Molecular measurable residual disease by immunoglobulin gene rearrangements on circulating tumor DNA predicts outcome in diffuse large B-cell lymphoma

Abstract

In diffuse large B-cell lymphoma (DLBCL) treatment response relies on imaging. We investigated the potential value of molecular measurable residual disease (MRD) on circulating tumor DNA (ctDNA) to predict the outcome of 73 DLBCL patients. At baseline, next-generation sequencing was used to detect clonal immunoglobulin (IG) gene rearrangements on tumor biopsies (N=57) and ctDNA (N=73). MRD monitoring was applied by tracking the IG clones in ctDNA samples collected during treatment (interim) and at the end of treatment (EOT). MRD results were correlated with clinical data and radiologic disease assessment. Before treatment, clonal IG were found in 91.2% (52/57) of tumor biopsies and in 93.2% (68/73) of ctDNA samples. In paired samples, the same clonotype was found in 69.2% (36/52) of cases. At the interim analysis, ctDNA MRD was negative in 32 of 45 evaluable patients and positive in 13 of 45, correlating significantly with progression-free survival (PFS) (78.1% MRD- vs. 30.8% MRD+; P<0.0001) after a median follow-up of 40 months. Moreover, ctDNA MRD could stratify prognosis of 27 patients in partial response (P=0.018). At EOT, ctDNA MRD was negative in 37 of 47 patients and positive in ten of 47 (PFS 83.8% MRD- vs. 0% MRD+; P<0.0001). All MRD+ patients in complete metabolic response relapsed (P<0.0001). At multivariate analysis, MRD at EOT independently predicted PFS and overall survival. Monitoring IG-based ctDNA MRD during and after treatment predicts DLBCL patients' outcome. This non-invasive method should be implemented in risk-adapted clinical trials and validated as a treatment decision-making tool.

Figure 1.

Prognostic value of molecular measurable residual disease on circulating tumor DNA during treatment. (A) Kaplan-Meier estimates of progression-free survival (PFS) from diagnosis for patients evaluated at interim time points stratified by measurable residual disease (MRD) positivity or negativity are shown. (B) Kaplan-Meier estimates show the PFS of patients in partial response at the interim computed tomography scan stratified by circulating tumor DNA MRD status.

Figure 2.

Prognostic value of molecular measurable residual disease on circulating tumor DNA at the end of treatment. (A) Kaplan-Meier estimates of progression-free survival (PFS) from diagnosis for patients evaluated at end of treatment (EOT) stratified by measurable residual disease (MRD) status (positive or negative) are shown. (B) Kaplan-Meier estimates show the impact of MRD status on PFS in patients achieving final complete metabolic response (CR) according to positron emission tomography/computed tomography (C) Kaplan-Meier estimates show the PFS of patients based on the combination of MRD status during and after treatment. Patients are categorized into 4 groups: double negative MRD (-/-), double positive MRD (+/+), MRD positive during treatment and MRD negative at EOT (+/-), MRD negative during treatment and MRD positive at EOT (-/+).