Biomarker-Adapted Treatment Effective in High-Risk LBCL

Stratifying patients based on biological risk factors is a feasible and effective way to achieve high rates of survival among patients with large B-cell lymphoma (LBCL), a new study found.1 The report, published in the journal HemaSphere, also found that circulating tumor DNA (ctDNA) levels were associated with patient outcomes and offer a reliable biomarker of treatment response.

Many patients with primary LBCLs can be effectively treated with the R-CHOP regimen of rituximab (Rituxan; Genentech and Biogen), cyclophosphamide, doxorubicin, and prednisone. However, the authors noted that an estimated 30-40% of patients will relapse and die from the disease.2

The findings show that ctDNA is worthy of additional study as a tool for assessing risk and treatment response in large B-cell lymphoma, the authors concluded. | Image credit: Connect world - stock.adobe.com

Attempts to create subtype-targeted or risk-adapted R-CHOP strategies for patients who relapse have generally failed to demonstrate a significant benefit, the authors explained.1 However, some evidence suggests that adding etoposide to the biweekly R-CHOP-14 regimen can improve overall survival (OS) in young, high-risk patients.3 The etoposide-inclusive regimen is known as R-CHOEP.

The authors wanted to more closely examine survival among patients with biologically high-risk LBCL, such as patients with BCL2 and MYC translocations, coexpression of BCL2 and MYC, CD5 positivity, and TP53 aberrations.1 In particular, they wanted to see if intensified risk-adapted treatment for young patients with biologically high-risk LBCL might be a helpful strategy.

The investigators recruited 123 patients with high-risk LBCL who were between the ages of 18 and 64 years. Those without risk factors were given the R-CHOEP-14 regimen (n = 62); those with risk factors were given the regimen of dose-adjusted etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, and rituximab (DA-EPOCH-R; n = 61). They also evaluated ctDNA at baseline and throughout therapy to see how it aligned with outcomes.

After 3 years, the rate of failure-free survival was 79%, and OS was 88%. Among biologically high-risk patients, the FFS was 76%, which the investigators noted was comparable to data from a previous study in which biologically high-risk patients were treated with R-CHOEP-14. In a subgroup of patients with biological risk factors who had age-adjusted International Prognostic Index (aaIPI) scores of 3, there was a trend toward improved survival when patients received the DA-EPOCH-R regimen.

Patients with a high ctDNA burden at baseline were also more likely to have advanced disease, elevated LDH levels, and high aaIPI scores. Those patients, and those with TP53 mutations in their ctDNA, had inferior progression-free survival and OS. Furthermore, patients who had early clearance of ctDNA, achieving minimal residual disease (MRD) negativity after 2 treatment cycles, tended to have favorable outcomes.

The authors then analyzed the value of ctDNA clearance (MRD negativity) as a marker of treatment response. They found that patients with MRD negativity following therapy had a significantly lower risk of recurrence, and nearly all patients who were MRD positive after therapy went on to experience disease progression. These findings show that ctDNA is worthy of additional study as a tool for assessing risk and treatment response, the authors concluded.

“While it is currently unclear which is the best method to assess ctDNA and its independence from imaging technologies, it is clear that ctDNA offers opportunities for better risk stratification and response evaluation,” the authors wrote. ctDNA negativity following treatment was “indicative of a cure,” and effectively countered false residual PET positivity.

References

1. Leppä S, Meriranta L, Arffman M, et al. Biomarker-adapted treatment in high-risk large B-cell lymphoma. Hemasphere. Published online May 12, 2025. doi:10.1002/hem3.70139
2. Sehn LH, Salles G. Diffuse large B-cell lymphoma. N Engl J Med. 2021;384(9):842-858. doi:10.1056/NEJMra2027612
3. Gang AO, Strøm C, Pedersen M, et al. R-CHOEP-14 improves overall survival in young high-risk patients with diffuse large B-cell lymphoma compared with R-CHOP-14. A population-based investigation from the Danish Lymphoma Group. Ann Oncol. 2012;23(1):147-153. doi:10.1093/annonc/mdr058