Indoleamine 2,3-dioxygenase (IDO) is endowed with intense immunomodulatory effects due to its enzymatic activities that catalyse the breakdown of the essential amino acid L-tryptophan. The activity of IDO can be estimated by measuring the serum concentration of L-kynurenine. We have previously described that high serum l-kynurenine level is associated with poor prognosis of DLBCL (Yoshikawa et al. Eur J Haematol 2009). Here, we investigated the tryptophan catabolism in T-cell lymphoma.
The study protocol employed a prospective, consecutive entry design. All patients provided written informed consent to participate in the study according to institutional guidelines and the Declaration of Helsinki. We investigated data from 23 patients between December 2002 and March 2011 who were histologically diagnosed with T-cell lymphoma according to the WHO classification and treated with CHOP. Patients received 6–8 therapeutic cycles of CHOP or THP-COP. Each regimen consisted of cyclophosphamide (CPA; 750 mg/m2, as a 2-h i.v. drip infusion on day 1), doxorubicin (DOX) or tetrahydropyranyl-adriamycin (THP; 50 mg/m2, 30-min i.v. drip infusion on day 1), vincristine (VCR; 1.4 mg/m2, maximal dose 2.0 mg i.v. as a bolus over 5 min on day 1), and prednisolone (PSL; 100 mg daily p.o. on days 1 to 5). The R-THP-COP regimen included THP, an anthracycline derivative of DOX with reportedly lower cardiotoxicity than DOX. Our prospective randomized study found no significant differences in remission and survival rates between CHOP and THP-COP therapy. All follow-up data were updated on June 1, 2011. Twenty healthy individuals (11 males and 9 females) served as the control group. All serum samples were obtained at admission, separated by low-speed centrifugation (800 g, 15 min) at 4°C and stored at −20°C until analysis. We measured serum L-kynurenine concentrations by high-performance liquid chromatography (HPLC) using a spectrophotometric (UV-8000, Tosohiba, Tokyo). Briefly, L-kynurenine was separated by reverse-phase column chromatography (column: Brave ODS 3 μ, 150 × 4.6 mm; Alltech, IL, USA) with a mobile phase of 0.1 M sodium acetate, 0.1 M acetic acid and 1% acetonitrile at a flow rate of 0.75 ml/min. The fluorescence excitation and emission wavelengths were set at 270 and 360 nm, respectively. The UV signals were monitored at 355 nm for L-kynurenine.
The pathology of underlying comprised PTCL-NOS (n = 17), anaplastic large cell lymphoma (n = 4) and NK/T cell lymphoma (n = 2). The median serum l-kynurenine levels in patients (3.84 ± 4.04 mM) were significantly higher than in healthy volunteers (1.13 ± 0.32 mM). We found no significant correlation between L-kynurenine and gender, age, extranodal lesions, B symptoms or PS. However, L-kynurenine significantly correlated with PIT (P < 0.05). We established the cut-off value of l-kynurenine at 2.6 mM which was essentially the median for all patients (2.63 mM). CR rates of patients with L-kynurenine <2.6 and ≥2.6 mM were 70% and 38%, respectively (P < 0.05). Other factors associated with a significantly worse outcome were higher age (≥60), poor PS (>1), elevated LDH, and unfavorable PIT. The 5-year overall survival (OS) rates for patients with L-kynurenine <2.6 and ≥2.6 mM were 77% and 38%, respectively (P < 0.005). Other significantly worse factors were higher age (≥60), poor PS (>1), and unfavorable PIT.
IDO activity might play an important role in the disease activity of T-cell lymphoma. Serum L-kynurenine might be a significant prognostic factor and a useful tool for selecting appropriate therapeutic strategies for patients with T-cell lymphoma.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.