ALBERT

Description: Prospective identification of patients whose chronic myeloid leukemia (CML) will progress to blast crisis is currently not possible. PP2A is a phosphatase and tumor suppressor that regulates cell proliferation, differentiation, and survival. Cancerous inhibitor of PP2A (CIP2A) is a recently described inhibitor of PP2A in breast and gastric cancer. The aim of this study was to investigate whether CIP2A played a role in CML and whether PP2A or its inhibitor proteins CIP2A or SET could predict clinical outcome. At the time of diagnosis of CML, patients who will later progress to blast crisis have significantly higher levels of CIP2A protein (P 〈 .0001) than patients who do not progress, suggesting that PP2A is functionally inactive. We show that the potential mechanism for disease progression is via altered phosphorylation of the oncogene c-Myc. Knockdown of CIP2A results in increased PP2A activity, decreased c-Myc levels, and a decrease in BCR-ABL1 tyrosine kinase activity. We demonstrate that CIP2A levels at diagnosis can consistently predict patients who will progress to blast crisis. The data show that CIP2A is biologically and clinically important in CML and may be a novel therapeutic target.

Description: Abstract 5098 Military Service in Vietnam/Korea and Serum Dioxin Levels Do Not Affect the Outcomes of Patients Diagnosed with Plasma Cell Dyscrasias. Background: Exposure to dioxin, a contaminant found in herbicides has been associated with increased risk of cancers including multiple myeloma and postulated to cause poorer survival in the exposed population. Military personnel, especially those who had served in Vietnam and Korea have an increased risk of dioxin (which contaminated the herbicide Agent Orange which was sprayed during these wars) exposure. We looked at the impact of dioxin exposure and blood levels of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) which is the most toxic of the poly-chlorinated dioxins on the survival outcomes of military veterans diagnosed with plasma cell dyscrasias (PCD). Methods: A prospective analysis of newly diagnosed and existing myeloma patients was done. Information regarding the patient and disease characteristics, the military record, and outcomes were collected. Approximately 60 ml of heparinised peripheral blood was collected and immediately frozen at −20 degrees. These samples were shipped to Eurofins Laboratory, Hamburg, Germany for dioxin level measurement. Patients' blood lipid levels were also measured and the dioxin toxic equivalent (Teq) was calculated. Overall survival (OS) was calculated from the date of diagnosis till death (Kaplan Meier method). Cox regression and log rank analysis were used to look for prognostic variables. Results: Fifty two (52) patients of PCD were available for analysis. Majority had a diagnosis of multiple myeloma. Forty one underwent treatment including stem cell transplant in 16 (Table 1 shows the patient characteristics, laboratory results and treatment outcomes). During a median follow up of 54 months (2–348), 21 patients died (progressive myeloma: 12(23%), cardiac failure: 3 (5.7%), infections: 1 (1.9%), acute myeloid leukemia: 1 (1.9%), pulmonary embolism: 1 (1.9%) and unknown: 3 (5.7%). The median OS was 111 mos (95% CI 56–155) and the estimated survival at 5 yrs was 69.5% (+/− SE 0.067). The 5 yr OS was negatively impacted by abnormal cytogenetics (40.3 % vs. 75.5%; p=0.012), and service in the army (non-army vs. army: 83% vs. 40%; p=0.032). Patients who had served in Vietnam had outcomes similar to others; Korean War veterans had a poorer OS, but this was not statistically significant (5 yr OS 68% vs. 48%; p=0.1). There was no association between TCDD levels or the Teq with OS. Abnormal cytogenetics was the only significant factor on multivariate analysis. Conclusions: We did not find an association between military service in Korea/Vietnam or serum dioxin levels and poor survival in military veterans diagnosed with Plasma cell dyscrasias. However, a study of a larger sample of myeloma patients with similar service and exposure histories maybe warranted. Disclosures: No relevant conflicts of interest to declare.