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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 (�M) 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*
|