Refining Remission Assessment in Aggressive B-Cell Lymphomas

Newer-generation methods of detecting circulating tumor DNA in patients who have aggressive B-cell lymphomas are capable of detecting measurable residual disease at an analytical detection threshold of 1 in 1 million cell-free DNA molecules—meaning they are considered ultrasensitive. Yet barriers remain to their implementation, according to review results published in JAMA Oncology.¹

“Achieving remission is the first step toward a cure in treating aggressive B-cell lymphomas,” the authors write. “Identifying measurable residual disease with ultrasensitive detection of circulating tumor DNA potentially offers the possibility of improving clinical outcomes.”

There are many steps in the current process to define remission:

• Step 1: frontline therapy
• Step 2: end-of-therapy assessment via Deauville score:
  • 1 to 3 indicates a complete response
  • 4 or 5 indicates an incomplete response
• Step 3: Deauville score of 1 to 3: with a 15% risk of relapse, the next step is relapse surveillance
• Step 4: Deauville score of 4 or 5: tissue biopsy or repeated PET scan; if negative, relapse surveillance; if positive, salvage therapy

A top obstacle in this space, the authors note, is being able to precisely define remission in patients who have aggressive B-cell lymphomas at end of therapy. CT scans are imprecise, and with PET scans, questions remain on scan uptake being consistent with remission. For example, results from the phase 3 GOYA study of patients with aggressive B-cell lymphoma showed that an end-of-therapy PET scan showed a 74% reduced risk of death (HR, 0.26; 95% CI, 0.19-0.38; P < .001) and was prognostic of progression-free survival; yet, at 2.5 years, the positive predictive value of the scan was below 50% and the negative predictive value was 84%.² Other research did not find any value to an end-of-therapy PET scan.³

For leukemias, measuring circulating tumor DNA works because of the presence of circulating tumor cells in the blood; the same cannot be said the B-cell lymphoma cells. Another challenge is the genetic heterogeneity of aggressive B-cell lymphomas.¹

Despite research showing the benefits of circulating tumor DNA as an indicator of disease remission in B-cell lymphoma, hurdles that include availability and cost remain to its widespread implementation. | Image Credit: © kalpis-stock.adobe.com.jpeg

“Aggressive B-cell lymphomas are genetically complex and differ across patients,” the study authors write, “which makes interrogation for a single altered gene inadequate.”

They also highlight that analytical sensitivity of current circulating tumor DNA assays is a major challenge, with levels of circulating tumor DNA rapidly diminishing upon therapy initiation, making analytical sensitivity a critical determinant of minimal residual disease detection. Polymerase chain reaction amplification is not effective to monitor for aggressive B-cell lymphoma because, again, of the disease’s heterogeneity—despite being effective for MRD detection in hematologic diseases.

Next-generation sequencing (NGS) tests have emerged, with data that show their potential. The study authors note, “Technologic improvements in the analytical sensitivity of circulating tumor methods now allow for a more precise determination of remission than the current response criteria.”

For example, one early assay used an immunoglobulin sequencing method that was highly tumor specific even though it was limited in its findings at low levels of circulating tumor DNA.⁴ The cancer personalized profiling by deep sequencing (CAPP-Seq) assay is another development, but it has a high background error rate.⁵ The phased variant enrichment and detection by sequencing (PhasED-Seq) assay uses single-nucleotide variants located close to the genome of B-cell lymphomas; it has improved analytical sensitivity and a lower background error tea vs CAPP-Seq.⁶

The authors emphasize that for a clinical tool to be not only precise but useful, its detectable circulating tumor DNA results “need to reflect the risk of recurrence given that it may be the basis for treatment decisions; the collection and processing procedures need to be standardized, widely available, and reproducible in distinct locations; and the test needs to provide actionable results in a clinically relevant timeframe at an affordable cost.”¹

Specifically, the cost of currently available tests ranges between $2000 and $3000, underscoring the importance of wide payer acceptance and cost-effectiveness analyses to bring these advancements to a wider patient and clinical audience.

As this field sees further treatment advancements, integrating ultrasensitive circulating tumor DNA detection into routing clinical practice will require overcoming technical, logistical, and financial hurdles, but there is great potential to refine remission assessment and guide personalized treatment decisions to improve outcomes for patients with aggressive B-cell lymphomas.

References

1. Roschewski M, Longo DL, Armitage JO. Circulating tumor DNA as measurable residual disease in aggressive B-cell lymphoma: a narrative review. JAMA Oncol. Published online February 6, 2025. doi:10.1001/jamaoncol.2024.6144

2. Kostakaglu L, Martelli M, Sehn LH, et al. End-of-treatment PET/CT predicts PFS and OS in DLBCL after first-line treatment: results from GOYA. Blood Adv. 2021;5(5):1283-1290. doi:10.1182/bloodadvances.2020002690

3. Schöder H, Polley MYC, Knopp MV, et al. Prognostic value of interim FDG-PET in diffuse large cell lymphoma: results from the CALGB 50303 Clinical Trial. Blood. 2020;135(25):2224-2234. doi:10.1182/blood.2019003277.

4. Faham M, Zheng J, Moorhead M, et al. Deep-sequencing approach for minimal residual disease detection in acute lymphoblastic leukemia. Blood. 2012;120(26):5173-5180. doi:10.1182/blood-2012-07-444042

5. Newman AM, Bratman SV, To J, et al. An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage. Nat Med. 2014;20(5):548-554. doi:10.1038/nm.3519

6. Kurtz DM, Soo J, Co Ting Keh L, et al. Enhanced detection of minimal residual disease by targeted sequencing of phased variants in circulating tumor DNA. Nat Biotechnol. 2021;39(12):1537-1547. doi:10.1038/s41587-021-00981-w