bims-hemali 2025-09-14 papers

bims-hemali

Biomed News

on Hematologic malignancies

Issue of 2025–09–14
sixteen papers selected by
Alexandros Alexandropoulos, Γενικό Νοσοκομείο Αθηνών Λαϊκό

Fixed-Duration Epcoritamab Plus R2 Drives Favorable Outcomes in Relapsed or Refractory Follicular Lymphoma.
Meta-analysis evaluating the efficacy and safety of various Bruton tyrosine kinase (BTK) inhibitors for central nervous system lymphoma: Novel covalent BTK inhibitors, except for ibrutinib, also demonstrate good efficacy in the treatment of primary central nervous system lymphoma.
Treatment with asciminib after a prior tyrosine kinase inhibitor in patients with chronic-phase chronic myeloid leukemia.
How I treat Ph+ acute lymphoblastic leukemia.
Bruton Tyrosine Kinase Inhibitors in Mantle Cell Lymphoma: What Are the Current Options?
Indirect Comparisons of the Efficacy and Safety of Zanubrutinib versus Venetoclax plus Obinutuzumab in Treatment-Naïve Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma.
ClpP: a new Achilles' heel in myeloma.
Zanubrutinib in the treatment of Waldenström Macroglobulinemia.
Good flatmates: immature neutrophils protect bone integrity.
Novel small-molecule therapies for myelodysplastic syndromes with IPSS-R ⩾3.5 in patients aged 60 or older: current landscape and challenges.
Minimal residual disease measurement in blood by mass spectrometry identifies long-term responders in multiple myeloma.
Synergistic MDM2-STAT3 Inhibition Demonstrates Strong Anti-Leukemic Efficacy in Acute Lymphoblastic Leukemia.
Clinical applications of mass spectrometry in multiple myeloma.
A phase 1 study of IO-202, an anti-LILRB4 antibody, in chronic myelomonocytic leukemia and acute myeloid leukemia.
Clinical Outcomes and Safety of Ultra-Low-Dose Radiotherapy for Ocular Adnexal Lymphoma: A Systematic Review.
European Myeloma Network Consensus Statement on Functional High-Risk Multiple Myeloma.

Blood. 2025 Sep 08. pii: blood.2025029909. [Epub ahead of print]

Fixed-Duration Epcoritamab Plus R2 Drives Favorable Outcomes in Relapsed or Refractory Follicular Lymphoma.

Lorenzo Falchi, Anna Sureda, Sirpa Leppä, Joost Sp Vermaat, Marcel Nijland, Jacob Haaber Christensen, Sven de Vos, Harald Holte, Reid W Merryman, Pieternella J Lugtenburg, Pau Abrisqueta, Kim Linton, Gauri Sunkersett, Daniela Hoehn, Ali Rana, Aqeel Abbas, Jennifer Marek, Yi Hao, Andrew J Steele, Christopher Morehouse, Martin Hutchings, David Belada.

Epcoritamab is a subcutaneous CD3xCD20 bispecific antibody approved as monotherapy for relapsed/refractory (R/R) follicular lymphoma (FL). We evaluated fixed-duration epcoritamab with rituximab plus lenalidomide (R2) in R/R FL in arm 2 of EPCORE® NHL-2 (phase 1b/2; NCT04663347). Patients received epcoritamab (2 step-up doses, then 48-mg full doses) for up to 2 years and R2 for up to 12 cycles (28 days/cycle). Primary endpoint was overall response rate (ORR) per investigator assessment (Lugano criteria). As of September 21, 2024, 108 patients received ≥1 epcoritamab dose in expansion (median follow-up, 28.2 months). Median age was 65 years; 57% had 1 prior line of therapy. ORR and complete response (CR) rate were 96% and 88%; CR rates in patients with high-risk features were 90% (primary refractory), 82% (refractory to anti-CD20 and an alkylating agent), and 83% (disease progression within 24 months of first-line therapy). Two-year estimates for remaining in CR, progression-free survival, overall survival, and not starting next antilymphoma therapy were 82%, 76%, 90%, and 84%, respectively. Minimal residual disease negativity was observed in 86% of evaluable patients (clonoSEQ® assay). Common treatment-emergent adverse events (TEAEs) included neutropenia (65%), COVID-19 (59%), and cytokine release syndrome (CRS; 51%). Grade (G) ≥3 TEAEs occurred in 87% of patients; 5 had G5 TEAEs (all COVID-19). CRS events were mostly low grade (38% G1, 11% G2, 2% G3), all resolved, and none led to epcoritamab discontinuation. Fixed-duration epcoritamab plus R2 demonstrated deep, durable responses with manageable safety and favorable outcomes in R/R FL, irrespective of risk features.

DOI: https://doi.org/10.1182/blood.2025029909
Cancer. 2025 Sep 15. 131(18): e70083

Meta-analysis evaluating the efficacy and safety of various Bruton tyrosine kinase (BTK) inhibitors for central nervous system lymphoma: Novel covalent BTK inhibitors, except for ibrutinib, also demonstrate good efficacy in the treatment of primary central nervous system lymphoma.

Shuai Tan, Huizhen He, Jing Ni, Yixian Guo, Huanyuan Wang, Zehao Cai, Mingyue Shang, Yaofang Cao, Yumeng Li, Yaochi Chen, Hong Zhao, Li Su, Ronghua Hu, Xiaoli Chang, Wanling Sun.

   BACKGROUND: Central nervous system lymphoma (CNSL) is aggressive, and treatment with Bruton tyrosine kinase (BTK) inhibitors (BTKis) plays a key role. For this systematic review and meta-analysis, the authors evaluated BTKis for the treatment of primary CNSL (PCNSL) and secondary CNSL (SCNSL).
METHODS: By May 1, 2025, the authors conducted a systematic search of databases, including PubMed, EMBASE, etc. Included studies were those that investigated BTKi-treated CNSL and analyzed the overall response rate (ORR) as well as the complete response (CR) and partial response (PR) rates using systematic review and meta-analysis software.
RESULTS: Forty studies (935 patients) were included in the meta-analysis. The pooled ORR and CR and PR rates were 73%, 49%, and 28%, respectively. The pooled ORR and CR rates for BTKi monotherapy were 60% and 34%, respectively; whereas the rates for BTKi plus chemotherapy or immunochemotherapy were 79% and 55%, respectively. For PCNSL, the pooled ORR and PR rates were 73% and 49%, respectively. For SCNSL, the pooled ORR and CR rates reached 75% and 53%, respectively. Among patients with PCNSL, zanubrutinib achieved pooled ORR and CR rates of 85% and 54%, respectively. Ibrutinib had pooled ORR and CR rates of 67% and 46%, respectively; whereas orelabrutinib demonstrated pooled ORR and CR rates of 70% and 59%, respectively. For SCNSL, zanubrutinib achieved pooled ORR and CR rates of 77% and 62%, respectively; whereas ibrutinib achieved rates of 72% and 54%, respectively. Hematologic toxicities and transaminase increases were grade 3-5 toxicities according to common toxicity criteria.
CONCLUSIONS: The combination of BTKis with traditional chemotherapy or immunochemotherapy offers superior response rates compared with BTKis alone, and the safety profile is acceptable. Efficacy varies by BTKi type and should be selected based on patient condition. Specifically, for PCNSL, the response rates of zanubrutinib and obinutuzumab are better; for SCNSL, there is a minimal difference in efficacy among the various BTKis; and, overall, regardless of whether it is PCNSL or SCNSL, the off-target effects and side effects of covalent BTKis (zanubrutinib, obinutuzumab), except for ibrutinib, have improved.

Keywords:  Bruton tyrosine kinase inhibitor (BTKi); central nervous system lymphoma (CNSL); meta‐analysis; primary central nervous system lymphoma (PCNSL); secondary central nervous system lymphoma (SCNSL)

DOI:  https://doi.org/10.1002/cncr.70083
Leuk Res. 2025 Sep 05. pii: S0145-2126(25)00579-X. [Epub ahead of print] 108089

Treatment with asciminib after a prior tyrosine kinase inhibitor in patients with chronic-phase chronic myeloid leukemia.

Ehab L Atallah, Islam Sadek, David Wei, Dominick Latremouille-Viau, Carmine Rossi, Andrea Damon, Daisy Yang, Remi Bellefleur, Annie Guérin, Kejal Jadhav.

   BACKGROUND: In chronic-phase chronic myeloid leukemia (CML-CP), switching tyrosine kinase inhibitor (TKI) therapy due to intolerance or resistance is common. While asciminib, an ABL/BCR::ABL1 TKI targeting the ABL myristoyl pocket, offers improved tolerability and efficacy, there is limited real-world effectiveness data, particularly among patients with treatment with one prior TKI.
PATIENTS AND METHODS: A retrospective, US physician panel-based chart review study was conducted on adult patients with CML-CP without T315I treated with asciminib after one prior TKI. Time-on-treatment, and time-to achieving or maintaining MR2 (BCR::ABL1 ≤ 1 %), MMR (BCR::ABL1 ≤ 0.1 %) and DMR (BCR::ABL1 ≤ 0.01 %) were assessed using Kaplan-Meier analyses. Subgroup analyses were performed among patients with first TKI discontinuation due to intolerance or resistance, and by first- or second-generation TKI as first TKI.
RESULTS: Overall, 255 patients (median age 62 years, 56.5 % male) were included. Imatinib (49.8 %), dasatinib (34.5 %), nilotinib (10.6 %), and bosutinib (5.1 %) were received as first TKI. Intolerance and resistance to first TKIs were reported for 43.5 % and 23.5 % of patients, respectively. At 48-weeks post-asciminib initiation, 95.0 % of patients (95 % CI: 91.3 %, 97.1 %) remained on asciminib, 84.0 % (95 % CI: 78.6 %, 88.6 %) achieved or maintained MR2, 68.3 % (95 % CI: 61.8 %, 74.5 %) MMR, and 40.6 % (95 % CI: 34.2 %, 47.8 %) DMR.
CONCLUSIONS: Overall, most patients remained on treatment and achieved or maintained MMR, suggesting that asciminib was well-tolerated and effective. Results were consistent among subgroups, indicating that asciminib is an effective option for patients regardless of prior TKI used, and including those intolerant or resistant to their first TKI.
MICRO-ABSTRACT: There is limited real-world data regarding the effectiveness of asciminib after one prior tyrosine kinase inhibitor (TKI) in chronic-phase chronic myeloid leukemia (CML-CP). In this US physician panel-based chart review, nearly all patients (95 %) remained on asciminib and 68 % achieved or maintained a major molecular response at 48 weeks, suggesting that asciminib is well-tolerated and effective after one prior TKI.

Keywords:  BCR::ABL1; Hematological malignancies; Molecular response; Real-world evidence

DOI:  https://doi.org/10.1016/j.leukres.2025.108089
Future Oncol. 2025 Sep 07. 1-11

How I treat Ph+ acute lymphoblastic leukemia.

Melanie Castro-Mollo, Daniel J DeAngelo, Marlise R Luskin.

  Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) is characterized by the BCR:ABL1 fusion gene which produces a constitutively active tyrosine kinase which drives disease pathogenesis and is associated with resistance to conventional chemotherapy. Intensive cytotoxic chemotherapy followed by allogeneic hematopoietic stem cell transplantation (HSCT), the historical treatment paradigm for Ph+ ALL, was associated with poor outcomes. The introduction of inhibitors of ABL1 revolutionized the treatment of Ph+ ALL. Imatinib, the first BCR:ABL1 tyrosine kinase inhibitor (TKI), significantly improved survival, and was followed by more potent TKIs (dasatinib, nilotinib, and ponatinib) with activity also against resistance mutations. The introduction of blinatumomab, a CD19-CD3 bispecific T-cell engager, has further transformed the treatment of Ph+ ALL, allowing some patients to be treated without cytotoxic chemotherapy and/or HSCT. Still, HSCT remains an essential treatment option for select high-risk cases. Ongoing investigation focuses on more accurately identifying clinical and genetic features which predict for systemic or central nervous system relapse and determining the most effective approach to successfully risk-adapt therapy, including appropriate allocation to HSCT. This review highlights recent advances in treatment, emphasizing the importance of TKIs, the emerging role of immunotherapy, and the evolving position of HSCT in the management of Ph+ ALL.

Keywords:  Hematologic/leukemia; chemotherapy; clinical trials; novel therapy; transplantation

DOI:  https://doi.org/10.1080/14796694.2025.2556647
Eur J Haematol. 2025 Sep 13.

Bruton Tyrosine Kinase Inhibitors in Mantle Cell Lymphoma: What Are the Current Options?

Santino Caserta, Enrica Antonia Martino, Ernesto Vigna, Antonella Bruzzese, Nicola Amodio, Eugenio Lucia, Virginia Olivito, Caterina Labanca, Francesco Mendicino, Fortunato Morabito, Massimo Gentile.

  Mantle Cell Lymphoma (MCL) is an aggressive B-cell non-Hodgkin lymphoma characterized by the hallmark t(11;14)(q13;q32) translocation, resulting in cyclin D1 overexpression. Predominantly affecting elderly males, MCL exhibits marked clinical and biological heterogeneity, ranging from indolent SOX11-negative variants to highly proliferative blastoid variants. Despite initial responsiveness to chemoimmunotherapy, relapse is frequent, and median overall survival remains limited. Aberrant B-cell receptor (BCR) signaling-mediated by kinases including Bruton's tyrosine kinase (BTK)-plays a central role in MCL pathogenesis. BTK inhibitors (BTKis) such as ibrutinib (as monotherapy or combined with R-CHOP/R-DHAP), acalabrutinib (with rituximab and bendamustine), and pirtobrutinib have significantly improved outcomes of relapsed/refractory disease. However, their efficacy is challenged by resistance mutations (e.g., BTK C481S) and off-target toxicities. Next-generation reversible BTKis represent an important advance, offering activity in the setting of resistance and improved tolerability. Resistance is further sustained by the tumor microenvironment through stromal support and immunosuppressive cellular interactions. Consequently, combination strategies incorporating BTKis with BCL-2 inhibitors, monoclonal antibodies, and cellular therapies are being investigated to enhance response depth and durability. In parallel, biomarker-driven approaches and precision-medicine strategies are emerging to personalize disease monitoring and treatment selection. Collectively, these developments underscore the evolving role of BTK inhibition within broader immune-based and targeted treatment paradigms in MCL.

Keywords:  BTKi; MCL; therapy

DOI:  https://doi.org/10.1111/ejh.70036
Oncol Ther. 2025 Sep 13.

Indirect Comparisons of the Efficacy and Safety of Zanubrutinib versus Venetoclax plus Obinutuzumab in Treatment-Naïve Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma.

Talha Munir, Nicolás Martinez-Calle, Sheng Xu, Keri Yang, Xiaoyun Ge, Ayad K Ali, Leyla Mohseninejad, Balázs Dobi, Pal Rakonczai, Han Ma, Rhys Williams, Wassim Aldairy, Nicole Lamanna.

   INTRODUCTION: Compared with chemoimmunotherapy, both zanubrutinib monotherapy and venetoclax plus obinutuzumab prolong progression-free survival (PFS) in patients with chronic lymphocytic leukemia (CLL). Matching-adjusted indirect comparison (MAIC) can be used to compare the efficacy and safety of different treatment regimens when no head-to-head trial has compared the treatments.
METHODS: Patient matching was conducted using unanchored MAIC propensity-score weighting to compare PFS, overall survival (OS), tolerability, and adverse events (AEs) of interest (AEIs; grade 3-4 infections, neutropenia, febrile neutropenia, and/or thrombocytopenia and AEs leading to treatment discontinuation) on the basis of data from patients in SEQUOIA for zanubrutinib and aggregate data from CLL14 for venetoclax plus obinutuzumab. Because SEQUOIA occurred during the pandemic, analyses were also conducted to adjust for coronavirus disease 2019 (COVID-19) infections.
RESULTS: After matching and adjustment, baseline characteristics of the zanubrutinib group in SEQUOIA were well balanced with the CLL14 population (N = 216), with an effective sample size of 163 for the zanubrutinib group. After matching for baseline characteristics, zanubrutinib demonstrated a robust PFS benefit compared with venetoclax plus obinutuzumab (hazard ratio, 0.66 [95% confidence interval, 0.44-0.97]; P = 0.0351) and higher PFS probability at landmark points (60-month landmarks of 73.9% versus 63%, respectively). OS trended in favor of zanubrutinib. Overall, AEs of any grade over time were comparable in the zanubrutinib safety and venetoclax plus obinutuzumab populations. Zanubrutinib was associated with lower rates of selected AEIs compared with venetoclax plus obinutuzumab at all time points, except for grade 3-4 infections after 156 weeks. After adjusting for COVID-19, zanubrutinib was associated with a significantly lower incidence of grade 3-4 infections at 104 weeks but similar incidences of grade 3-4 infections versus venetoclax plus obinutuzumab during the overall follow-up period.
CONCLUSIONS: Continuous treatment with zanubrutinib in treatment-naïve patients with CLL/small lymphocytic lymphoma resulted in prolonged PFS and a favorable safety profile compared with fixed-duration venetoclax plus obinutuzumab.
TRIAL REGISTRATION NO: SEQUOIA (NCT03336333); CLL14 (NCT02242942).

Keywords:  Bruton tyrosine kinase (BTK) inhibitor; Matching-adjusted indirect comparison (MAIC); Obinutuzumab; Treatment-naïve chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL); Venetoclax; Zanubrutinib

DOI:  https://doi.org/10.1007/s40487-025-00380-0
Blood. 2025 Sep 11. 146(11): 1254-1255

ClpP: a new Achilles' heel in myeloma.

Antonio Sacco, Aldo M Roccaro.

DOI: https://doi.org/10.1182/blood.2025029682
Future Oncol. 2025 Sep 11. 1-9

Zanubrutinib in the treatment of Waldenström Macroglobulinemia.

Elizabeth Goodall, Stephen Opat.

  Waldenström Macroglobulinemia (WM) is an uncommon malignancy of IgM-secreting lymphoplasmacytic cells. The spectrum of acquired somatic mutations is heterogeneous, with MYD88 mutations occurring in more than 90%. Recurrent mutations in CXCR4, KMT2D, ARID1A, TERT, and TP53 are also detected, with some of these impacting prognosis or treatment response. The recognition of B-cell receptor (BCR) signalling in B-cell neoplasm pathophysiology led to the clinical development of the first-in-class Bruton tyrosine kinase inhibitor (BTKi) ibrutinib. Despite efficacy, off-target inhibition of TEC, EGFR, CSK and other kinases impact its safety and tolerability. The second-generation BTKi, zanubrutinib and acalabrutinib, are better tolerated with lower rates of discontinuation. Zanubrutinib is more selective for BTK than other structurally related kinases. While there have not been any studies directly comparing acalabrutinib to zanubrutinib, the efficacy of zanubrutinib was superior to ibrutinib in WM patients with MYD88 wild type, CXCR4 or TP53 mutations. However, patients with CXCR4 and TP53 mutations receiving BTKi still fare worse than those without, highlighting the need for other therapeutic strategies. Herein, we review the clinical development of zanubrutinib in WM including the impact of genetic subtypes and advise on the management of adverse events and drug resistance.

Keywords:  B-cell malignancy; Bruton tyrosine kinase inhibitor; Zanubrutinib; lymphoplasmacytic lymphoma; waldenstrom macroglobulinemia

DOI:  https://doi.org/10.1080/14796694.2025.2558351
Blood. 2025 Sep 11. 146(11): 1259-1260

Good flatmates: immature neutrophils protect bone integrity.

Matthias Gunzer.

DOI: https://doi.org/10.1182/blood.2025030147
Ther Adv Hematol. 2025 ;16 20406207251371298

Novel small-molecule therapies for myelodysplastic syndromes with IPSS-R ⩾3.5 in patients aged 60 or older: current landscape and challenges.

Kehao Hou, Xue Dong, Wenyan Niu.

  Myelodysplastic syndromes (MDS), particularly in older adults aged 60 years and above, present significant therapeutic challenges due to poor prognosis and limited treatment options. Higher-risk MDS (HR-MDS), defined by the Revised International Prognostic Scoring System score of ⩾3.5, is characterized by increased myeloblasts, severe cytopenia, and a median survival of <2 years. The pathogenesis involves complex genetic mutations, cytogenetic abnormalities, and a dysregulated bone marrow microenvironment. Current standard therapies, such as hypomethylating agents and allogeneic stem cell transplantation, are often inadequate, especially in older patients with comorbidities and limited clinical trial eligibility. This review highlights emerging targeted therapies for older HR-MDS patients, focusing on small-molecule agents for their critical advantages like patient-friendly oral delivery, lower production barriers, improved access to intracellular targets, and flexible dosing strategies. Venetoclax, an oral B-cell lymphoma-2 (BCL-2) inhibitor, has shown promise in clinical trials but requires further validation. Isocitrate dehydrogenase 1 (IDH1) inhibitors, including ivosidenib and olutasidenib, have demonstrated efficacy and tolerability, while ongoing investigations explore other novel agents like IDH2 inhibitors and FMS-like tyrosine kinase 3 (FLT3) inhibitors. By summarizing the latest advancements, this review emphasizes the importance of developing safe, effective, and personalized therapies to improve outcomes and quality of life for older patients with HR-MDS, with a focus on age-specific clinical trials.

Keywords:  higher-risk myelodysplastic syndrome; novel agents; older adults; precision medicine; targeted therapies

DOI:  https://doi.org/10.1177/20406207251371298
Blood Neoplasia. 2025 Nov;2(4): 100124

Minimal residual disease measurement in blood by mass spectrometry identifies long-term responders in multiple myeloma.

Tadeusz Kubicki, Benjamin A Derman, Jennifer H Cooperrider, Anna Puła, David Barnidge, Dominik Dytfeld, Ken Jiang, Andrzej J Jakubowiak.

Modern multiple myeloma treatment enables deep and sustained responses, necessitating assessment of minimal residual disease (MRD) in the bone marrow to refine response categorization. Recently, mass spectrometry (MS)-based methods have emerged as highly sensitive tools for measuring MRD in the peripheral blood. However, the role specific MS techniques play in response categorization has yet to be established. We pooled data from 97 patients treated in 3 prospective phase 2 trials evaluating carfilzomib-based triplets and quadruplets, with or without autologous stem cell transplantation. MRD was assessed in the bone marrow using next-generation sequencing (NGS) and in the peripheral blood with 2 MS methods: matrix-assisted laser desorption ionization-time of flight (EXENT) and the more sensitive liquid chromatography-MS (LC-MS). EXENT negativity was associated with superior progression-free survival (PFS) and overall survival. LC-MS negativity identified patients with long-term responses. EXENT complemented NGS MRD, with patients with double negativity experiencing longer PFS than those negative in only 1 modality. Patients negative by both LC-MS and NGS MRD at 10-6 had a 5-year PFS rate of 89%. These findings support incorporating MS into MRD response assessment and in prognostic algorithms in myeloma. In addition, our results indicate that LC-MS can provide valuable end point in future studies aiming for functional cure.

DOI: https://doi.org/10.1016/j.bneo.2025.100124
Int J Mol Sci. 2025 Sep 05. pii: 8648. [Epub ahead of print]26(17):

Synergistic MDM2-STAT3 Inhibition Demonstrates Strong Anti-Leukemic Efficacy in Acute Lymphoblastic Leukemia.

Erhan Aptullahoglu, Emrah Kaygusuz.

  Acute lymphoblastic leukemia (ALL) remains a formidable therapeutic challenge, particularly within high-risk cohorts. Advances in next-generation sequencing have elucidated critical mutations that significantly influence prognosis and therapeutic decision-making. Tyrosine kinase inhibitors (TKIs) have significantly improved treatment outcomes in Philadelphia chromosome-positive (Ph+) ALL. Meanwhile, emerging therapies such as monoclonal antibodies and chimeric antigen receptor (CAR) T-cell therapies show promise for B-cell ALL, although they are associated with considerable toxicities. These developments underscore the persistent need for alternative therapeutic strategies that can benefit a wider range of patients. In this study, human ALL cell lines-characterized by either wild-type or mutant tumor protein p53 (TP53) status-were treated with RG7388 (an MDM2 (mouse double minute 2 homolog) inhibitor) and BBI608 (a STAT3 (signal transducer and activator of transcription 3) inhibitor), both as single agents and in combination. Cell viability was quantified using XTT assays, while apoptosis was assessed via flow cytometry. Additionally, immunoblotting and qRT-PCR were employed to evaluate changes in protein and gene expression, respectively. RG7388 demonstrated potent growth inhibition in the majority of ALL cell lines, with p53-mutant cell lines exhibiting resistance. BBI608 reduced cell viability across all tested cell lines, though with variable sensitivity. Notably, the combination of RG7388 and BBI608 elicited synergistic anti-proliferative effects in p53 wild-type and partially functional p53-mutant cells, enhancing apoptosis and stabilizing p53 protein levels. In contrast, MOLT-4 cells, which harbor concurrent TP53 and STAT3 mutations, did not benefit from the combination treatment, indicating an inherent resistance phenotype within this subset. Collectively, these findings highlight the therapeutic potential of combined MDM2 and STAT3 inhibition in ALL, particularly in p53 wild-type and partially functional p53-mutant contexts. This combinatorial approach augments apoptosis and tumor growth suppression, offering a promising avenue for expanding treatment options for a broader patient population. Further investigation is warranted to validate these preclinical findings and to explore translational implications in genetically diverse ALL subsets.

Keywords:  BBI608 (napabucasin); MDM2; RG7388 (idasanutlin); STAT3; acute lymphoblastic leukemia (ALL); targeted cancer therapies

DOI:  https://doi.org/10.3390/ijms26178648
Blood Adv. 2025 Sep 08. pii: bloodadvances.2024015685. [Epub ahead of print]

Clinical applications of mass spectrometry in multiple myeloma.

Benjamin A Derman, Andrew J Yee.

Mass spectrometry (MS) is an emerging tool in multiple myeloma that detects and quantifies monoclonal proteins in the peripheral blood with sensitivity several orders of magnitude greater than conventional serum protein electrophoresis and immunofixation. Both intact light chain (top-down) and clonotypic peptide (bottom-up) MS approaches have demonstrated sensitivity comparable to-or even surpassing-BM-based assessments using next generation flow cytometry or sequencing. However, due to the delayed clearance of paraproteins, MS may be less informative for early response assessment, underscoring the need to define the optimal timing for evaluation. MS assays have now transitioned from research settings to commercial availability, addressing the clinical demand for sensitive, non-invasive monitoring tools that avoids reliance on BM biopsies. This review provides an overview of MS and explores its growing role in clinical practice.

DOI: https://doi.org/10.1182/bloodadvances.2024015685
Blood Neoplasia. 2025 Nov;2(4): 100126

A phase 1 study of IO-202, an anti-LILRB4 antibody, in chronic myelomonocytic leukemia and acute myeloid leukemia.

Ahmed Aribi, Gabriel N Mannis, Yazan F Madanat, Brian A Jonas, Neil Dunavin, Gail J Roboz, Deepa Jeyakumar, Guillermo Garcia-Manero, Hongtao Liu, Hetty E Carraway, Jennifer N Saultz, William Blum, Gary Schiller, Tao Huang, Paul Woodard, Barbara Klencke, X Charlene Liao, Hong Xiang, Daniel A Pollyea, Courtney D DiNardo.

IO-202 is a humanized immunoglobulin G1 monoclonal antibody with high affinity and specificity for leukocyte immunoglobulin-like receptor B4 (LILRB4; ILT3), which is predominantly expressed in monocytes and monocytic blasts. IO-202 induces antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis in vitro and in patients with leukemia. Herein, we present the phase 1a dose escalation data of IO-202 as monotherapy and in combination with azacitidine (AZA) in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) and R/R chronic myelomonocytic leukemia (CMML), and the phase 1b dose expansion data of IO-202 combined with AZA for the treatment of hypomethylating agent (HMA)-naïve CMML. IO-202 was well tolerated as monotherapy and in combination with AZA. Patients with R/R monocytic AML expressing high LILRB4 on leukemia blasts demonstrated clinical activity, including a complete response (CR) in dose escalation with IO-202 + AZA. In patients with HMA-naïve CMML, IO-202 + AZA led to a 27.8% CR rate and 66.7% overall response rate, based on the 2015 International Working Group response criteria for myelodysplastic/myeloproliferative neoplasms. All 18 efficacy-evaluable patients with HMA-naïve CMML (100%) achieved some form of investigator-assessed clinical benefit, including symptomatic improvement, a decrease in transfusions, reduced blasts and/or monocytes, and resolution of thrombocytopenia. Seven patients (38.9%) proceeded to allogeneic hematopoietic cell transplantation. Translational data suggest that efficacy favors patients with high LILRB4 expression, supporting the mechanism of action of IO-202. Overall, the data support a future pivotal study of IO-202 + AZA in patients with HMA-naïve CMML. This trial was registered at www.clinicaltrials.gov as #NCT04372433.

DOI: https://doi.org/10.1016/j.bneo.2025.100126
Cancers (Basel). 2025 Aug 29. pii: 2845. [Epub ahead of print]17(17):

Clinical Outcomes and Safety of Ultra-Low-Dose Radiotherapy for Ocular Adnexal Lymphoma: A Systematic Review.

Miloš Grujić, Stanislav Volchenkov, Aidos Akhmetali, Marija Živković Radojević, Neda Milosavljević, Katarina Janković, Katarina Krasić, Milica Mihajlović, Mohamed Shelan, Luca Nicosia, Mladen Marinković.

  Background/Objectives: Ultra-low-dose radiotherapy (ULD-RT), an ultra-low-dose regimen delivering 4 Gy in two fractions, has emerged as a promising treatment for indolent ocular adnexal lymphoma (OAL), offering disease control with minimal toxicity. However, the clinical outcomes and safety profile of ULD-RT remain inconsistently reported across studies. Methods: We conducted a systematic review of peer-reviewed studies evaluating ULD-RT in patients with OAL, including prospective, retrospective, and comparative cohorts published between 2000 and 2025. A comprehensive search was performed in PubMed, Embase, and Scopus. Eligible studies reported clinical outcomes (e.g., response rates, local control, progression-free survival) and safety data (acute and late toxicities). Methodological quality was assessed using the Newcastle-Ottawa Scale (NOS). Results: Ten studies comprising 591 patients met the inclusion criteria. The overall response rate to ULD-RT ranged from 88% to 100%, with complete response rates of 50% to 95%. Local control rates ranged from 63% to 100%, and 2-year progression-free survival exceeded 85% in most studies. Importantly, no grade ≥ 3 toxicities were observed following the regimen of 4 Gy in two fractions. Acute toxicities occurred in up to 42% of patients, typically grade 1 dry eye or conjunctivitis. Late toxicities were uncommon (16-33%), with cataracts rarely requiring surgery. All included studies were rated as good quality (NOS score ≥ 7), indicating low risk of bias. Conclusions: ULD-RT is a highly effective and safe treatment modality for OAL, providing excellent local control with a favorable toxicity profile. These findings support the adoption of ULD-RT as a first-line radiotherapy strategy for indolent OAL. Future prospective trials with longer follow-up and standardized toxicity reporting are warranted to confirm and refine its clinical role.

Keywords:  indolent lymphoma; local control; ocular adnexal lymphoma; systematic review; toxicity; ultra-low-dose radiation; ultra-low-dose radiotherapy

DOI:  https://doi.org/10.3390/cancers17172845
Am J Hematol. 2025 Sep 09.

European Myeloma Network Consensus Statement on Functional High-Risk Multiple Myeloma.

Sueh-Li Lim, Monika Engelhardt, Evangelos Terpos, Francesca Gay, Niels W C J Van de Donk, Herman Einsele, Pieter Sonneveld, Martin Kaiser, Mario Boccadoro, Andrew Spencer.

  Multiple myeloma (MM) is an incurable blood cancer characterized by clonal bone marrow plasmacytosis, hypercalcemia, renal failure, anemia, and osteolytic bone disease. Approximately 20% of NDMM patients, not predicted to have high-risk disease at diagnosis, progress early, despite optimal induction +/- ASCT and lenalidomide maintenance, and are subsequently categorized as functional high-risk (FHR) disease. Standardized risk-stratification models incorporate biomarkers of tumor burden, existence of high-risk cytogenetics, with the presence/absence of plasma cell leukemia/extramedullary disease to attribute high-risk at diagnosis; however, depth/duration of response to novel agent-based induction (NA-IND) as dynamic markers of disease risk have not been defined. However, irrespective of diagnostic risk-stratification, response to NA-IND may be the single most effective method of identifying patients whose FHR biology portends an unacceptably short overall survival (OS). In this EMN consensus statement, we define FHR-MM as disease progression within 18 months of commencement of first-line therapy in the absence of high-risk cytogenetics, discuss the underlying disease biology, and strategies to improve outcomes for these patients.

Keywords:  European myeloma network; consensus statement; early progression; functional high‐risk disease; multiple myeloma

DOI:  https://doi.org/10.1002/ajh.70070