ctDNA dynamics demonstrates rapid treatment response to tafasitamab + R-CHOP +/- lenalidomide and predicts outcome in diffuse large B-cell lymphoma: results from the phase 1b First-MIND study.

The firstMIND trial (NCT04134936) evaluated the safety and efficacy of adding lenalidomide to R-CHOP+tafasitamab in the first-line treatment settings of patients with diffuse large B-cell lymphoma. To address response dynamics and the impact of measurable residual disease (MRD), we analyzed prospectively collected plasma samples from 56 study patients using the EuroClonality immunoglobulin gene (IG)-NGS assay. At baseline, disease-related clonotypes were identified in 50/56 (89%) patients by IG-NGS in cell-free (cf)DNA and/or FFPE samples. MRD markers were successfully identified in 49/52 (94%) cfDNA samples and 35/41 (85%) FFPE samples. Baseline cfDNA and circulating tumor (ct)DNA levels correlated with preclinical risk factors, and high cfDNA levels ≥3.35 log10hGE/ml plasma were significantly associated with poor progression-free survival (PFS) (hazard ratio (HR): 3.1). ctDNA clearance was rapid with 52% of patients MRD-negative at C2D1, 83% patients at C4D1, and 82% patients after finishing six 21-day cycles (end of treatment (EOT)) and a sustained treatment response (93% MRD negative) six months after EOT. ctDNA detection was associated with worse PFS outcomes at C2D1 (p = 0.039, HR:4.51, 95%Cl:0.93-21.74), C4D1 (p = 0.07, HR:3.34, 95%Cl:0.83-13.48) and EOT (p = 0.01, HR:6.38, 95%Cl:1.27-32.01) and inferior overall survival at these time points. In PET-positive patients, ctDNA-MRD had a higher specificity rendering PET/CT more precisely.