Interphase cytogenetics and cytokine therapy in myelodysplastic syndromes and acute myeloid leukemia

Sammanfattning: INTERPHASE CYTOGENETlCS AND CYTOKINE THERAPY IN MYELODYSPLASTIC SYNDROMES AND ACUTE MYELOID LEUKEMIA By Per Bernell Myelodysplastic syndromes (MDS) comprise a group of clonal hematopoietic bone marrow cell disorders, characterized by a variable degree of anemia, granulocytopenia and/or thrombocytopenia and with a substantial risk of transformation to acute myeloid leukemia (MDS-AML). In the present thesis a method based on fluorescence in situ hybridization (FISH) was developed which allows cytogenetic studies on morphological identified peripheral blood and bone marrow cells (MGG/FISH). The purpose was to study cytogenetic aberrations in different cell lineages in the bone marrow of patients (pts) with MDS and AML. Another aim was to scrutinise the role of therapy with GM-CSF, given together with EPO to MDS patients with anemia, and together with chemotherapy to patients with MDS-AML. The MGG/FISH method was used in the evaluation of lineage involvement in 12 pts with MDS, 14 with MDS-AML and 6 with de novo AML. In all cases of MDS and MDS-AML, both the myelopoietic and the erythropoietic cell lineages were involved but not the Iymphoid cells. In de novo AML, the abnormal chromosomal clone was generally confined to the immature myeloid cells. MGG/FISH was also evaluated as a method to detect minimal residual disease (MRD) in 12 pts with acute leukemia in complete remission (CR). Using MGG/FISH it was possible to detect MRD in 5 pts in CR, which was not detected using conventional methods. All these S pts subsequently relapsed within two to nine months. In the clinical studies, MDS pts were first treated with EPO (n=37) and non-responders were later given the combined GM-CSF/EPO (n=13) treatment. Fourteen of 37 MDS pts (38%) increased their hemoglobin levels by > l5 g/l during EPO therapy. Responders were more often of FAB subtypes RA or RAS, showed lower s-ElPO and s-LDH and had less pronounced transfusion requirements while their baseline hemoglobin levels were higher. Three of 13 pts (23%) increased their hemoglobin levels and their physical well-being during GM-CSF/EPO, suggesting possible synergism during the combined treatment. Five pts were studied before and after EPO therapy by MGG/FISH and the two responders showed an increase in non-clonal erythroid BM cells. Accordingly, it is likely that one important effect of EPO could be stimulation of remaining normal erythroid precursor cells. Pts with MDS-AML (n=14) were treated with GM-CSF before, during and after chemotherapy (TAD) and eight (58%) entered CR. We found higher CR rates, fewer early deaths, fewer fever days and fewer days with both neutropenia and thrombocytopenia among the responding pts compared to the historical control group, suggesting a better response of the combined GM-CSF/TAD treatment in MDS-AML. The MGG/FISH method is clinically useful and allows studies of cell lineage involvement and detection of MRD in MDS and acute leukemia as well as investigations into the nature of the hematological responses to growth factors. Keywords: myelodysplastic syndromes, acute myeloid leukemia, FISH, clonality, lineage involvement, minimal residual disease, EIPO, GM-CSF. ISBN-91-628-2202-0