bims-hemali 2025-07-27 papers

bims-hemali

Biomed News

on Hematologic malignancies

Issue of 2025–07–27
39 papers selected by
Alexandros Alexandropoulos, Γενικό Νοσοκομείο Αθηνών Λαϊκό

Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Can Be Treated With Chemotherapy-Free Regimens Without Transplant.
[How I treat pediatric chronic myeloid leukemia].
Cardiovascular toxicity from tyrosine kinase inhibitors in chronic myeloid leukemia with severe dilated cardiomyopathy.
Targeting B-cell identity: how EBF1 modulates InO response.
Acute myolysis in patients on tyrosine kinase inhibitor therapy for chronic myeloid leukemia.
Preclinical characterization of TGRX-678, a brain-penetrant allosteric inhibitor of BCR::ABL1.
Long-term results from the AGILE study of azacitidine plus ivosidenib vs placebo in newly diagnosed IDH1-mutated AML.
Heat stress targets and degrades BCR::ABL1 oncoproteins to overcome drug-resistance in Philadelphia chromosome-positive acute lymphoblastic leukemia.
The incidence of vascular adverse events and usefulness of novel risk assessment tool in Japanese patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors.
Cytolytic helper T cells: a new addition to myeloma immunity.
Adenovirus holds the platelet in flow.
Targeting leukemic stem cells: enhanced eradication via tivantinib (ARQ197) and asciminib (ABL001) with molecular docking-guided screening of therapeutic derivatives.
ZFAS1/STAT3 axis modulates imatinib resistance of chronic myeloid leukemia cells through glucose metabolism reprogramming.
TCA cycle mode switch determines the fate of pirtobrutinib-tolerant persister cells in mantle cell lymphoma.
Case Report: Primary cardiac diffuse large B-cell lymphoma with sick sinus syndrome and literature review on disease management and therapeutic strategies.
Clinical, morphological and genetic characteristics of patients with concurrent presence of JAK2 V617F and BCR::ABL1.
Dissecting JAK2V617F's double life with and without MPL.
Real-World Evidence on Outcomes and Safety of Ropeginterferon Alfa-2b in Patients With Myeloproliferative Neoplasms: A Retrospective Cohort Study.
Bruton's tyrosine kinase inhibitors for multiple sclerosis.
Inhibiting JAK1: lowering CRS, CAR stays on track.
Bispecific anti-CD38/CD28 antibodies for treatment of multiple myeloma.
Erythroid-predominant myelodysplastic neoplasms exhibit a distinct genomic landscape with poor outcomes after venetoclax-based therapy.
Novel CD19 Fast-CAR-T cells vs. CD19 conventional CAR-T cells for the treatment of relapsed/refractory CD19-positive B-cell acute lymphoblastic leukemia.
CHK1-S, a splicing variant of CHK1, suppresses chronic myeloid leukemia.
Allogeneic CAR-engineered cellular therapy for relapsed and refractory large B cell lymphoma: a systematic review and meta-analysis.
Treatment outcomes for patients with newly diagnosed or relapsed/refractory TP53-mutated mantle cell lymphoma: a systematic review and meta-analysis.
IVIG prophylaxis should be initiated following bispecific antibody therapy in multiple myeloma regardless of IgG levels.
YX0798 Is a Highly Potent, Selective, and Orally Effective CDK9 Inhibitor for Treating Aggressive Lymphoma.
Downregulation of CLEC2 Facilitates the Proliferation and Migration of Multiple Myeloma Cells via Regulating HIF-1α-Mediated Ferroptosis.
A BCMA-mRNA vaccine is a promising therapeutic for multiple myeloma.
Editorial: Advancements in hematopoietic stem cell proliferation and self-renewal maintenance.
SOHO State of the Art Updates and Next Questions | The Optimal Management of Waldenström Macroglobulinemia.
Low-dose PD-1 inhibition in relapsed/refractory classic Hodgkin lymphoma: systematic review and meta-analysis.
Belantamab mafodotin plus bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma (DREAMM-7): updated overall survival analysis from a global, randomised, open-label, phase 3 trial.
Uncommon Entities, Uncommon Challenges: A Review of Rare Plasma Cell Disorders.
CD200 immune checkpoint expression is associated with inferior outcome in multiple myeloma patients treated with anti-CD38 monoclonal antibodies.
Recommended Phase II Doses of Talquetamab in Patients With Relapsed/Refractory Multiple Myeloma From MonumenTAL-1: Clinical Pharmacology Results.
An observational study of disease management in adult patients with polycythemia vera: results from a large U.S. claims database.
Practical Management of Cardiovascular Adverse Events with BTKi Treatment in Patients with Chronic Lymphocytic Leukemia: A Consensus Report by Hematologists and Cardiologists.

Clin Lymphoma Myeloma Leuk. 2025 Jun 26. pii: S2152-2650(25)00235-6. [Epub ahead of print]

Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Can Be Treated With Chemotherapy-Free Regimens Without Transplant.

Fadi G Haddad, Hagop Kantarjian, Jayastu Senapati, Nitin Jain, Nicholas J Short, Elias Jabbour.

  The incorporation of ponatinib into the frontline regimens of Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) deepened the molecular responses and improved outcomes. Patients with Ph-positive ALL who achieve a complete molecular response (CMR, undetectable BCR::ABL1 transcripts by RT-PCR) by 3 months of therapy have a better survival compared to those with persistent disease. Studies showed that the next-generation sequencing (NGS) assay, with a sensitivity up to 1 × 10-6, is more sensitive than RT-PCR for the detection of measurable residual disease (MRD) in Ph-positive ALL and therefore carries a better prognostic value. Patients who achieve a 3-month CMR and undetectable MRD by NGS have excellent outcomes and may not need consolidation with allogeneic hematopoietic stem cell transplantation (HSCT) in first remission. However, omitting HSCT in certain patients with high-risk disease features, such as IKZF1plus, remains to be determined. Outcomes were significantly improved with the combination of blinatumomab and ponatinib. This chemotherapy-free regimen resulted in a CMR rate of 80% by RT-PCR and 99% by NGS, with a 3-year overall survival rate of 89%. Only 2 of 76 patients (3%) underwent HSCT in this study. Combinations of newer TKIs (such as asciminib or olverembatinib) with blinatumomab (intravenous, subcutaneous) might further improve outcomes and are being explored. Achieving durable NGS MRD negativity can identify patients at low risk of relapse who might be candidates for treatment discontinuation. In this review, we discuss the current progress in the management of Ph-positive ALL, particularly the role of chemotherapy-free regimens in mitigating the need for HSCT.

Keywords:  BCR::ABL1; Blinatumomab; Chemotherapy-free; Ponatinib; Tyrosine kinase inhibitor

DOI:  https://doi.org/10.1016/j.clml.2025.06.019
Zhongguo Dang Dai Er Ke Za Zhi. 2025 Jul 15. pii: 1008-8830(2025)07-0792-10. [Epub ahead of print]27(7): 792-801

[How I treat pediatric chronic myeloid leukemia].

Wen-Bin An, Wen-Yu Yang.

  Pediatric chronic myeloid leukemia (CML) is more aggressive than adult CML, with unique molecular characteristics and a higher propensity for lymphoid blast crisis. The application of tyrosine kinase inhibitors (TKIs) has significantly improved the prognosis of pediatric CML. Based on international consensus and clinical experience, this article proposes standardized diagnosis and treatment recommendations for pediatric CML, covering initial therapy selection, efficacy evaluation, drug switching, and management of adverse effects. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is recommended only for patients with disease progression or failure of multiple lines of TKI therapy. For children newly diagnosed with CML in accelerated phase, high-dose imatinib or second-generation TKIs are recommended as first-line therapy. Those achieving optimal responses should continue maintenance therapy, while non-responders require switching to alternative TKIs and consider allo-HSCT. For blast-phase CML, induction therapy requires a combination of TKIs and chemotherapy, with allo-HSCT serving as the core curative intervention. This article highlights common but challenging problems (poor response, drug intolerance, and disease progression) in pediatric CML treatment using three typical cases, aiming to optimize treatment strategies. Furthermore, the goal of achieving treatment-free remission needs to be further addressed through multi-center clinical studies.

Keywords:  Allogeneic hematopoietic stem cell transplantation; Child; Chronic myeloid leukemia; Diagnosis; Treatment; Tyrosine kinase inhibitor

DOI:  https://doi.org/10.7499/j.issn.1008-8830.2503021
Int J Hematol. 2025 Jul 22.

Cardiovascular toxicity from tyrosine kinase inhibitors in chronic myeloid leukemia with severe dilated cardiomyopathy.

Kenta Hayashino, Naoya Mochizuki, Akihiro Kawatsuki, Yuki Fujiwara, Hiroki Kobayashi, Tomoko Yamasaki, Takeru Asano, Shiro Kubonishi, Yasushi Hiramatsu.

  Tyrosine kinase inhibitors (TKIs) have significantly improved the prognosis of patients with chronic myeloid leukemia (CML). However, few patients maintain remission after discontinuing TKIs, and most require long-term treatment. Prolonged use of TKIs is associated with an increased risk of cardiovascular events (CVEs), particularly in patients with pre-existing cardiovascular comorbidities. We present the case of a 37-year-old man with a decade-long history of severe dilated cardiomyopathy that responded inadequately to standard pharmacologic management, who was under consideration for heart transplantation. Following a diagnosis of CML, the patient experienced various CVEs with TKIs, including dasatinib, bosutinib, imatinib, and nilotinib. These agents were discontinued, and treatment was switched to asciminib, a novel agent that targets the myristoyl pocket of the BCR::ABL1 protein distinct from the ATP-binding site targeted by conventional TKIs. This treatment was well tolerated without any CVEs. Given its minimal off-target activity and lower reported incidence of CVEs, asciminib may offer a viable and safer therapeutic option for CML patients with advanced cardiovascular comorbidities, including those awaiting heart transplantation.

Keywords:  Cardiovascular events, asciminib; Chronic myeloid leukemia; Dilated cardiomyopathy; Tyrosine kinase inhibitor

DOI:  https://doi.org/10.1007/s12185-025-04041-w
Blood. 2025 Jul 24. 146(4): 404-405

Targeting B-cell identity: how EBF1 modulates InO response.

Lorenz Bastian.

DOI: https://doi.org/10.1182/blood.2025029476
Am J Blood Res. 2025 ;15(3): 57-60

Acute myolysis in patients on tyrosine kinase inhibitor therapy for chronic myeloid leukemia.

Jeffrey H Lipton.

  Patients on tyrosine kinase inhibitor therapy for chronic myeloid leukemia are often found to have elevated creatinine kinase levels on routine bloodwork and are asymptomatic. Here we report 4 cases of significant acute symptomatic jumps in levels with associated rhabdomyolysis that resolved with drug cessation. Etiology of the acute jumps is not known and this finding does not appear to be related to any one specific tyrosine kinase inhibitor, as 4 different tyrosine kinases were involved.

Keywords:  Chronic myeloid leukemia; myolysis; tyrosine kinase inhibitor

DOI:  https://doi.org/10.62347/COLY8536
Blood. 2025 Jul 23. pii: blood.2025028539. [Epub ahead of print]

Preclinical characterization of TGRX-678, a brain-penetrant allosteric inhibitor of BCR::ABL1.

Yanxia Shi, Qian Jiang, Linxin Li, Yingying Zuo, Shuzhen Jiang, Tingting Yan, Cuifang Zheng, Shuo Zhang, Nannan Yu, Jingrong Cao, Yun Liu, Yixin Ai, Yihan Wang.

Clinical resistance or intolerance to tyrosine kinase inhibitors (TKIs) remains challenging for the treatment of chronic myeloid leukemia (CML) and Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph+ ALL) with central nervous system (CNS) relapse. Therapeutic options are currently limited for patients who developed the gatekeeper mutations or compound mutations. Here, we describe the preclinical profile of TGRX-678, an allosteric inhibitor designed to Specifically Target the ABL1 Myristoyl Pocket (STAMP), with potent anti-proliferative activity against the majority of ATP site mutants of BCR::ABL1 and minimal off-target cytotoxicity. When combined with ponatinib, TGRX-678 synergistically re-sensitizes the highly resistant compound mutants and T315M to growth inhibition at clinically achievable concentrations. TGRX-678 exhibits relatively high cell permeability and is not a substrate of drug efflux transporters, namely ABCB1 and ABCG2. It also demonstrates a markedly improved in vivo pharmacokinetic (PK) profile and higher oral bioavailability compared to asciminib. Importantly, TGRX-678 penetrates the blood-brain barrier (BBB) and exhibits in vivo efficacy in a murine CNS blast crisis leukemia model. Collectively, these findings suggest that TGRX-678 is a novel BCR::ABL1 allosteric inhibitor with high selectivity, potency and unique pharmacologic features, which has the potential to treat relapse or refractory CML and Ph+ ALL, even with CNS involvement.

DOI: https://doi.org/10.1182/blood.2025028539
Blood Adv. 2025 Jul 24. pii: bloodadvances.2025016399. [Epub ahead of print]

Long-term results from the AGILE study of azacitidine plus ivosidenib vs placebo in newly diagnosed IDH1-mutated AML.

Pau Montesinos, Dylan M Marchione, Christian Récher, Michael Heuser, Susana Vives, Ewa Zarzycka, Jianxiang Wang, Marta Riva, Rodrigo T Calado, Andre C Schuh, Su-Peng Yeh, Adriana E Tron, Jianan Hui, Diego A Gianolio, Sung Choe, Prapti A Patel, Stéphane De Botton, Courtney D DiNardo, Hartmut Döhner.

In the phase 3 AGILE study, after a 12.4-month median follow-up, ivosidenib, a mutant isocitrate dehydrogenase 1 (IDH1) inhibitor, combined with azacitidine significantly improved event-free survival, overall survival (OS), and complete remission rates compared with placebo-azacitidine in patients with newly diagnosed IDH1-mutated acute myeloid leukemia who were unfit for intensive chemotherapy. This post hoc analysis reports long-term follow-up results from AGILE after a median follow-up of 28.6 months. Overall, 148 patients were randomized to receive ivosidenib-azacitidine (N=73) or placebo-azacitidine (N=75). Median OS was significantly longer with ivosidenib (29.3 months; 95% CI 13.2, not reached) than with placebo (7.9 months; 95% CI 4.1, 11.3; hazard ratio 0.42 [0.27, 0.65]; p<.0001). Hematologic recovery was faster, more durable, and conversion to transfusion independence (53.8% vs 17.1%; p=.0004) was more common with ivosidenib than with placebo. Of 33 ivosidenib-treated patients evaluable for molecular measurable residual disease (MRD), 10 converted to MRD negativity. Although OS did not differ significantly between MRD-negative and MRD-positive responders at the 0.1% variant allele frequency (VAF) threshold, MRD-negative patients had numerically longer survival. MRD status appeared more predictive of long-term OS when an exploratory 1% VAF threshold was applied. MRD response was not associated with IDH1 variant, VAF, inferred clonality, or number of baseline comutations. The previously reported safety profile was maintained. These long-term efficacy and safety results confirm the benefit of ivosidenib-azacitidine in this challenging-to-treat population and support its use as a standard of care with the longest reported survival benefit for intensive chemotherapy-ineligible patients with IDH1-mutated AML. ClinicalTrials.gov registration ID: NCT03173248.

DOI: https://doi.org/10.1182/bloodadvances.2025016399
Leukemia. 2025 Jul 22.

Heat stress targets and degrades BCR::ABL1 oncoproteins to overcome drug-resistance in Philadelphia chromosome-positive acute lymphoblastic leukemia.

Chang Yang, Yuan-Yuan Kang, Chen-Ying Zhu, Yafang Ma, Pei-Han Yu, Tao Yang, Yong-Qin Liu, Ze-Yan Zhang, Noriyuki Suzuki, Yasumitsu Ogra, Mikael Björklund, Hua Naranmandura.

BCR::ABL1 oncofusion protein drives Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph+ ALL), making it a critical therapeutic target. Tyrosine kinase inhibitors (TKIs) targeting BCR::ABL1 have revolutionized the treatment of Ph+ ALL patients. However, mutations in the kinase domain of BCR::ABL1 commonly impair the sensitivity to TKIs, resulting in drug resistance and poor prognosis in Ph+ ALL. Here we report that heat stress selectively destabilizes BCR::ABL1 and its common drug-resistant mutants without affecting the native BCR and ABL proteins through inducing liquid-to-solid phase transition. Mechanistic studies revealed that heat stress facilitated recruitment of BCR::ABL1 signaling components (e.g., SHIP2, Sts1, PI3K-p85α and Shc) in a kinase activity dependent manner and stimulated BCR::ABL1 oligomerization through its coiled-coil domain, resulting in formation of a large, thermally unstable signaling complex. This process triggers non-canonical K27-linked ubiquitination mediated by c-Cbl E3 ubiquitin ligase, ultimately leading to BCR::ABL1 degradation via the ubiquitin-proteasome pathway. Functionally, heat stress effectively suppressed proliferation of BCR::ABL1-driven leukemia cells, including drug resistant mutants in vitro and decreased tumor burden in vivo. Our findings established that thermal-based therapy as a novel strategy to selectively target and degrade both unmutated and drug-resistant BCR::ABL1 oncoproteins, offering a promising adjuvant approach to overcome TKI resistance in Ph+ ALL.

DOI: https://doi.org/10.1038/s41375-025-02709-0
Cardiooncology. 2025 Jul 19. 11(1): 68

The incidence of vascular adverse events and usefulness of novel risk assessment tool in Japanese patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors.

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

BACKGROUND: Tyrosine kinase inhibitor (TKI) therapy improves the overall survival of patients with chronic myeloid leukemia (CML). However, the risk of vascular adverse events (VAEs) in these patients is reported to be higher than that in healthy individuals, because of both CML itself and the effects of TKIs. Appropriate and effective VAE risk assessment tools for TKI treatment have long been anticipated.
METHODS: Here, we investigated the usefulness of a newly developed VAE risk assessment tool, the Hisayama score, and presented data on the clinical characteristics of VAEs in Japanese patients with CML based on an analysis of a real-world, large-cohort database.
RESULTS: Patients with CML who developed VAEs were evaluated using three VAE risk assessment tools. Forty-four VAEs were reported in 41 out of 626 patients with CML, with three patients developing multiple VAEs during the observation period. There were 16 cases of cerebral infarction, 19 of ischemic heart disease, and nine of peripheral artery occlusive disease, with rates per 1,000 person-years of 3.23, 3.84, and 2.02, respectively. The Framingham and Hisayama scores stratified high-risk patients with VAEs more effectively than the SCORE chart. Smoking and hypertension are prominent risk factors for VAEs.
CONCLUSIONS: Our results clearly demonstrate that the Hisayama score can be used to evaluate VAE risk in high-risk patients. Selecting appropriate TKIs based on each patient risk, smoking cessation, and blood pressure control may contribute to selecting appropriate TKIs and managing VAE risk.

DOI: https://doi.org/10.1186/s40959-025-00366-x
Blood. 2025 Jul 24. 146(4): 402-403

Cytolytic helper T cells: a new addition to myeloma immunity.

Tom Cupedo.

DOI: https://doi.org/10.1182/blood.2025028916
Blood. 2025 Jul 24. 146(4): 408-409

Adenovirus holds the platelet in flow.

Renhao Li.

DOI: https://doi.org/10.1182/blood.2025029446
J Chemother. 2025 Jul 25. 1-20

Targeting leukemic stem cells: enhanced eradication via tivantinib (ARQ197) and asciminib (ABL001) with molecular docking-guided screening of therapeutic derivatives.

İlknur Karatekin Arik, Nurcan Gümüş, İlayda Alcitepe, Cumhur Gündüz, Belgin Sever, Halil İbrahim Ciftci, Güray Saydam, Burçin Tezcanli Kaymaz.

  This study is the first to investigate the therapeutic potential of a mono/combination treatment with the selective phase III BCR::ABL1 tyrosine kinase inhibitor (TKI) asciminib (ABL001) and the c-MET inhibitor tivantinib (ARQ197) in hematopoietic stem cells (HSCs) and leukaemia stem cells (LSCs) in terms of cytotoxicity, apoptosis, target gene expression profiles, and bioinformatics in vitro. In silico studies were also performed for various tivantinib and asciminib derivatives. Asciminib and tivantinib exhibited significant antileukaemic effects, with tivantinib showing the strongest apoptotic impact in LSCs and asciminib in HSCs. Although their combination exhibited an additive effect on LSCs, enabling dose reduction and potentially minimizing side effects; the treatment succeeded in promoting apoptosis as effectively as tivatinib monotherapy. Gene expression analysis showed increased pro-apoptotic and tumour suppressor markers, whereas decreased oncogenes' expressions following mono/combined treatment in LSCs. Molecular docking showed that a new analogue of tivantinib (compound-1) and CHEMBL5274046 are promising c-MET and ABL1 inhibitors, respectively. The findings highlight the antileukaemic potential of initially tivantinib and asciminib in LSCs. Despite an additive effect, combination therapy allowed dose reduction, giving rise to a potential decrease in side effects. Targeting c-MET, alone or in combination with BCR::ABL1 inhibition, presents a compelling strategy for eradicating LSCs, which underpin resistance and relapse in CML therapy - thus marking a crucial advancement in the pursuit of more effective treatment paradigms. In silico studies indicated that various tivantinib and asciminib analogues could also have potential therapeutic effects as c-MET and ABL1 inhibitors for future anti-leukaemia research.

Keywords:  HGF/c-MET; Leukaemia stem cell; asciminib; molecular docking; tivantinib

DOI:  https://doi.org/10.1080/1120009X.2025.2532948
Front Oncol. 2025 ;15 1603060

ZFAS1/STAT3 axis modulates imatinib resistance of chronic myeloid leukemia cells through glucose metabolism reprogramming.

Lan Yang, Yanqiu Han.

   Background: Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by the presence of the Philadelphia chromosome (chromosome 22). This cytogenetic abnormality gives rise to the BCR::ABL1 fusion gene, which encodes the constitutively active BCR-ABL1 protein tyrosine kinase, driving uncontrolled proliferation and impaired apoptosis of hematopoietic stem and progenitor cells, leading to leukemogenesis. Imatinib mesylate (IM), a first-generation tyrosine kinase inhibitor (TKI) specifically targeting the BCR-ABL1 oncoprotein, represents the standard first-line therapy for patients with CML. However, imatinib resistance remains a major therapeutic challenge.
Objective: This study aims to elucidate the role of the ZFAS1/STAT3 signaling axis in mediating imatinib resistance in CML by promoting metabolic reprogramming, with a particular focus on alterations in glucose metabolism.
Methods: Imatinib-resistant (IM-R) K562 cells were used to investigate the functional role of ZFAS1gene. Following ZFAS1 knockdown, assessments of cell viability, apoptosis, and glucose metabolism were performed. The interaction between ZFAS1 and IGF2BP2, as well as its regulatory effect on STAT3 expression and glycolysis-related genes (including HIF1α, LDHA, and PDK1) were examined using qRT-PCR and western blotting. Additionally, the impact of STAT3 overexpression and glycolysis inhibition (2-DG) on IM sensitivity were examined.
Results: Our findings revealed that ZFAS1 expression was significantly upregulated in IM-R CML patient samples and IM-R K562 cells. Silencing of ZFAS1 enhanced cellular sensitivity to IM, inhibited glucose metabolism reprogramming, and promoted apoptosis. Mechanistically, ZFAS1 was found to interact with IGF2BP2, facilitating the stabilization of STAT3 mRNA and leading to increased STAT3 expression. This, in turn, resulted in the upregulation of key glycolytic genes. Overexpression of STAT3 reversed the effects of ZFAS1 knockdown by restoring glycolytic activity and re-establishing IM resistance. Additionally, 2-DG treatment effectively reversed STAT3-induced IM resistance by inhibiting glycolysis.
Conclusion: These findings demonstrate that the ZFAS1/STAT3 signaling axis contributes to imatinib resistance in CML through the modulation of glucose metabolism. Targeting this regulatory pathway may represent a novel therapeutic strategy to overcome TKI resistance in CML.

Keywords:  ZFAS1; chronic myeloid leukemia; glucose metabolism reprogramming; imatinib resistance; stat3

DOI:  https://doi.org/10.3389/fonc.2025.1603060
Blood. 2025 Jul 23. pii: blood.2024026919. [Epub ahead of print]

TCA cycle mode switch determines the fate of pirtobrutinib-tolerant persister cells in mantle cell lymphoma.

Wei Wang, Qingsong Cai, Yang Liu, Lei Nie, Heng-Huan Lee, Fangfang Yan, Yue Fei, Yixin Yao, Yijing Li, Lin Tan, Philip L Lorenzi, Ying-Nai Wang, Jun Yao, Zhihong Chen, Joseph McIntosh, Cheng-Tai Yu, Preetesh Jain, Vivian Jiang, Jovanny Vargas, Xiaolin Li, Tianci Zhang, Shaoying Li, David Santos, Selvi Thirumurthi, Erin Heather Seeley, Lukas Mikolaj Simon, Christopher R Flowers, Chi Young Ok, Michael L Wang.

Bruton's tyrosine kinase inhibitors (BTKi) and cell therapy have successfully been used to treat mantle cell lymphoma (MCL); however, therapy resistance inevitably emerges. Cancer cells can progressively develop stable resistance by traversing through a transient drug-tolerant persister (DTP) state. The mechanisms enabling DTP cells to reversibly adapt to therapies and evolve to acquire heterogeneity remain poorly understood, and characterizing DTP cells in MCL continues to pose a challenge for clinic translation. Here using pirtobrutinib, a recently FDA-approved non-covalent BTKi, we identified pirtobrutinib-tolerant persister cells exhibiting morphological variability by presenting a unique population of enlarged cells (Giant cells) with reversible fate transitions. During treatment, Giant cells enter a non-proliferative, dedifferentiated state, addicted to an activated cytosolic tricarboxylic acid (TCA) cycle coupled with the malate-aspartate shuttle to engage in biosynthesis. Upon drug removal, the TCA cycle shifts to oxidative catabolism, promoting Giant cells to differentiate into regular-sized cells. Throughout the transition, acetyl-CoA modulates cell fate by fine-tuning stemness. Our biphasic model demonstrates that the metabolic switch governs the phenotypic plasticity of DTP cells in MCL, resulting a dynamic presence of DTP cells across various developmental states in response to systemic therapies. Targeting Giant cells prior to their differentiation offers a promising strategy to overcoming therapy resistance in MCL.

DOI: https://doi.org/10.1182/blood.2024026919
Front Oncol. 2025 ;15 1538786

Case Report: Primary cardiac diffuse large B-cell lymphoma with sick sinus syndrome and literature review on disease management and therapeutic strategies.

Xiaofen Qiu, Li Zhang, Shaojun Zhou, Wenbin Qian, Yun Liang, Huiqing Qiu, Xianggui Yuan.

   Background: Primary cardiac diffuse large B-cell lymphoma (DLBCL) is a rare but clinically challenging extranodal lymphoma. Diagnosis and management are often complicated due to its nonspecific symptoms and rarity.
Case Report: We reported a case of a 73-year-old male who initially presented with chest pain, high fever, dizziness, and amaurosis. Preliminary diagnostic assessments suggested sick sinus syndrome, necessitating the implantation of a dual-chamber pacemaker, and revealed a large mass in the interatrial septum. An endomyocardial biopsy confirmed the diagnosis of primary cardiac DLBCL. Initial treatment with R-miniCHOP chemotherapy yielded a partial response. However, due to treatment-related complications (grade 4 neutropenia and pneumonia), a change in the therapeutic regimen to OR-GemOx chemotherapy was made, leading to complete remission. A year later, the patient experienced a relapse, requiring a salvage treatment of the Pola-BR chemotherapy regimen, which again resulted in complete remission. Additionally, this review examines an in-depth literature review on the management and therapeutic strategies for this entity, focusing on the treatment recommendations for relapse/refractory disease.
Conclusion: Prompt diagnosis and effective management are crucial in treating primary cardiac DLBCL. While the emergence of new drugs has improved the prognosis by offering higher efficacy and fewer side effects, clinicians should be vigilant about potential cardiotoxicities.

Keywords:  diffuse large B-cell lymphoma; extranodal lymphoma; orelabrutinib; polatuzumab vedotin; primary cardiac lymphoma; sick sinus syndrome

DOI:  https://doi.org/10.3389/fonc.2025.1538786
Sci Rep. 2025 Jul 18. 15(1): 26046

Clinical, morphological and genetic characteristics of patients with concurrent presence of JAK2 V617F and BCR::ABL1.

Nicole Naumann, Vito Dangelo, Johannes Lübke, Jakob Bresser, Volker Hagen, Jolanta Dengler, Georgia Metzgeroth, Sebastian Kreil, Tabea Hockenberger, Wolf-Karsten Hofmann, Alice Fabarius, Susanne Saussele, Nicholas C P Cross, Andreas Reiter, Juliana Schwaab.

Diagnosis and treatment of chronic myeloid neoplasms with two concurrently present driver mutations is challenging. We report on 10 JAK2 V617Fpos/BCR::ABL1pos patients in whom both mutations were identified simultaneously in 5/10 (50%) patients or in whom BCR::ABL1 appeared a median of 14 years after the primary diagnosis of JAK2 V617Fpos myeloproliferative neoplasia (MPN) in the remaining 5 patients. Granulocyte-macrophage colony-forming unit (CFU-GM) analysis demonstrated subsequent acquisition of BCR::ABL1 in a pre-existing JAK2 V617Fpos clone in 8/9 (89%) of evaluable patients. Despite the presence of JAK2 V617F in all patients, atypical BCR::ABL1 transcripts (e1a2/e19a2) in 3/9 (33%) patients and additional somatic mutations in 5/9 (56%) patients, molecular remission of BCR::ABL1 was achieved with different ABL1 TKIs (imatinib, n = 2, dasatinib, n = 2, nilotinib, n = 3) in 7/9 (78%) patients. During a total of 217 months of treatment, concomitant treatment with ABL1 TKIs and ruxolitinib did not affect dosing, efficacy or side effects. We conclude that (i) a second driver mutation might occur in chronic phase MPNs, (ii) clonality analyses largely support a common disease origin, and (iii) the dose, efficacy and safety of ABL1 inhibitors and ruxolitinib are not mutually affected by concurrent treatment.

DOI: https://doi.org/10.1038/s41598-025-11096-6
Blood. 2025 Jul 24. 146(4): 406-408

Dissecting JAK2V617F's double life with and without MPL.

Isabelle Plo, Caroline Marty.

DOI: https://doi.org/10.1182/blood.2025029479
Clin Lymphoma Myeloma Leuk. 2025 Jun 25. pii: S2152-2650(25)00216-2. [Epub ahead of print]

Real-World Evidence on Outcomes and Safety of Ropeginterferon Alfa-2b in Patients With Myeloproliferative Neoplasms: A Retrospective Cohort Study.

Yu-Sung Chang, Chieh-Yu Liu, Yu-Wen Chen, Sheng-Hsuan Huang, Hsing-Yu Lin, Chien-Chin Lin, Xavier Cheng-Hong Tsai, Feng-Ming Tien, Chieh-Lung Cheng, Chang-Tsu Yuan, Yuan-Yeh Kuo, Bor-Sheng Ko, Ming Yao, Hwei-Fang Tien, Wen-Chien Chou, Hsin-An Hou.

   BACKGROUND: Ropeginterferon alfa-2b-njft (ropegIFN) has demonstrated superior efficacy over hydroxyurea in polycythemia vera (PV); however, real-world data on its application across Philadelphia chromosome-negative (Ph-) myeloproliferative neoplasms (MPNs) remain limited.
PATIENTS AND METHODS: This retrospective cohort study included 64 patients with Ph- MPNs (15 PV, 16 essential thrombocythemia [ET], 5 prefibrotic myelofibrosis [preMF], and 28 with overt myelofibrosis [MF]) treated with ropegIFN between October 2018 and June 2024.
RESULTS: After a median follow-up of 5.3 years, the hematological response (HR) rates at 36 months were 87% in PV, 75% in ET, 80% in preMF, and 45% in overt MF (P = .026). Best molecular response (MR) rates were 80% in PV, 69% in ET, 75% in preMF, and 47% in overt MF (P = .11). The median JAK2 variant allele frequency (VAF) declined significantly from 67.9% at baseline to 18.7% during follow-up (P < .001), with consistent reductions across MPN subtypes confirmed by GEE analysis. In patients with MF, neither HR nor MR was observed among those harboring high-molecular-risk (HMR) mutations (24-month HR: 0% vs. 72%; P = .002; 24-month MR: 0% vs. 18%; P = .4). Additionally, these patients exhibited a significantly higher cumulative incidence of adverse events (48% vs. 7%; P < .001).
CONCLUSIONS: RopegIFN demonstrated hematological and molecular efficacy across Ph- MPN subtypes and was generally well tolerated. However, its effectiveness appears limited in patients with MF, particularly those with high-molecular-risk (HMR) mutations. These findings support the potential disease-modifying role of ropegIFN and highlight the need for prospective multicenter studies to validate its long-term impact on disease progression and survival.

Keywords:  Essential thrombocythemia; Interferon; Myelofibrosis; Polycythemia vera; Prefibrotic primary myelofibrosis

DOI:  https://doi.org/10.1016/j.clml.2025.06.011
Lancet Neurol. 2025 Aug;pii: S1474-4422(25)00238-8. [Epub ahead of print]24(8): 627-628

Bruton's tyrosine kinase inhibitors for multiple sclerosis.

Laura Airas.

DOI: https://doi.org/10.1016/S1474-4422(25)00238-8
Blood. 2025 Jul 24. 146(4): 399-400

Inhibiting JAK1: lowering CRS, CAR stays on track.

Akiva Diamond, Leo Luznik.

DOI: https://doi.org/10.1182/blood.2025029068
Pharm Pat Anal. 2025 Jul 22. 1-6

Bispecific anti-CD38/CD28 antibodies for treatment of multiple myeloma.

Martin Perez-Santos, Maricruz Anaya-Ruiz, Donaciano Flores-Robles, Alejandro Millán-Vega, Pavel Sierra-Martínez.

   INTRODUCTION: Since CD38 is a protein expressed at high levels in multiple myeloma cells, it is an ideal target for antibody design for treatment.
AREAS COVERED: Patent US11905332, which describes two anti-CD38/CD28 bispecific antibodies (bsAb6031 and bsAb7945) with the potential for the treatment of multiple myeloma, was evaluated. The results described in the patent show that the anti-CD38/CD28 bispecific antibodies caused elevated in vitro cytotoxicity in tumor cells through increased proliferation of CD4+ and CD8+ cells, and the release of IFN-γ, IL-2, and TNF-α, as well as efficacy in a mouse model of multiple myeloma.
EXPERT OPINION: Anti-CD38/CD28 bispecific antibodies have the potential to be used alone or in combination with other antibodies, including anti-BCMA/CD3 antibodies, for the treatment of multiple myeloma.

Keywords:  CD28; CD38; bispecific antibody; multiple myeloma; patent

DOI:  https://doi.org/10.1080/20468954.2025.2535944
Leukemia. 2025 Jul 21.

Erythroid-predominant myelodysplastic neoplasms exhibit a distinct genomic landscape with poor outcomes after venetoclax-based therapy.

Alexandre Bazinet, Sanam Loghavi, Yue Wei, Alex Bataller, Koji Sasaki, Naszrin Arani, Faezeh Darbaniyan, Kelly Chien, Danielle Hammond, Ian Bouligny, Rashmi Kanagal-Shamanna, Natthakan Thongon, Guilin Tang, Samuel Urrutia, Tapan Kadia, Courtney DiNardo, Naval Daver, Nicholas Short, Ghayas Issa, Naveen Pemmaraju, Elias Jabbour, Sa A Wang, Wei Wang, Gautam Borthakur, Carlos Bueso-Ramos, Farhad Ravandi, L Jeffrey Medeiros, Hagop Kantarjian, Guillermo Garcia-Manero, Guillermo Montalban-Bravo.

Erythroid differentiation confers BCL-XL dependence and venetoclax resistance in acute myeloid leukemia (AML). However, whether myelodysplastic neoplasms (MDS) with erythroid predominance (EP), defined by ≥50% erythroid bone marrow elements, have distinct biology and drug sensitivities remains unknown. To study this, we evaluated an MDS patient cohort (n = 371) and showed that EP MDS (n = 67, 18%) are characterized by higher TP53 (multihit TP53: 36% vs 17%, p = 0.004), BCOR and WT1 and lower ASXL1 and SRSF2 mutation frequencies compared to non-EP (NEP) MDS (n = 304, 82%). TP53-mutant variant allele frequencies and allelic states correlated with erythroid population expansions. EP MDS was characterized by 3 genetic subgroups with distinct survival (TP53 mutant: 11.4 months; splicing mutant: not reached; not otherwise specifiable (NOS): 19.5 months, p < 0.001). EP MDS had a higher incidence of leukemic transformation (32% vs 12%, p = 0.040) and worse survival (8.3 months vs not reached, p = 0.041) after HMA-venetoclax therapy among 112 HMA-venetoclax-treated MDS patients. Expansion of erythroid populations during venetoclax failure was observed in 11 (33%) patients. EP MDS had higher BCL-XL expression levels at the RNA and protein levels compared to NEP MDS. These data support the dynamic assessment of erythroid predominance in MDS and warrant evaluation of BCL-XL inhibitors in these patients.

DOI: https://doi.org/10.1038/s41375-025-02711-6
Chin Med J (Engl). 2025 Jul 21.

Novel CD19 Fast-CAR-T cells vs. CD19 conventional CAR-T cells for the treatment of relapsed/refractory CD19-positive B-cell acute lymphoblastic leukemia.

Xu Tan, Jishi Wang, Shangjun Chen, Li Liu, Yuhua Li, Sanfang Tu, Hai Yi, Jian Zhou, Sanbin Wang, Ligen Liu, Jian Ge, Yongxian Hu, Xiaoqi Wang, Lu Wang, Guo Chen, Han Yao, Cheng Zhang, Xi Zhang.

   BACKGROUND: Treatment with chimeric antigen receptor-T (CAR-T) cells has shown promising effectiveness in patients with relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL), although the process of preparing for this therapy usually takes a long time. We have recently created CD19 Fast-CAR-T (F-CAR-T) cells, which can be produced within a single day. The objective of this study was to evaluate and contrast the effectiveness and safety of CD19 F-CAR-T cells with those of CD19 conventional CAR-T cells in the management of R/R B-ALL.
METHODS: A multicenter, retrospective analysis of the clinical data of 44 patients with R/R B-ALL was conducted. Overall, 23 patients were administered with innovative CD19 F-CAR-T cells (F-CAR-T group), whereas 21 patients were given CD19 conventional CAR-T cells (C-CAR-T group). We compared the rates of complete remission (CR), minimal residual disease (MRD)-negative CR, leukemia-free survival (LFS), overall survival (OS), and the incidence of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) between the two groups.
RESULTS: Compared with the C-CAR-T group, the F-CAR-T group had significantly higher CR and MRD-negative rates (95.7% and 91.3%, respectively; 71.4% and 66.7%, respectively; P = 0.036 and P = 0.044). No significant differences were observed in the 1-year or 2-year LFS or OS rates between the two groups: the 1-year and 2-year LFS for the F-CAR-T group vs.C-CAR-T group were 47.8% and 43.5% vs. 38.1% and 23.8% (P = 0.384 and P = 0.216), while the 1-year and 2-year OS rates were 65.2% and 56.5% vs. 52.4% and 47.6% (P = 0.395 and P = 0.540). Additionally, among CR patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) following CAR-T-cell therapy, there were no significant differences in the 1-year or 2-year LFS or OS rates: 57.1% and 50.0% vs. 47.8% and 34.8% (P = 0.506 and P = 0.356), 64.3% and 57.1% vs. 65.2% and 56.5% (P = 0.985 and P = 0.883), respectively. The incidence of CRS was greater in the F-CAR-T group (91.3%) than in the C-CAR-T group (66.7%) (P = 0.044). The incidence of ICANS was also greater in the F-CAR-T group (30.4%) than in the C-CAR-T group (9.5%) (P = 0.085), but no treatment-related deaths occurred in the two groups.
CONCLUSION: Compared with C-CAR-T-cell therapy, F-CAR-T-cell therapy has a superior remission rate but also leads to a tolerably increased incidence of CRS/ICANS. Further research is needed to explore the function of allo-HSCT as an intermediary therapy after CAR-T-cell therapy.

Keywords:  Allo-HSCT; CD19 Fast-CAR-T cells; CD19 conventional CAR-T cells; CD19-positive B-cell ALL; Relapse/refractory

DOI:  https://doi.org/10.1097/CM9.0000000000003479
Leuk Res. 2025 Jul 22. pii: S0145-2126(25)00282-6. [Epub ahead of print]156 107922

CHK1-S, a splicing variant of CHK1, suppresses chronic myeloid leukemia.

Hu Lei, Hanzhang Xu, Yingying Wang, Yingli Wu.

  Checkpoint kinase 1 (CHK1) is a crucial protein involved in the cell cycle checkpoint during the DNA damage response and is essential for sustaining leukemia cell activity. CHK1-S (excluded exon 3) is an alternative splice variant of CHK1. Here, we demonstrate that CHK1-S is highly expressed in wild-type mouse bone marrow, and the ratio of CHK1-S to CHK1 is significantly higher compared to other tissues. The BCR-ABL protein reduces the expression of CHK1-S while increasing CHK1 levels in vitro and in vivo. Furthermore, the expression of CHK1-S is significantly reduced in the bone marrow mononuclear cells of newly diagnosed chronic myeloid leukemia (CML) patients. Inhibition of BCR-ABL activity with imatinib or knockdown of BCR-ABL can restore the expression of CHK1-S in K562 cells. Additionally, restoring CHK1-S can inhibit the proliferation of K562 cells and increase the proportion of cells in the G2/M phase. Mechanistically, the splicing factors transformer 2α (TRA2A) and TRA2B are associated with the selective splicing of CHK1-S in K562 cells. Our findings demonstrate that CHK1-S functions in opposition to CHK1, acting as a suppressor of CML.

Keywords:  CHK1; CHK1-S; Chronic myeloid leukemia; TRA2

DOI:  https://doi.org/10.1016/j.leukres.2025.107922
Front Immunol. 2025 ;16 1585556

Allogeneic CAR-engineered cellular therapy for relapsed and refractory large B cell lymphoma: a systematic review and meta-analysis.

Alexander Biederstädt, Florian Bassermann, Judith S Hecker.

   Introduction: Relapsed/refractory (r/r) large B-cell lymphoma (LBCL) remains a difficult-to-treat disease with limited treatment options and high unmet clinical need, necessitating the development of new therapies with greater potency and broader applicability. While autologous chimeric antigen receptor (CAR)-T cell therapies have transformed the treatment landscape, 60-65% of patients receiving these therapies eventually relapse, underscoring the need for improved approaches. Allogeneic CAR-T and CAR-NK cell therapies have recently emerged as promising alternatives, offering the potential to shorten manufacturing times, reduce costs, and expand access to a broader patient population. This systematic review and meta-analysis compiles the currently available clinical trial data on the efficacy and safety of these novel therapies in adult patients with r/r LBCL.
Methods: A systematic search of MEDLINE, EMBASE, Web of Science, and the Cochrane Central Register of Controlled Trials was conducted for studies published up to January 12, 2025, involving allogeneic CAR-T and CAR-NK cell therapies in R/R LBCL. The primary outcomes assessed were the best overall response rate (bORR) and best complete response rate (bCRR) at any time point. Secondary outcomes included rates of grade 1-2 and grade 3+ cytokine release syndrome (CRS), grade 1-2 and grade 3+ immune effector cell-associated neurotoxicity syndrome (ICANS), grade 1-2 and grade 3+ infections and incidence of graft-versus-host disease (GvHD).
Results: Nineteen studies met the inclusion and exclusion criteria, encompassing 334 patients (155 CAR-NK; 179 CAR-T) evaluable for safety and 235 patients evaluable for response (77 CAR-NK; 158 CAR-T). The pooled estimates for the best overall response rate (bORR) and the best complete response rate (bCRR) were 52.5% [95% CI, 41.0-63.9] and 32.8% [95% CI, 24.2-42.0], respectively. Safety analysis revealed very low incidences of grade 3+ CRS (0.04% [95% CI 0.00-0.49]) or grade 3+ ICANS (0.64% [95% CI 0.01-2.23]) and only one occurrence of a GvH-like reaction across 334 infused patients enrolled in the included studies, highlighting the remarkable safety profile of CAR-engineered "off-the-shelf" allogeneic approaches. The estimated overall incidence of low-grade CRS was 30% [95% CI, 14-48], while the estimated overall incidence of low-grade ICANS was 1% [95% CI, 0%-4%], markedly lower than current-generation autologous CAR-T cell products. The incidence of low-grade and severe infections was 25% [95% CI 14-36%) (n=252) and 7% [95% CI 2-14%] (n=291), respectively.
Discussion: Together, allogeneic CAR-T and CAR-NK cell therapies demonstrate encouraging efficacy in heavily pretreated patients with r/r LBCL. Coupled with their favorable safety profiles and the potential for off-the-shelf availability, allogeneic cell therapies hold great promise to broaden the reach of live cell-based treatments, delivering impactful results to a wider patient population in the coming years.

Keywords:  CRISPR gene editing; adoptive cell therapy (ACT); allogeneic CAR-NK cells; allogeneic CAR-T cells; cellular engineering; clinical trial; large B cell lymphoma; precision gene editing

DOI:  https://doi.org/10.3389/fimmu.2025.1585556
EClinicalMedicine. 2025 Jul;85 103336

Treatment outcomes for patients with newly diagnosed or relapsed/refractory TP53-mutated mantle cell lymphoma: a systematic review and meta-analysis.

Na Zhang, Jiegang Xu, Chengxin Luo, Rushuang Xu, Yan Zeng, Dongfeng Zeng, Shuangnian Xu, Xi Li.

   Background: TP53 mutation is a critical predictor of early disease progression and poor prognosis in mantle cell lymphoma (MCL). Optimal treatment for these patients remains unclear. This systematic review and meta-analysis evaluated various strategies for achieving remission in TP53-mutated (TP53m) MCL.
Methods: We searched EMBASE, MEDLINE and conference proceedings from inception to May 7, 2025, without language restrictions. Randomised controlled trials, single-arm trials, and prospective or retrospective observational studies assessing remission strategies in newly diagnosed or relapsed/refractory TP53m MCL were included. Case reports, case series, and non-human studies were excluded. Two authors independently selected studies, extracted summary data from published reports, and assessed bias risk. Outcomes of interest were complete remission (CR) rate, overall response rate (ORR), overall survival (OS), and progression-free survival (PFS). Random-effects meta-analyses were used for summary estimation. The study is registered with PROSPERO, CRD42024594152.
Findings: A total of 9833 studies were identified, of which 39 studies involving 734 patients with TP53m MCL were eligible. For newly diagnosed TP53m MCL, targeted therapy (TT) had a CR rate of 89% (95% confidence interval (CI) 80-99; n = 52; I2 = 0%), an ORR of 96% (95% CI 89-100; n = 48; I2 = 0%), a median OS of 38.5 months (95% CI 37.74-39.26; n = 6), a 2-year OS rate of 76% (19/25) (95% CI 55-91; n = 25), a median PFS of 38.5 months (95% CI 37.74-39.26; n = 6) and a 2-year PFS rate of 62% (95% CI 33-87; n = 30; I2 = 44%). For relapsed/refractory TP53m MCL, allogeneic hematopoietic stem cell transplantation (Allo-HSCT) had a CR rate of 100% (95% CI 65-100; n = 4; I2 = 0%) and an ORR of 100% (95% CI 65-100; n = 4; I2 = 0%); Chimeric antigen receptor-T (CAR-T) cell therapy had a CR rate of 85% (95% CI 69-100; n = 75; I2 = 66%), an ORR of 90% (95% CI 83-98; n = 67; I2 = 0%), a 2-year OS rate of 44% (37/61) (95% CI 32-58; n = 61), and 2-year PFS rates of 31% (19/61) (95% CI 20-44; n = 61); TT had a CR rate of 53% (95% CI 39-73; n = 95; I2 = 60%), an ORR of 64% (95% CI 53-77; n = 139; I2 = 50%), a median OS of 10.87 months (95% CI 6.41-15.33; n = 57; I2 = 0%), a 2-year OS rate of 53% (95% CI 45-62; n = 141; I2 = 0%), a median PFS of 7.83 months (95% CI -0.89-16.55; n = 31; I2 = 80%) and a 2-year PFS rate of 28% (95% CI 14-44; n = 141; I2 = 72%).
Interpretation: Our findings indicate that TT may benefit patients with newly diagnosed TP53m MCL, and Allo-HSCT, CAR-T cell therapy, or TT could be considered for relapsed/refractory cases. However, -suboptimal long-term survival highlights the urgent need for innovative therapies. Key limitations, including small sample sizes and few randomised controlled trials (RCTs), emphasize the need for well-designed RCTs with adequate sample size in this field.
Funding: The Chongqing Natural Science Foundation and Talent Innovation Capability Cultivation Program of the Army Medical Center.

Keywords:  Mantle cell lymphoma; Remission strategies; TP53 mutations

DOI:  https://doi.org/10.1016/j.eclinm.2025.103336
Blood Adv. 2025 Jul 21. pii: bloodadvances.2025016490. [Epub ahead of print]

IVIG prophylaxis should be initiated following bispecific antibody therapy in multiple myeloma regardless of IgG levels.

Rahul Banerjee, Meera Mohan, Kai Rejeski, Benjamin R Puliafito, Diana D Cirstea, Gurbakhash Kaur, Shonali Midha, Georgia J McCaughan, Nikhil M Kumar, Nikita Mehra, Bhausaheb Bagal, Noopur S Raje.

Bispecific antibodies (bsAbs) such as teclistamab, elranatamab, linvoseltamab, and talquetamab have impressive efficacy in multiple myeloma (MM) but come with substantial infectious risks that do not dissipate over time. Immunoglobulin replacement therapy (IgRT), which includes intravenous immunoglobulin (IVIG) and subcutaneous immunoglobulin (SCIG), may lower these risks. In this Viewpoint, we contrast primary IgRT prophylaxis (initiation regardless of IgG levels) with preemptive IgRT treatment (initiation only once IgG levels fall below a certain threshold) in this setting. We make evidence-based arguments for primary prophylaxis as a safer and simpler approach compared to preemptive IgG-guided IgRT. We also discuss strategies to improve the cost-effectiveness of IVIG and SCIG across the world. Given the overwhelmingly favorable benefit-risk profile of IgRT coupled with the limitations inherent to IgG measurements in MM, withholding IgRT access based on arbitrary IgG thresholds is neither scientifically sound nor clinically appropriate for patients with MM receiving bsAb therapy.

DOI: https://doi.org/10.1182/bloodadvances.2025016490
Blood Adv. 2025 Jul 21. pii: bloodadvances.2025016511. [Epub ahead of print]

YX0798 Is a Highly Potent, Selective, and Orally Effective CDK9 Inhibitor for Treating Aggressive Lymphoma.

Vivian Jiang, Yu Xue, Hong Kim, Qingsong Cai, Tianci Zhang, Lei Nie, Joseph McIntosh, Yang Liu, Haiying Chen, Jia Zhou, Michael L Wang.

Non-genetic transcription evolution has been increasingly explored and recognized to drive tumor cell progression and therapeutic resistance. As the regulation hub of transcription machinery, cyclin-dependent kinase 9 (CDK9) is the gatekeeper of RNA polymerase II (Pol II) transcription, and CDK9 dysfunction results in transcriptomic reprogramming and tumor cell progression. We recently reported that the HSP90-MYC-CDK9 network drives therapeutic resistance in mantle cell lymphoma (MCL) through transcriptomic reprogramming. We also showed that targeting CDK9 by AZD4573 and enitociclib is a safe and effective treatment in preclinical MCL models, supporting CDK9 as a valid therapeutic target for MCL. However, current CDK9 inhibitors (CDK9i) under therapeutic development have room for improvement due to limited target selectivity and oral bioavailability. To this end, YX0798 was discovered to be a novel CDK9i through structural optimization. YX0798 demonstrated remarkable target selectivity and high affinity in binding to CDK9. Furthermore, YX0798 showed good oral bioavailability. YX0798, when administrated orally (5 mg/kg, daily), led to an efficacious anti-tumor activity in vivo and showed the potency in overcoming therapeutic resistance. Mechanistically, YX0798 downregulated the short-lived oncoprotein c-MYC and pro-survival protein MCL-1 as a common mechanism of CDK9 inhibition. Moreover, YX0798 disrupted the cell cycle and resulted in transcriptomic reprogramming, eventually leading to cell death. Furthermore, YX0798 has the potential to be used in combination therapy with clinical agents to improve treatment efficacy. Together, these data demonstrate that YX0798 has oral bioavailability, exquisite selectivity, and anti-tumor potency that results from driving transcription reprogramming towards tumor cell killing.

DOI: https://doi.org/10.1182/bloodadvances.2025016511
J Biochem Mol Toxicol. 2025 Aug;39(8): e70387

Downregulation of CLEC2 Facilitates the Proliferation and Migration of Multiple Myeloma Cells via Regulating HIF-1α-Mediated Ferroptosis.

Fangbing Zhu, Lili Hang, Pingping Zhang, Yuan Yuan, Ji Shen, Feng Zhang.

  Multiple myeloma (MM) is a hematologic cancer affecting plasma cells, characterized by the abnormal proliferation of malignant plasma cells in the bone marrow. Research in recent years has shown that the inhibition of ferroptosis is involved in the pathogenesis of MM. CLEC2 is a C-type lectin receptor family member mainly related to the activation of platelets, which is reported to be lowly expressed in multiple tumors. However, the role of CLEC2 in MM remain unknown. The present study clarified CLEC2's function in MM by exploring its impacts on ferroptosis. Comparing to normal plasma cells (NPCs), CLEC2 was found markedly downregulated in MM cell lines. In CLEC2-overexpressed U266 cells, largely declined cell viability and migrated cell counts, markedly enhanced ROS and MDA levels, and declined SOD activities were observed, accompanied by increased Fe2+ levels, upregulated ACSL4, and downregulated GPX4, HIF-1α, and SLC7A11. Moreover, in CLEC2-knockdown OPM-2 cells, greatly increased cell viability and migrated cell counts, sharply repressed ROS and MDA levels, and enhanced SOD activities were observed, along with reduced Fe2+ levels, downregulated ACSL4, and upregulated GPX4, HIF-1α, and SLC7A11. In addition, influences of CLEC2 overexpression on proliferation, Fe2+ levels, and expressions of ACSL4, GPX4, HIF-1α, and SLC7A11 in U266 cells were remarkably abolished by Fer-1 (an inhibitor of ferroptosis) or HIF-1α overexpression. Collectively, downregulation of CLEC2 in MM facilitated the proliferation and migration of MM cells via regulating HIF-1α-mediated ferroptosis.

Keywords:  CLEC2; HIF‐1α; ferroptosis; multiple myeloma

DOI:  https://doi.org/10.1002/jbt.70387
Blood. 2025 Jul 23. pii: blood.2025028597. [Epub ahead of print]

A BCMA-mRNA vaccine is a promising therapeutic for multiple myeloma.

Debasmita Dutta, Jiye Liu, Kenneth Wen, Arghya Ray, Alessandro Salatino, Xiangdong Liu, Annamaria Gulla, Teru Hideshima, Yan Song, Kenneth C Anderson.

Cancer vaccines are emerging as promising therapies to not only prevent cancer but to treat cancer. Here, we developed a therapeutic vaccine for multiple myeloma (MM) using BCMA protein as a target. Given the remarkable efficacy of COVID 19 mRNA vaccines, we first packaged sequence- and base- optimized BCMA mRNA into lipid nanoparticles (LNPs) using next-generation ionizable lipid enhancing their accumulation in the spleen. A TLR3 agonist, polyinosinic:polycytidylic acid (Poly(I:C)), was also encapsulated in LNPs to further elicit BCMA-specific immune response. BCMA-mRNA LNPs were internalized by dendritic cells (DCs) in vitro, triggering proliferation and activation of BCMA-specific CD8+ cytolytic T cells (CTLs). Importantly, these CTLs lysed BCMA+ U266 MM cells and CD138+ patient MM cells, without affecting BCMA-knockout (KO) U266 or CD138- patient derived bone marrow cells. Vaccination of C57BL/6J mice with BCMA-mRNA LNPs activated splenic DCs and induced BCMA-specific CTLs, assessed by tetramer staining, which selectively killed murine 5TGM1 BCMA overexpressing (5TGM1-BCMA-OE) MM cells. Finally, vaccination of C57BL/KaLwRijHsd mice bearing BCMA-overexpressing 5TGM1 cells inhibited tumor growth associated with BCMA-specific CD8+ T cell responses. The combination treatment with Poly(I:C) further triggered the immune response induced by BCMA-mRNA LNPs in all instances. Our findings provide the framework for clinical evaluation of BCMA-mRNA LNP vaccines to improve patient outcome in MM.

DOI: https://doi.org/10.1182/blood.2025028597
Front Cell Dev Biol. 2025 ;13 1607145

Editorial: Advancements in hematopoietic stem cell proliferation and self-renewal maintenance.

Pawan Kumar Raghav, Gurudutta Gangenahalli, Takahiko Hara.



Keywords:  Bone marrow-pathology; Hematopoietic stem and progenitor cells (HSPCs); Hematopoietic stem cells (HSCS); Induced pluripotent stem cells (iPSCs); Long-term culture-initiating cells (LTC-ics); Proliferation; Self-renewal; Self-renewing populations (SRPs)

DOI:  https://doi.org/10.3389/fcell.2025.1607145
Clin Lymphoma Myeloma Leuk. 2025 Jun 22. pii: S2152-2650(25)00217-4. [Epub ahead of print]

SOHO State of the Art Updates and Next Questions | The Optimal Management of Waldenström Macroglobulinemia.

Alberto Guijosa, Alicia de Las Heras, Shayna Sarosiek, Jorge J Castillo.

  Waldenström macroglobulinemia (WM) is a rare IgM-secreting lymphoplasmacytic lymphoma with recurrent somatic mutations in MYD88 and CXCR4 observed in the malignant cells of >90% and 30% to 40% of the patients. Given its rarity, WM poses specific diagnostic and management challenges. The diagnosis of WM is clinicopathological and no pathognomonic findings exist. The combination of a monoclonal IgM paraproteinemia, lymphoplasmacytic lymphoma in the bone marrow or other organs, and the MYD88 L265P mutation makes a diagnosis of WM with a high specificity. Approximately, a third of the patients will be asymptomatic at diagnosis and the best approach is to observe, as these patients have similar survival rates than age, sex and year of diagnosis-matched individuals of the general population. Eighty percent of patients diagnosed with asymptomatic WM will need treatment within 10 years. Treatment is indicated in symptomatic patients in whom the symptoms affect the patients' activities and are likely to be caused by the disease process. Multiple standard treatment options are safe and effective in symptomatic patients, including rituximab in combination with alkylating agents or proteasome inhibitors, covalent BTK inhibitors, and BCL2 antagonists. Noncovalent BTK inhibitors have emerged as a novel treatment option. Second-generation BCL2 antagonists, BTK degraders, antibody-drug conjugates and bispecific T-cell engagers are being evaluated in clinical trials. Multinational collaborative consortia to accelerate clinical trial design and execution in WM have emerged in Europe and the United States.

Keywords:  BCL2 antagonists; BTK inhibitors; Diagnosis; Prognosis; Treatment

DOI:  https://doi.org/10.1016/j.clml.2025.06.017
Invest New Drugs. 2025 Jul 21.

Low-dose PD-1 inhibition in relapsed/refractory classic Hodgkin lymphoma: systematic review and meta-analysis.

Mobil Akhmedov, Pervin Zeynalova, Alexander Fedenko, Andrey Kaprin.

   INTRODUCTION: No correlation between the dose, adverse events, and efficacy was detected in clinical trials of anti-PD-1 antibodies across a range of solid and hematological malignancies. Given that dose reduction with potentially comparable clinical efficacy may improve access to treatment, particularly in low-income regions, we conducted a systematic review and meta-analysis to evaluate the efficacy and safety of low-dose PD-1 inhibitor monotherapy in relapsed/refractory (r/r) classic Hodgkin lymphoma (cHL).
MATERIALS AND METHODS: Relevant reports were identified through PUBMED, MEDLINE, Cochrane, ScienceDirect databases, and major international conference proceedings, from inception till December 1, 2024. The risk of bias was assessed independently by two authors using the Joanna Briggs's critical appraisal checklist for studies reporting prevalence data. Heterogeneity was assessed using Cochran's Q test, with statistical significance defined as p < 0.05; I2 statistic was used to quantify heterogeneity. Random effects models (Der-Simonian method) was used to pool results from primary studies in the presence of significant heterogeneity.
RESULTS: After screening, 13 reports including 148 patients were included in the systematic review. After exclusion of duplicated reports, studies with less than 5 patients, and studies with unextractable data, five studies with a total of 84 patients were included in the meta-analysis. The pooled objective response rate (ORR) with low-dose PD-1 inhibition in r/r cHL, as determined by meta-analysis, was 87% (95% CI, 71.9%-100%), with a corresponding complete response (CR) rate of 53.9% (95% CI, 34.7%-73.1%). The ORR with low-dose nivolumab was 83.8% (95% CI, 64.2%-100%), with a CR rate of 43.3% (95% CI, 29.7%-56.9%). The pooled rate of any-grade adverse events after low-dose PD-1 inhibition was 55.7% (95% CI, 36.1%-75.3%), with a grade 3-4 adverse event rate of 7.5% (95% CI, 1.7%-13.3%).
CONCLUSIONS: This systematic review and meta-analysis demonstrated the high efficacy and acceptable toxicity of low-dose PD-1 inhibition in r/r cHL.

Keywords:  Flat dose; Hodgkin; Low-dose; Nivolumab; Pembrolizumab; Relapsed

DOI:  https://doi.org/10.1007/s10637-025-01565-0
Lancet Oncol. 2025 Jul 15. pii: S1470-2045(25)00330-4. [Epub ahead of print]

Belantamab mafodotin plus bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma (DREAMM-7): updated overall survival analysis from a global, randomised, open-label, phase 3 trial.

DREAMM-7 study investigators

BACKGROUND: In the primary (first interim) analysis of the DREAMM-7 trial (median follow-up 28·2 months), belantamab mafodotin, bortezomib, and dexamethasone (BVd) showed a statistically significant and clinically meaningful progression-free survival benefit versus daratumumab, bortezomib, and dexamethasone (DVd) in patients with relapsed or refractory multiple myeloma (RRMM) after at least one line of therapy. The aim of this study is to report overall survival from the second interim analysis, with extended follow-up.
METHODS: In the ongoing global, open-label, randomised, phase 3 DREAMM-7 trial done at 142 study centres (research facilities, hospitals, and institutions) in 20 countries across North America, South America, Europe, and the Asia-Pacific region, eligible patients were aged at least 18 years and had confirmed multiple myeloma (according to International Myeloma Working Group criteria), an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, and progression on or after at least one previous line of therapy. Patients were randomly assigned (1:1) by use of a central interactive response technology system to receive BVd, which comprised belantamab mafodotin 2·5 mg/kg intravenously every 3 weeks plus bortezomib 1·3 mg/m2 subcutaneously (twice weekly in 21-day cycles, for up to eight cycles) plus dexamethasone 20 mg orally or intravenously (on the day of, and after, bortezomib; for up to eight cycles), or DVd, which comprised daratumumab 16 mg/kg intravenously (21-day cycles; once weekly in cycles 1-3, every 3 weeks in cycles 4-8, and every 4 weeks in cycle 9 and beyond) plus bortezomib and dexamethasone; bortezomib and dexamethasone doses and schedules were the same as those in the BVd group. Randomisation was stratified by number of previous lines of therapy, previous bortezomib, and Revised International Staging System stage. Treatment assignments were unmasked for study personnel and patients; however, they were masked to the independent review committee. Patients received treatment until progressive disease, death, unacceptable toxicity, withdrawal of consent, or loss to follow-up, whichever occurred first. The primary endpoint was progression-free survival; key secondary endpoints were overall survival, minimal residual disease negativity in patients with a complete response or better, duration of response to treatment, and safety. Analysis of efficacy endpoints was based on assessments in all patients who were randomly assigned (ie, the intention-to-treat population). The safety population included all randomly assigned patients who received one or more doses of study treatment. This trial is registered with ClinicalTrials.gov, NCT04246047, and is ongoing.
FINDINGS: From May 7, 2020, to June 28, 2021, of 623 patients assessed for eligibility, 494 were randomly assigned to receive BVd (n=243) or DVd (n=251); 272 (55%) were male, and 409 (83%) were White. The median age of the patients was 64·5 years (IQR 57·0-71·0). At the updated data cutoff (Oct 7, 2024) and median follow-up (39·4 months [IQR 14·6-42·9]), early, sustained, and significant overall survival benefit was observed with BVd versus DVd. Median overall survival was not reached (NR; 95% CI NR-NR) with BVd and NR (41·0 months-NR) with DVd (hazard ratio [HR] 0·58; 95% CI 0·43-0·79; p=0·0002). BVd versus DVd led to greater than double the minimal residual disease-negativity rates in patients with a complete response or better (25% [95% CI 19·8%-31·0%] vs 10% [6·9%-14·8%]) and median duration of response (40·8 months [95% CI 30·5 months-NR] vs 17·8 months [13·8-23·6]). Analysis of progression-free survival 2 showed that the treatment benefit favouring BVd versus DVd was maintained following subsequent antimyeloma therapy; median progression-free survival 2 was NR with BVd (95% CI 45·6-NR) versus 33·4 months (95% CI 26·7-44·9) with DVd (HR, 0·59; 95% CI, 0·45-0·77). The most common grade 3 or 4 adverse event was thrombocytopenia (135 [56%] of 242 with BVd vs 87 [35%] of 246 with DVd). Serious adverse events occurred in 129 (53%) of 242 patients receiving BVd and 94 (38%) of 246 patients receiving DVd; the most common events were pneumonia (29 [12%] vs 11 [4%]), pyrexia (12 [5%] vs 10 [4%]), and COVID-19 (11 [5%] vs 10 [4%]). Treatment-related serious adverse events that led to death occurred in seven (3%) of 242 patients receiving BVd (pneumonia [n=4], gastrointestinal haemorrhage [n=1], subdural haemorrhage [n=1], or mesenteric vessel thrombosis [n=1]) and two (1%) of 246 receiving DVd (COVID-19 [n=2]).
INTERPRETATION: DREAMM-7 showed significant and clinically meaningful overall survival, progression-free survival, minimal residual disease negativity, and duration of response benefits with BVd versus DVd. BVd could be a new standard of care for RRMM.
FUNDING: GSK.

DOI: https://doi.org/10.1016/S1470-2045(25)00330-4
Hematol Rep. 2025 Jun 27. pii: 31. [Epub ahead of print]17(4):

Uncommon Entities, Uncommon Challenges: A Review of Rare Plasma Cell Disorders.

Amr Hanbali, Abdullah Alamer, Saud Alhayli.

  Rare plasma cell disorders-including IgD, IgE, and IgM multiple myeloma, non-secretory myeloma (NSMM), plasma cell leukemia (PCL), and heavy chain disease (HCD)-are biologically heterogeneous and often present with atypical features and aggressive behavior. This review synthesizes current evidence on their epidemiology, pathophysiology, diagnosis, and treatment. Advances in proteasome inhibitors, immunomodulatory agents, and autologous transplantation have improved outcomes in select subtypes. However, challenges persist in distinguishing IgM myeloma from Waldenström macroglobulinemia, monitoring non-secretory disease, and treating highly aggressive forms such as IgE myeloma and PCL. Standardized diagnostic criteria and prospective trials are essential to guide future management.

Keywords:  IgD multiple myeloma; IgE multiple myeloma; IgM multiple myeloma; diagnostic challenges; heavy chain disease; non-secretory myeloma; plasma cell leukemia; rare plasma cell disorders

DOI:  https://doi.org/10.3390/hematolrep17040031
Oncoimmunology. 2025 Dec;14(1): 2532226

CD200 immune checkpoint expression is associated with inferior outcome in multiple myeloma patients treated with anti-CD38 monoclonal antibodies.

Djamila Chemlal, Camille Pochard, Valentin Jacquier, Angélique Bruyer, Ludovic Gabellier, Léa Fornero, Clément Vempère, Amélie Machura, Guilhem Requirand, Nicolas Robert, Caroline Bret, Guillaume Cartron, Laure Vincent, Hugues de Boussac, Jérôme Moreaux, Charles Herbaux.

  In multiple myeloma (MM), the anti-CD38 monoclonal antibody Daratumumab has become essential in the therapeutic arsenal, although very few predictive factors of response to Daratumumab have been identified in clinical studies. We have prospectively collected biological data from 97 patients treated with Daratumumab in first line or at relapse in our center between 2016 and 2020. These data included multiparameter flow cytometry phenotype (CD200, CD117, CD56, CD38, CD45, and CD27), cytogenetic, and transcriptomic gene expression profiling (GEP) of tumor plasma cells before treatment with Daratumumab. We first looked for predictive factors of response to Daratumumab. We found that high CD56 expression and CD45 expression were significantly associated with better progression free survival (PFS) whereas high CD200 expression was significantly associated with poorer PFS. Then, we showed that the CD200-CD200R immune synapse is responsible for a decrease in Daratumumab response through the alteration of NK cells' activity. Finally, we demonstrated that inhibition of CD200 increase response to Daratumumab in MM patient samples, highlighting its potential as a predictive biomarker for Daratumumab response and as a possible therapeutic target in combination with Daratumumab. This study is the first to identify phenotypic and molecular factors' predictor of response to Daratumumab.

Keywords:  CD200; Myeloma; immunotherapies; resistance

DOI:  https://doi.org/10.1080/2162402X.2025.2532226
Clin Pharmacol Ther. 2025 Jul 24.

Recommended Phase II Doses of Talquetamab in Patients With Relapsed/Refractory Multiple Myeloma From MonumenTAL-1: Clinical Pharmacology Results.

Jue Gong, Jie Zhou, Dongfen Yuan, Xuewen Ma, Deeksha Vishwamitra, Brandi Hilder, Tara J Masterson, Jaszianne Tolbert, Thomas Renaud, Christoph Heuck, Colleen Kane, Mahesh N Samtani, Suzette Girgis, Nahor Haddish-Berhane, Jesus Berdeja, Amrita Krishnan, Daniele Ouellet.

Talquetamab is the first and only GPRC5D × CD3 bispecific antibody approved for relapsed/refractory multiple myeloma (RRMM). In the phase I/II MonumenTAL-1 study, overall response rates (ORRs) were > 66% in patients with RRMM treated with subcutaneous talquetamab at the recommended phase II doses (RP2Ds): 0.4 mg/kg weekly and 0.8 mg/kg every other week. We characterized the pharmacokinetics (PK), pharmacodynamics, immunogenicity, and exposure-response relationships for efficacy and safety following talquetamab administration in phase I and II. In phase I, talquetamab exposure increased in an approximately dose-proportional manner across intravenous and subcutaneous doses and was maintained around or above the 90% maximum effective concentration identified in an ex vivo cytotoxic assay at the RP2Ds. Higher levels of T-cell activation and cytokine induction were observed at the RP2Ds compared with lower doses. Talquetamab demonstrated time-dependent clearance with a half-life of 7.56 days at initial treatment and 12.2 days at steady state. Patients with immunoglobulin G multiple myeloma and International Staging System (ISS) stage II/III exhibited higher clearance of talquetamab, which resulted in lower exposure. Dose adjustment based on myeloma subtype and ISS stage was not required. In exposure-response analyses, a near-flat relationship was demonstrated for ORR, duration of response, and progression-free survival at the exposure range of the RP2Ds. In safety exposure-response analyses, rates of grade 1/2 dysgeusia increased with higher exposures. The incidence of anti-talquetamab antibodies had no apparent impact on the PK, efficacy, or safety of talquetamab. These clinical pharmacology results support the selection of the talquetamab RP2Ds.

DOI: https://doi.org/10.1002/cpt.70004
Expert Rev Hematol. 2025 Jul 23.

An observational study of disease management in adult patients with polycythemia vera: results from a large U.S. claims database.

Andrew Kuykendall, Lucy Bellamy, Lopa Desai, Omari Morrison, Larisa Gofman, Arturo Molina.

   BACKGROUND: Polycythemia vera (PV) is characterized by erythrocytosis and an increased risk of thrombotic events (TEs). Currently, standard-of-care therapies for PV have limitations, which warrants the need to understand real-world treatment patterns and treatment burden in PV.
RESEARCH DESIGN AND METHODS: This retrospective observational study analyzed real-world claims data in adult patients with PV using Komodo Health claims database (2016-2022) in the United States. Burdensome treatment was classified as patients receiving ≥ 3 phlebotomies (PHLs) within a 6-month period and/or high dose hydroxyurea (HU) ≥ 1,000 mg per day.
RESULTS: Of 44,766 treated patients (mean age: 65 years; 64% male), 55% received burdensome treatment, which included frequent PHL (33%), high-dose HU (17%), or combination of both (frequent PHL + high-dose HU, 5%). PHL and HU were the most common first-line treatments (PHL, 71%; HU, 27%), and 87% of patients initiating treatment with PHL monotherapy never advanced to another therapy regimen. TEs occurred in 16% of the treated patients.
CONCLUSIONS: These data suggest a substantial proportion of patients with PV receive burdensome treatments, with 55% of treated patients receiving frequent PHL and/or high-dose HU, highlighting need for therapy optimization. However, inherent limitations of using claims data should be taken into consideration.

Keywords:  Disease management; hydroxyurea; phlebotomy; polycythemia vera; thrombotic events; treatment patterns

DOI:  https://doi.org/10.1080/17474086.2025.2538542
Acta Haematol. 2025 Jul 18. 1-24

Practical Management of Cardiovascular Adverse Events with BTKi Treatment in Patients with Chronic Lymphocytic Leukemia: A Consensus Report by Hematologists and Cardiologists.

Talha Munir, Eglė Čiburienė, Vasko Graklanov, Mariana Gospodinova, Ozren Jakšić, Luka Lipar, Imelda Marton, Anna Panovská, Lucia Petríková, Regina Pileckyte, Zoltan Pozsonyi, Miroslav Slanina, Matevž Škerget, Nikola Bulj.

BACKGROUND: Cardiovascular (CV) adverse events (AEs), especially atrial fibrillation (AF) and hypertension, have been reported in patients receiving treatments for chronic lymphocytic leukemia (CLL), including Bruton's tyrosine kinase inhibitors (BTKis). Although these AEs are managed effectively in most cases and AE management guidelines exist, practical management approaches are inconsistent across regions and practices. We aimed to address these inconsistencies by developing consensus recommendations.
SUMMARY: A European expert panel was assembled comprising eight hematologists and six cardiologists. Literature analysis, expert interviews, and the Delphi method were used to gain consensus on screening, monitoring, and treatment of AF and hypertension statements.
KEY MESSAGES: Maintaining BTKi treatment is paramount to maximize time to next treatment; for patients at high risk of progression, this can be achieved by appropriately treating hypertension and AF and adjusting the BTKi dose. Patients should be risk-stratified as low, moderate, high, or very high risk of cancer therapy-related CV toxicity and treated according to their disease status so that CLL treatment can be maintained. Patient education on symptom monitoring, home blood pressure monitoring, and electrocardiograms (baseline, every 3 months) are recommended to detect/monitor AF and hypertension. Close collaboration between hematologists and cardiologists is vital to achieve optimal patient outcomes.

DOI: https://doi.org/10.1159/000547426