Recognizing that present-day chemotherapy for adult ALL is unsatisfactory, that routinely available biological parameters such as immunophenotyping have not uniformly predicted prognosis, and that there is a need to identify patients with good-risk or high-risk prognoses in a timely fashion prior to the initiation of therapy, we are proposing to apply a panel of new biological markers to the systematic evaluation of adult ALL lymphoblasts. The hypothesis is that tumor suppressor gene (Rb, p53), mutation, heterozygous or homozygous deletion, especially in combination with other events, such as BCR-ABL translocation, CD34 or myeloid antigen co-expression, or expression of proliferation-associated antigen, Ki-67, or the lL-2 receptor (lL2-R) may identify subgroups of adult ALL patients with poor prognosis. Conversely, patients with blast cells lacking these biological features might be expected to have a good prognosis. We will use pretreatment bone marrow or blood specimens from patients registered to the new Southwest Oncology Group adult ALL protocol 9145 entitled, """"""""Treatment of Adult Acute Lymphoblastic Leukemia: A Phase III Trial of G- CSF vs. No Growth Factor After Induction Therapy on Previously Untreated Patients, with Allogeneic Bone Marrow Transplantation or Further Chemotherapy in First Remission."""""""" lt is estimated that this study will accrue 486 patients, all of whom will receive central laboratory determinations of immunophenotyping, cytogenetics, and pathology review. Pretreatment specimens will be collected from all patients. Immunophenotyping will employ reagents recognizing the following cell surface antigens: CD1, CD2, CD3, CD4, CD5, CD7, CD8, CD1O (CALLA), CD13, CDW14, CD15, CD19, CD2O, CD22, CD33, CD34, CD38, CD71, and HLA-DR and multicolor combinations will be used to confirm co-expression of certain antigens by single blast cells. Blast cells will be analyzed for """"""""ALL- type"""""""" and """"""""CML-type"""""""" BCR-ALL translocations by polymerase chain reaction (PCR). Lymphoblasts will be tested for expression of Rb and p53 proteins by immunoblotting and immunohistochemistry, respectively. Samples with aberrant Rb or p53 expression by these techniques will be analyzed further for Rb gene deletion by Southern blotting or for p53 gene mutation by PCR- single strand conformation polymorphism (SSCP) analyses and nucleotide sequencing. Immunocytochemistry will be used to examine lymphoblast expression of lL-2Ralpha and lL-2Rbeta subunits and the Ki-67 antigen. These biologic data will be tied to an extensive clinical and therapeutic data base maintained by the Southwest Oncology Group Statistical Center, allowing the data to be correlated with clinical parameters and the statistical significance of various biological parameters on prognosis to be determined.
| Hu, N; Gulley, M L; Kung, J T et al. (1997) Retinoblastoma gene deficiency has mitogenic but not tumorigenic effects on erythropoiesis. Cancer Res 57:4123-9 |
| Tsai, T; Davalath, S; Rankin, C et al. (1996) Tumor suppressor gene alteration in adult acute lymphoblastic leukemia (ALL). Analysis of retinoblastoma (Rb) and p53 gene expression in lymphoblasts of patients with de novo, relapsed, or refractory ALL treated in Southwest Oncology Group studies. Leukemia 10:1901-10 |
