Early ctDNA clearance signals stronger Ordspono responses in relapsed lymphomas

A new exploratory analysis from the phase 2 ELM-2 trial demonstrated the potential of circulating tumor DNA (ctDNA) as a prognostic biomarker for patients with relapsed/refractory follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) treated with Ordspono (odronextamab), a CD20×CD3 bispecific antibody. Published in Blood Advances, the study reveals that early ctDNA clearance, particularly when combined with complete response (CR) on PET-CT, correlates with prolonged progression-free survival (PFS), offering insights for response-adapted therapies

Bispecific antibodies are emerging as important treatment options for B‑cell non‑Hodgkin lymphomas. Ordspono has shown encouraging activity in heavily pretreated patients with follicular lymphoma (FL) and diffuse large B‑cell lymphoma (DLBCL). In the phase 2 ELM‑2 study, Ordspono monotherapy produced objective response rates of 80.5% in FL and 52% in DLBCL, with manageable safety.

Ordspono has, though, run into problems at the FDA. In August 2025, for the second time, the drug regulator issued a complete response letter (CRL) for its biologics license application (BLA). The complete response letter cited issues with a site inspection. The European Medicines Agency approved Ordspono in August 2024.

Jon Arnason, M.D., from the Department of Medicine, Division of Hematology and Hematologic Malignancies, Beth Israel Deaconess Medical Center in Boston and team explored whether ctDNA, a marker of minimal residual disease (MRD), could serve as a prognostic tool for patients receiving Ordspono. ctDNA is increasingly recognized as a noninvasive biomarker that can detect MRD and provide insight into treatment response.

The exploratory analysis included patients with relapsed or refractory FL and DLBCL enrolled in ELM‑2. The ctDNA was measured at baseline and at cycle 4, day 15 (C4D15), using a next‑generation sequencing assay. Researchers examined whether ctDNA clearance correlated with PFS and whether molecular profiling via ctDNA aligned with tumor biopsy results. Tumor biopsies assessed cell of origin, LymphGen subtypes, and key mutations, such as TP53 and MYD88.

At data cutoff, 60 patients with FL and 77 with DLBCL had ctDNA results available at C4D15. Undetectable ctDNA at C4D15 was strongly linked to better outcomes. In FL, median PFS was 42.4 months for ctDNA‑negative patients versus 21.6 months for ctDNA‑positive patients (HR, 0.31). In DLBCL, median PFS was 19.4 months versus 3.2 months, respectively (HR, 0.42).

Combined imaging and ctDNA improves prognostic value. Patients achieving complete response on PET‑CT and undetectable ctDNA at C4D15 had the most favorable outcomes. Most patients with progressive disease per Lugano criteria had detectable ctDNA at C4D15 (79% in FL; 80% in DLBCL), highlighting its predictive power.

Molecular insights from ctDNA were informative as ctDNA analysis suggested that the MCD subtype, defined by MYD88 mutations and CD79B mutations, which drive chronic active B-cell receptor signaling and NF-κB pathway activation, of DLBCL trended toward shorter PFS, while the EZB subtype, EZH2 + BCL2 mutations, trended toward longer PFS. TP53 mutations were frequently detected, though concordance between ctDNA and tumor biopsy varied.

These data underscore ctDNA as a dependable biomarker for assessing response to bispecific antibody treatment. For doctors, early ctDNA clearance may offer assurance that patients are progressing towards sustained benefit. In contrast, persistent ctDNA may indicate an elevated risk of advancement, necessitating increased monitoring or the exploration of alternate therapies.

Furthermore, ctDNA testing is minimally invasive and can be conducted repeatedly, providing a pragmatic method to monitor disease state without only depending on imaging. This may result in more efficient resource allocation for payers and potentially lower downstream costs related to relapses or ineffective treatment.

Arnason observes that the analysis was exploratory and not designed for conclusive statistical testing. The relationship between ctDNA status and the efficacy of Ordspono necessitates confirmation through prospective trials. The concordance between ctDNA and tissue biopsies for molecular subtyping was inconsistent, highlighting the necessity for additional test refinement.

Prompt clearance of ctDNA was significantly correlated with extended progression-free survival in patients administered Ordspono. Integrating ctDNA findings with imaging improves prognostic precision. These data indicate that ctDNA may assist clinicians and payers in making treatment decisions and enhancing the efficacy of bispecific antibody therapy in relapsed/refractory lymphomas.