| The following article features coverage from the 2021 American Society of Hematology Annual Meeting. Click here to read more of Cancer Therapy Advisor’s conference coverage. |
Newer sequencing technologies may overcome prior limitations of circulating tumor DNA (ctDNA) profiling in central nervous system (CNS) lymphoma, according to a presentation at the 2021 American Society of Hematology (ASH) Annual Meeting.
Using ultrasensitive sequencing, researchers were able to diagnose CNS lymphoma based on ctDNA mutational profiles. They also found that ctDNA status before and during treatment could predict progression-free survival (PFS) and overall survival (OS).
“ctDNA has been established as an important noninvasive biomarker in various malignancies. However, the role of ctDNA in CNS lymphoma has been very limited so far,” said Florian Scherer, MD, of University Medical Center Freiburg in Germany, when presenting the research at ASH 2021.
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Limitations include very low concentrations of ctDNA in plasma, which leads to low detection rates by sequencing technologies, and the limited applicability of single-gene assays, he explained.
To overcome these limitations, Dr Scherer and colleagues used 2 ultrasensitive sequencing technologies — CAPP-seq and PhasED-seq — in their study.
The researchers sequenced samples from 67 patients with CNS lymphoma. The team collected tumor, plasma, and cerebrospinal fluid (CSF) samples at diagnosis, during treatment, and at progression.
The researchers also analyzed samples from 44 patients with non-CNS lymphoma brain tumors and 24 healthy control individuals.
Detection
CAPP-seq detected somatic mutations in 100% of tumor samples and revealed a median of 288 mutations per patient. MYD88, PIM1, and CD79B were the most frequently mutated genes.
PhasED-seq detected ctDNA in 78% of pretreatment plasma samples and 100% of pretreatment CSF samples. The specificity was 96% and 97%, respectively. ctDNA levels were 80-fold higher in CSF than in plasma.
The researchers also found that concentrations of ctDNA were associated with radiographic features assessed by MRI.
ctDNA levels in plasma were significantly associated with total radiographic tumor volume (TRTV), and ctDNA levels in CSF were associated with periventricular localization of the tumor. In fact, ctDNA concentrations in CSF were more than 80 times higher in cases with periventricular involvement.
“These results indicate that the proximity of CNS lymphomas to the ventricular system is the crucial factor for ctDNA shedding into the CSF, while tumor burden, on the other hand, seems to be the essential variable for ctDNA detection in the blood,” Dr Scherer said.
Prognostication and Diagnosis
The researchers also found that pretreatment plasma ctDNA can be used as a prognostic biomarker. Patients with positive ctDNA before treatment had significantly worse PFS (P <.0001) and OS (P =.0001).
By combining ctDNA and TRTV, the researchers were able to further stratify patients. Those with detectable pretreatment ctDNA and a high TRTV had a 2-year OS rate of 14%, while patients with no detectable pretreatment ctDNA and a low TRTV had a 2-year OS rate of 100%.
ctDNA status during induction therapy was “highly predictive” for PFS (P =.0002) and OS (P =.004) as well, Dr Scherer noted.
Lastly, the researchers found evidence to suggest that ctDNA could be used to diagnose CNS lymphomas. The team used a training cohort of 30 patients with CNS lymphoma and 2647 patients with non-CNS lymphoma tumors.
In a validation cohort of 183 samples, the researchers were able to correctly classify CNS lymphoma in 97% of tumor samples, 59% of CSF samples, and 25% of plasma samples. The specificity and positive-predictive value were 100% across the sample types.
“We believe that, in the future, ctDNA could help stratify patients into risk groups that might benefit from treatment reduction or treatment intensification,” Dr Scherer said. “And furthermore, we envision a potential role of ctDNA for surgery-free CNS lymphoma detection or even the identification of occult CNS involvement.”
Disclosures: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.
Read more of Cancer Therapy Advisor’s coverage of the ASH 2021 meeting by visiting the conference page.
Reference
Mutter JA, Alig S, Lauer EM, et al. Profiling of circulating tumor DNA for noninvasive disease detection, risk stratification, and MRD monitoring in patients with CNS lymphoma. Presented at ASH 2021; December 11-14, 2021. Abstract 6.
