cytosine arabinoside and daunorubicin (TAD 9) a morphologic bone marrow evaluation revealed aplasia without leukemic blasts. By FCM DNA analysis, however, 8% residual aneuploid cells were found. No growth of CFU-L was observed at this time point neither spontaneously nor after the addition of GM-CSF which induced the growth of CFU-GM, only. In-vivo application of GM-CSF (250 micrograms/mg2/day by continuous 24-h infusion) led to the recovery of normal granulopoiesis without evidence of a concomitant stimulation of aneuploid leukemic cells. These data indicate a change in the susceptibility of leukemic blasts to GM-CSF before and after chemotherapy. A reduction of the leukemic cell burden below a critical level or a selection of GM-CSF non-responsive early leukemic precursor cells may account for these observations.
Department of Internal Medicine, University of Münster, F.R.G.
W
W
Hiddemann
M
M
Zühlsdorf
B
B
Wörmann
M
M
Koenigsmann
T
T
Büchner
D000368:Aged; D000616:Aminoglutethimide / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols; D001853:Bone Marrow / Q000473:pathology; D003115:Colony-Stimulating Factors / Q000627:therapeutic use*; D004273:DNA, Neoplasm / Q000032:analysis; D003613:Danazol / Q000627:therapeutic use; D004341:Drug Evaluation; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D006133:Growth Substances / Q000627:therapeutic use*; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000628:therapy*; D008297:Male; D013629:Tamoxifen / Q000627:therapeutic use
D003115:Colony-Stimulating Factors; D004273:DNA, Neoplasm; D006133:Growth Substances; D013629:Tamoxifen; D000616:Aminoglutethimide; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D003613:Danazol