MONITORING CIRUCLATING TUMOR DNA IMPROVES EARLY RELAPSE DETECTION AFTER STANDARD OF CARE 2L+ AXI-CEL IN LBCL: A PROSPECTIVE STUDY

Abstract

Introduction: Large B-cell lymphoma (LBCL) circulating tumor DNA (ctDNA)-based measurable residual disease (MRD) assessment is a prognostic tool for outcomes following CD19-CAR T-cell therapy and frontline treatment. CtDNA can risk stratify and predict outcomes providing additive benefit to standard PET-CT assessments for 3L+ Axicabtagene Ciloleucel (axi-cel, Frank et al., JCO 2021). The role for ctDNA monitoring for 2L axi-cel is unknown. Here, we present a prospective ctDNA analysis of 2L+ axi-cel patients with 6+ months (mo) of follow-up and compare this analysis to prior 3L+ data.

Method: Plasma was collected from patients with LBCL receiving standard-of-care axi-cel at pre-lymphodepletion (PLD), days 14, and 28, totaling 222 plasma samples. (VDJ) clonotype (Clono-Seq) was identified from archival paraffin-embedded tissue to track MRD. PET-CT scans were performed before and at 1, 3, 6, and 12 mo post axi-cel; responses assessed per Lugano criteria (Deauville 1–3 was considered PET-negative). Any detectable ctDNA was considered detectable MRD. Significance for PFS was determined by log-rank p values and prognostic value of ctDNA was evaluated by a Cox proportional hazards model.

Results: Patients in 2L+ (n = 84 enrolled 2022–2024) versus 3L+ (n = 64, enrolled 2018–2019) were median age of 65 (23–83) versus 59 (19–76), 61% versus 56% male, 55% versus 60% had elevated LDH, 73% versus 72% Stage 3/4, median 1 (1–5) versus 3 (1–7) prior lines (60% vs. 3% only 1 prior line; 12 % vs. 58% for 3+ prior lines). 60% (n = 50) versus 55% (n = 35) of 2L+ versus 3L+ patients received bridging. Median follow-up for 2L+ versus 3L+ was 18 versus 11 mo. Polatuzumab-based bridging (48% vs. 0%) was more common in 2L+; similar rates received radiation (36% vs. 26%). 2L+ versus 3L+ showed lower median PLD ctDNA levels (1.606307 [0–35,248] versus 63 [0–17,903] LG/mL) and a higher proportion of patients with undetectable MRD (uMRD) (38% vs. 26%) (Panel A). Lower levels of ctDNA suggests improved disease control and more effective bridging therapy in the 2L+ era.

For 2L+, ctDNA levels were prognostic before and at all time points in the early post-CAR-T setting. UMRD was associated with improved outcomes at all timepoints, including PLD (p = 0.04, HR 2.866, 1.287–6.382), Day 14 (p < 0.0001, HR 5.302, 2.342–12.00) and Day 28 (p = 0.001, HR 5.778, 2.606–12.81) (Panel A). PLD MRD levels did not associate with CRS or ICANS grade (not shown). MRD status at Day 14 and 28 stratified patients after 2L+ axi-cel (Panel B-C); uMRD was significantly associated with improved PFS. Patients with Day 28 radiographic PR/SD with uMRD (n = 12) versus detectable MRD (dMRD, n = 10) had improved PFS; 92% versus 40% of uMRD versus dMRD patients had durable remissions (panel D).

Conclusion: This prospective study shows ctDNA assessments can predict for progression events with added value to standard PET-CT scans for patient receiving 2L+ axi-cel. Achieving uMRD as early as Day 14 after 2L+ axi-cel was strongly correlated with improved PFS.

Research funding declaration: Adaptive- Consultant

Keywords: minimal residual disease; aggressive B-cell non-Hodgkin lymphoma

Potential sources of conflict of interest:

S. Ananth

Consultant or advisory role: Adaptive

I. Kirsch

Employment or leadership position: Adaptive Biotechnologies

A. Jacob

Employment or leadership position: Adaptive Biotechnologies

H. Simmons

Employment or leadership position: Adaptive Biotechnologies

L. W. Lee

Employment or leadership position: Adaptive Biotechnologies

M. D. Jain

Consultant or advisory role: Kite

S. Dahiya

Consultant or advisory role: Kite

F. L. Locke

Consultant or advisory role: Adaptive, Kite

D. Miklos

Consultant or advisory role: Adaptive, kite

M. Frank

Consultant or advisory role: Adaptive, Kite