Highlights in indolent non-Hodgkin lymphoma

At EHA 2025, Dr Dima El-Sharkawi of the Royal Marsden hospital in Londen (UK) chaired the oral abstract session on indolent non-Hodgkin lymphoma. This session featured interesting updates and new clinical trial data across different low-grade lymphoma subtpes, including mantle cell lymphoma (MCL), follicular lymphoma (FL), Waldenstrøm macroglobulinemia (WM) and marginal zone lymphoma (MZL).

In the field of MCL, EHA 2025 featured updated results of the randomized, phase III ECHO trial. In this study, 299 previously untreated MCL patients who were deemed unfit for intensive therapy were randomly assigned to receive bendamustine-rituximab with or without acalabrutinib.¹ Previosuly, this trial demonstrated that the addition of acalabrutinib resulted in a significantly longer progression-free survival (PFS). Results presented at EHA 2025 show that this PFS benefit was preserved in patients with poor risk features, such as the presence of a TP53 mutation, a high Ki-67 index and a blastoid/pleomorphic hisotlogy.¹ Despite the fact that this trial allowed cross-over to acalabrutinib for patients in the control arm, a trend for a better overall survival (OS) was seen in favour of patients receiving the BR-acalabrutinib triplet in frontline. Longer follow-up will be needed to see if this OS benefit matures into a significant advantage.

In relapsed/refractory MCL, phase I data were presented for the combination of a novel Bcl-2 inhibitor (sonrotoclax) and the BTK inhibitor zanubrutinib. This combination induced deep responses across all dose levels, with an objective response rate (ORR) in the entire study population of 79%. Despite toxicity concerns with this combination, the trial indicates that the treatment is tolerable, without an excessive incidence of infections.²

Switching gears to FL, the oral abstract session featured updated results of the randomized, phase III INMIND trial. In this study, 548 FL patients who received ≥1 prior line of treatment (including an anti-CD20 antibody), were randomly assigned to receive lenalidomide-rituximab (R²) with or without tafasitamab.³ The addition of tafasitiamab to R² significantly improved the median PFS of patients in the study from 13.9 months with R² alone to 22.4 months with the R²-tafasitamab combination. Importantly, this benefit did not come at the cost of excessive toxicity.³

With respect to WM, Frustaci and colleagues presented the resuls of a phase I trial evaluating the BTK degrader BGB16673 (CADANCE-1). This trial included a total of 36 patients with a median age of 72 years who received a median of 3 prior treatment lines (range: 1-11). All these patients were previously treated with a covalent BTK inhibitor, with a fifth also being exposed to a non-covalent BTK inhibitor. In this heavily pretreated cohort, BGB16673 proved to be associated with an ORR of 84.4%, with 31.1% of patients obtaining a very good partial response or better. Furthermore, the treatment was well-tolerated, warranting further evaluation of this agent in an ongoing phase II trial.⁴

The final presentation of the oral abstract session concerned a small phase I study evaluating the bispecific antobody mosunetuzumab as first line treatment for patients with MZL (MorningSun).⁵ First line mosunetuzumab proved to be associated with an ORR of 78%, including a complete response (CR) in 64% of the patients. Interestinbgly, this high CR rate was seen across all investigated subgroups, irrespective of the presence of high-risk features such as an elevated LDH level, extranodal involvement or a higher Ann Arbor disease stage. For Dr El-Sharkawi, this trial was particularly interesting as it was mainly performed in non-academic, peripheral centers in the US. As such, this trial demonstrates that bispecifics can be delivered safely and effectively in a non-academic setting.⁵