The treatment of acute non-lymphocytic leukemia in the elderly, is still associated with high morbidity and mortality rates. This proposal is aimed at interfacing with the planned ECOG phase III study (EST 1490) of granulocyte-macrophage colony-stimulating factor (GM-CSF) in adult patients (55-70 years) with acute non-lymphocytic leukemia (ANLL). This research is focused on correlating the in-vitro effects of GM-CSF on ANLL blasts at diagnosis, with the clinical outcome of patients receiving GM-CSF (or no GM-CSF) in a multi-center randomized clinical trial.
The specific aims i nclude the following: 1) the quantitation of the proliferative fraction of ANLL blasts at diagnosis using cell cycle analysis combined with staining for the Ki-67 nuclear antigen; when possible correlate Ki-67 antigen staining in-vitro with the extent of GM-CSF induced proliferation; 2) evaluate the growth characteristics of leukemic blasts in defined serum- free media, focusing on proliferative responses to recombinant cytokines such as GM-CSF, granulocyte colony-stimulating factor (G-CSF), interleukin 3 (IL-3) and macrophage colony-stimulating factor (M-CSF); 3) perform binding studies of 125I-GM-CSF and G-CSF to ANLL cells, and evaluate the extent of up-regulation of GM-CSF receptor expression by G-CSF. The acquired information will be analyzed to derive correlations with immunophenotype (myeloid markers), histochemical features (FAB subtype), and clinical outcome after GM-CSF therapy. While the intent of the clinical study is to minimize the toxicity and magnitude of the neutropenic period in these patients, a hastening of the in-vivo resurgence of the leukemic cell populations is a distinct possibility, especially if ANLL blasts display functional GM-CSF receptors. Our studies will provide the opportunity to delineate the relevance of these in-vitro GM-CSF mediated effects on leukemic cells to the patient's outcome and onset of leukemic relapse in GM-CSF treated subjects, in the context of a multi-institutional randomized clinical trial.
| Liesveld, J L; Frediani, K E; Harbol, A W et al. (1994) Characterization of the adherence of normal and leukemic CD34+ cells to endothelial monolayers. Leukemia 8:2111-7 |
| Liesveld, J L; Keng, P C; Rowe, J M et al. (1994) Effects of GM-CSF on Ki67 expression and cell cycle traverse in acute myelogenous leukemia specimens and cell lines. Leuk Res 18:609-16 |
| Freeman, S M; Abboud, C N; Whartenby, K A et al. (1993) The ""bystander effect"": tumor regression when a fraction of the tumor mass is genetically modified. Cancer Res 53:5274-83 |
