Indoleamine 2,3-Dioxygenase (IDO) Is Associated with High Incidence of Chemorefractory Disease in Acute Myeloid Leukemia (AML) Patients

Abstract 4787

Indoleamine 2,3-dioxygenase (IDO) is a heme-containing enzyme that catalyzes the first and rate-limiting step in tryptophan degradation along the kynurenine pathway. IDO is able to inhibit T-cell function and to induce the transformation of T-cells into regulatory T-cells. Several studies demonstrated that IDO expression is involved in immune tolerance induction during pregnancy, infection, transplantation, autoimmune diseases and neoplasias, including acute myeloid leukemia (AML). In particular, our and other groups demonstrated that IDO is expressed in a significant proportion of AML patients and that it increases along with disease progression. Here, we addressed the correlation between IDO expression by AML cells, risk factors at diagnosis and patients' outcome.

Adult AML patients from the Hematology Institute “L. and A. Seràgnoli” in Bologna were analyzed for risk characteristics at diagnosis and for IDO expression by RT-PCR and by Western-Blot analysis. Patients were stratified according to age at diagnosis, de novo or secondary disease (pre-existing myelodysplastic syndrome or radio-chemotherapy), leucocytosis, cytogenetics (on the basis of cytogenetic characteristics patients were divided into low, intermediate and high risk groups) and FLT3 and NPM mutational status.

Fifty-two patients with AML at diagnosis were analyzed for IDO expression both at gene and protein level. According to IDO transcript levels, patients were divided into IDO-negative (21%) and IDO positive (79%). Positive patients were further subdivided into three different subgroups according to IDO level: IDO-low expression (78%), IDO-intermediate expression (10%) and IDO-high expression (12%) patients. When IDO protein was assessed, we found a correlation between IDO mRNA level and the detection of IDO protein. In particular, IDO protein was detectable only in IDO-high-expressing patients.

No statistically significant differences in the recurrence of prognostic characteristics at diagnosis among the groups considered were observed, even though IDO-negative and IDO-low expressing patients showed a higher median age at diagnosis than IDO-intermediate and IDO-high expressing patients and an increased frequency of high-risk cytogenetics was found in IDO-high expressing patients. Response to induction chemotherapy regimen was then analyzed among the four groups of patients. Only patients who received cytotoxic chemotherapy were evaluated for response. Intriguingly, we found that refractory patients were 60% among patients who express IDO at high level and 27% among IDO-negative patients.

In conclusion, IDO-high expressing patients show an increased proportion of refractory disease than IDO negative patients. To support our preliminary findings, a multivariate analysis on a larger cohort of patients is currently ongoing.