Contributions
Abstract: PB1757
Type: Publication Only
Background
Indoleamine 2,3-dioxygenase 1 (IDO1, IDO) is an enzyme catabolizing tryptophan (Trp) into the kynurenine (Kyn), and is a tumor microenvironment factor that suppresses antitumor immune responses. IDO is an attractive target for malignant tumor immunotherapy.
Aims
This study determined the prognostic significance of tryptophan (Trp) catabolism in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) and primary mediastinal large B-cell lymphoma (PMBCL).
Methods
A total of 133 DLBCL and 5 PMBCL patients who received at least 1 cycles of rituximab-CHOP like regimen were enrolled. Baseline serum Trp and Kyn levels in 138 lymphoma patients and 50 healthy volunteers were measured using an ultra-performance liquid chromatography–tandem mass spectrometry system, and associations with various clinical parameters analyzed. IDO expression was histologically evaluated within affected tumor sites of 103 patients.
Results
Enrolled patients comprised 77 males and 61 females (age range 24 – 90, median 69 years), with estimated overall survival (OS) at 5 years of 74.0 %. The serum Kyn concentration was significantly higher in the patients than in the healthy volunteers (median: 1.63 µM, 1.09 µM, respectively, P < 0.001). The serum Trp concentration was significantly lower in the patients than in the healthy volunteers (median: 50.9 µM, 63.4 µM, respectively, P < 0.001). Therefore, the serum Kyn/Trp ratio was significantly higher in the patients than in the healthy volunteers (median: 31.2, 16.5, respectively, P < 0.001). Patients were divided into two groups according to their serum Kyn/Trp ratio (Kyn [μmol/L)/Trp [μmol/L] x 103) since high IDO activity results in increased Kyn and decreased Trp concentrations, meaning a high serum Kyn/Trp ratio. Of four factors determining the international prognostic index for DLBCL, a high serum Kyn/Trp ratio (> 27.5) was significantly associated with advanced Ann Arbor stage (III - IV), high LDH (> upper normal limit), high age (≥ 61), poor performance status (2 - 4), but was not associated with extranodal sites (> 1). Interestingly, hypoalbuminemia (Alb < 4) was also significantly associated with high serum Kyn/Trp ratio. OS was significantly shorter in patients with a high serum Kyn/Trp ratio compared to those with a low ratio (OS rate at 5 years, 62.8 vs. 92.7 %, P = 0.0025; Figure), however, high serum Kyn/Trp ratio was not an independent risk factor for OS in multivariate analysis. In immunostaining analyses, lymphoma cells were negative, but macrophages and dendritic cells in the microenvironment were positive for IDO. No significant correlation existed between the serum Kyn/Trp ratio and the degree of histologically IDO positive cells in the tumor microenvironment. There were no significant differences in OS according to the degree of histologically IDO positive cells in the tumor microenvironment.
Conclusion
Baseline high serum Kyn/Trp ratio was associated with poor prognosis in DLBCL patients, however the immunohistological evaluation of IDO expression in the tumor sites was associated with neither serum Kyn/Trp ratio nor prognosis. Furthermore, high serum Kyn/Trp ratio was significantly associated with known poor prognostic factors of DLBCL. Wherefore, novel treatment strategy targeting IDO is attractive for DLBCL patients with high serum Kyn/Trp ratio.
Session topic: 21. Aggressive Non-Hodgkin lymphoma - Clinical
Keyword(s): Diffuse large B cell lymphoma, immunomodulation
Abstract: PB1757
Type: Publication Only
Background
Indoleamine 2,3-dioxygenase 1 (IDO1, IDO) is an enzyme catabolizing tryptophan (Trp) into the kynurenine (Kyn), and is a tumor microenvironment factor that suppresses antitumor immune responses. IDO is an attractive target for malignant tumor immunotherapy.
Aims
This study determined the prognostic significance of tryptophan (Trp) catabolism in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) and primary mediastinal large B-cell lymphoma (PMBCL).
Methods
A total of 133 DLBCL and 5 PMBCL patients who received at least 1 cycles of rituximab-CHOP like regimen were enrolled. Baseline serum Trp and Kyn levels in 138 lymphoma patients and 50 healthy volunteers were measured using an ultra-performance liquid chromatography–tandem mass spectrometry system, and associations with various clinical parameters analyzed. IDO expression was histologically evaluated within affected tumor sites of 103 patients.
Results
Enrolled patients comprised 77 males and 61 females (age range 24 – 90, median 69 years), with estimated overall survival (OS) at 5 years of 74.0 %. The serum Kyn concentration was significantly higher in the patients than in the healthy volunteers (median: 1.63 µM, 1.09 µM, respectively, P < 0.001). The serum Trp concentration was significantly lower in the patients than in the healthy volunteers (median: 50.9 µM, 63.4 µM, respectively, P < 0.001). Therefore, the serum Kyn/Trp ratio was significantly higher in the patients than in the healthy volunteers (median: 31.2, 16.5, respectively, P < 0.001). Patients were divided into two groups according to their serum Kyn/Trp ratio (Kyn [μmol/L)/Trp [μmol/L] x 103) since high IDO activity results in increased Kyn and decreased Trp concentrations, meaning a high serum Kyn/Trp ratio. Of four factors determining the international prognostic index for DLBCL, a high serum Kyn/Trp ratio (> 27.5) was significantly associated with advanced Ann Arbor stage (III - IV), high LDH (> upper normal limit), high age (≥ 61), poor performance status (2 - 4), but was not associated with extranodal sites (> 1). Interestingly, hypoalbuminemia (Alb < 4) was also significantly associated with high serum Kyn/Trp ratio. OS was significantly shorter in patients with a high serum Kyn/Trp ratio compared to those with a low ratio (OS rate at 5 years, 62.8 vs. 92.7 %, P = 0.0025; Figure), however, high serum Kyn/Trp ratio was not an independent risk factor for OS in multivariate analysis. In immunostaining analyses, lymphoma cells were negative, but macrophages and dendritic cells in the microenvironment were positive for IDO. No significant correlation existed between the serum Kyn/Trp ratio and the degree of histologically IDO positive cells in the tumor microenvironment. There were no significant differences in OS according to the degree of histologically IDO positive cells in the tumor microenvironment.
Conclusion
Baseline high serum Kyn/Trp ratio was associated with poor prognosis in DLBCL patients, however the immunohistological evaluation of IDO expression in the tumor sites was associated with neither serum Kyn/Trp ratio nor prognosis. Furthermore, high serum Kyn/Trp ratio was significantly associated with known poor prognostic factors of DLBCL. Wherefore, novel treatment strategy targeting IDO is attractive for DLBCL patients with high serum Kyn/Trp ratio.
Session topic: 21. Aggressive Non-Hodgkin lymphoma - Clinical
Keyword(s): Diffuse large B cell lymphoma, immunomodulation