Biomarker-adapted treatment in high-risk large B-cell lymphoma

Abstract

Survival rates for patients with high-risk large B-cell lymphoma (LBCL), particularly those with biological risk factors, remain inadequate. We conducted a biomarker-driven phase II trial involving 123 high-risk patients aged 18-64 with LBCL. Based on their biological risk profiles, patients received either R-CHOEP-14 (without risk factors) or DA-EPOCH-R-based regimens (with risk factors). Biological high-risk factors included C-MYC translocation, C-MYC and BCL2 co-translocation, 17p/TP53 deletion, co-expression of MYC and BCL2, and P53 and/or CD5 immunopositivity. Additionally, we evaluated circulating tumor DNA (ctDNA) kinetics during therapy. Sixty-one patients (50%) were classified into biologically high-risk group. Three-year failure-free survival and overall survival rates for the entire study population were 79% and 88%, respectively. DA-EPOCH-R did not improve survival compared to our previous trial, where patients with the same biological risk factor criteria received R-CHOEP-14-based therapy. High pretreatment ctDNA levels, 17p/TP53 deletion, and TP53 mutations were associated with worse outcomes. In contrast, ctDNA negativity at the end of therapy (EOT) was indicative of a cure and effectively addressed false residual PET positivity. The findings demonstrate promising survival for high-risk LBCL patients, aside from those with TP53 aberrations, high ctDNA levels, and/or EOT ctDNA positivity.

Figure 1

Study schema. (A) Trial profile and sampling schedule. (B) Patient disposition. CT, computer tomography; DHL, double hit lymphoma; IHC, immunohistochemistry; OS, overall survival; P, prednisone; PD, progressive disease; PET, positron emission tomography; RT, radiotherapy; SD, stable disease; V, vincristine.

Figure 2

Kaplan–Meier survival estimates. (A) FFS, PFS, and OS rates in the LBC‐06 trial. (B) FFS according to aaIPI in the LBC‐06 trial. (C) Comparison of FFS rates of biological high‐risk groups in the LBC‐06 versus LBC‐05 trials. (D) Comparison of OS rates of biological high‐risk groups in the LBC‐06 versus LBC‐05 trials. (E) Comparison of FFS rates in patients with biological high‐risk and aaIPI3 in the LBC‐06 versus LBC‐05 trials. (F) Comparison of OS rates in patients with biological high‐risk and aaIPI3 in the LBC‐06 versus LBC‐05 trials.

Figure 3

Kaplan–Meier estimates of survival and Cox multivariable analysis. (A) PFS according to TP53 deletion status. (B) PFS according to HGBL‐DH status. (C) Cox multivariable analyses on OS and PFS including age, aaIPI, and TP53 deletion as covariates.

Figure 4

Baseline ctDNA burden and TP53 mutations. (A) Oncoprint of the coding driver mutation landscape according to pretreatment ctDNA concentration. Columns represent individual patients, and rows represent different clinical variables or driver genes. Genes mutated in ≥15% of the patients included, and the percentages are indicated. (B) Pretreatment ctDNA concentrations (log hGE/mL) according to aaIPI scores. (C) Pretreatment ctDNA concentrations (log hGE/mL) in the biological high‐ and low‐risk groups. (D) PFS of patients with high (≥3.60 hGE/mL) versus low (<3.60 hGE/mL) pretreatment ctDNA concentration. (E) PFS of patients with or without TP53 mutations detected from ctDNA. Subclonal mutations were excluded from the analysis.

Figure 5

Prognostic impact of PET and MRD. (A) PFS according to end‐of‐therapy PET. (B) Dynamics of ctDNA burden during therapy. (C) PFS according to ctDNA‐based molecular response after two courses of therapy. (D) PFS according to ctDNA‐based molecular response at the EOT.