bims-hemali 2025-12-14 papers

bims-hemali

Biomed News

on Hematologic malignancies

Issue of 2025–12–14
forty papers selected by
Alexandros Alexandropoulos, Γενικό Νοσοκομείο Αθηνών Λαϊκό

Is there a best frontline therapy in chronic myeloid leukemia?
Venetoclax and ibrutinib induces durable clinical responses in marginal zone lymphoma.
Combined asciminib and olverembatinib in blast-phase chronic myeloid leukemia.
Improving quality of life for patients with chronic myeloid leukemia through supportive care, low-dose therapy, switching, and treatment-free remission.
Atypical chronic myeloid leukemia: From diagnosis to molecular features and therapeutic options.
Development of a blood test-based predictive scoring tool for treatment response in chronic myeloid leukemia.
Phase II Trial of an Orelabrutinib-Based Combination Therapy in Newly Diagnosed Primary Central Nervous System Lymphoma.
Chronic Myeloid Leukemia and the T315I BCR::ABL1 Mutation.
Targeting Musashi-2 to counteract senescence and resistance in chronic myeloid leukemia: enhancing the efficacy of imatinib therapy.
Teclistamab plus Daratumumab in Relapsed or Refractory Multiple Myeloma.
Prognosis and patterns of progression in smoldering multiple myeloma.
Dual Targeting of Extramedullary Myeloma with Talquetamab and Teclistamab.
Luminal hepcidin targets intestinal DMT1.
Improving MM outcomes with bispecific antibody combinations.
Pirtobrutinib Versus Ibrutinib in Treatment-Naïve and Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma.
Linvoseltamab in Patients With Relapsed/Refractory Multiple Myeloma in the LINKER-MM1 Study: Longer Follow-Up and Subgroup Analyses.
Large B-cell lymphoma: The LYSA pragmatic guidelines.
Fixed-Duration versus Continuous Treatment for Chronic Lymphocytic Leukemia.
Glu(tamine)ing together myeloma metabolism and CAR T efficacy.
Enhancing the targeting of the undruggable.
A Phase I Study of Combination Duvelisib and Nivolumab in Patients With Diffuse Large B-Cell Lymphoma, Transformed Follicular Lymphoma, and Richter Transformation.
Venetoclax-Dexamethasone Versus Pomalidomide-Dexamethasone in t(11;14)-Positive Relapsed/Refractory Multiple Myeloma: Primary Results of the Randomized, Phase III CANOVA Study.
Epcoritamab, lenalidomide, and rituximab versus lenalidomide and rituximab for relapsed or refractory follicular lymphoma (EPCORE FL-1): a global, open-label, randomised, phase 3 trial.
Interferon alpha in myeloproliferative neoplasms: evidence and practical considerations for clinical care.
Epcoritamab monotherapy for Richter transformation (EPCORE CLL-1): findings from a single-arm, multicentre, open-label, phase 1b/2 trial.
Bispecific antibody combination regimens for B-cell non-Hodgkin's lymphomas.
Towards New Therapy Endpoints in Polycythemia Vera: Targeting Clonal and Inflammatory Pathways.
Defusing AML: targeting t(8;21) forces myeloid maturation.
Outcomes of Radiation Integrated with T-cell-engaging Bispecific Antibodies in Relapsed/Refractory Multiple Myeloma.
Clarifying comparative evidence on epcoritamab.
Clinical Outcomes of Adult Patients With Newly Diagnosed Mixed Phenotype Acute Leukemia.
Prospective Validation of Circulating Tumor DNA Measurable Residual Disease After First-Line Therapy in Large B-Cell Lymphoma.
A new standard for relapsed or refractory follicular lymphoma.
Successes and Challenges of Bispecific T-cell Engager Antibodies in the Treatment of Multiple Myeloma.
Harnessing the innate immune system: a novel bispecific antibody targeting CD47 and CD24 for selective tumor clearance.
Tafasitamab, lenalidomide, and rituximab in relapsed or refractory follicular lymphoma (inMIND): a global, phase 3, randomised controlled trial.
Relapsed Classical Hodgkin Lymphoma in Pregnancy in Two Patients Managed With a Multidisciplinary Approach.
Plasma cell extravaganza: anaplastic variant.
Rilzabrutinib: First Approval.
Response and remission after first-line corticosteroid therapy in primary immune thrombocytopenia.

Haematologica. 2025 Dec 11.

Is there a best frontline therapy in chronic myeloid leukemia?

Akriti G Jain, Mark Dalgetty, Jorge E Cortes.

The management of chronic myeloid leukemia in chronic phase (CML-CP) was transfigured with the introduction of imatinib in 2001. Since then, four other tyrosine kinase inhibitors (TKIs), dasatinib, nilotinib, bosutinib and most recently asciminib, have garnered approval for frontline management of CML-CP. The second generation TKIs (2G-TKIs) and asciminib have all been shown to be significantly superior to imatinib in attaining molecular responses, and asciminib possibly superior to 2G-TKIs. With limited prospective comparisons between the 2G-TKIs and similar survival outcomes with imatinib compared to 2G-TKIs, the selection of a TKI for patients with newly diagnosed CML-CP must be individualized to the needs of that specific patient. Important factors to consider when choosing a drug include patient related factors (age, comorbidities, lifestyle considerations, quality of life, patient preferences, shared-decision making and whether treatment free remission [TFR] is a goal), disease related factors (risk stratification, transcript type, presence of high risk gene mutations such as ASXL1) and drug related factors (major molecular response rates with each TKI, adverse events, rates of treatment discontinuation and TFR rates).

DOI: https://doi.org/10.3324/haematol.2025.287813
Blood Adv. 2025 Dec 11. pii: bloodadvances.2025016646. [Epub ahead of print]

Venetoclax and ibrutinib induces durable clinical responses in marginal zone lymphoma.

Sasanka M Handunnetti, Amit Khot, Piers Blombery, Kate Burbury, Philip A Thompson, David Ritchie, Rodney John Hicks, Glenda Burke, Rachel M Koldej, Mathias Bressel, Juliana L Di Iulio, David A Westerman, Stephen Lade, Andrew W Roberts, John F Seymour, Constantine S Tam, Mary Ann Anderson.

Oral ibrutinib (I) and venetoclax (V) demonstrate activity as monotherapy in marginal zone lymphoma (MZL), with low complete response (CR) rates. I+V has shown good clinical activity with acceptable tolerability in other malignancies. We conducted a single-site, phase 2 trial of daily I+V in patients with MZL. Ibrutinib commenced at 560mg daily, after 4 weeks venetoclax commenced with weekly dose escalation to 400mg daily. Combination therapy continued until disease progression or toxicity. The primary end point was week 16 CR. Minimal residual disease (MRD) was assessed by flow cytometry in bone marrow and peripheral blood. Patients achieving eradication of MRD could enter elective treatment interruption (ETI). 15 patients with MZL were treated, 14 are included in efficacy analysis and 15 evaluable for safety. Overall response was 79% (95% CI 49-95) by FDG PET (43% (95% CI 18-71) CR rate). By CT 16-week CR rate was 29% (95% CI 8-58). Best response within 56 weeks was 57% (95% CI 37-80) CR, which is higher than historic ibrutinib monotherapy control (3% CR) (p < 0.001). MRD clearance at week 56 was 40%. Six MRD negative CR patients entered ETI with 4 remaining disease-free at median 4 years. With median follow up 5.5 years for the whole cohort, the 5-year progression free survival estimate was 56% (95% CI 27 - 78). I+V is safe and effective for MZL, with higher CR than with ibrutinib. Durable, ongoing CR was observed in MRD negative patients. Trial registered at www.clinicaltrials.gov as NCT02471391.

DOI: https://doi.org/10.1182/bloodadvances.2025016646
Haematologica. 2025 Dec 11.

Combined asciminib and olverembatinib in blast-phase chronic myeloid leukemia.

Fang Cheng, Weiming Li.

Not available.

DOI: https://doi.org/10.3324/haematol.2025.289085
Haematologica. 2025 Dec 11.

Improving quality of life for patients with chronic myeloid leukemia through supportive care, low-dose therapy, switching, and treatment-free remission.

Kathryn E Flynn, Ehab Atallah.

Chronic myeloid leukemia (CML) is a hematologic malignancy that has become a largely manageable condition when treated with tyrosine kinase inhibitors (TKIs). However, the lifelong treatment course required for most patients is associated with side effects and toxicities that can impact patients' health-related quality of life (HRQOL). This review synthesizes current evidence on strategies to optimize HRQOL for patients on TKIs. This can be achieved through supportive care to manage TKI-related symptoms, dose adjustments, switching to a different TKI, or treatment discontinuation for select patients. We examine the clinical rationale and empirical support for each approach. Emphasis is placed on the importance of clear patient-physician communication and authentic shared decision-making and individualized care to address the needs and experiences of patients and to improve HRQOL.

DOI: https://doi.org/10.3324/haematol.2025.287766
Hemasphere. 2025 Dec;9(12): e70270

Atypical chronic myeloid leukemia: From diagnosis to molecular features and therapeutic options.

Alessandra Iurlo, Daniele Cattaneo, Umberto Gianelli, Francesco Passamonti.

Atypical chronic myeloid leukemia (aCML) is a rare form of myelodysplastic (MDS)/myeloproliferative neoplasm (MPN) overlap disorder characterized by neutrophilic leukocytosis with circulating immature myeloid cells (IMC), frequent hepatosplenomegaly, and poor prognosis with high rates of leukemic transformation. In the 2022 World Health Organization (WHO) classification, aCML was therefore renamed to "MDS/MPN with neutrophilia." Diagnostic criteria for aCML include leukocytosis ≥ 13 × 109/L, circulating IMC ≥ 10%, dysgranulopoiesis, and at least one cytopenia for MDS-thresholds (per International Consensus Classification [ICC]). Bone marrow is hypercellular due to granulocytic proliferation, associated with dysplasia in granulocytes ± other cell lines. Mutations can be used to support the diagnosis in both classifications, that is, SETBP1 and ASXL1 or SETBP1 and/or ETNK1. Absence of monocytosis, basophilia, or eosinophilia, <20% blasts, and exclusion of other MPN, MDS/MPN, and tyrosine kinase fusions are mandatory. Cytogenetic abnormalities are identified in roughly 20%-40% of aCML patients, along with a complex genomic context with high rates of recurrent somatic mutations in ASXL1, SETBP1, SRSF2, TET2, EZH2, and, less frequently, in NRAS/KRAS, CBL, CSF3R, JAK2, and ETNK1. Unfortunately, effective risk stratification systems for identifying prognostic subgroups of aCML patients are lacking, resulting in the absence of a standard of care for its management. The most used agents include hydroxyurea, interferon, hypomethylating agents, and JAK inhibitors, although none of them are disease-modifying. Allogeneic hematopoietic stem cell transplant remains the only potentially curative approach and should be considered in all eligible patients. Actionable mutations (CSF3R, NRAS/KRAS, and KIT) have also been identified, supporting the development of new agents targeting the involved pathways.

DOI: https://doi.org/10.1002/hem3.70270
Int J Hematol. 2025 Dec 13.

Development of a blood test-based predictive scoring tool for treatment response in chronic myeloid leukemia.

Kohjin Suzuki, Tomoiku Takaku, Naoki Watanabe, Noriyoshi Iriyama, Eisaku Iwanaga, Yuta Kimura, Maho Ishikawa, Hitomi Nakayama, Eriko Sato, Takayuki Tabayashi, Toru Mitsumori, Tomonori Nakazato, Michihide Tokuhira, Hiroyuki Fujita, Miki Ando, Yoshihiro Hatta, Tatsuya Kawaguchi.

  The European LeukemiaNet recommendations for the management of chronic myeloid leukemia (CML) consider achievement of major molecular response (MMR) within 12 months to be an optimal response (OR). However, no currently available tool can predict treatment response at diagnosis. This study aimed to develop a predictive scoring tool for OR and subsequent deep molecular response (DMR) using peripheral blood parameters at diagnosis. A retrospective analysis was conducted in 535 patients with CML from the CML Cooperative Study Group database. Patients were categorized into OR (MMR within 12 months; n = 355) and non-OR groups (MMR after 13 months; n = 180). Logistic regression analysis identified white blood cell count, platelet count, eosinophil percentage, and imatinib use as significant predictors of OR. These variables were used to construct a novel score. The score was significantly higher in the non-OR group and showed superior predictive accuracy for OR compared with existing prognostic scores. Furthermore, lower scores correlated with higher rates of DMR achievement. Notably, the score effectively predicted OR achievement among patients with low/intermediate ELTS risk treated with imatinib. This new scoring tool may facilitate individualized treatment selection in CML, guiding upfront tyrosine kinase inhibitor selection and advancing precision medicine.

Keywords:  Chronic myeloid leukemia; Optimal response; Treatment response prediction

DOI:  https://doi.org/10.1007/s12185-025-04132-8
Blood Lymphat Cancer. 2025 ;15 203-216

Phase II Trial of an Orelabrutinib-Based Combination Therapy in Newly Diagnosed Primary Central Nervous System Lymphoma.

Yajing Zhao, Xinguang Liu, Qiang He, Yafei Yu, Lei Xu, Caifeng Sun, Guoqiang Liu, Liang Wang, Ji Ma.

   Purpose: Primary central nervous system lymphoma (PCNSL) is a rare, yet highly aggressive non-Hodgkin lymphoma confined to the central nervous system (CNS). High-dose methotrexate (HD-MTX) remains the baseline chemotherapy for newly-diagnosed PCNSL. Intensive chemotherapies combined with HD-MTX have improved patient outcomes. However, the substantial toxicities limited their applicability, especially among elderly patients with poor physical status. Optimal composition of induction and consolidation treatment are still warranted.
Patients and methods: In this prospective single-arm phase II trial (ChiCTR2200061485), we evaluated the efficacy and safety of HD-MTX combined with rituximab and orelabrutinib, a second-generation BTK inhibitor with high CNS penetration, as induction therapy in newly diagnosed PCNSL. Twenty-two patients received up to six cycles of the combined induction therapy. Patients who achieved remission proceeded to non-randomized consolidation therapies with ASCT (autologous hematopoietic stem cell transplantation), WBRT (whole-brain radiotherapy), or orelabrutinib maintenance, based on patient eligibility and physician discretion. The primary endpoint was the centrally assessed response post-induction. Secondary endpoints included progression free survival (PFS), overall survival (OS), and safety.
Results: Among the 22 enrolled patients, the overall response rate (ORR) at the end of induction therapy was 91.0%, including 9 patients (41.0%) with complete remissions (CRs), and 11 patients (50.0%) with partial remissions (PRs). With a median follow-up of 22.3 months (range 2.3-42.4 months), the 1-year and 2-year PFS rates were 66.6% and 59.2%, respectively; OS rates were 81.8% and 66.3%, respectively. Consolidation was performed in 15 patients: 5 underwent ASCT, 4 received WBRT, and 6 received maintenance orelabrutinib. The most common adverse effects were grade 1 anemia (45.5%). Grade ≥ 3 events included neutropenia (13.6%) and pneumonia (9.0%).
Conclusion: The combination of HD-MTX, rituximab, and orelabrutinib demonstrates high response rates and manageable toxicity in newly diagnosed PCNSL, supporting further evaluation in randomized trials.

Keywords:  high-dose methotrexate; orelabrutinib; primary central nervous system lymphoma; rituximab

DOI:  https://doi.org/10.2147/BLCTT.S556657
Int J Mol Sci. 2025 Nov 21. pii: 11285. [Epub ahead of print]26(23):

Chronic Myeloid Leukemia and the T315I BCR::ABL1 Mutation.

Federico Pierro, Stefania Stella, Manlio Fazio, Sabina Russo, Michele Massimino, Giuseppe Mirabile, Daniela Belletti, Alessandro Allegra, Fabio Stagno.

  Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by both an abnormal expansion of the granuloblastic clone and the pathognomonic presence of the Philadelphia (Ph) chromosome that generates the BCR::ABL1 oncoprotein. Despite the surfacing of tyrosine kinase Inhibitors (TKIs) in 2001, which changed the evolution of the disease, resistance due to point mutation or compound alteration during treatment with target therapy may occur. One of the mutations that is still an on-going challenge in clinical and scientific field is the T315I mutation, since it gives patients a poor prognosis attributable to acquired resistance to therapy. In the following narrative review, we will discuss the current knowledge on the T315I mutation, explore the most suitable treatment options, examine the role of third-generation tyrosine kinase inhibitors, and outline potential future therapeutic strategies.

Keywords:  BCR::ABL1; CML mutation; CML therapy; T315I mutation; acquired resistance; chronic myeloid leukemia; prognosis

DOI:  https://doi.org/10.3390/ijms262311285
BMC Cancer. 2025 Dec 07.

Targeting Musashi-2 to counteract senescence and resistance in chronic myeloid leukemia: enhancing the efficacy of imatinib therapy.

Khadija Arif, Maryam Yousaf, Dilawar Khan.

   BACKGROUND: Chronic myeloid leukemia (CML) is a myeloproliferative malignancy marked through the excessive proliferative growth of functional myeloid cells. Approximately 95% of CML patients harbor the BCR-ABL fusion gene (Philadelphia chromosome), key driver of leukemogenesis. Despite therapeutic advancements with tyrosine kinase inhibitors (TKIs) such as imatinib, challenges including drug resistance, tumor cell senescence, and minimal residual disease (MRD) persist, primarily due to leukemic stem cells (LSCs) and senescent cells that evade TKI-mediated eradication. Musashi-2 (MSI2), an RNA-binding protein, is elevated in aggressive CML and is associated with poor disease prognosis. While its role in LSCs is emerging, its contribution to resistance and senescence remains unclear.
METHODS: This study investigated the role of MSI2 in proliferation and senescence by using pharmacological and biochemical approaches in imatinib sensitive (K562 S) and resistant (K562 R) models. Proliferation was assessed by MTT and colony formation assays. Apoptosis and expression analysis were performed using DNA fragmentation assay and Real time polymerase chain reaction (RT-PCR) respectively.
RESULTS: MSI2 was significantly overexpressed in both models (p = 0.0004 and p < 0.001). Pharmacological targeting of MSI2 reduced cell viability and colony formation in both sensitive (p < 0.001) and resistant (p < 0.001) cells. Combined therapy with imatinib and MSI2 inhibition had an additive effect on K562 S (p = 0.002) and a synergistic effect in K562 R (p = 0.0017). Mechanistically, MSI2 inhibition moderately induced apoptosis and significantly upregulated p53 (p = 0.004), indicating activation of apoptotic pathways. Notably, the levels of senescence-associated cell cycle regulators, p16, p21, and p27, were significantly decreased (p = 0.0025, 0.0052, and 0.0015, respectively), suggesting that growth suppression was not due to classical cell cycle arrest. MSI2 inhibition also disrupted Wnt/β-catenin signaling by downregulating Eya3 (p = 0.0008), c-Myc (p = 0.0128), and HIF-1α (p = 0.0050) expression. Imatinib monotherapy increased p16, p21, and p27 expression, indicating therapy-induced senescence (TIS). Subsequent MSI2 inhibition reduced the levels of these markers and IL-6, highlighting its role in regulating TIS at the transcriptional level.
CONCLUSION: In conclusion, MSI2 inhibition, in combination with TKI therapy, has shown to overcome drug resistance and mitigate senescence in preclinical CML models, and suggesting a potential strategy to target CML LSCs.

Keywords:  Apoptosis; Chronic myeloid leukemia; Imatinib resistance; Musashi-2; Senescence; Wnt Signaling

DOI:  https://doi.org/10.1186/s12885-025-15214-5
N Engl J Med. 2025 Dec 09.

Teclistamab plus Daratumumab in Relapsed or Refractory Multiple Myeloma.

MajesTEC-3 Trial Investigators

BACKGROUND: In a phase 1-2 trial, teclistamab, a bispecific antibody targeting CD3 on T-cell surfaces and B-cell maturation antigen on myeloma cells, showed durable responses in heavily pretreated patients with relapsed or refractory multiple myeloma. Daratumumab, a monoclonal antibody targeting CD38 protein, has shown survival benefit in patients with multiple myeloma.
METHODS: In this phase 3 trial, we randomly assigned patients with one to three previous lines of therapy to receive combination therapy with teclistamab-daratumumab or daratumumab combined with dexamethasone plus the investigator's choice of pomalidomide (DPd) or bortezomib (DVd) - the DPd or DVd group. The primary end point was progression-free survival, as assessed by an independent review committee.
RESULTS: A total of 587 patients underwent randomization (291 to receive teclistamab-daratumumab and 296 to receive DPd or DVd). At a median of 34.5 months, progression-free survival was significantly longer with teclistamab-daratumumab than with DPd or DVd. The estimated 36-month progression-free survival was 83.4% in the teclistamab-daratumumab group and 29.7% in the DPd or DVd group (hazard ratio, 0.17; 95% confidence interval, 0.12 to 0.23; P<0.001). More patients in the teclistamab-daratumumab group than in the DPd or DVd group had a complete response or better (81.8% vs. 32.1%), an overall response (89.0% vs. 75.3%), and minimal residual disease negativity (10-5; 58.4% vs. 17.1%) (P<0.001 for all comparisons). Serious adverse events occurred in 70.7% of the patients in the teclistamab-daratumumab group and in 62.4% of those in the DPd or DVd group; death from adverse events occurred in 7.1% and 5.9%, respectively.
CONCLUSIONS: In patients with multiple myeloma who had received one to three previous lines of therapy, those in the teclistamab-daratumumab group had significantly longer progression-free survival than those in the DPd or DVd group. (Funded by Johnson & Johnson; ClinicalTrials.gov number, NCT05083169.).

DOI: https://doi.org/10.1056/NEJMoa2514663
Blood Adv. 2025 Dec 11. pii: bloodadvances.2025018021. [Epub ahead of print]

Prognosis and patterns of progression in smoldering multiple myeloma.

Theresia Akhlaghi, Kylee H Maclachlan, Adriana Wiggins, Saad Z Usmani, Andriy Derkach, Malin L Hultcrantz.

DOI: https://doi.org/10.1182/bloodadvances.2025018021
N Engl J Med. 2025 Dec 07.

Dual Targeting of Extramedullary Myeloma with Talquetamab and Teclistamab.

RedirecTT-1 Investigators Study Group

BACKGROUND: Patients with plasmacytomas that are noncontiguous with bone marrow (true extramedullary myeloma) are at high risk for disease progression or relapse. Phase 1 of the RedirecTT-1 study showed promising efficacy with dual-antigen targeting of myeloma with talquetamab (anti-G protein-coupled receptor family C group 5 member D) plus teclistamab (anti-B-cell maturation antigen) in patients with triple-class-exposed relapsed or refractory multiple myeloma, including those with true extramedullary myeloma.
METHODS: In this phase 2 study, we investigated talquetamab plus teclistamab exclusively in patients with drug-resistant, true extramedullary myeloma. The primary end point was overall response, evaluated with the use of functional imaging. Secondary end points included the duration of response, progression-free survival, overall survival, and safety.
RESULTS: A total of 90 patients were enrolled in the study and received treatment (median follow-up, 12.6 months). A response occurred in 79% of the patients (95% confidence interval [CI], 69 to 87). Among the patients with a response, the percentage with a response duration of at least 12 months was 64% (95% CI, 48 to 76). At 12 months, progression-free survival was 61% (95% CI, 50 to 71), and overall survival was 74% (95% CI, 63 to 83). Common adverse events of any grade included oral symptoms, such as dysgeusia, dry mouth, and dysphagia (in 87% of the patients); cytokine release syndrome (in 78%); and nonrash skin effects (in 69%). Grade 3 or 4 adverse events (most commonly hematologic events) occurred in 76% of the patients; 31% had grade 3 or 4 infection. A nonfatal adverse event led to discontinuation of one or both agents in 6% of the patients. Among 10 deaths that occurred during follow-up, 5 were due to infection and 5 were considered to be related to the study treatment.
CONCLUSIONS: Most patients with drug-resistant, true extramedullary myeloma had a response with talquetamab plus teclistamab. The incidence of adverse events of grade 3 or above was high and was consistent with previous observations for each agent as monotherapy. (Funded by Johnson & Johnson; RedirecTT-1 ClinicalTrials.gov number, NCT04586426.).

DOI: https://doi.org/10.1056/NEJMoa2514752
Blood. 2025 Dec 11. 146(24): 2849-2850

Luminal hepcidin targets intestinal DMT1.

James F Collins.

DOI: https://doi.org/10.1182/blood.2025031293
Blood. 2025 Dec 11. 146(24): 2850-2851

Improving MM outcomes with bispecific antibody combinations.

Faith E Davies, Gareth J Morgan.

DOI: https://doi.org/10.1182/blood.2025031256
J Clin Oncol. 2025 Dec 07. JCO2502477

Pirtobrutinib Versus Ibrutinib in Treatment-Naïve and Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma.

Jennifer A Woyach, Lugui Qiu, Sebastian Grosicki, Tomasz Wrobel, Marcelo Capra, Jaroslaw Czyz, Shuhua Yi, Ki-Seong Eom, Anna Panovská, Wojciech Jurczak, Kamel Laribi, Lutz Jacobasch, Ross Baker, Richy Agajanian, Alejandro Berkovits, Muhit Özcan, Stéphane Lepretre, Catherine C Coombs, Paula Cramer, Katharine L Lewis, Marisa Hill, Katherine Bao, Yuanyuan Bian, Silvia Ramalho De Batista Ribeiro, Naleen Raj Bhandari, Amy S Ruppert, Ching Ching Leow, William G Wierda.

PURPOSE: Pirtobrutinib, a highly selective, noncovalent Bruton tyrosine kinase inhibitor (BTKi), has shown efficacy and safety in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who received prior covalent BTKi. We report results, to our knowledge, from the first randomized head-to-head comparison of pirtobrutinib versus ibrutinib in BTKi-naïve CLL/SLL in both treatment-naïve (TN) patients and patients with relapsed/refractory (R/R) disease.
PATIENTS AND METHODS: Patients (N = 662) were randomly assigned 1:1 to receive pirtobrutinib or ibrutinib. All patients were BTKi-naïve. Primary end points were overall response rate (ORR) by independent review committee (IRC) among all randomly assigned patients (intention to treat [ITT]) and in patients with R/R disease.
RESULTS: The study met its primary end points, demonstrating statistically significant noninferiority (NI) of IRC-ORR for pirtobrutinib versus ibrutinib in both the ITT (87.0% [95% CI, 82.9 to 90.4] v 78.5% [95% CI, 73.7 to 82.9]; ORR ratio = 1.11 [95% CI, 1.03 to 1.19]; two-sided P < .0001) and R/R populations (n = 437; 84.0% [95% CI, 78.5 to 88.6] v 74.8% [95% CI, 68.5 to 80.4]; ORR ratio = 1.12 [95% CI, 1.02 to 1.24]; two-sided P < .0001). In TN patients (n = 225), IRC-ORR was 92.9% (95% CI, 86.4 to 96.9) with pirtobrutinib versus 85.8% (95% CI, 78.0 to 91.7) with ibrutinib. Investigator assessed ORR results were consistent. Investigator-assessed progression-free survival (PFS) favored pirtobrutinib in the ITT (hazard ratio [HR], 0.57 [95% CI, 0.39 to 0.83]), R/R (HR, 0.73 [95% CI, 0.47 to 1.13]), and TN (HR, 0.24 [95% CI, 0.10 to 0.59]) populations. Cardiac adverse event rates of atrial fibrillation/flutter and hypertension were lower with pirtobrutinib.
CONCLUSION: Pirtobrutinib demonstrated NI of ORR versus ibrutinib, with a favorable early PFS trend, particularly in TN patients, and a favorable safety profile including low rates of atrial fibrillation and hypertension.

DOI: https://doi.org/10.1200/JCO-25-02477
Clin Lymphoma Myeloma Leuk. 2025 Nov 12. pii: S2152-2650(25)04283-1. [Epub ahead of print]

Linvoseltamab in Patients With Relapsed/Refractory Multiple Myeloma in the LINKER-MM1 Study: Longer Follow-Up and Subgroup Analyses.

Hans C Lee, Jeffrey A Zonder, Madhav V Dhodapkar, Sundar Jagannath, James E Hoffman, Attaya Suvannasankha, Mansi R Shah, Suzanne Lentzsch, Rachid Baz, Joseph J Maly, Swathi Namburi, Matthew J Pianko, Jing Christine Ye, Ka Lung Wu, Rebecca Silbermann, Chang-Ki Min, Marie-Christiane Vekemans, Markus Munder, Ja Min Byun, Joaquín Martínez-Lopez, Michelle DeVeaux, Tito Roccia, Dhruti Chokshi, Megan Seraphin, Kate Knorr, Anita Boyapati, Anasuya Hazra, Karen Rodriguez Lorenc, Glenn S Kroog, Naresh Bumma, Joshua Richter.

   BACKGROUND: Linvoseltamab, a BCMA × CD3 bispecific antibody, demonstrated durable efficacy and generally manageable safety in patients with relapsed/refractory multiple myeloma (RRMM) in the LINKER-MM1 study (NCT03761108).
METHODS: We conducted an updated analysis with a longer median follow-up of 21.3 months for 117 patients from LINKER-MM1 who received linvoseltamab 200 mg, including response data in high-risk subgroups.
RESULTS: As of July 23, 2024 (data cutoff), the objective response rate (ORR) was 71% (complete response or better [≥CR], 52%), with median duration of response of 29.4 months. Median progression-free survival was not reached, and median overall survival was 31.4 months. Minimal residual disease negativity (10-5 threshold) was achieved in 94% of evaluable patients with ≥CR. High response rates were observed across subgroups defined by baseline patient characteristics (age and race) and treatment history (eg, penta-refractory status). Response rates and survival outcomes were favorable in patients with markers of high disease burden (elevated % bone marrow plasma cells or soluble BCMA) or difficult-to-treat RRMM (including extramedullary plasmacytoma, International Staging System stage 3, and high-risk cytogenetic status); ORR was ≥50% in all subgroups assessed. The most common treatment-emergent adverse events were cytokine release syndrome (46%; Grade 3, 1%; most events occurred during step-up dosing) and neutropenia (44%; Grade ≥3, 43%). Infections were reported in 75% of patients (Grade ≥3, 48%), with the rate decreasing after 6 months of treatment.
CONCLUSIONS: Long-term treatment with linvoseltamab 200 mg provided deep and durable responses, with no new safety signals, and thus represents an effective therapeutic option in RRMM.

Keywords:  B-cell maturation antigen; Bispecific antibody; Clinical study; High-risk features; Long-term treatment

DOI:  https://doi.org/10.1016/j.clml.2025.11.004
Eur J Cancer. 2025 Dec 03. pii: S0959-8049(25)00956-6. [Epub ahead of print]232 116070

Large B-cell lymphoma: The LYSA pragmatic guidelines.

Pierre Sesques, Guillaume Manson, Sydney Dubois, Francois Xavier Gros, Gabriel Brisou, Clémentine Sarkozy, Sophie Bernard, Estelle Bourbon, Luc Matthieu Fornecker, Eric Durot, Laurent Martin, Catherine Chassagne-Clément, Francisco Llamas Gutierrez, Charlotte Syrykh, Marie-Hélène Delfau-Larue, Salim Kanoun, Laetitia Vercellino, Caroline Bodet-Milin, Haifa Bahri, Jules Zhang Yin, Arthur Dony, Laure Lebras, Marlène Ochmann, Marine Baron, Helène Monjanel, Ronan Le Calloch, Fabien Claves, Youlia Kirova, Christian Gisselbrecht, Stéphanie Guidez, Jean Baptiste Bossard, Roberta Di Blasi, Caroline Delette, Ludovic Fouillet, Maryem Rhomdani, Maya Belhadj, Gilles Crochet, Sandy Amorim, Firas Safa, Laurianne Drieu La Rochelle, Julie Abraham, Catherine Thieblemont, Fabrice Jardin, Robin Noel, Sébastien Bailly, Loic Renaud, Yann Guillermin, Baptiste Delapierre, Sylvain Choquet, Louise Roulin, Sylvain Lamure, Lionel Galicier, Yassine Al Tabaa, Carole Soussain, Romain Guièze, Roch Houot, Benoit Tessoulin.

  The management of large B-cell lymphomas (LBCL) has undergone major changes over the last 5 years. These changes reflect the availability of new therapies (immunotherapies, cell therapies, targeted molecules), but also a better compartmentalization of the entities and their specific clinical characteristics. Numerous first-, second- and third-line therapeutic strategies are available, and each practitioner is committed to selecting the treatment that offers the best balance between efficacy and toxicity. Advances in the understanding of LBCL biology, coupled with improvements in diagnostic and monitoring tools and therapeutic approaches, have significantly enhanced patient outcomes in recent years. In this article, we present a set of pragmatic guidelines developed by the LYSA (Lymphoma Study Association) for the management of LBCL. These guidelines address key aspects of diagnosis, staging, response evaluation, and treatment, integrating the latest evidence from clinical trials, expert consensus, and real-world practice. They aim to provide clinicians with a clear, practical framework to optimize care for patients with LBCL, ensuring that the best available evidence is translated into clinical practice.

Keywords:  Guidelines; LYSA; Large B-cell lymphoma; Level of evidence

DOI:  https://doi.org/10.1016/j.ejca.2025.116070
N Engl J Med. 2025 Dec 06.

Fixed-Duration versus Continuous Treatment for Chronic Lymphocytic Leukemia.

CLL17 Trial Investigators

BACKGROUND: Treatment of chronic lymphocytic leukemia (CLL) currently consists of two main approaches - continuous therapy with Bruton's tyrosine kinase inhibitors and fixed-duration regimens combining venetoclax with either CD20 antibodies or Bruton's tyrosine kinase inhibitors. Comparisons of these two therapeutic approaches are lacking.
METHODS: We conducted an investigator-initiated, phase 3, randomized trial involving patients with previously untreated CLL. Patients were randomly assigned to receive continuous ibrutinib or fixed-duration venetoclax-obinutuzumab or venetoclax-ibrutinib. The primary end point was investigator-assessed progression-free survival (noninferiority margin for the hazard ratio, 1.608, corresponding to a noninferiority margin of 8 percentage points at 3 years). Secondary end points included minimal residual disease (MRD), response, overall survival, and safety.
RESULTS: A total of 909 patients were assigned to venetoclax-obinutuzumab (303 patients), venetoclax-ibrutinib (305 patients), or ibrutinib (301 patients). The median follow-up was 34.2 months. In this prespecified interim analysis, 3-year progression-free survival was 81.1% in the venetoclax-obinutuzumab group, 79.4% in the venetoclax-ibrutinib group, and 81.0% in the ibrutinib group (hazard ratio for venetoclax-obinutuzumab vs. ibrutinib, 0.87 [98.3% confidence interval {CI}, 0.54 to 1.41]; hazard ratio for venetoclax-ibrutinib vs. ibrutinib, 0.84 [98.0% CI, 0.53 to 1.32]); the results for each comparison met the criterion for noninferiority. After the end of treatment, MRD in peripheral blood was undetectable in 73.3% of the patients in the venetoclax-obinutuzumab group, 47.2% in the venetoclax-ibrutinib group, and 0% in the ibrutinib group. Three-year overall survival was 91.5%, 96.0%, and 95.7%, respectively. The most common adverse events were infections, gastrointestinal disorders, and cytopenias.
CONCLUSIONS: In patients with previously untreated CLL, fixed-duration treatment with venetoclax-obinutuzumab or venetoclax-ibrutinib was noninferior to continuous ibrutinib with regard to investigator-assessed progression-free survival. (Funded by the University of Cologne and others; CLL17 ClinicalTrials.gov number, NCT04608318; EudraCT number, 2019-003854-99.).

DOI: https://doi.org/10.1056/NEJMoa2515458
Blood. 2025 Dec 11. 146(24): 2854-2855

Glu(tamine)ing together myeloma metabolism and CAR T efficacy.

Arun P Wiita.

DOI: https://doi.org/10.1182/blood.2025031096
Blood. 2025 Dec 11. 146(24): 2855-2857

Enhancing the targeting of the undruggable.

Benjamin G Barwick, Lawrence H Boise.

DOI: https://doi.org/10.1182/blood.2025031097
Eur J Haematol. 2025 Dec 09.

A Phase I Study of Combination Duvelisib and Nivolumab in Patients With Diffuse Large B-Cell Lymphoma, Transformed Follicular Lymphoma, and Richter Transformation.

Aseel Alsouqi, Ying Huang, Beth Christian, John Reneau, Seema A Bhat, Jonathan Brammer, Yazeed Sawalha, Robert A Baiocchi, Michael Grever, Kerry A Rogers, Julie Reeser, Amy Smith, Eric Samorodnitsky, Sameek Roychowdhury, Kami Maddocks, Jennifer A Woyach, David Bond.

DOI: https://doi.org/10.1111/ejh.70064
J Clin Oncol. 2025 Dec 10. JCO2500924

Venetoclax-Dexamethasone Versus Pomalidomide-Dexamethasone in t(11;14)-Positive Relapsed/Refractory Multiple Myeloma: Primary Results of the Randomized, Phase III CANOVA Study.

Rakesh Popat, Meral Beksac, Meletios A Dimopoulos, Moshe E Gatt, Francesca Gay, Jae-Cheol Jo, Prashant Kapoor, Eirini Katodritou, K Martin Kortüm, Silvia Ling, Chandramouli Nagarajan, Kenshi Suzuki, Lugui Qiu, Maika Onishi, Grace Ku, Monique Dail, Nabanita Mukherjee, Jeremy A Ross, Mohamed Ali Badawi, Mary Jean Fusco, Edyta Dobkowska, Emma Arriola, Orlando F Bueno, Nizar J Bahlis, Shinsuke Iida, Philippe Moreau, Jason Valent, María-Victoria Mateos.

PURPOSE: Venetoclax, an oral BCL-2 inhibitor, has efficacy in t(11;14)-positive relapsed/refractory multiple myeloma (RRMM), which is enhanced by dexamethasone, which promotes BCL-2 dependency.
METHODS: The randomized, open-label, phase III CANOVA study (ClinicalTrials.gov identifier: NCT03539744) enrolled adults with t(11;14)-positive RRMM who had received ≥2 previous lines of therapy. Patients were randomly assigned (1:1) to venetoclax-dexamethasone or pomalidomide-dexamethasone until progression or intolerable toxicity. The primary end point was independent review committee assessed-progression-free survival (PFS) in the intention-to-treat population analyzed by stratified log-rank test (two-sided type I error rate, α = .05), with hazard ratio (HR) and 95% CI estimated by stratified Cox proportional hazard model. Secondary end points included response rates, overall survival (OS), minimal residual disease (MRD) negativity rate (<10-5), and safety.
RESULTS: Overall, 263 patients were randomly assigned (venetoclax-dexamethasone, n = 133; pomalidomide-dexamethasone, n = 130). Median PFS was 9.9 months (95% CI, 6.9 to 12.6) with venetoclax-dexamethasone versus 5.8 months (95% CI, 3.8 to 9.2) with pomalidomide-dexamethasone (HR, 0.823 [95% CI, 0.596 to 1.136]; P = .24). Overall response and very good partial response or better rates were 62% and 39%, respectively, with venetoclax-dexamethasone versus 35% and 14% with pomalidomide-dexamethasone. MRD negativity rate was 8% with venetoclax-dexamethasone and 0% with pomalidomide-dexamethasone. Median OS was 32.4 months (95% CI, 26.4 to 40.7) with venetoclax-dexamethasone and 26.9 months (95% CI, 20.4 to 38.9) with pomalidomide-dexamethasone (HR, 0.856 [95% CI, 0.612 to 1.197]). Grade ≥3 treatment-emergent adverse event rates were 67% with venetoclax-dexamethasone versus 83% with pomalidomide-dexamethasone. There were 16 (12%) treatment-emergent deaths with venetoclax-dexamethasone versus 8 (6%) with pomalidomide-dexamethasone.
CONCLUSION: The primary end point of PFS was not met. PFS and OS were numerically longer with venetoclax-dexamethasone versus pomalidomide-dexamethasone in t(11;14)-positive RRMM. Consistent with previous studies, infections were associated with venetoclax-dexamethasone; no new safety signals were observed.

DOI: https://doi.org/10.1200/JCO-25-00924
Lancet. 2025 Dec 07. pii: S0140-6736(25)02360-8. [Epub ahead of print]

Epcoritamab, lenalidomide, and rituximab versus lenalidomide and rituximab for relapsed or refractory follicular lymphoma (EPCORE FL-1): a global, open-label, randomised, phase 3 trial.

EPCORE FL-1 Investigators

BACKGROUND: An unmet need persists for chemotherapy-free regimens that induce durable responses for relapsed or refractory follicular lymphoma. Lenalidomide and rituximab (R2) is an accepted standard of care in this population. The EPCORE FL-1 trial aimed to evaluate the efficacy and safety of epcoritamab plus R2 versus R2 in participants with relapsed or refractory follicular lymphoma after at least one previous line of chemoimmunotherapy.
METHODS: In this multicountry, open-label, phase 3 trial, participants were randomly allocated (1:1) to fixed-duration epcoritamab plus R2 or R2 for up to 12 cycles. Epcoritamab was administered weekly in cycles 1-3 and every 4 weeks in cycles 4-12, lenalidomide once daily during cycles 1-12 (days 1-21), and rituximab weekly during cycle 1 and monthly in cycles 2-5. The dual primary endpoints were overall response rate and progression-free survival by independent review committee. The data reported here are from a planned interim analysis carried out after 78% of progression-free survival events had occurred. This study is registered with ClinicalTrials.gov, NCT05409066, and EudraCT, 2021-000169-34, and is ongoing (closed to recruitment).
FINDINGS: Out of 668 participants screened for eligibility across 189 academic and non-academic centres in 30 countries across Africa, Asia, Australia, Europe, North America, and South America, a total of 488 participants were randomly allocated, 243 to epcoritamab plus R2 and 245 to R2. The trial met its dual primary endpoints, showing superiority of epcoritamab plus R2 over R2 in overall response rate and progression-free survival. With a median follow-up of 14·8 months (IQR 11·4-19·0), overall response rate was 95% (95% CI 92-97) with epcoritamab plus R2 versus 79% (74-84; p<0·0001) with R2. Progression-free survival was longer with epcoritamab plus R2 versus R2 (hazard ratio 0·21 [95% CI 0·14-0·31], p<0·0001); estimated 16-month progression-free survival favoured epcoritamab plus R2 (85·5% vs 40·2%). Grade 3 or higher adverse events were more frequent with epcoritamab plus R2 (219 [90%] of 243 participants) versus R2 (161 [68%] of 238 participants). Cytokine release syndrome was low grade with epcoritamab plus R2 (grade 1 in 28 [21%] participants and grade 2 in seven [5%] participants) and manageable, and all events were resolved.
INTERPRETATION: Epcoritamab plus R2 resulted in significantly higher response rate and longer progression-free survival versus R2 among participants with follicular lymphoma who had received at least one line of therapy. Epcoritamab plus R2 had more grade 3 or higher adverse events versus R2. Adverse events were manageable and consistent with the established safety profiles of the individual components, with no new safety findings identified. These findings position epcoritamab plus R2 as a new standard of care for second-line or subsequent treatment of follicular lymphoma.
FUNDING: AbbVie and Genmab.

DOI: https://doi.org/10.1016/S0140-6736(25)02360-8
Leuk Lymphoma. 2025 Dec 08. 1-23

Interferon alpha in myeloproliferative neoplasms: evidence and practical considerations for clinical care.

Megan Metzger, John Mascarenhas.

  Myeloproliferative neoplasms (MPNs) are a spectrum of clonal hematologic malignancies, characterized by an acquired somatic mutation in hematopoietic stem cells (HSC). Consequent constitutive activation of the JAK/STAT signaling pathway ultimately leads to HSC clonal expansion, a heightened inflammatory state, and aberrant trafficking of the malignant stem cells to sites of extramedullary hematopoiesis. While polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF) are distinct disease entities, each with their own diagnostic criteria, risk stratification, and molecular profiles, they share a common pathogenesis and exist on a spectrum, with overlapping clinical features, propensity for thrombohemorrhagic events, and risk for transformation to acute leukemia. Interferon alpha (IFN-α) has both anti-proliferative and immunomodulatory effects on MPN HSCs, and therefore is an effective treatment modality for PV, ET, and MF. In this review, we discuss the rationale for IFN-α use in MPNs, examine the evidence supporting its use, and convey practical considerations.

Keywords:  Interferon-alpha; essential thrombocythemia; myelofibrosis; myeloproliferative disorders; neoplasia; pegylated interferon alpha-2a; polycythemia vera

DOI:  https://doi.org/10.1080/10428194.2025.2594038
Lancet Haematol. 2025 Dec 08. pii: S2352-3026(25)00327-8. [Epub ahead of print]

Epcoritamab monotherapy for Richter transformation (EPCORE CLL-1): findings from a single-arm, multicentre, open-label, phase 1b/2 trial.

Arnon P Kater, Ann Janssens, Herbert Eradat, Fritz Offner, Jose D Sandoval-Sus, Mazyar Shadman, Christian Bjørn Poulsen, Jacob Haaber Christensen, Meghan C Thompson, Meijian Guan, Andrew J Steele, Marcia Rios, Marie Holst Mørch, Toshihiko Oki, Rebecca Valentin, Mar Bellido, Barbara Eichhorst.

BACKGROUND: Richter transformation is one of the most challenging B-cell lymphomas to treat, particularly in patients with high-risk chronic lymphocytic leukaemia features or who have had previous therapy for chronic lymphocytic leukaemia. Median survival remains 6-12 months across various therapeutic approaches. We evaluated the safety and preliminary activity of epcoritamab monotherapy, a subcutaneous CD3×CD20 bispecific antibody, in patients with Richter transformation.
METHODS: This multicentre, open-label, phase 1b/2 trial was conducted at 24 centres in nine countries (Australia, Belgium, Denmark, Germany, Israel, Italy, Spain, The Netherlands, and USA). Eligible patients were aged 18 years or older and had histologically confirmed Richter transformation (diffuse large B-cell lymphoma [DLBCL]), an Eastern Cooperative Oncology Group performance status of 0-2, and up to two previous lines of Richter transformation-directed therapy. The trial includes dose-escalation and dose-expansion phases. The expansion groups evaluate epcoritamab monotherapy (group 2A), epcoritamab plus lenalidomide (group 2B), and epcoritamab plus the combination of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP; group 2C). The current report describes results from group 2A. Epcoritamab was administered subcutaneously in step-up doses followed by 48 mg every week for cycles 1-3, every 2 weeks for cycles 4-9, and every 4 weeks thereafter until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed overall response rate per Lugano 2014 criteria in the full analysis set (all patients who received ≥1 dose of epcoritamab). It was evaluated against a null hypothesis of 30% versus an alternative of 50%. Prespecified subgroup analyses by line of therapy for Richter transformation and TP53 aberration and/or del(17p) status were performed. Safety was assessed in all treated patients. This trial is ongoing and registered with ClinicalTrials.gov, NCT04623541.
FINDINGS: Between Oct 18, 2021, and March 21, 2025, we enrolled 42 patients with Richter transformation. The median age was 69 years (range 50-80); and 32 (76%) of 42 patients were male and ten (24%) were female. Race or ethnicity data were available for 40 patients (37 [88%] identified as White, two [5%] as Asian, and one [2%] as Black or African American; ethnicity was not reported for two patients). The median time from diagnosis of chronic lymphocytic leukaemia or small lymphocytic lymphoma to Richter transformation was 7·6 years (range 0-23·9). 21 (50%) of 42 patients received epcoritamab as first-line Richter transformation-directed therapy. At a median follow-up of 22·9 months (range 0·5-39·9), 20 of 42 patients had a response with an investigator-assessed overall response rate of 47·6% (95% CI 32·0-63·6), which did not meet the prespecified alternative hypothesis (50%). Overall response occurred in 12 of 21 patients in the first-line population (overall response rate 57·1%, 34·0-78·2), in eight of 21 patients in the second-line or later-line population (38·1%, 18·1-61·6), and in eight of 20 patients with TP53 aberration and/or del(17p) alteration at baseline (40%, 19·1-63·9). The most common grade 3-4 adverse events were neutropenia in 19 (45%) of 42 patients, anaemia in 16 (38%) patients, thrombocytopenia in 16 (38%) patients, infection in nine (21%) patients, pneumonia in four (10%) patients, and COVID-19 in two (5%) patients. Cytokine release syndrome occurred in 36 (86%) patients with three (7%) being grade 3, immune effector cell-associated neurotoxicity syndrome in five (12%; all grade 1-2) patients and clinical tumour lysis syndrome in two (5%; all grade 1-2) patients. Three fatal adverse events were reported, one each due to general physical health deterioration in the context of progressive disease, sepsis, and cerebrovascular accident; none were considered by the investigator to be related to study treatment.
INTERPRETATION: In patients with Richter transformation, epcoritamab monotherapy showed clinically meaningful antitumour activity, although the investigator-assessed overall response rate was below the alternative hypothesis of 50%, with a safety profile consistent with previous studies. These findings support further investigation of epcoritamab as a potential treatment option for patients with Richter transformation.
FUNDING: Genmab A/S and AbbVie.

DOI: https://doi.org/10.1016/S2352-3026(25)00327-8
Expert Opin Biol Ther. 2025 Dec 12. 1-10

Bispecific antibody combination regimens for B-cell non-Hodgkin's lymphomas.

Khushali Jhaveri, Aditi Saha, Luis Miguel Juarez-Salcedo, Julio C Chavez.

   INTRODUCTION: Bispecific antibodies (BsAbs) are a novel class of immunotherapy agents that engage endogenous T cells to target and eradicate malignant B cells by simultaneously binding CD3 and CD20. BsAbs such as epcoritamab, glofitamab, and mosunetuzumab have demonstrated substantial efficacy across both aggressive and indolent B-cell non-Hodgkin lymphomas (B-NHL), with largely manageable safety profiles. Their off-the-shelf administration offers a practical alternative to CAR T-cell therapy, particularly for patients who are transplant-ineligible or lack access to cellular approaches.
AREAS COVERED: This review provides a comprehensive overview of BsAbs in B-NHL. We detail pivotal studies in relapsed/refractory (R/R) DLBCL, FL, and MCL, highlighting single-agent outcomes and emerging combination strategies. Approaches incorporating BsAbs into cytotoxic backbones and antibody-drug conjugates, as well as chemotherapy-free regimens such as BsAbs combined with lenalidomide, are discussed. We also examine their potential to address poor-risk disease features and historically refractory subsets.
EXPERT OPINION: BsAbs represent a major advance in B-NHL, offering high rates of deep remission with predictable safety and outpatient feasibility. As trial data continues to mature, BsAb-based regimens are poised to become foundational across multiple lines of therapy, reshaping expectations for patients with both aggressive and indolent lymphomas.

Keywords:  B-cell lymphoma; Bispecific antibody; T-cell engager therapy; cytokine release syndrome; immunotherapy

DOI:  https://doi.org/10.1080/14712598.2025.2597847
Blood Adv. 2025 Dec 10. pii: bloodadvances.2025018011. [Epub ahead of print]

Towards New Therapy Endpoints in Polycythemia Vera: Targeting Clonal and Inflammatory Pathways.

Tiziano Barbui, Joseph Michael Scandura.

Although phlebotomy and hydroxyurea (HU) are standard first-line therapies for polycythaemia vera (PV), they do not adequately address clonal expansion and chronic inflammation - key drivers of thrombosis, myelofibrosis and mortality. Biomarkers such as JAK2 V617F VAF and the neutrophil-to-lymphocyte ratio (NLR) are emerging as valuable tools for guiding therapy. Ropeginterferon alfa-2b has been shown to reduce both JAK2 VAF and NLR, improving event-free survival as demonstrated in the Low-PV and PROUD-PV/CONTINUATION-PV trials. In contrast, propensity score matching of the ECLAP trial showed that HU has limited effect on these biomarkers, suggesting weaker disease-modifying potential. Although no data on NLR dynamics with ruxolitinib have been published, the anti-inflammatory effects of ruxolitinib and its suppression of JAK2 VAF suggest it may exert similar biological activity. These findings support a shift towards biology-guided treatment in PV, recognising that inflammation and JAK2 VAF could serve as surrogate endpoints in future clinical trials.

DOI: https://doi.org/10.1182/bloodadvances.2025018011
Blood. 2025 Dec 11. 146(24): 2857-2859

Defusing AML: targeting t(8;21) forces myeloid maturation.

Esther A Obeng.

DOI: https://doi.org/10.1182/blood.2025031252
Blood Adv. 2025 Dec 12. pii: bloodadvances.2025017939. [Epub ahead of print]

Outcomes of Radiation Integrated with T-cell-engaging Bispecific Antibodies in Relapsed/Refractory Multiple Myeloma.

Heta Patel, Harper Hubbeling, Kyle L Yu, Maribel Carpenter, Michael J LaRiviere, John P Plastaras, Adam D Cohen, Shivani Kapur, Dan T Vogl, Adam J Waxman, Edward A Stadtmauer, Alfred L Garfall, Sandra Patricia Susanibar-Adaniya.

DOI: https://doi.org/10.1182/bloodadvances.2025017939
Blood Adv. 2025 Dec 09. pii: bloodadvances.2025018707. [Epub ahead of print]

Clarifying comparative evidence on epcoritamab.

Alexey V Danilov.

DOI: https://doi.org/10.1182/bloodadvances.2025018707
JCO Precis Oncol. 2025 Dec;9 e2500494

Clinical Outcomes of Adult Patients With Newly Diagnosed Mixed Phenotype Acute Leukemia.

Hannah Goulart, Farhad Ravandi, Nicholas J Short, Nitin Jain, Naval Daver, Tapan M Kadia, Courtney DiNardo, Gautam Borthakur, Koichi Takahashi, Naveen Pemmaraju, Fadi G Haddad, Guillermo Montalban Bravo, Yesid Alvarado, Ghayas C Issa, Alex Bataller, Sherry Pierce, Sanam Loghavi, Guilin Tang, Sa A Wang, Beenu Thakral, Elizabeth Shpall, Richard Champlin, Issa Khouri, Partow Kebriaei, Guillermo Garcia-Manero, Koji Sasaki, Elias J Jabbour, Jayastu Senapati.

PURPOSE: Mixed phenotype acute leukemia (MPAL) is a rare clinical entity with historically poor outcomes.
METHODS: We conducted a retrospective analysis of adults 18 years and older with newly diagnosed B-cell (B/M) or T-cell/myeloid (T/M) MPAL treated at our institution between 2017 and 2024.
RESULTS: We identified 42 patients (median age 70 years); 20 (48%) had B/M MPAL, and 22 (52%) had T/M MPAL; 57% of patients had adverse risk cytogenetics, and 41% had a TP53 mutation. Sixty-two percent of patients were treated with a hybrid regimen, and 45% of patients received intensive therapy. A composite complete remission (CRc; CR + CRi) was achieved in 57% of patients (86% measurable residual disease [MRD]-negative). After a median follow-up of 27.9 months, the median relapse-free survival in patients achieving an overall response (CRc + morphological leukemia-free state) was 10.1 months, 17.8 months in those who achieved a CRc, and not reached (NR) in patients with MRD-negative CRc. The median overall survival (OS) for all patients was 9.5 months and NR for patients achieving a CRc. Although patients with T/M MPAL had a trend toward improved survival compared with those with B/M MPAL (median OS of 9.1 v 25 months P = .28), this difference abrogated when comparison was stratified by treatment intensity. Twelve patients (29%) underwent allogeneic hematopoietic stem-cell transplantation (HSCT); on landmark analysis, HSCT trended to improve OS (NR v 22.8, P = .12). Multivariate Cox analysis demonstrated that TP53 mutation was associated with increased hazards for death (hazard ratio [HR], 3.5, P = .01), whereas the use of intensive chemotherapy trended to be favorable (HR, 0.45, P = .11).
CONCLUSION: Overall, these data demonstrate the need for treatment intensification in MPAL with HSCT in first remission for best outcomes.

DOI: https://doi.org/10.1200/PO-25-00494
J Clin Oncol. 2025 Dec 12. JCO2501712

Prospective Validation of Circulating Tumor DNA Measurable Residual Disease After First-Line Therapy in Large B-Cell Lymphoma.

Steven Wang, Marcel Nijland, Leonie Strobbe, Margriet Oosterveld, Rinske Boersma, Harry Koene, Clara Klerk, Eva de Jongh, Ad Koster, Hans Pruijt, Marjolein van der Poel, Erik van Werkhoven, Helma Zanders, Avinash Dinmohamed, Michiel Pegtel, Stephanie Meek, Sierra Love Stowell, Hayley Warinske, Ash A Alizadeh, David M Kurtz, Martine E D Chamuleau.

PURPOSE: End-of-treatment (EOT) response evaluation by positron emission tomography (PET) remains suboptimal in patients with large B-cell lymphoma (LBCL), because of its limited positive predictive value (PPV). Circulating tumor DNA (ctDNA)-based measurable residual disease (MRD) detection offers a minimally invasive approach and may improve prognostication. We prospectively evaluated EOT MRD using phased variant enrichment and detection sequencing (PhasED-Seq) in patients with first-line LBCL.
METHODS: Patients were enrolled in the HOVON-902 prospective cohort and received curative-intent first-line treatment. Phased variants (PVs) were identified and tracked using tumor biopsies or pretreatment plasma. The prognostic significance of EOT ctDNA-MRD status in progression-free survival (PFS) and overall survival (OS) was compared with that of the International Prognostic Index (IPI) and EOT PET-computed tomography (CT).
RESULTS: PV identification was successful in 134 of 136 (99%) using either tissue or plasma. At EOT, 83% of patients were MRD-negative and 17% of patients were MRD-positive. MRD positivity was strongly associated with inferior outcomes: the 3-year PFS was 17% in MRD-positive versus 85% in MRD-negative patients (hazard ratio [HR], 9.8 [95% CI, 5.1 to 19]; P = 9.63 × 10-12), and the OS was 43% versus 92%, respectively (HR, 7.7 [95% CI, 3.4 to 17.4]; P = 1.27 × 10-6). In multivariate analysis, MRD was an independent prognostic factor when controlling for IPI and EOT PET-CT. MRD positivity had a higher PPV for 2-year PFS than positive PET (68% v 56%, P ≤ .001), whereas negative predictive value was similar between negative MRD and PET (89% v 88%, P = .71). MRD positivity was associated with a significantly higher relapse risk within both complete metabolic response (CMR) and non-CMR subgroups.
CONCLUSION: This study validates ultrasensitive ctDNA-MRD detection using PhasED-Seq in a uniformly treated, prospective real-world LBCL cohort. These findings support further evaluation of MRD integration into clinical response assessment.

DOI: https://doi.org/10.1200/JCO-25-01712
Lancet. 2025 Dec 05. pii: S0140-6736(25)01965-8. [Epub ahead of print]

A new standard for relapsed or refractory follicular lymphoma.

Reut Harel, Jonathon B Cohen.

DOI: https://doi.org/10.1016/S0140-6736(25)01965-8
Intern Med. 2025 Dec 11.

Successes and Challenges of Bispecific T-cell Engager Antibodies in the Treatment of Multiple Myeloma.

Ichiro Hanamura, Sivasundaram Karnan, Akinobu Ota, Akiyoshi Takami.

  Recent advances in drug development have revolutionized the field of oncology, leading to the development of novel therapeutic strategies. Among them, bispecific antibodies (BsAbs) targeting CD3 and tumor antigens have shown significant efficacy in relapsed or refractory multiple myeloma (RRMM). In triple-class exposed RRMM, where the median survival is less than 2 years, BsAbs redirect T cells toward targets such as BCMA and GPRC5D, achieving response rates of approximately 60%-70% with durable efficacy, resulting in regulatory approvals. Adverse events, such as cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, and infections, are generally manageable. However, reduced efficacy in patients with high tumor burden, antigen loss, and T-cell exhaustion remains a challenge. Ongoing research is focused on optimizing dosing, combination strategies, and earlier use. BsAbs offer a promising therapeutic option with the potential to reshape treatment paradigms and improve long-term outcomes in multiple myeloma patients.

Keywords:  BCMA; FcRH5; GPRC5D; T-cell engager; bispecific antibody; multiple myeloma

DOI:  https://doi.org/10.2169/internalmedicine.6617-25
J Immunother Cancer. 2025 Dec 11. pii: e013283. [Epub ahead of print]13(12):

Harnessing the innate immune system: a novel bispecific antibody targeting CD47 and CD24 for selective tumor clearance.

Lidi Nan, Liandi Chen, Weifeng Huang, Shaogang Peng, Chao Wang, Huayuan Liao, Yifei Wang, Ziyue Cui, Yanqing Lv, Xiaomu Wang, Yi Luo, Andy Tsun, Xiaoniu Miao, Juan Zhang.

   BACKGROUND: Tumor-associated macrophages (TAMs) abundantly infiltrate tumors and possess potent antitumor capabilities. "Don't eat me" signals like CD47 allow tumors to evade macrophages and proliferate unchecked. CD47 is upregulated in many tumors and interacts with the SIRPα expressed on macrophages to restrict effector function. Similarly, CD24 interacts with the Siglec-10 on TAMs to inhibit engulfment. Despite their potential, there is still a lack of effective therapeutics targeting macrophages. Recent clinical trials targeting CD47 have demonstrated limited efficacy and significant side effects in solid tumors, primarily due to the expression of CD47 on healthy cells such as red blood cells (RBCs). We therefore developed novel anti-CD47 variable domain of heavy chain of heavy-chain antibodies (vHHs) with strong ligand-blocking activity while demonstrating minimal binding to RBCs and incorporated these vHHs to generate an anti-CD47/CD24 bispecific antibody that preserves Fc-effector function and achieves improved tumor targeting while maintaining the blockade of antiphagocytic signals elicited by both CD47 and CD24.
METHODS: Yeast display was employed to generate vHHs targeting CD47 and fully human monoclonal antibodies against CD24, respectively. The antigen binding epitopes of the vHHs to CD47 were predicted using AlphaFold3. Bispecific antibodies were designed, constructed, and characterized in vitro. Antitumor efficacy was evaluated in a human immune cell reconstitution mouse model, while safety was evaluated using a humanized syngeneic mouse model. Furthermore, the underlying mechanisms and alterations in tumor microenvironment were explored ex vivo.
RESULTS: VHHs targeting CD47 and a fully human antibody against CD24 were identified, all exhibiting potent ligand-blocking activity. The bispecific antibody BiAb-103C, engineered on a human IgG1 scaffold, had strong binding to CD47+CD24+ tumor cells and could effectively inhibit the CD47-SIRPα interaction. Fc-effector activity was observed towards CD24 (but not CD47) single-positive cells to promote phagocytosis and antibody-dependent cellular cytotoxicity of CD47+CD24+ tumor cells. In mice, antibody candidates demonstrated notable antitumor activity alongside favorable safety observations.
CONCLUSIONS: Our study presents the discovery of an anti-CD47/CD24 bispecific antibody that offers a promising therapeutic strategy to address the challenges associated with both the efficacy and safety of CD47-targeting agents, offers insight into macrophage-driven cancer immunotherapy, and could potentially provide a therapeutic option for patients non-responsive to immunotherapy.

Keywords:  Antibody; Immune Checkpoint Inhibitor; Immunotherapy; Macrophage

DOI:  https://doi.org/10.1136/jitc-2025-013283
Lancet. 2025 Dec 05. pii: S0140-6736(25)01778-7. [Epub ahead of print]

Tafasitamab, lenalidomide, and rituximab in relapsed or refractory follicular lymphoma (inMIND): a global, phase 3, randomised controlled trial.

inMIND Study team

BACKGROUND: Follicular lymphoma is characterised by episodes of remission and relapse, with patients requiring multiple lines of therapy. Lenalidomide plus rituximab is a commonly used immunotherapy combination in patients with relapsed or refractory follicular lymphoma. We aimed to assess the efficacy and safety of adding tafasitamab, a CD19-targeted Fc-enhanced monoclonal antibody, to lenalidomide and rituximab in this setting.
METHODS: This phase 3, double-blind, randomised, placebo-controlled trial (inMIND) was done in 210 centres (including community-based haematology clinics, major hospitals, and academic institutions) in North America, Europe, and the Asia-Pacific region. Adults with relapsed or refractory follicular lymphoma, who had received at least one previous line of systemic therapy, were eligible for enrolment and randomly assigned (1:1) to receive treatment with up to 12 cycles (28-day cycle length) of tafasitamab (12 mg/kg by intravenous infusion on days 1, 8, 15, and 22 of cycles 1-3 and days 1 and 15 of cycles 4-12) or placebo, both with lenalidomide (20 mg/day orally on days 1-21 of cycles 1-12) and rituximab (375 mg/m2 by intravenous infusion on days 1, 8, 15, and 22 of cycle 1 and day 1 of cycles 2-5). Treatment assignment was achieved via an interactive voice or web response system; patients, investigators, and the funder were masked until the primary analysis. Study endpoints were investigator assessed unless otherwise specified. The primary endpoint was progression-free survival in the intention-to-treat population of all randomised patients; safety was assessed in all randomised patients who received at least one dose of study drug. The trial is registered with ClinicalTrials.gov (NCT04680052) and EUDRA-CT (2020-004407-13) and is active but no longer enrolling.
FINDINGS: Between April 16, 2021, and Aug 10, 2023, a total of 817 patients were assessed for eligibility; 548 patients with relapsed or refractory follicular lymphoma were enrolled and randomly assigned to treatment with either tafasitamab (n=273) or placebo (n=275). 299 (55%) of all randomised patients were male and 249 (45%) were female. The addition of tafasitamab to lenalidomide and rituximab resulted in significantly lower risk of progression, relapse, or death versus placebo (median progression-free survival by investigator 22·4 months [95% CI 19·2 to not evaluable] in the tafasitamab group vs 13·9 months [11·5-16·4] in the placebo group; hazard ratio 0·43 [95% CI 0·32-0·58]; p<0·0001) in the planned primary analysis. Improvement in progression-free survival was confirmed by independent review committee. Adverse events were reported in 272 (99%) of 274 patients in the tafasitamab group and 270 (99%) of 272 patients in the placebo group. Most common adverse events occurring in either the tafasitamab group or placebo group were neutropenia (133 [49%] vs 123 [45%]) and diarrhoea (103 [38%] vs 77 [28%]). There were no deaths due to treatment-related adverse events in the tafasitamab group; two (1%) patients had fatal adverse events related to treatment in the placebo group.
INTERPRETATION: The addition of tafasitamab to lenalidomide and rituximab resulted in a statistically significant and clinically meaningful improvement in progression-free survival, with an acceptable safety profile in patients with relapsed or refractory follicular lymphoma. This combination represents a potential new standard-of-care treatment.
FUNDING: Incyte.

DOI: https://doi.org/10.1016/S0140-6736(25)01778-7
Case Rep Oncol Med. 2025 ;2025 3286507

Relapsed Classical Hodgkin Lymphoma in Pregnancy in Two Patients Managed With a Multidisciplinary Approach.

Minhal Zaidi, Amna Naqvi, Jacqueline Rios, Meera Khosla, Hala Hassanain, Noah Giese, Ethan A Burns, Hanh Mai, Carrie Yuen, Shilpan Shah, Siddhartha Ganguly, Sai Ravi Pingali.

Relapsed or refractory (r/r) classical Hodgkin lymphoma (cHL) during pregnancy is rare, and management is often complex. The following two cases of r/r cHL during pregnancy highlight management considerations and outcomes in this unique patient population. The first patient with Stage IIIB cHL achieved a complete response (CR) with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) prior to pregnancy but relapsed at 10 weeks of gestation. She was maintained with methylprednisolone and vinblastine with no complications until she underwent cesarean section at 34 weeks. The second patient, diagnosed with Stage IIIb cHL, achieved CR after five cycles of ABVD and one cycle of AVD. She began consolidation radiation but halted treatment after two cycles upon discovering an intrauterine twin pregnancy. At 10 weeks of gestation, she experienced a relapse of her disease. The patient received one cycle of vinblastine and methylprednisolone weekly. At 31 weeks, the patient underwent an elective cesarean section. After delivery, both patients underwent ICE (ifosfamide, carboplatin, and etoposide), followed by consolidation with autologous hematopoietic cell transplantation (auto-HCT). These cases highlight the balance needed to maintain control of disease to allow a safe and uneventful pregnancy.

DOI: https://doi.org/10.1155/crom/3286507
Ann Biol Clin (Paris). 2025 Dec 09. 83(6): 0

Plasma cell extravaganza: anaplastic variant.

Radu Chiriac.



Keywords:  anaplastic plasma cells; cytological atypia; multiple myeloma; t(4;14)

DOI:  https://doi.org/10.1684/abc.2025.2010
Drugs. 2025 Dec 08.

Rilzabrutinib: First Approval.

Arnold Lee.

Rilzabrutinib (WAYRILZ™) is a small-molecule, reversible, highly specific, covalent BTK inhibitor being developed by Sanofi for the treatment of multiple immune-related and inflammatory disorders, including immune thrombocytopenia, warm autoimmune haemolytic anaemia, sickle cell disease, IgG4-related disease, asthma, chronic spontaneous urticaria, among others. As a BTK inhibitor, rilzabrutinib demonstrates multiple immunomodulatory effects, including reduced B cell activation and autoantibody production, inhibition of macrophage activity, and anti-inflammatory effects. In clinical trials, rilzabrutinib was associated with durable platelet responses in patients with previously treated immune thrombocytopenia. This article summarizes the milestones in the development of rilzabrutinib leading to its first approval for the treatment of adults with persistent or chronic immune thrombocytopenia who have had an insufficient response to previous treatment.

DOI: https://doi.org/10.1007/s40265-025-02259-w
S Afr Med J. 2025 Feb 28. 115(2): e2191

Response and remission after first-line corticosteroid therapy in primary immune thrombocytopenia.

D Mapimhidze, J Bailly, K Brown, J Bailey, E Verburgh.

BACKGROUND: Primary immune thrombocytopenia (ITP) is an acquired autoimmune disease characterised by an isolated thrombocytopenia of <100 × 109/L in the absence of identifiable secondary causes. Treatment is indicated when the platelet count is <20 - 30 × 109/L, but may be commenced at higher platelet counts when the risk of bleeding is high. Corticosteroids are the backbone of initial treatment of ITP. There is a paucity of data in South Africa (SA) on the outcomes of newly diagnosed ITP patients treated with corticosteroids.
OBJECTIVES: To describe the response, remission and clinical outcomes of newly diagnosed primary ITP patients on first-line corticosteroids.
METHODS: This was a retrospective cohort study of 68 patients with a new diagnosis of ITP, seen at the Clinical Haematology Unit at Groote Schuur Hospital, Cape Town, SA, over a 5-year period (2016 - 2020). Demographic and clinical data were obtained from paper and electronic record systems. All participants with secondary causes were excluded. The initial platelet responses to corticosteroids and the final outcomes at last follow-up were determined. Initial platelet responses were classified into no response (NR), partial response (PR) and complete response (CR) in accordance with consensus definitions. Remission was defined as maintenance of a CR after being off corticosteroids for ≤6 months. Categorical variables were described by frequencies and percentages, while numerical variables were described by medians and interquartile ranges (IQRs) as data were non-parametric.
RESULTS: The majority of patients were female (88.2%) and the median (IQR) age at diagnosis was 36 (23.0 - 55.5) years. The female to male ratio was 7.5:1. Most (92.4%) patients responded to corticosteroids, with 74.2% achieving a CR and 18.2% achieving a PR. Only five patients failed to respond (7.6%). The median (IQR) time to achieve CR was 15 (8 - 25) days, and the median (IQR) time to achieve PR was 10.5 (8 - 22) days. Half of the patients went into remission. Following remission, two patients (6.1%) subsequently relapsed at day 344 and day 777, respectively. Hypertension and/or diabetes mellitus were newly diagnosed in 10.6% of patients.
CONCLUSION: Corticosteroids are effective first-line therapy for ITP, but are not remission-inducing in all patients. For those patients progressing to chronic ITP, there is a need to investigate cost-effective treatment. Some patients are at high risk of developing new hypertension and diabetes mellitus on corticosteroids, and should be monitored.

DOI: https://doi.org/10.7196/SAMJ.2025.v115i2.2191