Serum TARC Dynamics Correlate with Clinical Response and Metabolic Tumor Volume during Anti-PD1-Based First-Line HL Treatment in the GHSG Phase II Nivahl Trial

Background
Serum Thymus and Activation Regulated Chemokine (TARC) is a well-established tumor cell derived biomarker for monitoring early treatment response in classic Hodgkin lymphoma (cHL), offering higher positive predictive value compared to interim FDG-PET imaging. However, data on TARC in patients receiving anti-PD1-based first-line treatment is limited. To our knowledge, this is the first study correlating TARC dynamics with metabolic tumor volume (MTV, determined by SUV4.0) and clinical response during either sequential or concomitant nivolumab and doxorubicin, vinblastine, and dacarbazine (N-AVD) first-line treatment of early-stage unfavorable cHL patients.

Methods
Patients in the prospective randomized GHSG NIVAHL phase II trial were evaluated for early treatment response by PET/CT (PET2) after two cycles of concomitant N-AVD (arm A) or four infusions of nivolumab (N; arm B), respectively (NCT03004833, Bröckelmann et al. JCO 2023). The present study included all 78 NIVAHL patients with available serum samples at baseline and at least one additional timepoint: after 1 week, at PET2, post chemotherapy and/or post 30Gy IS-RT. TARC levels were measured using a standardized ELISA, with a predefined positivity threshold of >1000 pg/ml, while being blinded to treatment and response. For longitudinal analysis, only patients with elevated baseline TARC were included and findings were correlated with MTV.

Results
TARC levels were positive in 71/78 patients (91%) at baseline, with a median level of 14,830 pg/ml (range 203 - 339,000 pg/ml). TARC-negative patients were significantly more often diagnosed with EBV-positive cHL compared to baseline TARC-positive patients (4/7: 57% vs 9/71: 13%, p=0.013). Baseline TARC levels significantly correlated with baseline MTV (Spearman r=0.41, p =.007). Already after 1 week of anti-PD1 based first-line treatment, a sharp decline in TARC levels was observed in both treatment groups. At PET2, only 3% and 19% of cases remained TARC-positive in arm A (i.e. after 2x N-AVD) and arm B (4x N), respectively. This early deep responses in the vast majority of patients, including those treated with nivolumab monotherapy, are in line with (near) complete resolution of MTV at PET2. Notably, TARC negativity was observed in 12 out of 18 patients (67%) with a positive PET2 and 4 out of 4 cases (100%) with PET-positive residuals at end of treatment. Importantly, none of the patients did experience cHL relapse with a median follow-up of 41 months.

Conclusion
Serum TARC levels correlate with MTV and treatment response in cHL patients receiving anti-PD1-based first-line treatment. Importantly, TARC negativity is achieved very early also during nivolumab monotherapy and associated with excellent outcomes despite interim or end-of-treatment PET positivity. Taken together, the present study provides a rationale to explore individualized anti-PD1 based treatment approaches, guided by TARC dynamics and PET/CT.