Liquid biopsy may transform the ability to characterize, monitor lymphoma
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In medical oncology, liquid biopsy is a groundbreaking technique that has the potential to screen, diagnose, monitor response or resistance to treatments, and measure molecular residual disease.
In lymphoma, it has the potential to assist in the molecular characterization of tumors and in deciding a targeted treatment for precision medicine.
High potential, remaining gaps
“Liquid biopsy generally means looking at free DNA in blood plasma and trying to find features in that DNA that reflect a cancer’s genetic alterations that can be detected in the blood,” Ash A. Alizadeh, MD, PhD, associate professor, divisions of oncology & hematology, Stanford Cancer Institute, told Healio. “By and large, the work we have done has been through analysis of cell-free DNA that circulates in the blood and gives a non-invasive window into the tumor.”
Next-generation sequencing of cell-free DNA (cfDNA) and circulating tumor DNA (ctDNA) in blood plasma may allow the genotyping of lymphomas and may enable a better understanding of lymphoma pathogenesis, according to a study published in Journal of Cancer Metastasis and Treatment.
Despite its potential, significant gaps remain. Unlike tissue biopsy, liquid biopsy is not a routine test in clinical practice.
“Liquid biopsies are generally used largely for research purposes, not clinically approved reasons, for lymphoma,” Alizadeh said. “For lymphoma, these tests are not FDA-approved. They’re largely research tools, but they can be used for a variety of applications.”
Alizadeh discussed a range of applications currently being explored with liquid biopsies, such as:
- non-invasive genotyping of a tumor, which may inform their eligibility for trials or use of particular therapies, at the time of diagnosis;
- to estimate the tumor burden in the blood;
- to assess how the tumor burden changes during the course of therapies to monitor response;
- to detect whether there’s any presence of disease (ie, minimal or molecular residual disease) after a therapy; and
- to continue monitoring the tumor burden in a non-invasive way and possibly as a way to avoid imaging recurrent exposure to ionizing radiation when using a CAT scan or a PET scan.
What the research says
In 2018, Alizadeh and colleagues led a study that monitored ctDNA levels in more than 200 patients with diffuse large B-cell lymphoma before and after the first and second rounds of conventional chemotherapy.3 He said that by tracking the levels of ctDNA in a patient’s blood, the researchers could predict nonresponders as early as 21 days after treatment initiation.
“We have done some published studies with large cell lymphoma and a similar study has been done in Hodgkin disease, so both Hodgkin and non-Hodgkin lymphomas, with measurements as early as after one chemotherapy cycle, so 21 days or so into therapy, as a reflection of the efficacy of that therapy,” Alizadeh said.
The results of this study, which examined early molecular response (after one cycle of therapy) and major molecular response (after two cycles), have been replicated by other researchers, who have applied the same ideas in Hodgkin disease, according to Alizadeh.
“Most of the work [in liquid biopsy] has focused on non-Hodgkin lymphoma, but there have been a few studies that have shown the same kind of ideas can apply to Hodgkin disease,” Alizadeh said. “We are working on figuring out how the information can be applied for making decisions in Hodgkin lymphoma. The key challenge is: what are we going to do with this information? How are we going to act on this information to improve the outcomes of our patients?”
There’s a need for prospective clinical trials; currently, there are no such trials ongoing where liquid biopsies are being used to guide therapy for lymphoma, he said. However, Alizadeh said they are designing and executing such trials at Stanford now.
Currently, Alizadeh and colleagues are continuing their research in a larger, prospective way, both in the frontline as well as in the context of experimental therapies and approved therapies.
At the most recent ASH Meeting and Exposition, they presented results from a study where they applied cfDNA analysis to patients with relapsed/refractory DLBCL receiving axicabtagene ciloleucel (Axi-cel), an anti-CD19 CAR -T cell therapy, to characterize molecular responses, resistance mechanisms and to track CAR19 cells.5 The data indicated that cfDNA analysis predicted response to CAR19 therapy, identified genomic determinants of resistance and quantified CAR19 cells.
The future in lymphoma
For the diagnosis of the lymphoma, current guidelines recommend analysis of tissue biopsy to diagnose lymphoma, and Alizadeh said that it would be hard for liquid biopsy to take its place. “Maybe someday because right now those mutations don’t tell you the exact subtype of lymphoma,” he said. “We’ve been doing some work to see if we could take that information and make a diagnostic classification, but that’s work in progress.”
A major unmet challenge standing in the way of using liquid biopsy in lymphoma is the clinical availability of these research assays to run in an environment that meets the regulatory requirements of their use in clinical decision making, such as Clinical Laboratory Improvement Amendments (CLIA) lab environments, Alizadeh said during the interview.
“This has been the active topic of several discussions over the last couple of years from working groups of hematologists that have met at the big lymphoma meeting in Switzerland a few years ago and then just a few weeks ago in Orland at ASH with a plan to build a framework for bringing these assays into such environments and allowing such clinical trials to be done,” he said.
Alizadeh also discussed the need to distribute these tests to hospitals around the world so other researchers can conduct the necessary prospective studies. Another hurdle could possibly the cost of the assays.
“Even though you don’t get anatomical information from the liquid biopsy, if one can avoid a biopsy or avoid a scan there may be opportunities for economic savings, but I don’t think right now it would be totally honest to say that these are going to make things way cheaper because we don’t really know how much they will cost when a commercial provider offers them,” he told Healio.
However, Alizadeh noted that competition between providers may end up reducing overall costs, like when more than one company started providing non-invasive ways to diagnose Downs Syndrome in pregnant mothers.
“Those non-invasive ways that have now become kind of the first step in an evaluation process, the competition has allowed the test to become less and less expensive and to have savings over the invasive procedures that were usually done at the first step before and also improve the overall quality of care and safety of the pregnant patient,” he said. “The question is can we do something similar with liquid biopsies by decreasing the cost of the alternative methods. I think how much these things will cost is an open question.”
References
- Melani C, et al. Hematol Oncol. 2019;doi:10.1002/hon.2587..
- Moia R, et al. J Cancer Metastasis Treat. 2019;doi:10.20517/2394-4722.2019.020..
- Stanford Medicine. ‘Liquid biopsy’ predicts lymphoma therapy success within days. http://med.stanford.edu/news/all-news/2018/08/liquid-biopsy-predicts-lymphoma-therapy-success-within-days.html. . Accessed on January 15, 2020.
- Spina V, et al. Blood. 2018;doi:10.1182/blood-2017-11-812073..
- Sworder B, et al. Abstract 550. Presented at: ASH Annual Meeting and Exposition; December 7-10, 2019; Orlando.
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