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Background: Indoleamine 2,3-dioxygenase (IDO), the rate limiting enzyme of tryptophan metabolism, in part mediates allogeneic tolerance and may be important in allogeneic HSCTand GVHD.
Objective: To prospectively evaluate in vivo IDO activity in allogeneic HSCT recipients and test our hypothesis that IDO activity is associated with acute GVHD.
Methods: Patients (>1 year-old) receiving allogeneic HSCT were eligible. Plasma samples were collected at baseline and days -3, 0, +7, 14, 21, 30, 45, 60, 100, 180, and 365 relative to HSCT for tryptophan (Trp) and kynurenine (Kyn) quantification (µM) by high performance liquid chromatography. Mann-Whitney rank tests were used to test associations between Kyn/Trp ratio (IDO activity) and area under the curve (AUC) Kyn/Trp ratio and GVHD. Potential confounders were tested for association with GVHD using Fisher's exact tests (#) or Mann-Whitney rank tests (*). Analyses were performed using R (ver 2.12.1) and GraphPad Prism (ver 5.04).
Results: Twenty patients were evaluable for IDO activity and GVHD. AML was the most common diagnosis (n = 9, 45%). All patients engrafted at mean (SD) 17.2 (+/- 5) days. Acute GVHD occurred in 13 (59.1%) patients: 10 were Grade I-II and 3 were Grade III. Median time to GVHD diagnosis was 46 days. Table 1 summarizes cohort data. Elevated Kyn/Trp ratio correlated with GVHD compared to non-GVHD cohort (p = 0.027). Likewise AUC Kyn/Trp ratio correlated with GVHD (p = 0.007). Mortality rate was 50% at a median of 98 days post-HSCT.
Conclusions: IDO activity is associated with acute GVHD and may be a useful biomarker to assist with GVHD diagnosis. Future validation studies are needed to confirm these findings, which should be considered in clinical trials that target IDO induction for prevention or treatment of GVHD
Table 1. Risk Factor and IDO Activity Correlations for GVHD
Clinical Characteristics and GVHD Risk Factors
| GVHD (n= 13)
| No GVHD (n =7)
| P-value
|
Age at HSCT, median (range) years | 20 (2-69)
| 31 (1-49)
| 1.000*
|
Malignant disease, n (%) Non-malignant disease, n (%)
| 10 (76.9) 3 (23.1)
| 7 (100.0) 0
| 0.521#
|
Malignant Disease Status at HSCT
| |||
CR1 CR2 Active/Refractory
| 3 (23.1) 4 (30.8) 3 (23.1)
| 3 (42.9) 1 (14.3) 3 (42.9)
| 0.415#
|
Conditioning Regimen
| |||
Myeloablative Reduced-intensity
| 7 (53.8) 6 (46.2)
| 5 (71.4) 2 (28.6)
| 0.484#
|
HSCT Product
| |||
Bone marrow Peripheral Blood Umbilical cord blood
| 6 (46.2) 5 (38.5) 2 (15.3)
| 1 (14.3) 3 (42.9) 3 (42.9)
| 0.199#
|
HLA-Mismatch
| |||
0 1 2
| 9 (69.2) 4 (30.8) 0
| 4 (57.1) 1 (14.3) 2 (28.6)
| 0.207#
|
Unrelated Donor
| 9 (69.2)
| 5 (71.4)
| 1.000#
|
CD34+ cells/kg dose
| 3.63 x 106
| 3.19 x 106
| 0.757*
|
TNC cells/kg dose
| 4.81 x 108
| 4.18 x 108
| 0.699*
|
Post-HSCT Disease Relapse, n (%)
| 6 (46.2)
| 2 (28.6)
| 0.642#
|
Kyn/Trp (IDO) Ratio, median (range)
| 1.55 (0.41-15.15)
| 0.69 (0.16-2.06)
| 0.027*
|
AUC (Kyn/Trp IDO Ratio), median (range) | 43.20 (6.10-666.80)
| 11.76 (8.03-35.49)
| 0.007*
|