Circulating tumor DNA predicts therapeutic outcome in mantle cell lymphoma

Abstract

Mantle cell lymphoma (MCL) is biologically and clinically heterogeneous and would benefit from prognostic biomarkers to guide management. Circulating tumor DNA (ctDNA) is a novel prognostic biomarker in diffuse large B-cell lymphoma that may have applicability in MCL. We analyzed ctDNA dynamics in previously untreated patients with MCL who received induction therapy with bortezomib and DA-EPOCH-R for 6 cycles followed by random assignment to observation or bortezomib maintenance in responding patients in a prospective phase 2 study. Most patients also underwent initial treatment window of bortezomib alone prior to induction. Serum was collected pretreatment, after the window, after cycles 1 and 2, at the end of induction, and at each follow-up visit along with restaging computed tomography scans. Next-generation sequencing was used to identify and quantify ctDNA encoding the immunoglobulin receptor sequences in serum as markers of minimal residual disease. Fifty-three patients were enrolled, with a median follow-up of 12.7 years. Patients without detectable ctDNA after 2 cycles of induction had longer progression-free survival (PFS) and overall survival (OS) compared with those with detectable ctDNA (median PFS, 2.7 vs 1.8 years; overall P = .005; median OS, 13.8 vs 7.4 years; overall P = .03). Notably, in vivo assessment of ctDNA dynamics during the bortezomib window was not prognostic, and there was no difference in PFS or OS with bortezomib maintenance. ctDNA monitoring after induction showed that molecular relapse preceded clinical relapse in some cases. In conclusion, interim ctDNA negativity strongly correlates with improved survival and supports the investigation of response-adapted strategies. This trial was registered at www.clinicaltrials.gov as #NCT00114738.

© Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.

Figures

Graphical abstract

Figure 1.

CONSORT diagram. Patients first received bortezomib as monotherapy in a window for 21 days, except for those with rapidly progressive disease, who proceeded directly to induction therapy. Patients who responded to induction and did not have significant peripheral neuropathy were randomly assigned to bortezomib maintenance or initial observation. DA-EPOCH-R, dose-adjusted etoposide, doxorubicin, and cyclophosphamide with prednisone, vincristine, and rituximab; CNS, central nervous system.

Figure 2.

Kaplan-Meier estimates of PFS and OS of patients enrolled with untreated MCL. Median follow-up was 12.7 years. (A) The 5-year PFS of all patients was 23.1% (95% CI, 13-35). (B) The 5-year OS of all patients was 78.3% (95% CI, 64-87). (C) The 5-year PFS of patients randomly assigned to bortezomib maintenance vs observation was 14.3% (95% CI, 2-37) vs 37.5% (95% CI, 15-60; P = .39). (D) The 5-year OS of patients randomly assigned to bortezomib maintenance vs observation was 69.2% (95% CI, 37-87) vs 87.5% (95% CI, 59-97; P = .32).

Figure 3.

Pretreatment ctDNA is associated with other prognostic variables. (A) Scatter plot shows the median pretreatment ctDNA for all patients and the relationship of pretreatment ctDNA in classic histology compared with blastoid histology. (B) Scatter plot shows pretreatment ctDNA across MIPI categories. (C) Scatter plot demonstrates the relationship of pretreatment ctDNA and the Ki67 proliferation index. (D) Spearman correlation of pretreatment ctDNA and SUVmax on baseline FDG-PET scan. (E) Spearman correlation of pretreatment ctDNA and TMTV on baseline FDG-PET scan. (F) Kaplan-Meier estimates of PFS in patients above the median (ctDNA high) compared with below the median (ctDNA low). *P < .05.

Figure 4.

Circulating tumor DNA dynamics during induction therapy. (A) Qualitative ctDNA response to induction therapy after 1 cycle, after 2 cycles, and at the end of induction therapy. (B) Quantitative ctDNA response after the bortezomib window and after 1 cycle, after 2 cycles, and at the end of induction therapy.

Figure 5.

Kaplan-Meier estimates of PFS and OS based on ctDNA detection at landmark time points during induction therapy. (A) PFS in patients with no detectable ctDNA (blue) compared with patients with detectable ctDNA (red) at the end of induction therapy. (B) OS in patients with no detectable ctDNA (blue) compared with patients with detectable ctDNA (red) at the end of induction therapy. (C) PFS in patients with no detectable ctDNA (blue) compared with patients with detectable ctDNA (red) after 2 cycles of induction therapy. (D) OS in patients with no detectable ctDNA (blue) compared with patients with detectable ctDNA (red) after 2 cycles of induction therapy. (E) PFS in patients with no detectable ctDNA (blue) compared with patients with detectable ctDNA (red) after 1 cycle of induction therapy. (F) OS in patients with no detectable ctDNA (blue) compared with patients with detectable ctDNA (red) after 1 cycle of induction therapy.

Figure 6.

Circulating tumor DNA after induction therapy. Patients (n = 47) who responded to induction therapy and proceeded to part C of therapy (maintenance or observation) were included. Serum collected at protocol-defined time points was analyzed blinded to clinical outcomes for the detection of ctDNA (red circle) or absence of detectable ctDNA (green circle). Six patients (blue shade and above bold line) had no detectable ctDNA at end of induction therapy (EOT) and were without radiologic progression at the time of data cutoff. Thirty-four patients (below bold line and above dotted line) had no detectable ctDNA at EOT and were monitored until radiologic progression (square). Seven patients (below dotted line) had detectable ctDNA at EOT and were monitored until radiologic progression. Twenty-eight patients (red shade) progressed and had ctDNA positivity at the time of or before progression, whereas 13 patients (green shade) progressed with no prior detectable ctDNA. 1C, end of the first cycle of induction therapy; 2C, end of the second cycle of induction therapy.