There has been remarkable progress in the treatment of CLL during the last decade. The introduction of fludarabine and other purine nucleoside analogs generated a significant improvement in responses relative to alkylating agents.1-3 Subsequently combinations of these two classes of agents, in particular fludarabine and cyclophosphamide, were proved superior to single agent fludarabine.4-6 Recently strategies to include antibody therapy, particularly with rituximab have given substantial increases in the complete response rate for CLL patients.4, 7-11 and an indication of increased overall survival in response to fludarabine-cytoxan-rituximab (FCR) therapy.12 Nevertheless, relapses remain problematic and development of drug resistance continues to be a major challenge in CLL treatment.11. Such drug resistance may in part be due to certain genetic alterations. A deletion at 11q22-23, the site of the ATM gene, occurs in half of relapsed/refractory patients. Mutation of the residual allele in approximately 50% of these patients inactivates homologous recombination (HR) repair of double strand breaks in CLL cells. Because Sapacitabine causes one-ended double strand breaks, cells that lack ATM are selectively sensitized. We hypothesize that the novel mechanism of action of Sapacitabine in CLL cells that lack ATM function, and are therefore are in repairing the lesion by homologous recombination, will create synthetic lethality and confer specificity of killing. We will conduct a clinical trial of Sapacitabine combined with cyclophosphamide and rituximab in relapsed/refractory patients with CLL who exhibit deletion 11q22-23 with the following specific aims: 1) test the hypothesis that CLL lacking ATM function (homologous recombination repair) will be selectively sensitized to Sapacitabine- containing therapy as indicated by a greater overall response rate and longer response duration;2) identify CLL patients whose disease lacks ATM function, and analyze clinical response with respect to this parameter. Demonstrating efficacy in patients with deletion 11q22-23, lacking ATM function, would be a significant advance in treatment for this high-risk group of patients, and would validate ATM as a target for Sapacitabine- containing therapy in CLL, and 3) conduct investigations with CLL samples obtained from patients entered on the trial that will translate the findings in models systems to these primary CLL cells.
Patients with CLL who have leukemia cells with deletion of the long arm of chromosome 11 (11q), the location of the ATM gene, are high-risk for rapid disease progression, short remission duration, and short overall survival. The function of ATM is critical to repairing breaks in DNA and is frequently lost in this group of patients. This applicaton proposes to treat these patients with Sapacitabine, a drug that causes DNA strand breaks, with the view that the leukemia cells that lack ATM function will be specifically affected, resulting in improved clinical responses and remission rate.