ctDNA Testing Beneficial For Lymphoma Management During Multiple Stages of Treatment

Kieron Dunleavy, MD

Kieron Dunleavy, MD

The use of treatments for managing lymphomas could be more strategic when liquid biopsies testing for circulating tumor DNA (ctDNA) are used in one or more phases of treatment. Testing for ctDNA can provide important information before, during, and after treatment that can guide patient management. For example, based on the result of the test, physicians could potentially decide on which therapy to use or which therapy to switch to, based on response, mutations, and more.

Liquid biopsy “is a sensitive way of assessing tumor activity,” says Kieron Dunleavy, MD, professor of medicine, director of the Lymphoma Program, and co-director of the Microbial Oncology Program, GW Cancer Center. By evaluating ctDNA in tissue compartments such as the blood, physicians can gain insights into the characteristics of the disease and its response to treatment.

One potential benefit of ctDNA testing with liquid biopsies that Dunleavy highlights is the ability to survey for resistance mutations during following specific treatments without the need for new invasive tissue biopsies. Such testing could determine if an alternative targeted agent could be given to target the new acquired alteration.

The role of liquid biopsy in the management of lymphomas is evolving as more research is underway, and more sensitive ctDNA assays are being developed.

In an interview withTargeted Oncology, Dunleavy examined the role of liquid biopsy throughout the course of disease for all lymphomas, and specifically for patients with mantle cell lymphoma, and how its role may change in the future.

TARGETED ONCOLOGY: What is the role of ctDNA and liquid biopsy in lymphoma treatment?

Dunleavy:Liquid biopsy that measures ctDNA in the blood is an important area of investigation in the assessment of lymphomas currently and is incorporated in many ongoing clinical trials. It represents a sensitive way of assessing tumor activity and, importantly, it is non-invasive compared to tissue biopsies, which may be associated with significant complications.

This [form of testing] can have an important role at many different time points of the [disease]. It can be looked at in newly diagnosed patients. It can [also] be looked at in interim disease assessment. For example, in a retrospective study looking at the up-front treatment of diffuse large B-cell lymphoma, MRD negativity (ctDNA negativity) in the middle of therapy was associated with a much better survival outcome than interim MRD positivity. Additionally, end-of-therapy liquid biopsies to confirm remission and surveillance assays in follow-up to assess for disease relapse could potentially be very helpful tools.

Additionally, liquid biopsy can be used to look at genetic changes in the tumor [within the blood] and the acquisition of specific mutations. In mantle cell lymphoma, as targeted agents are becoming increasingly used, the ability to survey for the development of certain mutations in the course of a patient's disease might be a useful tool in informing on future targeted therapies without the need for a tissue biopsy.

TARGETED ONCOLOGY: What research helps define the role of liquid biopsy in these patient populations?

Dunleavy:At this point, liquid biopsy is still experimental, but it is being incorporated into many lymphoma clinical trials and the results of these should guide its wider clinical indications in the future.

In mantle cell lymphoma, the prognostic impact of MRD negativity after the completion of induction therapy has been controversial. Overall though, MRD negativity at the end of therapy appears to be associated with a better outcome. It will be interesting when the results from many ongoing trials using ctDNA are available—these results should be informative as to how it can be applied in standard practice in managing patients with [lymphoma].

TARGETED ONCOLOGY: How can liquid biopsy improve outcomes for patients with lymphomas?

Dunleavy:In many lymphomas, if a liquid biopsy is positive in the middle of or at the end of therapy, this is likely to be associated with an inferior outcome. An important question is what to do in cases that have interim or end of therapy positivity? At this point in time, we have no data that support switching therapy to affect a better outcome.

In the induction setting, for example, if a liquid biopsy is positive in the middle of therapy, should that prompt switching therapy, continuing the same therapy, or considering a specific adjuvant therapy after induction therapy? These are important questions in many lymphomas for the future.

Then, following induction therapy, (particularly with respect to mantle cell lymphoma), what approach is best if a patient has a positive liquid biopsy? We do not know the answer but ongoing studies such as the NCI Intergroup MCL study—where patients who are liquid biopsy—negative are randomized to high-dose therapy and transplant versus maintenance—will be very informative on this question.

TARGETED ONCOLOGY: How will the role of liquid biopsy evolve over the next 10 years?

Dunleavy:As results from ongoing clinical trials become available, we will gain more insights into the role of liquid biopsy in different lymphomas and at different disease assessment time points. We will better define the impact of end of therapy positivity versus negativity; we should have more information on what interim ctDNA positivity means with respect to outcome across different types of lymphoma, including mantle cell lymphoma. We will also likely identify that monitoring ctDNA in follow-up is more sensitive and specific in detecting relapse compared to imaging.