Abstract
Abstract
OCT-2 and its co-activator, BOB.1, are B-cell associated transcription factors, and are expressed in a subset of pts with acute myelogenous leukemia (AML). Pathways downstream of OCT-2 may serve as therapeutic targets. However, the prognostic significance of OCT-2 and BOB.1 expression in pts with AML is unclear. We evaluated OCT-2 and BOB.1 expression in pts with newly diagnosed AML, and the prognostic impact of expression on achievement of complete remission (CR), risk of relapse, and overall survival (OS).
Methods: Between 1998–2005, adult pts with newly diagnosed AML and an available diagnostic BM biopsy performed at the Cleveland Clinic were evaluated. B5-fixed core biopsies were reviewed for areas with the highest concentration of blasts. A tissue microarray was constructed, and the cores were arrayed in duplicate. Immunohistochemistry was performed for OCT-2 (1:200 dilution; polyclonal; Santa Cruz Biotechnology) and BOB.1 (1:500 dilution, polyclonal; Santa Cruz Biotechnology) using automated stainers and heat induced epitope retrieval. Staining was scored as the percent of blasts with nuclear staining. For the purposes of dichotomous classification, nuclear staining in ≥ 10% of the blasts was considered positive. OCT-2 and BOB.1 expression were analyzed both per 10% increase, and as dichotomous variables. Cox proportional hazards analysis was used to identify univariate and multivariate risk factors. Variables included: age at diagnosis, cytogenetic (CG) risk group, gender, OCT-2 expression, BOB.1 expression, history of antecedent hematologic disorder (AHD), CD117 (c-kit) expression, and white blood count (WBC) at diagnosis.
Results: One-hundred and seventy-nine pts with newly diagnosed AML were treated with induction chemotherapy, and 99 pts had evaluable BM core biopsies. The median age at diagnosis was 57 yrs (range 17–79), and 52% were male. Fourteen percent of pts had favorable CG, 54% intermediate risk, 25% unfavorable, and 7% unknown CG as defined by CALGB criteria. The median WBC at diagnosis was 10.6 k/uL (range 0.4–259.0), and 28% of pts had an AHD. Nineteen percent of pts co-expressed OCT-2 and BOB.1, 35% expressed neither OCT-2 or BOB.1, and 12% expressed BOB.1 alone. Seventy-seven percent of pts achieved a CR with induction therapy. In first CR, 16% received an allogeneic BMT, 9% received autologous BMT, and 56% received consolidation chemotherapy. The median OS for all pts was 15.5 months after diagnosis, and the median time from diagnosis to relapse was 9.4 months. On univariate analysis, pts with co-expression of OCT-2 and BOB.1 (HR 0.45, 95% CI 0.24–0.84, p=0.013) or poor risk CG had a lower CR rate. OCT-2 expression (per 10% increase) (HR 1.11, 95% CI 1.02–1.21, p=0.013), age at diagnosis (per 10 year increase), and poor risk CG were associated with a decreased PFS. Pts with co-expression of OCT-2 and BOB.1 (HR 2.25, 95% CI 1.00–5.05, p=0.049), poor risk CG, or history of an AHD had an increased risk of relapse. OCT-2 expression (per 10% increase) (HR 1.10, CI 1.01–1.20, p=0.024), age at diagnosis, or poor risk CG, were associated with a decreased OS. On multivariate analysis, age at diagnosis and CG risk group remained statistically significant prognostic factors. The co-expression of OCT-2/BOB.1 also remained prognostic for achievement of CR (HR 0.44, 0.23–0.82, p=0.010) and increased risk of relapse (HR 2.30, 1.01–5.24, p=0.047) (Table 1). In the subgroup of pts without an AHD, the risk of relapse was more striking in pts with co-expression of OCT-2 and BOB.1 (HR 3.24, 1.38–7.64, p=0.007). When OCT-2 and BOB.1 were evaluated separately, and co-expression was not included in the multivariate analysis, OCT-2 (per 10% increase), was associated with a decreased PFS (HR 1.10, 1.01–1.20, p=0.036) and a trend towards a worse OS (HR=1.10, 0.99–1.21, p=0.063) (Table 1).
Conclusions: OCT-2 expression and OCT-2/BOB.1 co-expression are associated with a poor prognosis in pts with newly diagnosed AML. OCT-2 may act as a cell survival factor by mediating expression of other factors, such as BCL-2. Therefore, targeting pathways activated downstream of OCT-2, such as the anti-apoptotic gene, BCL-2; the cell surface antigen CD36; and interleukin-2 may potentially improve the prognosis of these particular pts.
Table 1 Multivariate Analysis
CR Risk of Relapse PFS OS OCT-2/BOB.1 Co-Expression HR.44, p=.01 HR 2.30, p=.047 OCT-2 (per 10% increase) HR 1.10, p=.036 HR=1.10, p=.06