Augusta University
Ravindra Kolhe, MD, PhD Photo courtesy of Phil Jones/
New research has shown an increased risk of early death in patients with acute myeloid leukemia (AML) who have high levels of indoleamine 2,3 dioxygenase-1 (IDO-1), an enzyme known to suppress the immune system.
Researchers quantified IDO-1 expression in diagnostic samples from patients with AML and discovered that high levels of IDO-1 were significantly associated with induction failure and poor overall survival (OS).
Ravindra Kolhe, MD, PhD, of the Medical College of Georgia at Augusta University, and his colleagues recounted these findings in Scientific Reports.
The researchers reviewed data from 40 AML patients. They had a median age at diagnosis of 60 (range, 27–89), 60% were female, and 55% were self-reported as Caucasian.
Most patients (72.5%) received standard anthracycline and cytarabine as induction, 10% received hypomethylating agents, and 17.5% were untreated or had unknown treatment status.
Fifteen percent of patients underwent allogeneic hematopoietic stem cell transplant (allo-HSCT) at the time of first complete remission.
Half of all patients achieved remission, and half of those patients (n=10, 25%) had a subsequent relapse. The median OS was 283 days (range, 32–1941). Twenty percent of patients (n=8) were still alive at the time of data analysis.
IDO-1 analysis
“We wanted to look at what makes this leukemia so aggressive that initial induction chemotherapy is not working,” Dr Kolhe said. “Early relapse tends to predict early mortality in these patients, and one of the things we looked at was IDO.”
The researchers extracted IDO-1 mRNA from diagnostic bone marrow samples from 29 of the patients but assessed IDO-1 protein expression in all 40 patients via immunohistochemistry.
The team quantified IDO-1 expression using a “composite IDO-1 score.” They used a cut-off point of 0.45 and divided patients’ samples into 2 groups: high (≥0.45) and low (<0.45) IDO-1 score.
The researchers compared IDO-1 results across 4 survival groups, which included patients surviving:
- Less than 6 months
- More than 6 months to 1 year
- More than 1 year to less than 5 years
- Beyond 5 years.
The team found a direct correlation between poor OS and higher composite IDO-1 score (P=0.0005).
“The patients who died at 6 months had a high expression of IDO, while the blasts produced relatively little IDO in the patients who lived 5 years or more,” Dr Kolhe said.
Independent predictor
The researchers conducted a univariate analysis and identified several factors that were significantly associated with poor OS, including:
- Higher IDO-1 mRNA (P=0.005)
- Higher composite IDO-1 score (P<0.0001)
- Higher age (P=0.0018)
- Male gender (P=0.019)
- High-risk cytogenetics (P=0.002)
- Not undergoing allo-HSCT (P=0.0005).
In a multivariate analysis including the above variables, the researchers found that a higher composite IDO-1 score (P=0.007) and not undergoing allo-HSCT (P=0.007) were significantly associated with poor OS.
The team also found that patients who failed induction had a higher composite IDO-1 score (P=0.01).
“Most of the time, we don’t know why patients are not responding to chemotherapy,” Dr Kolhe noted. “But when the researchers adjusted for other risk factors for AML, like increased age and severe anemia, IDO levels were a standout. Right now, we know it’s high in patients who die at 6 months, and we show that it’s an independent indicator if you adjust for other known variables.”
Dr Kolhe said these results suggest IDO-1 expression should be measured when the diagnostic bone marrow biopsy is performed. This may help identify AML patients who could benefit from receiving an IDO inhibitor along with standard therapy.
Researchers are currently conducting a phase 1/2 trial of the IDO inhibitor indoximod in combination with idarubicin and cytarabine in patients with newly diagnosed AML (NCT02835729).
