Risk profiling of patients with relapsed/refractory diffuse large B-cell lymphoma by measuring circulating tumor DNA

Abstract

Patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) have heterogeneous outcomes; durable remissions are infrequently observed with standard approaches. Circulating tumor DNA (ctDNA) assessment is a sensitive, potentially prognostic tool in this setting. We assessed baseline ctDNA to identify patients with R/R DLBCL at high risk of relapse after receiving polatuzumab vedotin and bendamustine plus rituximab (BR) or BR alone. Patients were transplant ineligible and had received ≥1 prior line of therapy. The ctDNA assay, based on a customized panel of recurrently mutated genes in DLBCL, measured mutant molecules per mL (MMPM) at baseline and end of treatment (EOT). Endpoints included progression-free survival (PFS) and overall survival (OS) in subgroups stratified by baseline ctDNA and log-fold change in ctDNA at EOT vs baseline. In biomarker-evaluable patients (n = 33), baseline ctDNA level correlated with serum lactate dehydrogenase (LDH) concentration, number of prior therapies, stage, and International Prognostic Index (IPI). After adjusting for number of prior therapies ≥2, IPI score ≥3, and LDH above the upper limit of normal, high (greater than median) baseline ctDNA MMPM was independently prognostic for shorter PFS (adjusted hazard ratio [HR], 0.18 [95% CI, 0.05-0.65]) and OS (adjusted HR, 0.20 [95% CI, 0.06-0.68]). In 23 patients with baseline and EOT samples, a significantly greater decrease in ctDNA MMPM was observed in patients with complete response (CR) (n = 13) than those without CR (n = 10); P = .0025. Baseline ctDNA assessment may identify patients at high risk of progression and should be further evaluated as a monitoring tool in R/R DLBCL. This trial was registered at www.clinicaltrials.gov as #NCT02257567.

Graphical abstract

Figure 1.

Flow diagram of patient disposition in the ITT population.

Figure 2.

Correlation between baseline ctDNA MMPM and known prognostic factors. (A) serum LDH, (B) IPI score, (C) Ann Arbor stage, and (D) number of prior therapies.

Figure 3.

Survival outcomes according to baseline ctDNA levels. (A) Progression-free survival in patients stratified by ctDNA MMPM at baseline (above and below median), (B) patients with baseline ctDNA MMPM above and below the lower quartile of quantitative values, and (C) patients with baseline ctDNA MMPM above and below the upper quartile of quantitative values. (D) OS in patients stratified by ctDNA MMPM at baseline (above and below median). INV, investigator-assessed.

Figure 4.

ctDNA MMPM at baseline in patients with or without CR at EOT; P = .049 for difference between patients with CR and no CR by Wilcoxon test.

Figure 5.

Correlation between post-treatment ctDNA levels and patient response. (A) Log-fold change in ctDNA at EOT vs baseline in patients with or without a CR at EOT. (B) Swimlane plot of individual response to treatment showing patients with baseline ctDNA MMPM above and below the median and ctDNA clearance at EOT; P indicates patients who received polatuzumab vedotin. BL, baseline; PR, partial response; SD, stable disease.

Figure 6.

Heatmap showing most frequently mutated genes (mutated in at least 3 patients) in the BEP at EOT. Dark red squares indicate presence of mutation.