Abstract
Indoleamine 2,3 dioxygenase-1 (IDO-1) is an enzyme in the kynurenine pathway which augments tumor-induced immune tolerance. Previous studies in childhood acute myeloid leukemia (AML) have shown a negative correlation of IDO-1 mRNA expression with outcomes. The aim of our study was to develop a practical and objective immunohistochemical technique to quantify IDO-1 expression on diagnostic bone marrow biopsies of AML patients in order to facilitate its use in routine clinical practice. IDO-1 mRNA was extracted from diagnostic bone marrow specimens from 29 AML patients. IDO-1 protein expression was assessed in 40 cases via immunohistochemistry and quantified by a novel ‘composite IDO-1 score’. In a univariate analysis, higher age (p = 0.0018), male gender (p = 0.019), high risk cytogenetics (p = 0.002), higher IDO-1 mRNA (p = 0.005), higher composite IDO-1 score (p < 0.0001) and not undergoing allogeneic stem cell transplant (SCT, p = 0.0005) predicted poor overall survival. In a multivariate model that included the aforementioned variables, higher composite IDO-1 score (p = 0.007) and not undergoing allogeneic SCT (p = 0.007) was found to significantly predict poor outcomes. Further, patients who failed induction had higher composite IDO-1 score (p = 0.01). In conclusion, ‘composite IDO-1 score’ is a prognostic tool that can help identify a certain subset of AML patients with ‘early mortality’. This unique subset of patients can potentially benefit from specific IDO-1 inhibitor therapy, currently in clinical trials.
Highlights
Indoleamine 2,3 dioxygenase (IDO-1), an enzyme in the kynurenine pathway, plays a critical role in tumor-mediated immune tolerance[1]
In the case of Acute Myeloid Leukemia (AML), preclinical studies in both adults and children have found a positive correlation of increased expression of IDO1 Messenger RNA (mRNA) or functional activity in leukemic blasts correlated with worse overall survival (OS)[19,20,21]
Our study shows that increased IDO-1 mRNA and protein expression correlates with a lower OS
Summary
Indoleamine 2,3 dioxygenase (IDO-1), an enzyme in the kynurenine pathway, plays a critical role in tumor-mediated immune tolerance[1]. In the case of Acute Myeloid Leukemia (AML), preclinical studies in both adults and children have found a positive correlation of increased expression of IDO1 mRNA or functional activity in leukemic blasts correlated with worse overall survival (OS)[19,20,21] This has prompted initiation of a clinical trial in which the IDO-pathway inhibitor indoximod will be combined with standard idarubicin/cytarabine chemotherapy in newly-diagnosed adult AML (NCT02835729). The subset of patients with by far the worst prognosis, fails to enter remission with induction chemotherapy These patients often have a relentlessly downhill course despite best available therapy, and in certain high-risk populations such as elderly patients, over half will be dead within 6 months of diagnosis. We hypothesized that immunohistochemical staining of initial diagnostic bone-marrows biopsies for a combination of extent and intensity of IDO-1 staining might be used to generate an objective pathologic score of IDO-1 expression; and that this would allow accurate prospective identification of those patients at highest risk of induction-failure and early mortality
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