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Expert Insights on 6 Key Abstracts
Evolving Paradigms in Hematologic Malignancies: Expert Insights on 6 Key Abstracts From EHA and ICML 2025

Released: August 29, 2025

Max S. Topp
Max S. Topp, MD
Pier Luigi Zinzani
Pier Luigi Zinzani, MD, PhD
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Key Takeaways
  • New targeted and immune-based therapies, such as the CD3xCD19 bispecific T-cell engager surovatamig, the small molecule EZH2 inhibitor SHR2554, and the BTK degrader catadegbrutinib, are reshaping hematologic oncology.
  • Antibody- and immune-based combinations are emerging as effective alternatives to conventional chemotherapy regimens.
  • Multiple studies have demonstrated meaningful efficacy in heavily pretreated populations and subgroups at high risk.

Recent advances in oncology continue to reshape therapeutic strategies across a range of hematologic malignancies, expanding treatment options and challenging existing standards of care. Max S. Topp, MD, from University Hospital Würzburg in Würzburg, Germany, and Pier Luigi Zinzani, MD, PhD, from Bologna University School of Medicine in Bologna, Italy, recently discussed 6 impactful abstracts presented at the annual European Hematology Association and International Conference on Malignant Lymphoma Congresses. These studies illustrate how such advances are being translated into tangible therapeutic opportunities across diverse malignancies. Of importance, the findings highlight a growing focus on tolerability, sequencing, and quality of life. Read on to gain expert insights into how these findings have broad impact and clinical significance.

SYRUS

Max S. Topp, MD:
SYRUS is an international phase I/II trial evaluating surovatamig (eg, AZD0486), a novel CD3×CD19 bispecific T-cell engager (BiTE), in patients 16-80 years of age with Ph- CD19+ relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL), one of the most difficult-to-treat B-cell lymphomas. Patients were heavily pretreated (≥2 prior lines of therapy), mostly with blinatumomab, CAR T-cell therapy, or both. The trial design follows a step-up dosing strategy, aiming to identify a safe and effective biologically active dose. Safety and efficacy data from 31 patients were presented. The DL3 cohort (step-up doses: 0.27/1.0/2.4 mg​; target dose: 15 mg) showed remarkable efficacy, with 83% of patients (5 of 6) achieving complete response (CR)/complete response with incomplete blood count recovery (CRi) and minimal residual disease (MRD) negativity.

Responses were observed regardless of prior therapy, and activity was retained in patients who were double exposed, suggesting that surovatamig can overcome prior resistance and that sequential use of multiple CD19-directed agents may be feasible in B-ALL, addressing a major prior concern of antigen loss. Cytokine release syndrome (CRS) was observed in 31% after step-up dose 1, 72% after step-up dose 2, and 30% at the target dose. However, only 1 patient experienced grade 3 CRS and, overall, CRS was generally manageable with step-up dosing included in the study protocol. Immune effector cell-associated neurotoxicity syndrome (ICANS) was rare, with a single ICANS event reported, a rate that is substantially lower than that seen in the same setting with blinatumomab. Other adverse events included infection, neutropenia, and elevated liver enzymes, supporting continued investigation into the phase II expansion.

Data from the SYRUS trial suggests that surovatamig may be a highly active BiTE with a favorable safety profile in 1 of the most refractory leukemia subtypes. This opens up new sequencing strategies in B-ALL, offering efficacy even in patients resistant to prior CD19-directed therapies. Surovatamig represents not just another drug, but a new strategic opportunity in sequencing and improving patient outcomes.

Pivotal Study of SHR2554 in R/R PTCL

Pier Luigi Zinzani, MD, PhD:
SHR2554, an oral inhibitor for EZH2, is being investigated in a phase I trial in patients with R/R peripheral T-cell lymphoma (PTCL) with histologic subtypes including angioimmunoblastic T-cell lymphoma (AITL), PTCL not otherwise specified, and anaplastic large cell lymphoma (ALCL; both ALK-positive and ALK-negative). The maximum tolerated dose (MTD) was determined to be 350 mg twice daily. Eligible patients were aged 18-70 years and had received prior chemotherapy and at least 1 class of approved medications in China such as pralatrexate or tucidinostat. The primary endpoint was overall response rate (ORR), which was 64.2% in the overall cohort (CR: 32.8%) and ORR varied by subtype, from 42.9% in ALK-negative ALCL to up to 70.3% in AITL. The median time to response was less than 2 months, demonstrating rapid clinical activity. The median duration of response reached almost 19 months, which is quite remarkable in this setting, and median progression-free survival (PFS) was 10 months while median overall survival (OS) was not reached. These data suggest that EZH2 inhibition has broad and consistent activity across various subtypes of PTCL. The safety profile was manageable, with no new toxicities. Of importance, no histopathologic toxicities were observed.

These results compare favorably with conventional salvage therapies such as pralatrexate or belinostat, which typically achieve ORRs around 30% to 40%. This trial provides proof of concept that EZH2 inhibition is a promising strategy in R/R PTCL, addressing a substantial unmet clinical need and highlights the potential of SHR2554 as both a monotherapy and in combination regimens. Given the aggressive biology and limited treatment options in PTCL, these results are highly encouraging and warrant further phase II/III investigation.

CaDAnCe-101

Pier Luigi Zinzani, MD, PhD:
The phase I/II CaDAnCe-101 trial is evaluating catadegbrutinib (eg, BGB-16673), a BTK degrader, in patients with R/R B-cell malignancies, including chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Most participants were considered heavily pretreated, representing a population with significant unmet clinical need. The primary study objectives were safety, tolerability, and MTD, while efficacy outcomes were explored as secondary objectives. Patients with CLL/SLL were treated across 6 dose cohorts ranging from 50 mg to 600 mg, and the MTD was determined to be 200 mg. In the phase I portion of the trial, the ORR exceeded 80%, with CR observed in 4.5% of all patients. Median time to first response was nearly 3 months, reflecting relatively rapid disease control.

Among patients who had previously received both a covalent BTK inhibitor and BCL2 inhibitor, the ORR with catadegbrutinib was 90.5%. In triple-exposed patients (ie, those previously treated with a covalent and noncovalent BTK inhibitor as well as a BCL2 inhibitor), the ORR was 75%. Subgroup analyses demonstrated consistent activity across adverse genetic backgrounds, including patients with del(17p) and/or TP53 mutation (ORR: 81.4%), a complex karyotype (ORR: 72.7%), and BTK mutations (ORR: 75.0%). At a median follow-up of 15.6 months, the PFS rate at 1 year was 77.4%. The overall safety profile was favorable, with the most common adverse events being fatigue and bruising, mostly grades 1-2. As with many cancer therapies, cytopenias occurred but most improved rapidly, and no dose-limiting cardiac or hepatic toxicities were noted. Atrial fibrillation occurred in 2 patients, and major hemorrhage was rare.

Preliminary data on catadegbrutinib suggest encouraging safety and efficacy in high-risk, heavily pretreated patients with CLL/SLL but warrant further exploration. Overall, CaDAnCe-101 positions BTK degradation as a promising therapeutic avenue in B-cell malignancies.

ECHO

Max S. Topp, MD:
The randomized, double-blind phase III ECHO trial is evaluating the addition of acalabrutinib, a covalent BTK inhibitor, to bendamustine and rituximab (BR) in patients 65 years of age or older with previously untreated mantle cell lymphoma (MCL). The addition of acalabrutinib significantly improved PFS (the primary endpoint of the study) vs BR alone across the entire study population (HR: 0.73; 95% CI: 0.57-0.94; P = .0160). Of importance, the PFS benefit extended to high-risk subgroups (HR: 0.74; 95% CI: 0.55-0.99; P = .0432), as defined by high MIPI scores, a Ki-67 of ≥30%, presence of a p53 mutation, and/or blastoid histology. These patients are traditionally difficult to treat, yet ECHO demonstrated a clear PFS advantage across subgroups, suggesting that BTK inhibition can meaningfully alter outcomes even in patients with aggressive MCL biology. Toxicity data were consistent with the known profiles of each class of therapy. COVID-19–related deaths confounded early OS data in this trial, but when excluded, a trend toward improved median OS with acalabrutinib was seen (HR: 0.75; 95% CI: 0.53-1.04; P = .0797).

Overall, ECHO establishes acalabrutinib/BR as a superior regimen to BR alone in untreated elderly patients with MCL or those at high risk, with consistent efficacy across challenging-to-treat subgroups, and marks a significant advancement in the field, positioning BTK inhibition as a cornerstone of modern MCL therapy. These results complement those from the phase III TRIANGLE trial in patients 65 years of age or younger with previously untreated stage II-IV MCL who were eligible for autologous stem cell transplant, which investigated alternating R-CHOP/R-DHAP with or without ibrutinib and also showed improved OS with the addition of ibrutinib, thereby redefining MCL therapy across age groups.

We could be experiencing a revolution for the treatment of patients with MCL, as BTK inhibitors are reshaping both frontline and R/R treatment paradigms. Future combinations, including venetoclax plus covalent BTK inhibitors, and novel agents like glofitamab will likely further expand nonchemotherapy options. MRD-guided treatment may also represent a new frontier, as determining whether MRD negativity allows therapy cessation and/or MRD positivity allows treatment escalation could help to further refine therapy and avoid or minimize unnecessary toxicities.

inMIND

Max S. Topp, MD:
inMIND is an international, double-blind, randomized phase III trial evaluating tafasitamab, an anti-CD19 antibody, plus lenalidomide and rituximab (R²) vs placebo plus R² in R/R follicular lymphoma (FL). Meeting the primary endpoint, a significant improvement in PFS was observed with tafasitamab plus R² vs R² (HR: 0.41; 95% CI: 0.29-0.56; P <.0001). In addition, similar improvements were seen across subgroups, with HRs in the range of 0.2-0.4. Of importance, PFS benefit was observed even in patients who experienced disease progression within 24 months of initial diagnosis, those with refractoriness to prior anti-CD20 therapy, and regardless of the number of prior lines of therapy (1 previous line or ≥2 previous lines).

Investigators also evaluated histologic transformation to either diffuse large B-cell lymphoma (DLBCL) or a higher-grade morphology, which is a concern in a small proportion of FL cases. However, longer follow-up is needed to determine whether tafasitamab reduces transformation risk.

In my opinion, inMIND reinforces the movement toward a chemo-free regimen in FL, aligning with broader efforts to move toward targeted and immune-based regimens. inMIND complements the evolving treatment landscape and establishes tafasitamab plus R² as a safe, effective, and chemo-free regimen for R/R FL, with durable benefit and preserved sequencing options.

POLARGO

Pier Luigi Zinzani, MD, PhD:
The randomized, open-label phase III POLARGO trial evaluated polatuzumab vedotin plus rituximab, gemcitabine, and oxaliplatin (Pola-R-GemOx) vs R-GemOx alone in patients with R/R DLBCL ineligible for transplant—a particularly difficult group to treat. The primary endpoint of OS was met, with the median OS significantly longer with Pola-R-GemOx (19.5 months) vs R-GemOx alone (12.5 months) (HR: 0.60; 95% CI: 0.43-0.83; log-rank P = .0017​). PFS also favored the addition of polatuzumab vedotin, with a median PFS of 7.4 months vs 2.7 months, respectively, demonstrating a clear and clinically meaningful benefit of adding polatuzumab vedotin to R-GemOx. The ORR was nearly doubled, at approximately 53% for Pola-R-GemOx vs approximately 25% for R-GemOx. The CR rate reached approximately 40% in the Pola-R-GemOx arm vs 19% in the control arm. Of importance, these gains were achieved without a major increase in toxicity. Overall toxicity profiles were generally comparable between the 2 arms. The incidence of peripheral neuropathy was higher in the Pola-R-GemOx arm, but the percentage of patients who experienced grade 3 peripheral neuropathy did not exceed 4%, and it was generally reversible.

In the evolving treatment landscape, this regimen may be most relevant for elderly patients who are ineligible for transplant and CAR T-cell therapy. While chemo-free regimens are gaining traction, POLARGO highlights that integrating an antibody–drug conjugate into a conventional chemoimmunotherapy regimen remains effective. Patient characteristics, comorbidities, and prior treatment history should be considered when selecting among regimens, but overall, POLARGO establishes Pola-R-GemOx as a viable and evidence-based standard-of-care option for this underserved population.

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