ASH 2025 Breakthroughs: Key Studies Shaping Hematology and Community Oncology
January 7, 2026
The 2025 ASH Annual Meeting (ASH 2025) showcased groundbreaking research in hematology. Among the highlights were several pivotal abstracts that could redefine treatment paradigms. Here, we dive into five standout studies in lymphoma and leukemia: EPCORE FL-1, CLL17, BRUIN CLL-313/314, S1826, and PARADIGM.
EPCORE FL-1: Epcoritamab Elevates Responses in Relapsed/Refractory Follicular Lymphoma
The EPCORE FL-1 trial evaluated epcoritamab, a CD3xCD20 bispecific antibody, in combination with rituximab and lenalidomide (R2) versus R2 alone in patients with relapsed/refractory follicular lymphoma (R/R FL). This global phase 3 study randomized 488 patients to either epcoritamab plus rituximab and lenalidomide (n=243) or rituximab and lenalidomide (n=245). Dual primary end points, progression-free survival (PFS) and overall response rate (ORR), were assessed.
With a median follow-up of 14.8 months, the trial met both primary endpoints. Epcoritamab plus R2 achieved an ORR of 95% compared with 79% for R2, with complete response (CR) rates of 83% versus 50%, respectively. PFS was markedly superior with epcoritamab plus R2 compared with R2 alone, with a 16-month increase in PFS. Overall survival (OS) data also favored epcoritamab plus R2 compared with R2 alone (HR, 0.38). The 12-month response rate was 91.4% with epcoritamab plus R2 versus 57% in the control arm.
The toxicity profile showed elevated rates of grade 3/4 neutropenia (6.2% vs 2.1%) and infections (29.2% vs 13.4%) in the epcoritamab plus R2 arm compared with the control arm. However, these were manageable, and none were fatal. Cytokine release syndrome was observed in 24.4% of patients, most occurring at the first 48 mg full epcoritamab dose and all resolved.
Epcoritamab received FDA approval in November 2025 based on data from EPCORE FL-1, establishing epcoritamab plus R2 as a viable option for patients with R/R FL. Although an increase in the amount of toxicities was observed, many of them appear to be attributed to rituximab and lenalidomide, and were manageable. It signals a shift toward bispecific antibodies in lymphoma care, balancing efficacy with convenience.
CLL17: Fixed-Duration Therapies Challenge Continuous Treatment in CLL
In the phase 3 CLL17 trial, researchers compared fixed-duration venetoclax-based doublets of venetoclax plus obinutuzumab (VO) or venetoclax plus ibrutinib (VI) against continuous ibrutinib (I) in previously untreated chronic lymphocytic leukemia (CLL). The study involved 909 patients in VO (N=303), VI (N=305), and I (N=301). After a median follow-up of 34.2 months, the study met non-inferiority end points of VO versus I and VI versus continuous ibrutinib. The 3-year PFS overlapped with the OS curves.
VO achieved deeper responses, including higher rates of undetectable minimal residual disease (uMRD). Safety was comparable, although VO had more neutropenia but similar infection risks. In TP53-mutated patients, outcomes were worse with fixed-duration approaches. However, the cohort was small.
The trial provides the first head-to-head evidence supporting time-limited therapies in frontline CLL, potentially reducing long-term treatment burdens while maintaining efficacy. Although a longer follow-up is needed, the trial could help reshape guidelines and serve as a preferred treatment for patients with previously untreated CLL.
BRUIN CLL-313/314: Pirtobrutinib Outperforms Standards in CLL/SLL
The BRUIN CLL-313 and -314 trials assessed pirtobrutinib, a non-covalent Bruton tyrosine kinase inhibitor (BTKi), in CLL/small lymphocytic lymphoma (SLL).
BRUIN CLL-313 showed that pirtobrutinib monotherapy significantly improved PFS compared with bendamustinee plus rituximab (BR) in treatment-naïve, high-risk CLL/SLL (HR, 0.49). The trial showed one of the most significant treatment effects ever observed with a single-agent BTKi compared with the comparator. Pirtobrutinib was well tolerated, with a known safety profile and low discontinuation rates. This marked a win for targeted therapy over chemoimmunotherapy in the frontline setting.
BRUIN CLL-314 compared pirtobrutinib with ibrutinib in both treatment-naïve and relapsed/refractory patients. As the first head-to-head study of non-covalent versus covalent BTK inhibitors, it showed favorable outcomes, with improved ORR and a trend toward improved PFS with pirtobrutinib in patients with treatment-naïve CLL.
These studies highlight pirtobrutinib’s potential as a best-in-class BTKi, offering better tolerability and efficacy for patients with CLL, including those with prior BTKi exposure.
S1826: Nivolumab-AVD Sets New Benchmark in Advanced Hodgkin Lymphoma
The S1826 trial provided follow-up data on nivolumab plus AVD (N-AVD) versus brentuximab vedotin plus AVD (BV-AVD) in advanced-stage (stage III-IV) classical Hodgkin lymphoma (cHL). The study enrolled 994 patients who were randomized 1:1 to receive either 6 cycles of N-AVD or BV-AVD.
At 3 years, N-AVD sustained a PFS of 91% compared with 82% for BV-AVD (HR, 0.48). PFS outcomes were consistent across subgroups defined by age, disease stage, and risk factors. There was also a notable improvement in event-free survival (EFS), from 80% to 87% (HR=0.56), and in OS, from 97% to 98% (HR=0.48). No new safety signals were identified for the study. These results affirm N-AVD as the new preferred frontline treatment regimen in patients with advanced-stage cHL, including high-risk patients.
PARADIGM: Azacitidine-Venetoclax Challenges Intensive Chemo in AML
In the phase 2 PARADIGM trial, fit patients who were newly diagnosed with acute myeloid leukemia (AML) were randomized to azacitidine plus venetoclax (Aza-Ven) versus conventional induction chemotherapy (7+3 or CPX-351). The majority of the patients (72%) were ELN 2022 adverse risk, without a difference in distributions across risk categories or mutations (TP53, NPM1, or IDH1/2).
The study’s primary end point of EFS was met with Aza-Ven showing superior EFS (53%) compared with chemotherapy (39%). Moreover, ORR was also greater in the Aza-Ven arm (88% vs 62%, respectively). The combination also trended toward a better OS. Compared with chemotherapy, Aza-Ven increased the number of patients bridged to transplant (61% vs 40%). At 2 weeks, patients on the combination reported significantly better quality of life, symptom burden, and depression symptom scores.
These findings raise the question of whether Aza-Ven may represent a superior pfront option for fit patients with AML. More data are needed as OSdata continues to mature, and phase 3e confirmation is awaited.
Looking Ahead: A Transformative Year for Hematology
ASH 2025 delivered practice-affirming and paradigm-shifting data across lymphoma and leukemia. As these findings translate to practice, they could improve survival and quality of life for countless patients. These advances provide broader access and enhanced patient experiences in community settings. Stay tuned for Part 2, which will cover key updates in multiple myeloma.