Arginase-1 Is Increased in Hodgkin Lymphoma, Associated to Poor Outcome and Positively Correlated to Semiquantitative PET Parameters

Background:

In Hodgkin Lymphoma (HL) elevated neutrophil (HL-N) count is a well-known negative prognostic factor but its biological meaning is not elucidated. Our previous work showed that HL-N are dysfunctional and can suppress T-cell activation in vitro, as consequence of increased amount of Arginase-1 (Arg-1).

Aim:

Investigating clinical meaning of arginase increase in HL, correlating its amount to features at diagnosis, including some semiquantitative parameters of 18-FDG- PositronEmission Tomography (PET) acquired with a novel operator-independent algorithm.

Material and methods: We prospectively measured soluble Arg-1 (s-Arg-1) in 135 sera obtained from 90 patients with HL, distinguished in a training set (N=35) and a validation set (N=55) and 20 healthy participants. In the training set, blood was taken at three fixed time-points prior, during, and after first-line therapy. In the first ten patients, a correlation between s-Arg-1 and semiquantitative parameters of PET at diagnosis was explored, including the Metabolic Tumor Volume (MTV) and the Total Lesion Glycolysis (TLG). Briefly, our group developed ad hoc tool independent from the operator: PET images are represented as a graph in which the voxels are its nodes and the edges are defined by a cost function which maps a change in image intensity to edge weights. This approach is an efficient and accurate method to segment lesion in low contrast images characterized by noise and weak edges as metabolic images (Stefano, 2013).

Results:

s-Arg-1 was increased in HL patients compared to healthy subjects, reduced after therapy in responders and increased in relapsed patients (p<0.0001). s-Arg-1 was positively correlated to the amount of Neutrophils and Arg-1 in N detected by RT-PCR. A cut-off level of 205 ng/mL for Arg-1 was chosen (equal to 2 times the 95th percentile in controls and ROC value with sensitivity and specificity of at least 80%) to predict response status at 24 months.

In the training set, 32% patients had high s-Arg-1, 24% had positive PET-2 and were addressed to an early salvage therapy accordingly to BEACOPP scheme. A level of 205 ng/mL s-Arg-1 resulted in 83% (95% C.I. 58-96) sensitivity and 81% (95% C.I. 42-96) specificity in predicting response status in the training set (area under curve, AUC, 0.81, p=0.02).

In the validation set, baseline levels of s-Arg-1>205 ng/mL resulted in 83% (C.I. 95% 62-95) sensitivity and 87% (C.I. 95% 47-99) specificity in predicting response status. Patients with s-Arg-1 ≥ 205 ng/mL had shorter PFS than patients carrying Arg-1 < 205 ng/mL (despite both groups did not reach the median, because of the short follow-up, p=0.005).

In first 10 patients enrolled in the study, semiquantitative parameters of PET at diagnosis were explored: SUVmax was 12.7 (range 5.9-14.2), MTV median was45.5 (range 8.9-308.7), TLG mean was 43.7 (range 25.2-2475.3). MTV and TLG, but not SUVmax, were positively correlated to s-Arg-1 (respectively, r=0.68, p=0.003 and r=0.59, p=0.002). Conclusion

S-Arg-1 is a predictor of PFS in HL and it is positively correlated with MTV in PET scans at baseline calculated with a novel operator-independent tool for imaging analysis. An update will be provided at the conference.