In Hodgkin Lymphoma (HL) elevated neutrophil (HL-N) count is a well-known negative prognostic factor. 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 (s-Arg-1), novel biomarker of immune-suppression. Aim of this work is to correlate Arg-1 amount to features at diagnosis, including some FDG-PET parameters acquired with a novel operator-independent algorithm.
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 10 patients, a correlation between s-Arg-1 and PET parameters at diagnosis was explored, including the Metabolic Tumor Volume (MTV) and the Total Lesion Glycolysis (TLG). Our group developed ad hoc user independent tool to segment lesion in low contrast images characterized by noise and weak edges as metabolic images (Stefano et al, 2013).
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 30 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, PET parameters at diagnosis were explored: SUVmax mean was 12.7 (range 5.9-14.2), MTV mean was 45.5 (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).
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.