Jul 10, 2021
Minimal residual disease positivity is predictive of disease progression in patients with large B-cell lymphoma treated with anti-CD19 CAR T-cells.
This JCO Podcast provides observations and commentary on the JCO article 'Monitoring of Circulating Tumor DNA Improves Early Relapse Detection After Axicabtagene Ciloleucel in Large B-Cell Lymphoma: Results of a Prospective Multi-Institutional Trial' by Frank et al. My name is Patrick Reagan, and I am an Assistant Professor of Medicine at the Wilmot Cancer Institute, University of Rochester in Rochester, NY. My oncologic specialties are lymphoma and cellular therapy. I would like to disclose consultancy for Kite Pharma.
Frank and colleagues present data from a prospective, multicenter trial examining serial testing of circulating tumor DNA in 72 patients with large B-cell lymphoma who received treatment with the anti-CD19 CAR T-cell, axicabtagene ciloleucel, abbreviated as axi-cel. These patients had circulating tumor DNA monitored in plasma prior to lymphodepletion chemotherapy, as well as at multiple times following axi-cel infusion. Ninety-six percent of patients had adequate DNA to identify a clonotype to track over time at study enrollment, and 60 patients had an adequate sample for analysis at day 28 after axi-cel infusion.
There are several key findings in this study. The first key finding is that circulating tumor DNA may serve as a surrogate for tumor burden. A lower level of circulating tumor DNA was associated with both improved disease and toxicity outcomes. Patients who had a lower baseline circulating tumor DNA had improved progression-free and overall survival, as well as less severe cytokine release syndrome and immune effector cell associated neurotoxicity syndrome.
A second key finding of this study is that circulating tumor DNA can serve as a marker for minimal residual disease in large B-cell lymphoma patients treated with CAR T-cells, and can be predictive of disease relapse. Seventy percent of patients who had durable response were negative for circulating tumor DNA one week following CAR T infusion. All patients with disease progression had at least one sample that was positive for minimal residual disease, and all but one were positive for minimal residual disease concurrently with radiographic progression. At day 28-post CAR T-cell treatment, negativity for minimal residual disease by circulating tumor DNA was strongly associated with improved progression-free and overall survival.
A third key finding in this study was that positivity for minimal residual disease was highly predictive in patients who have a partial response or stable disease at day 28-post CAR T-cell treatment. Deepening of response over time has been reported with various CAR T-cell treatments suggesting that there are limitations of PET CT to assess response, particularly at early time points. In the patients who had stable disease or partial response who were positive for minimal residual disease at day 28 following axi-cel, 15 of 17 patients had a progression-free survival event, while only two of ten who were negative for minimal residual disease had a progression-free survival event.
This study has multiple implications for future clinical research, which may influence routine clinical care over time. High tumor burden defined by the sum of product diameters or metabolic tumor volume has been associated with both treatment failure and excess toxicity with axi-cel, as well as tisagenlecleucel. As a potential surrogate for tumor burden, baseline circulating tumor DNA could be useful in determining high-risk groups to target for clinical trial participation. Additionally, this could be a stratification factor for randomized studies involving CAR T-cells. Additional studies with axi-cel as well as tisagenlecleucel and lisocabtagene maraleucel, which are also commercially available for large B-cell lymphoma, are important to confirm this observation.
Management of patients who initially achieve a partial response or have stable disease at the first disease assessment is a common clinical problem in patients with large B-cell lymphoma treated with CAR T-cells. A proportion of patients with large B-cell lymphoma who initially have partial response or stable disease will go on to develop a complete response over time. This has been reported in all of the commercially available anti-CD19 CAR T-cell products. In the ZUMA-1, JULIET and TRANSCEND trials, approximately one third to one half of patients who initially had partial response or stable disease went on to achieve a complete response. Patients who ultimately have progressive disease have poor outcomes with a median overall survival of 180 days. Those who have stable or progressive disease as best response have a medial overall survival of only approximately 50 days. Predicting which patients are at risk to relapse is important given the small window of time to intervene. It would also potentially spare low risk patients from additional therapy, which may be difficult to tolerate given the acute toxicity of CAR T-cell therapy, as well as the prolonged hematologic toxicity seen in some patients.
Disease progression following anti-CD19 CAR T-cell therapy is a pressing clinical problem in patients with large B-cell lymphoma and there is a need for clinical trials. Clinical trials should be considered in all patients who relapse following CAR T cell therapy. Early detection of relapse can help to facilitate enrollment prior to the development of complications related to progressive disease that may preclude their enrollment. There are now multiple clinically active, targeted therapeutics in large B-cell lymphoma, and a trial of maintenance or consolidative therapy could be considered in this population. This could target only the highest risk patients by using positivity for minimal residual disease as assessed by circulating tumor DNA as a criterion for inclusion. Alternatively, this could focus more broadly on the patients with stable disease or partial response, but given these results, outcomes by circulating tumor DNA status would be important secondary endpoints. Either way, circulating tumor DNA would be critical to the study design and interpretation of results.
This concludes this JCO Podcast. Thank you for listening.