ctDNA Monitoring May Improve Early Relapse Detection in Large B-Cell Lymphoma Following Axi-Cel Treatment

Noninvasive circulating tumor DNA (ctDNA) monitoring my be used to assess risk and predict outcomes for patients with large B-cell lymphoma (LBCL) who are undergoing treatment with axicabtagene ciloleucel (axi-cel; Yescarta), according to the results of a prospective trial published in the Journal of Clinical Oncology.

Of the 72 patients who enrolled on the study, 96% had adequate DNA that allowed for tumor clonotype tracking. Investigators noted that patients who had higher pre-treatment concentrations of ctDNA had a higher chance of disease progression as well as cytokine release syndrome and/or immune effector cell–associated neurotoxicity syndrome following treatment with axi-cel. By day 7, it was noted that 70% of patients who experienced durable responses had no detectable ctDNA vs 13% of patients who progressed on treatment (P <.0001). On day 90, all patients within this group had no detectable ctDNA. Conversely, patients who progressed had a nadir median ctDNA concentration of 6 LG/mL on day 28, which then began to rise.

Additionally, patients who had a ctDNA concentration below 10 LG/mL or between 10 to 100 LG/mL had a 1-year progression-free survival (PFS) rate of 78% and 77%, as well as a 1-year overall survival (OS) rate of 90% and 91%, respectively. These groups of patients had significantly better survival rates vs patients who had a pre-lymphodepletion ctDNA concentration of 100 to 1000 LG/mL and above 1000 LG/mL (median PFS, 3 months and not reached [NR]; median OS, 19 and 7.4 months, respectively; P = .0080).

“This multicenter prospective study demonstrates that early after axi-cel therapy, peripheral blood ctDNA assessments can predict for progression events with added value to standard PET-CT scans,” the study investigators wrote.

The multi-institutional study, which aimed to assess the value of ctDNA-based testing as a tool for risk stratification and early monitoring before and after axi-cel infusion in LBCL, enrolled patients who were 18 years or older and had been diagnosed with diffuse LBCL, transformed follicular lymphoma, or primary mediastinal B-cell lymphoma. Prior to enrollment, patients underwent lymphodepleting chemotherapy for axi-cel treatment. Additionally, patients were required to have archival formalin-fixed paraffin-embedded tissue that was available for clonotype identification as well as measurable PET-avid disease.

The primary end point of the study was to determine the ability of ctDNA-based assessment prior to starting lymphodepleting chemotherapy to predict PFS with at least 6 months of follow-up. Additionally, investigators examined the association between ctDNA-based minimal residual disease (MRD) assessment on day 28 to predict PFS.

Outcomes in this patient population—including overall response rate (84.7%), complete response (CR) rate (63.9%), median PFS (10.3 months), duration of response (NR; 1-year rate, 79.5%), and median OS (NR; 1-year rate, 71.2%)—were comparable with those seen in the phase 1/2 ZUMA-1 trial (NCT02348216), which examined axi-cel in adult patients with refractory aggressive non-Hodgkin lymphoma.

One of 10 patients who experienced a radiographic partial response (PR) or stable disease on day 28 who had concurrently undetectable ctDNA had relapsed. Conversely, 15 of 17 patients who had concurrently detectable ctDNA experienced relapsed disease (P = .0001). Moreover, 94% of patients had detectable ctDNA prior to or during radiographic relapse. Every patient who experienced a durable response had undetectable ctDNA prior to or after 3 months of axi-cel infusion.

Additional findings indicated that patients who were MRD-positive vs -negative on day 28 had a median PFS of 3.03 months vs NR (P <.0001), as well as a median OS of 19.0 months vs NR (P = .0080). Moreover, on day 28, those who experienced a PR or stable disease by PET-CT vs those who had a CR on day 28 had a median PFS of 3.1 vs NR (P = .0018) and a median OS of 19.0 vs NR (P = .0033).

“Despite [the study’s] limitations, [these] data suggest that serial ctDNA monitoring may be a noninvasive approach to assess progression after axi-cel,” the investigators concluded.

References

Frank MJ, Hossain NM, Bukhari A, et al. Monitoring of circulating tumor DNA improves early relapse detection after axicabtagene ciloleucel infusion in large B-cell lymphoma: results of a prospective multi-institutional trial. J Clin Oncol. Published online June 16, 2021. doi:10.1200/JCO.21.00377