Serum Concentration of L-Kynurenine Can Determine Clinical Outcome of Patients with Diffuse Large B-Cell Lymphoma Treated with R-CHOP

Background: Indoleamine 2,3-dioxygenase (IDO) exerts powerful immunomodulatory effects through its enzymatic activity that leads to catabolism of the essential amino acid L-tryptophan. Pro-inflammatory cytokines such as IFN-g induce IDO during the inflammatory response in many human cell types. The induction of IDO is synergistic in the presence of TNF-a, IL-1 or IL-6, and might be mediated by a signaling pathway from NF-kB and/or MAPKs. Furthermore, some metabolites derived from tryptophan generated by IDO such as L-kynurenine, block Ag-driven specific T-cell proliferation and induce T-cell death. Increments in IDO activity correlate with tumor progression in various malignancies. Therefore, IDO activity might play an important role in regulation of the immune response exerted by antigen presenting cells and also provide transformed cells with a potent tool to help escape from assault by the immune system. The activity of IDO can be estimated by measuring the serum concentration of kynurenine. Here, we investigated the relevance of L-kynurenine as a prognostic factor for DLBCL with R-CHOP therapy.

Patients and methods: The study protocol comprised a prospective, consecutive entry design that was approved by our Institutional Review Board. We investigated 75 patients between December 2002 and March 2007 who were histologically diagnosed with DLBCL according to the WHO classification. We measured L-kynurenine by high-performance liquid chromatography using a spectrophotometric or a fluorescence spectrometric detector. Patients aged <70 y received 8 cycles of either R-CHOP or R-THP-COP therapy. Each regimen consisted of rituximab (R: 375 mg/m²), cyclophosphamide (CPA: 750 mg/m²), doxorubicin (DOX) or tetrahydropyranyl-adriamycin (THP; 50 mg/m²), vincristine (VCR; 1.4 mg/m², maximal dose 2.0 mg), and prednisolone (PSL; 100 mg daily). The R-THP-COP regimen included THP, an anthracycline derivative of DOX. Patients aged ≥70 y received 6 cycles of R-THP-COP therapy, which is often applied to elderly patients with NHL. The regimen consisted of rituximab (R: 375 mg/m²), CPA (650 mg/m²), THP (40 mg/m²), VCR (1.4 mg/m²; maximal dose, 2.0 mg), and PSL (40 mg daily). The R-CHOP and R-THP-COP chemotherapy cycles were repeated at 14-day intervals in patients aged <70 y, and the THP-COP chemotherapy cycles were repeated at 21-day intervals in patients aged ≥70 y. Patients with bulky disease received radiotherapy ranging from 30 to 40 Gy. Responses to treatment were categorized as defined by Cheson et al.

Results: The median age was 68 y (range, 24 – 82 y) and the median follow-up was 20.6 mo (range, 0.6 – 42.3 mo). The median serum L-kynurenine level was 1.575 mM (range, 0.537 – 9.588). We found no significant correlations between L-kynurenine and gender, LDH, or sIL-2R. However, L-kynurenine significantly correlated with age (r = 0.279, P <0.05) and a high serum level was significantly associated with advanced disease, and many extranodal involvements (P <0.05). W established the cut-off value of L-kynurenine at 1.5 mM. The CR rates of patients with L-kynurenine <1.5 and ≥1.5 mM were 80.6% and 64.1%, respectively (P <0.05). Other factors associated with a significantly worse outcome were many extranodal involvements, advanced clinical stage, B-symptoms, elevated sIL-2R, and unfavorable IPI. The 2-year OS rates for patients with L-kynurenine <1.5 and ≥1.5 mM were 89.2% and 44.8%, respectively (P <0.05).

Discussion: The increase in serum L-kynurenine levels is thought to be caused by enhanced L-TRP catabolism, which inhibits tumoral local immunity. The result of a poor prognosis among patients with high L-kynurenine levels suggests that depressed local immunity due to enhanced IDO activity contributes to DLBCL becoming refractory to treatment.