bims-hemali 2025-10-12 papers

bims-hemali

Biomed News

on Hematologic malignancies

Issue of 2025–10–12
28 papers selected by
Alexandros Alexandropoulos, Γενικό Νοσοκομείο Αθηνών Λαϊκό

Clinical and biological predictors of treatment-free remission in CML.
Circulating tumor cells predict myeloma outcomes in patients treated with daratumumab, bortezomib, lenalidomide, and dexamethasone.
Emerging Significance and Implications of a Durable Complete Molecular Remission in the Treatment of Polycythemia Vera.
Mel200 or BuMel conditioning in myeloma: is there a winner?
Smarter combos, stronger T cells in lymphoma.
An overview of strategies and challenges adopted to silence BCR-ABL gene by small interfering RNA.
Phase 2 trial of rituximab with either pentostatin or bendamustine for multiply relapsed or refractory hairy cell leukemia.
Mutation profiling of chronic myeloproliferative neoplasms: improving clinical-molecular prognostic models.
Efficacy and safety of OB756 (a novel selective JAK2 inhibitor) for essential thrombocythemia in patients intolerant of or resistant to hydroxyurea or intolerant of interferon: A phase 2, open-label, multicenter study.
Polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) therapy in diffuse large B-cell lymphoma in patients aged 80 years or older: a real-world study.
Genomic Determinants of Response and Resistance to Pirtobrutinib in Relapsed/Refractory Chronic Lymphocytic Leukemia.
Introduction to a review series on follicular lymphoma: solved or insoluble problem?
Real-world outcomes and prognostic factors in primary mediastinal B-cell lymphoma: a multicenter study of 157 patients.
Polatuzumab vedotin in CNS lymphoma: proof-of-concept study for blood-brain barrier penetration.
Vaccination during bispecific antibody treatment for myeloma.
Long-term cardiac morbidity in adolescent and young adult survivors of classical Hodgkin lymphoma: the British Columbia experience.
Newly Diagnosed High-Risk Multiple Myeloma: Outcomes and Management.
Zanubrutinib plus salvage chemotherapy in patients with refractory/relapsed diffuse large B-cell lymphoma non-candidate for autologous stem cell transplantation: A retrospective study.
Venetoclax plus hypomethylating agents versus priming regimen as the first-line therapy for newly diagnosed acute myeloid leukemia with myelodysplasia-related changes: a propensity score-matched analysis.
Blinatumomab demonstrates MRD eradication in MRD-positive/chemotherapy-delayed pediatric B-ALL and high response in relapsed/refractory cases: a multicenter cohort study.
Brutons tyrosine kinase inhibitor Zanubrutinib modulates Fc gamma receptors to inhibit platelet destruction for alleviation of refractory immune thrombocytopenia.
Unlocking myeloma's spatial world at the micrometer scale.
The tumor microenvironment in hairy cell leukemia (HCL) and splenic B cell lymphoma with prominent nucleoli (SBLPN).
Discovery of Potent and Selective BCL6 Ligand-Directed Degrader (LDD), BCL6-760.
Lisaftoclax: First Approval.
Review of the Management of Relapsed/Refractory Follicular Lymphoma: An Italian Perspective.
Icefish: Peculiar Creatures Without Hemoglobin or Red Blood Cells.
Myeloid landscape profiling identifies DLBCL-specific suppressive macrophages colocalized with blood endothelial cells.

Leuk Lymphoma. 2025 Oct 10. 1-10

Clinical and biological predictors of treatment-free remission in CML.

Edwina Sutton, Naranie Shanmuganathan, David Ross.

  Chronic Myeloid Leukemia (CML) is characterized by the Philadelphia chromosome t(9:22) and results in the BCR::ABL1 fusion gene. Since the evolution of targeted therapy in the form of tyrosine kinase inhibitors (TKIs), overall survival has improved to 94% at 5 years. Early studies identified that approximately half of patients could maintain a major molecular remission (MMR), i.e. BCR::ABL1 ≤ 0.1%, in the absence of TKI therapy. This is termed treatment-free remission (TFR). Identifying clinical and biological predictors of TFR has become a major goal in CML. In this review, we discuss clinical predictors of TFR, including features at diagnosis, molecular response and kinetics, depth and duration of molecular response, and dose reduction prior to TKI cessation in determining TFR success. We also discuss advances in highly sensitive Minimal Residual Disease (MRD) assays, consider the genomic profile of CML patients and review the role of the immune environment in sustaining TFR.

Keywords:  BCR::ABL1; CML; TFR; TKI; biomarkers; drug discontinuation

DOI:  https://doi.org/10.1080/10428194.2025.2560081
Blood. 2025 Oct 08. pii: blood.2025030113. [Epub ahead of print]

Circulating tumor cells predict myeloma outcomes in patients treated with daratumumab, bortezomib, lenalidomide, and dexamethasone.

Luca Bertamini, Cathelijne Fokkema, Paula Rodriguez-Otero, Mark van Duin, Evangelos Terpos, Mattia D'Agostino, Vincent H J van der Velden, Niels W C J van de Donk, Michel Delforge, Christoph Driessen, Roman Hajek, Hermann Einsele, Annette Juul Vangsted, Diego Vieyra, Ricardo M Attar, Anna Sitthi-Amorn, Robin Carson, Fredrik Schjesvold, Pawel Robak, Meral Beksac, Andrew Spencer, Annemiek Broijl, Tom Cupedo, Philippe Moreau, Mario Boccadoro, Pieter Sonneveld.

Circulating tumor cells (CTC) represent a high-risk biomarker in newly diagnosed multiple myeloma (NDMM); however, their prognostic value among transplant-eligible (TE) patients receiving daratumumab with bortezomib/lenalidomide/dexamethasone (D-VRd) remains unknown. Here, we analyzed CTC in the phase 3 PERSEUS trial (EMN017/NCT03710603). TE patients with NDMM were randomized (1:1) to D-VRd with daratumumab/lenalidomide maintenance (D-VRd group) or VRd with lenalidomide maintenance (VRd group), both with transplant. A subset of 451/709 patients from PERSEUS (D-VRd, 231/355; VRd, 220/354) had screening blood samples collected for CTC analysis by flow cytometry (median follow-up, 47.6 months). CTC were detected in 370/451 (82%) patients (median limit of detection, 0.0004%). CTC were prognostic of progression-free survival (PFS), independently of other factors, as a continuous (HR, 1.36 [95% CI, 1.15-1.60]; P<0.001) and categorical variable (≥0.175% CTC-high, optimal threshold). D-VRd improved PFS versus VRd in CTC-low patients (4-year rates: 88% vs 74%; HR, 0.42 [95% CI, 0.25-0.70]; P=0.0013). Regardless of study treatment, minimal residual disease (MRD)-negativity rates were lower in CTC-high versus CTC-low patients (10-5: 52.2% vs 66.2%; 10-6: 34.8% vs 52.4%). D-VRd significantly increased MRD-negativity rates versus VRd among CTC-high (10-5: 69.4% vs 33.3%; 10-6: 47.2% vs 21.2%; both P<0.05) and CTC-low patients (10-5: 74.4% vs 57.8%; 10-6: 65.6% vs 38.5%; both P<0.001), with similar observations for sustained MRD negativity. CTC levels are an independent prognostic factor in TE-NDMM patients treated with standard-of-care frontline quadruplet. D-VRd improved overall and sustained MRD-negativity rates in CTC-high and CTC-low patients, and improved PFS for CTC-low with a positive trend in CTC-high patients. NCT03710603.

DOI: https://doi.org/10.1182/blood.2025030113
Curr Hematol Malig Rep. 2025 Oct 08. 20(1): 13

Emerging Significance and Implications of a Durable Complete Molecular Remission in the Treatment of Polycythemia Vera.

Minghui Duan, Prithviraj Bose, Anthony M Hunter, Albert Qin, Long Chang, Wenxin Li, Daoxiang Wu, Raajit K Rampal.

   PURPOSE OF REVIEW: Polycythemia vera (PV) is a Philadelphia chromosome-negative myeloproliferative neoplasm (MPN) caused by a somatic gain-of-function mutation of the Janus kinase2 (JAK2) gene in hematopoietic stem and peripheral blood cells, leading to erythrocytosis which is often accompanied by leukocytosis and thrombocytosis. Historically, PV management has mainly focused on maintaining hematocrit (HCT) levels below 45% to reduce major thrombotic risk, improving symptoms and monitoring disease progression. Phlebotomy alone or in combination with cytoreductive therapy, where indicated, form the current standard of care. This review explores the potential correlation between the depletion of neoplastic clones in patients with PV with the achievement of durable complete molecular remission (CMR), and long-term treatment effects on thrombotic events and survival, as well as implications for re-defining treatment goals. RECENT FINDINGS: Past management practices do not ideally optimize outcomes for patients with PV. Specifically, these approaches do not adequately address the underlying risk of disease progression driven by the neoplastic cells carrying mutated JAK2 and additional mutations. Patients with PV who are treated with interferon-based therapies can achieve complete hematologic response, together with a significant reduction of JAK2V617F Variant Allele Frequency (VAF). Continued reduction of the JAK2VAF may lead to CMR and is correlated with in vivo drug exposures and durable improvement of thrombotic risk, as well as increased probability of event-free survival (EFS). The results indicate that reduction in JAK2V617F VAF, and by extension depletion of neoplastic cells, is essential for favorable long term clinical outcomes in patients with PV. Emerging data suggest a direct correlation between deep reduction in JAK2V617F VAF as a measure of suppressing neoplastic cells and improved probability of EFS and delayed disease progression. These observations suggest a treatment paradigm shift from solely managing symptoms and preventing thrombotic events, toward achieving durable clonal depletion with potential for remission and preventing transformation to myelofibrosis or acute myeloid leukemia. Integration of molecular biomarkers into risk-adapted treatment algorithms may enable personalized approaches to achieve deep molecular responses and durable disease modification in PV. Clonal molecular response, therefore, deserves attention as a biomarker of response that should be evaluated in clinical trials, as well as for treatment monitoring.

Keywords:  Hematocrit; Interferon-based therapy; Molecular remission; Polycythemia vera; Transition of therapeutic goals; Treatment-free remission

DOI:  https://doi.org/10.1007/s11899-025-00758-x
Blood. 2025 Oct 09. 146(15): 1741-1742

Mel200 or BuMel conditioning in myeloma: is there a winner?

Donna E Reece.

DOI: https://doi.org/10.1182/blood.2025030399
Blood. 2025 Oct 09. 146(15): 1742-1744

Smarter combos, stronger T cells in lymphoma.

Santosha A Vardhana.

DOI: https://doi.org/10.1182/blood.2025030331
Nanomedicine (Lond). 2025 Oct 11. 1-20

An overview of strategies and challenges adopted to silence BCR-ABL gene by small interfering RNA.

Laura Fancello, Maria Manconi, Maria Letizia Manca.

  BCR-ABL oncogene associated with chronic myeloid leukemia (CML) encodes for tyrosine kinase with enhanced activity that drives the uncontrolled proliferation of white blood cells. The therapy with tyrosine kinase inhibitors improves the life expectancy of patients without curative effects. However, lifelong treatments are required and usually associated with adverse effects and drug resistance. Alternatively, gene-silencing using nucleic acids has been proposed to avoid the synthesis of protein kinase. The use of RNA Interference seems to be the most promising strategy for new therapy. This review provides an overview of clinically used therapy with tyrosine kinase inhibitors and explores future advances using RNA interference, especially siRNA, as it is the one tested the most up to now. The studies reporting the use of siRNA to silence BCR-ABL gene are analyzed based on the used sequence, chemical modifications, and delivery systems. The sequence that targets specific regions of BCR-ABL gene and chemical modifications that improve stability, specificity, and potency are underlined. Finally, the studies devoted to delivering siRNA have been examined based on the vector nature (natural or synthetic) and delivery mechanism (conjugation or loading). The level of maturity reached (in vitro, in vivo, pre-clinical) in the studies has been underlined. No clinical studies were found.

Keywords:  BCR-ABL; RNA interference; chemical modifications; chronic myeloid leukemia; delivery systems; siRNA

DOI:  https://doi.org/10.1080/17435889.2025.2571019
Blood. 2025 Oct 08. pii: blood.2025031243. [Epub ahead of print]

Phase 2 trial of rituximab with either pentostatin or bendamustine for multiply relapsed or refractory hairy cell leukemia.

Brett Schroeder, Constance M Yuan, Hao-Wei Wang, Chirayu Mohindroo, Hong Zhou, Mark Raffeld, Liqiang Xi, Evgeny Arons, Julie Catherine Feurtado, Lacey James-Echenique, Katherine R Calvo, Irina Maric, Robert J Kreitman.

The primary objective in multiply-relapsed hairy cell leukemia and variant (HCL/HCLv) was to determine if pentostatin-rituximab (DCFR) and bendamustine-rituximab (BR) each have overall response rate (ORR) exceeding that historically achieved by rituximab alone (~40%) in favor of 65%. Prospective data was unreported for either regimen. Fifty-six patients received six 28-day cycles of rituximab (375 mg/m² days 1, 15) with either bendamustine (90 mg/m² days 1, 2) or pentostatin (4 mg/m² days 1, 15). Eligibility required ≥2 purine analogs, or one plus rituximab for initial response <1 year. Complete remission (CR) and minimal residual disease (MRD) were studied, and progression-free survival (PFS) with hazard ratios (HR) determined. Although patients were assigned to either regimen through randomization for increasing homogeneity of the two treatment groups, the DCFR arm had fewer prior purine analogs (p=0.021) and lower baseline marrow HCL/HCLv infiltration (p=0.013). ORRs for DCFR and BR were 93% and 86%, 95% confidence intervals (95%CI) 83-102% and 73-99%, each exceeding the primary objective (40% in favor of 65%, p<0.0001 for each). Rates for CR and MRD-free CR and median PFS (141 vs 50 months, HR 0.63, 95%CI 0.32-1.25) numerically favored DCFR but that arm was significantly enriched with lower prior purine analogs and marrow infiltration each of which was associated post hoc with better response. Post hoc subgroup analysis particularly for the 41 patients with classic HCL suggested any superiority of DCFR vs BR might apply to the more favorable patients. DCFR and BR were highly effective in multiply relapsed HCL/HCLv. Possible DCFR superiority was hypothesis-generating, given uneven baseline risks and trial design. NCT01059786.

DOI: https://doi.org/10.1182/blood.2025031243
Expert Rev Mol Diagn. 2025 Oct 10.

Mutation profiling of chronic myeloproliferative neoplasms: improving clinical-molecular prognostic models.

Giuseppe G Loscocco, Naseema Gangat, Paola Guglielmelli, Alessandro M Vannucchi, Ayalew Tefferi.

   INTRODUCTION: Classic myeloproliferative neoplasms (MPN), comprising polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF), both primary and secondary to PV and ET, are clonal hematopoietic disorders characterized by abnormal proliferation of largely mature cells, commonly associated with JAK2, CALR, or MPL mutations. These mutations result in the constitutive activation of the JAK-STAT pathway. Furthermore, most patients - especially with MF- have additional mutations in genes associated with myeloid neoplasms, which encode proteins that play roles in chromatin modification, DNA methylation, mRNA splicing, transcriptional regulation, and oncogenesis.
AREA COVERED: This review details the molecular landscape of MPN and examines its impact on patient management. It also evaluates emerging artificial intelligence-based prognostic models, highlighting their advantages and limitations.
EXPERT OPINION: High throughput genomic characterization of MPN has identified clinically relevant driver and non-driver mutations. Driver mutations are crucial for diagnosis, monitoring post-transplantation, and treatment response in clinical trials and increasingly in routine practice. Mutation profiles, along with cytogenetic, histopathologic, and clinical data, are used to categorize patients by risk for thrombosis, survival, and progression to secondary leukemia. The identification of a molecular enhanced scoring system for secondary myelofibrosis and clinically relevant co-mutation patterns capable to predict specific outcomes are under investigation.

Keywords:  essential thrombocythemia; myelofibrosis; myeloproliferative neoplasms; polycythemia vera; prognosis; survival

DOI:  https://doi.org/10.1080/14737159.2025.2573466
Cancer. 2025 Oct 15. 131(20): e70101

Efficacy and safety of OB756 (a novel selective JAK2 inhibitor) for essential thrombocythemia in patients intolerant of or resistant to hydroxyurea or intolerant of interferon: A phase 2, open-label, multicenter study.

Jian Huang, Rumeng Li, Tiejun Gong, Pengxiang Guo, Lihong Shou, Hu Zhou, Zongjiu Jiao, Feng Zhang, Qinchi Liu, Lidong Zhao, Guocai Wu, Lili Chen, Yile Zhou, Yi Zhang, Jie Jin.

   BACKGROUND: OB756 is a novel oral selective JAK2 inhibitor targeting the JAK-STAT pathway. This study assessed its safety and efficacy in patients with essential thrombocythemia (ET) who were resistant to or intolerant of hydroxyurea or intolerant of interferon.
METHODS: This phase 2, single-arm, open-label, multicenter clinical trial evaluated the efficacy and safety of OB756 in patients with ET who were intolerant of or resistant to hydroxyurea, or intolerant of interferon. The primary end point was the complete hematologic response (CHR) rate at week 24, whereas secondary end points included hematologic response (HR), the proportion of patients with ≥35% spleen volume reduction at week 24, molecular response, and safety.
RESULTS: At week 24, the CHR was 22% (11 of 50) based on intention-to-treat analysis. Among evaluable patients, the HR rate reached 65.6% at week 24. At week 24, 94.7% of patients (36 of 38) experienced spleen volume reduction, with 50.0% achieving ≥35% reduction. Additionally, 74.2% of patients (23 of 31) had a ≥50% reduction in myeloproliferative neoplasm symptom assessment form total symptom score. Among evaluable patients, 84.7% (11 of 13) had a reduction in JAK2-V617F allele burden post-treatment. In terms of safety, most treatment-related adverse events (TEAEs) were grade 1-2. Grade ≥3 hematologic TEAEs included anemia (10%) and neutropenia (6%). The incidence of grade ≥3 infections was 16% and grade ≥3 thrombotic events was 2%.
CONCLUSIONS: Overall, OB756 was well-tolerated and demonstrated acceptable efficacy, offering a promising therapeutic option for ET patients who are resistant to or intolerant of hydroxyurea or intolerant of interferon.

Keywords:  JAK2 inhibitor; OB756; clinical trial; essential thrombocythemia

DOI:  https://doi.org/10.1002/cncr.70101
Ann Hematol. 2025 Oct 10.

Polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) therapy in diffuse large B-cell lymphoma in patients aged 80 years or older: a real-world study.

Toshiki Yamada, Nobuhiko Nakamura, Hideko Goto, Takeshi Hara, Senji Kasahara, Kenji Fukuno, Michio Sawada, Hiroshi Nakamura, Naoki Hayase, Takayuki Goto, Tomomi Suzaki, Kei Fujita, Shin Lee, Nobuhiro Kanemura, Masahito Shimizu, Hisashi Tsurumi.

  Diffuse large B-cell lymphoma (DLBCL) predominantly affects older adults, with an increasing proportion of patients aged ≥ 80 years. Although the POLARIX trial demonstrated improved progression-free survival with polatuzumab vedotin (Pola) combined with R-CHP (Pola-R-CHP), its applicability to very elderly patients remains unclear. A multicenter, retrospective, cohort study was conducted at seven hospitals in Japan, enrolling 172 previously untreated DLBCL patients who initiated Pola-R-CHP between August 1, 2022 and May 1, 2024. Patients were stratified by age (< 80 vs. ≥80 years). Initial dose intensity (IDI), average relative dose intensity (ARDI), treatment efficacy, and safety outcomes were evaluated. In patients aged ≥ 80 years (n = 44), the overall response rate (ORR) was 89.5%, comparable to the 97.3% in patients aged < 80 years. However, treatment-related mortality (TRM) was higher in the older group (11.4% vs. 2.3%). In this cohort, median IDI and ARDI for doxorubicin and cyclophosphamide were markedly lower, whereas Pola dosing was relatively preserved. Higher Pola IDI was associated with an increased incidence of severe adverse events (sAEs), and a lower Geriatric Nutritional Risk Index (GNRI) was independently correlated with both reduced ORR and increased sAEs. Pola-R-CHP demonstrates promising efficacy in DLBCL patients aged ≥ 80 years. However, the increased TRM highlights the importance of cautious toxicity management. Individualized dose modifications, particularly for cytotoxic agents, and comprehensive nutritional assessments may improve treatment tolerability and outcomes in this vulnerable population.

Keywords:  Chemotherapy dose intensity; Diffuse large B-Cell lymphoma; Geriatric oncology; Pola-R-CHP; Polatuzumab vedotin

DOI:  https://doi.org/10.1007/s00277-025-06619-0
Blood. 2025 Oct 07. pii: blood.2024027009. [Epub ahead of print]

Genomic Determinants of Response and Resistance to Pirtobrutinib in Relapsed/Refractory Chronic Lymphocytic Leukemia.

Jennifer R Brown, Bastien Nguyen, Sai Prasad Desikan, Helen Won, Shady I Tantawy, Samuel C McNeely, Narasimha Marella, Hetal S Randeria, Lauren M Hanson, Andrew Parker, Salome Calado Botelho, Jennifer A Woyach, Krish Patel, Constantine S Tam, Toby A Eyre, Chan Y Cheah, Nirav N Shah, Paolo Ghia, Wojciech Jurczak, Minna Balbas, Binoj Chandrasekharan Nair, Paolo B Abada, Chunxiao Wang, Denise Wang, Lindsey Elizabeth Roeker, Varsha Gandhi, William G Wierda.

Pirtobrutinib, a non-covalent, reversible Bruton tyrosine kinase inhibitor (BTKi), demonstrated efficacy in patients with chronic lymphocytic leukemia (CLL), resistant to covalent BTKi (cBTKi). Genomic correlations with response and resistance to pirtobrutinib were analyzed in relapsed/refractory (R/R) CLL patients pretreated with cBTKi and enrolled in the phase 1/2 BRUIN trial. DNA sequencing was performed on PBMCs at baseline, on treatment, and at progressive disease (PD). Common alterations at baseline included mutations in BTK (43%), TP53 (38%), SF3B1 (25%), NOTCH1 (23%), ATM (19%), XPO1 (11%), PLCG2 (9%), BCL2 (8%) and 17p deletion (28%). Common baseline BTK mutations included C481S (85%), C481R (10%), C481F (6%) and C481Y (4%). At PD, 60/88 patients (68%) acquired ≥1 mutation, including 44% with acquired BTK mutations and 24% with other acquired mutations. A total of 55 acquired BTK mutations were detected in 39 patients, including gatekeeper mutations (T474I/F/S/L/Y/P, 26%), kinase-impaired L528W (16%), C481F/R/Y (5%), V416L (2%), and A428D (1%) and others proximal to the ATP-binding pocket, D539G/H/A (1%) and Y545N (1%). Decrease or complete clearance of BTK C481x was observed at PD in 36/43 patients (84%). Using a more sensitive assay, 37% (18/49) of acquired BTK mutations were detected at baseline at low allele frequency. Using the highly sensitive assay at progression, a similar frequency of acquired BTK mutations (39%) was detected, and all patients had detectable acquired mutations. This study highlights the complex clonal dynamics of BTK mutations in R/R CLL patients undergoing pirtobrutinib treatment, and the extent of resistance without an obvious genomic driver. NCT03740529.

DOI: https://doi.org/10.1182/blood.2024027009
Blood. 2025 Oct 09. 146(15): 1739-1740

Introduction to a review series on follicular lymphoma: solved or insoluble problem?

Philippe Armand.

DOI: https://doi.org/10.1182/blood.2025030824
Ann Hematol. 2025 Oct 11.

Real-world outcomes and prognostic factors in primary mediastinal B-cell lymphoma: a multicenter study of 157 patients.

Selin Küçükyurt, Oguzhan Koca, Esra Terzi Demirsoy, Serkan Akın, Ali Doğan, Deniz Gören, Ahmet Yiğitbaşı, Osman Şahin, Yıldız İpek, Rafiye Çiftçiler, Fahri Şahin, Meral Uluköylü Mengüç, Işıl Erdoğan Özünal, Özge Soyer Kösemehmetoğlu, Yasemin Özgür, Figen Atalay, Hacer Berna Afacan Öztürk, Merve Yüksel, Nesibe Taşer Kanat, Ayşe Uysal, Utku İltar, Abdulkerim Yıldız, Fatma Keklik Karadağ, Mehmet Baysal, Mehmet Can Uğur, Serkan Güven, İbrahim Ethem Pınar, Özgür Mehtap, İbrahim Barışta, Ahmet Muzaffer Demir, Mahmut Yeral, Cem Selim, Güray Saydam, Işık Kaygusuz Atagündüz, Pınar Tığlıoğlu, İmdat Dilek, Mesut Ayer, Ahmet Kürşad Güneş, Meltem Kurt Yüksel, Ali Ünal, Ozan Salim, Nur Soyer, Elif Birtaş Ateşoğlu, Ahmet Emre Eşkazan.

  Primary mediastinal B-cell lymphoma (PMBCL) is a rare and distinct subtype of non-Hodgkin lymphoma. No consensus exists on optimal frontline treatment, and the use of R-CHOP ± radiotherapy (RT) and DA-EPOCH-R ± RT remains common, yet comparative real-world data are limited. In our multicenter retrospective study, we analyzed PMBCL patients, stratified by the first-line therapy (R-CHOP-21 ± RT or DA-EPOCH-R ± RT). Primary outcomes were complete response (CR) rate, progression-free survival (PFS), and overall survival (OS), alongside assessment of treatment-related toxicities and prognostic factors for PFS and OS. We included 157 patients [R-CHOP ± RT group (n = 80) and DA-EPOCH-R ± RT group (n = 77)] with a median age of 31 years, of whom 68.2% were female. CR rates were similar for R-CHOP ± RT (75%) and DA-EPOCH-R ± RT (76.6%). RT use was higher in the R-CHOP group (41.2% vs. 19.5%, p = 0.002). DA-EPOCH-R had significantly higher toxicity (29.9% vs. 16.2%, p = 0.033). The median follow-up of the entire cohort was 29 months with 2-year PFS and OS rates of 73.9% and 83.6%, respectively. Also, PFS and OS did not differ between regimens. In patients achieving CR with R-CHOP, RT omission did not impact survival. Multivariate analysis identified older age, poor performance status, superior vena cava syndrome and splenic involvement as independent OS predictors, while pericardial effusion, splenic involvement and hemoglobin < 10.5 g/dL were linked to inferior PFS. R-CHOP-21 ± RT and DA-EPOCH-R ± RT provide comparable efficacy in PMBCL. Due to the higher toxicity of DA-EPOCH-R, for those achieving CR following R-CHOP, selective RT omission may be a reasonable alternative. Established and disease-specific prognostic factors should guide individualized treatment strategies.

Keywords:  AaIPI; DA-EPOCH-R; IPI; NCCN-IPI; PMBCL; Primary mediastinal B-cell lymphoma; R-CHOP; Radiotherapy

DOI:  https://doi.org/10.1007/s00277-025-06644-z
Blood Adv. 2025 Oct 08. pii: bloodadvances.2025017181. [Epub ahead of print]

Polatuzumab vedotin in CNS lymphoma: proof-of-concept study for blood-brain barrier penetration.

Lei Gao, Avyakta Kallam, Geoffrey Shouse, John H Baird, Stacy Pak, Yue Qin, Joo Y Song, Guido Marcucci, Lucy Y Ghoda, Claire Guillen, Suk-Joon Hyung, Ola M Saad, Helen Davis, Randall Dere, Connie Lee Lee Batlevi, Joshua Meinert, L Elizabeth E Budde, Alexey V Danilov, Alex F F Herrera, Larry W Kwak, Stephen J Forman, James K Godfrey.

Polatuzumab vedotin (pola) is a CD79B-targeting antibody-drug conjugate with significant clinical activity in systemic diffuse large B-cell lymphoma. However, the ability of pola to penetrate the blood-brain barrier (BBB) and induce responses in central nervous system lymphoma (CNSL) is unknown. Since other antibody-based therapies can partially penetrate the BBB to induce clinical responses in CNSL and other CNS malignancies, we hypothesized that pola would also partially penetrate the BBB, which could support its evaluation in future CNSL clinical trials. To test this hypothesis, we first evaluated the pre-clinical efficacy of pola in primary and secondary CNSL xenografts, where we observed pola significantly decreased CNS tumor burden and prolonged the survival of mice. To extend these findings, we compiled a clinical case series of 3 CNSL patients treated with pola-based treatment. Here, on-treatment cerebrospinal fluid (CSF) samples revealed pola CSF drug concentrations in excess of its established IC50 with CSF drug levels being 0.56% - 1.31% of that in the plasma. Interestingly, 2 of the 3 CNSL patients achieved a complete response to pola-based treatment. In summary, these data indicate pola is effective against pre-clinical CNSL models and can partially penetrate the BBB in CNSL patients, which together provide support for the evaluation of pola-based treatment in future clinical trials of primary and secondary CNSL.

DOI: https://doi.org/10.1182/bloodadvances.2025017181
Blood Adv. 2025 Oct 08. pii: bloodadvances.2025018225. [Epub ahead of print]

Vaccination during bispecific antibody treatment for myeloma.

Rahul Banerjee, Noopur S Raje.

DOI: https://doi.org/10.1182/bloodadvances.2025018225
Haematologica. 2025 Oct 09.

Long-term cardiac morbidity in adolescent and young adult survivors of classical Hodgkin lymphoma: the British Columbia experience.

Kristin C Marr, Terry Tang, Jonathan Simkin, Jewon Kim, Andrea C Lo, Diego Villa, Alina S Gerrie, Greg Hapgood, David W Scott, Laurie H Sehn, Ryan R Woods, Kerry J Savage.

Adolescents and young adults (AYA) with classic Hodgkin lymphoma (cHL) have excellent survival outcomes, however the late effects of treatment, including cardiovascular disease (CVD), can impact long-term disease-free morbidity and mortality. Using population-level administrative data, we evaluated rates of CVD in 2-year AYA survivors of cHL, aged 16-39 years, treated with ABVD or equivalent chemotherapy, with or without radiotherapy (RT). With a median follow up of 17 years (range 2.3-29 years), risk of CVD was 2.9-fold higher relative to controls, with a 5.2-fold risk of heart failure (HF) and 2.4-fold risk of ischemic heart disease (IHD). Risk of HF was associated with anthracycline-containing chemotherapy regimens alone or with combined modality therapy; whereas higher IHD risk was identified only in those treated with RT. At 20 years after the most recent cHL diagnosis or relapse, the cumulative incidence (CI) of HF was 4.3% in cases vs 0.8% in controls; and for IHD was 8.3% in cases vs 2.8% in controls. Treatment after 2005 using a PET scan guided approach reduced the overall use of RT (56.0% < 2005 vs 14.9% > 2005), and was associated with a lower 15-year CI of IHD (< 2005: 3.4% (95% CI 1.8-5.1%), > 2005: 0.7% (95% CI 0-1.7%) with the latter era comparable to controls; (1.6% (95% CI 1.3-1.9%)). cHL survivors had increased 20-year cumulative mortality above that of age-matched controls (5.0% vs 2.0%). These results can inform surveillance strategies, screening guidelines, and recommendations for risk factor modification for AYA cHL survivors.

DOI: https://doi.org/10.3324/haematol.2025.288058
Adv Hematol. 2025 ;2025 6622365

Newly Diagnosed High-Risk Multiple Myeloma: Outcomes and Management.

Fatma Zehra Yasar, Elan Gorshein.

  Multiple myeloma (MM) is a heterogeneous hematologic malignancy, with high-risk cytogenetic abnormalities (HRCAs) such as del(17p), t(4; 14), t(14; 16), and gain(1q) contributing to poor prognosis in approximately 20%-25% of newly diagnosed patients. These abnormalities are associated with aggressive disease, frequent relapses, and inferior progression-free and overall survival. This review explores the evolving therapeutic landscape for high-risk MM, focusing on induction strategies for both transplant-eligible and transplant-ineligible patients, the role of autologous stem cell transplantation (ASCT), and the use of consolidation and maintenance therapies. Emerging modalities such as bispecific antibodies and chimeric antigen receptor T-cell (CAR-T) therapies are examined, particularly in the context of their integration into earlier lines of treatment. Quadruplet induction regimens incorporating proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies have shown promise in improving outcomes and are becoming a cornerstone of frontline therapy. The review also emphasizes the potential of personalized, risk-adapted approaches based on cytogenetic profiling and minimal residual disease (MRD) monitoring. Ongoing clinical trials investigating the early use of CAR-T cells and bispecific antibodies may further transform the standard of care for patients with high-risk MM.

Keywords:  CAR-T therapy; bispecific antibodies; cytogenetics; high-risk multiple myeloma

DOI:  https://doi.org/10.1155/ah/6622365
Ann Hematol. 2025 Oct 09.

Zanubrutinib plus salvage chemotherapy in patients with refractory/relapsed diffuse large B-cell lymphoma non-candidate for autologous stem cell transplantation: A retrospective study.

Sha He, Jie Sun, Dani Zhong, Chao Rong, Chengcheng Liao, Xiaohong Tan.

  Salvage chemotherapy followed by autologous stem cell transplantation (auto-SCT) is effective for relapsed or refractory DLBCL (R/R DLBCL), but many patients are ineligible due to age, comorbidities, tolerance, economy and other factors. Zanubrutinib, a selective Bruton's tyrosine kinase inhibitor, has modest antitumor activity in R/R DLBCL. This study aimed to evaluate the efficacy and safety of zanubrutinib plus salvage chemotherapy in transplant-ineligible patients with R/R non-GCB DLBCL. We retrospectively reviewed patients with R/R non-GCB DLBCL treated with zanubrutinib combined with BR (bendamustine + rituximab; ZBR) or R2 (lenalidomide + rituximab; ZR2) between January 2019 and July 2023. A total of 49 patients were enrolled with a median age of 60 years. The best objective response rate (ORR) was 57.1% with a complete response (CR) rate of 12.2% in the entire cohort. 19 patients were treated with ZBR and 30 patients were treated with ZR2. The ORR of ZBR and ZR2 cohort was 63.2% and 53.3% respectively. With a median follow-up duration of 22 months, the median progression free survival (PFS) was 6.0 months, and overall survival (OS) was 21.0 months. Patients in CD79B ± MYD88 mutated subgroup had a significantly higher ORR (86.7% v 44.1%, P = 0.006) and longer PFS (8.1 v 4.9 months, P = 0.009) compared to those in CD79B ± MYD88 non-mutated subgroup. A significant PFS and OS benefit was observed in the patients who responded to the treatment. The most common grade 3/4 adverse events were neutropenia (46. 9%) and thrombocytopenia (44.9%). Zanubrutinib combined with BR or R2 showed promising efficacy and manageable toxicity, which may be a potential treatment option for patients with transplant-ineligible R/R non-GCB DLBCL.

Keywords:  Relapsed/refractory diffuse large b-cell lymphoma; Salvage chemotherapy; Treatment outcomes; Zanubrutinib

DOI:  https://doi.org/10.1007/s00277-025-06673-8
Leuk Lymphoma. 2025 Oct 06. 1-11

Venetoclax plus hypomethylating agents versus priming regimen as the first-line therapy for newly diagnosed acute myeloid leukemia with myelodysplasia-related changes: a propensity score-matched analysis.

Yuan-Hong Huang, Fang-Tong Liu, Chao-Ling Wan, Zi-Jin Wang, Yu-Qing Liu, Han-Yu Cao, Si-Man Huang, Kai-Wen Tan, Shuai-Shuai Ge, Miao Wang, Mei-Jing Liu, Zi-Hao Wang, Xiao-Yu Lyu, Hai-Ping Dai, Zheng Li, Sheng-Li Xue.

  Acute myeloid leukemia with myelodysplasia-related changes (AML-MR), a high-risk subtype affecting older patients intolerant to intensive chemotherapy. Venetoclax-based regimens are approved for such patients, while studies suggest priming regimens combining aclarubicin, homoharringtonine or idarubicin and low-dose cytarabine with granulocyte colony-stimulating factor may replace intensive therapy, while direct comparisons are lacking in two groups. This retrospective study compared venetoclax plus hypomethylating agents (VEN+HMA) and priming regimens in 150 propensity score-matched AML-MR patients. VEN+HMA demonstrated superior overall remission (ORR: 78.7% vs. 60.0%, p = 0.013) and complete remission (CR: 48.0% vs. 21.3%, p < 0.001) rates. Notably, VEN+HMA significantly improved median overall survival (OS: not reached vs. 36.37 months, p = 0.026) and event-free survival (EFS: not reached vs. 7.37 months, p = 0.003). Multivariate analysis confirmed VEN+HMA as an independent predictor of better ORR (OR = 2.855, p = 0.014), OS (HR = 0.449, p = 0.036), and EFS (HR = 0.458, p = 0.003). These findings suggest VEN+HMA may be a preferable low-intensity induction therapy over priming regimens for AML-MR.

Keywords:  Acute myeloid leukemia with myelodysplasia-related changes; hypomethylating agents; priming regimen; propensity score-matched analysis; venetoclax

DOI:  https://doi.org/10.1080/10428194.2025.2566317
Front Immunol. 2025 ;16 1607138

Blinatumomab demonstrates MRD eradication in MRD-positive/chemotherapy-delayed pediatric B-ALL and high response in relapsed/refractory cases: a multicenter cohort study.

Na Zhang, Wenting Hu, Yunpeng Dai, Jian Wang, Lijun Qu, Dan Wang, Bingju Liu, Jingbo Shao, Shuhong Shen, Hui Jiang.

   Background: Blinatumomab, a bispecific T-cell engager targeting CD3+ and CD19+, promotes T cell-mediated cytotoxicity against B-cell precursor acute lymphoblastic leukemia (B-ALL). While its efficacy is established in relapsed/refractory (R/R) disease, its role as preemptive therapy for minimal residual disease (MRD)-positive patients or those experiencing chemotherapy delays remains undefined. Predictors of treatment failure also require further investigation.
Methods: In this multicenter retrospective study, 105 patients who received blinatumomab were enrolled. Of these, 30 had R/R ALL, 21 were in complete remission (CR) with MRD positivity (CR-MRDpos), and 54 experienced chemotherapy delays. Eight patients received blinatumomab directly as reinduction therapy and 22 patients received burden-reduction chemotherapy prior to blinatumomab. In total, 11 children were in R/R status and 40 were in CR-MRDpos before treatment. Patients were subsequently bridged to stem cell transplantation, chimeric antigen receptor T-cell therapy (CAR-T), or protocol continuation. Treatment response was analyzed across CR-MRDpos, R/R, and CR with MRD negativity (CR-MRDneg). Immune reconstitution profiles (T-cell subsets, cytokine dynamics), cytogenetic markers, and clinical outcomes were assessed to identify predictors of treatment resistance.
Results: The CR rate was 81.8% in R/R and 82.5% in CR-MRDpos patients (P = 1.000). Of 74 courses with CR-MRDneg, 73 remained MRD-negative during treatment. Univariate analysis revealed poor cytogenetics (P = 0.0001), CD19+ B-cell loss (P = 0.046), and BCR-ABL1 positivity (P = 0.002) as predictors of poor response. Cox regression analysis identified high MRD (P = 0.014), BCR/ABL1 (P = 0.065), and poor cytogenetics (P = 0.025) as independent risk factors. Blinatumomab significantly increased CD3+ T cells [0.96 (0.03-3.79) to 1.13 (0.26-7.74) ×109/L, P = 0.016], along with CD4+ [0.35 (0.01-1.39) to 0.47 (0.07-2.94) ×109/L] and CD8+ T cells [0.41 (0.01-2.39) to 0.56 (0.07-6.07) ×109/L] (P = 0.005 and P = 0.006, respectively).The 1-year event-free survival for CR-MRDneg, CR-MRDpos, and R/R patients was 97.8% ± 2.2%, 86.7% ± 6.2%, and 73.3% ± 8.1%, respectively (P = 0.001), while overall survival was 97.8% ± 2.2%, 100%, and 93.3% ± 4.6% (P = 0.029).
Conclusions: Blinatumomab effectively clears MRD as preemptive therapy and serves as a bridging strategy during chemotherapy delays in pediatric B-ALL, while maintaining high response rates in R/R cases.

Keywords:  B-cell acute lymphoblastic leukemia; T cell activation; blinatumomab; children; minimal residual disease; relapsed/refractory

DOI:  https://doi.org/10.3389/fimmu.2025.1607138
Hematology. 2025 Dec;30(1): 2545078

Brutons tyrosine kinase inhibitor Zanubrutinib modulates Fc gamma receptors to inhibit platelet destruction for alleviation of refractory immune thrombocytopenia.

Xin-Xin Yang, Guo-Li Yao, Yu-Jing Yang, Ya-Hui Han, Lin Yang, Yue-Feng Zhang.

   BACKGROUND: Primary immune thrombocytopenia (ITP) is an autoimmune disorder characterized by low platelet count (PLT). Bruton tyrosine kinase (BTK) is a therapeutic target in immune-mediated diseases. This study aimed to evaluate the effects of a BTK inhibitor, zanubrutinib (Zan), on refractory ITP.
METHODS: Peripheral blood was collected from healthy controls (HC) and refractory ITP patients (n = 15), and peripheral blood mononuclear cell (PBMC) extraction was performed. The proportion of myeloid-derived suppressor cells (MDSCs) in PBMCs and Arg-1, iNOS, Fc gamma receptor (FcγR), GPIIb/IIIa, and GPIb/IX autoantibody levels were measured. ITP monocytes were separated into control (Con), Zan (Zan), dexamethasone (DXM), and combination (Zan + DXM) groups. Detection ophagocytosis and platelet activation by flow cytometry; FcγR expression by qRT-PCR and western blot; and IFN-γ, IL-4, IL-2, and IL-10 levels were determined by ELISA.
RESULTS: PBMCs from the ITP group demonstrated lower MDSCs proportions and Arg-1 levels, but higher iNOS, FcγRIII, FcγRIIb, FcγRI, GPIIb/IIIa, and GPIb/IX autoantibody levels than those in the HC group. Following Zan intervention, ITP monocytes exhibited decreased phagocytosis, FcγRIIa, FcγRI protein, IFN-γ, IL-2, p-mTOR/mTOR levels, and increased FcγRIIb, PLTs, IL-4, PAC-1, and CD62p levels.
CONCLUSION: Zan may modulate FcγR toward FcγRIIb to inhibit platelet destruction, thereby improving refractory ITP.

Keywords:  Brutons tyrosine kinase; FcγR; Primary immune thrombocytopenia; antibody; platelet

DOI:  https://doi.org/10.1080/16078454.2025.2545078
Blood. 2025 Oct 09. 146(15): 1744-1746

Unlocking myeloma's spatial world at the micrometer scale.

Leo Rasche, Niels Weinhold.

DOI: https://doi.org/10.1182/blood.2025030205
Leuk Lymphoma. 2025 Oct 06. 1-10

The tumor microenvironment in hairy cell leukemia (HCL) and splenic B cell lymphoma with prominent nucleoli (SBLPN).

Titus Watrin, Marc Seifert, Sascha Dietrich.

  Hairy cell leukemia (HCL) is an indolent B-cell malignancy characterized by distinctive morphologic features (hairy cytoplasmatic protrusions'hairy cells', HCs), cytopenia, and splenomegaly. Classical HCL is characterized by the BRAFV600E mutation. Splenic B-Cell Lymphoma with Prominent Nucleoli (SBLPN) - previously known as HCL variant - lacks the BRAFV600E mutation and shows a more aggressive clinical course. Current treatment approaches achieve remission rates above 95%, but high relapse rates highlight the necessity for tailored strategies. The unique dissemination profile of HCs into bone marrow, spleen, and blood, and their unusually low abundance in lymph nodes, indicates that HCs must have a particular interaction capacity with accessory cells and matrix proteins. However, the micro environmental interactions of HCs are incompletely understood. This review highlights the interaction between HCs and the tumor microenvironment, including T-cell dysfunction and hematopoietic inhibition due to cytokine production and bone marrow fibrosis, playing a crucial role in disease progression.

Keywords:  Lymphoma and Hodgkin disease; Neoplasia; T-cell mediated immunity; immunobiology; manipulation of the immune response; structure of the antibody molecule and immunoglobulin genes

DOI:  https://doi.org/10.1080/10428194.2025.2562951
J Med Chem. 2025 Oct 07.

Discovery of Potent and Selective BCL6 Ligand-Directed Degrader (LDD), BCL6-760.

Hunter P Shunatona, Natalie Holmberg Douglas, Jayce Rhodes, William Thomas, Diogo Da Silva, Jim Gamez, Matt Groza, Andy Christoforou, Jinyi Zhu, Scott Johnson, Dharmpal Dodd, Dehua Huang, Jennifer Griffin, Giulianna Miseo, Brandon Whitefield, Dahlia Weiss, James Rader, Elif Kuzu, Jim Leisten, Joselyn Del Rosario, Lihong Shi, Mary Matyskiela, Philip P Chamberlain, Peter Belmont, Matt Alexander, Christoph W Zapf, Lynda Groocock, Deborah S Mortensen.

The discovery of a potent and selective BCL6 ligand-directed degrader (LDD), BCL6-760 (45) is described. Through structure-activity relationships, the most potent heterobifunctional degraders of BCL6 were found to be those containing short aminopiperidine linkers in combination with an indazole-based cereblon (CRBN)-binding moiety (CBM). In vitro ADME profiling of potent molecules identified BCL6-760 as an ideal molecule for use in in vivo experiments due to its good passive permeability, solubility, and microsomal stability. Mechanistic studies confirmed that BCL6 degradation is CRBN mediated, and proteomic assessment indicates a clean and selective degradation profile. BCL6-760 exhibited good oral mouse PK and was capable of penetrant and sustained PD effects. At 60 mg/kg BID dosing, BCL6-760 achieves >90% BCL6 reduction and leads to an overall 64% tumor volume reduction in an OCI-LY-1 mouse xenograft efficacy model.

DOI: https://doi.org/10.1021/acs.jmedchem.5c01645
Drugs. 2025 Oct 08.

Lisaftoclax: First Approval.

Yahiya Y Syed.

Lisaftoclax is a B-cell lymphoma 2 (BCL-2) inhibitor developed by Ascentage Pharma for the treatment of haematological malignancies. It is administered using a 5-day ramp-up schedule, reaching the target dose on day 6. Lisaftoclax received its first approval on 10 July 2025 in China for the treatment of chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma (SLL) in adult patients who had received at least one prior systemic therapy, including a Bruton's tyrosine kinase (BTK) inhibitor. This article summarizes the milestones in the development of lisaftoclax leading to this first approval for CLL/SLL.

DOI: https://doi.org/10.1007/s40265-025-02251-4
Hematol Oncol. 2025 Nov;43(6): e70140

Review of the Management of Relapsed/Refractory Follicular Lymphoma: An Italian Perspective.

Giacomo Loseto, Maria Chiara Tisi, Antonella Anastasia, Alessandro Broccoli, Ilaria Del Giudice, Caterina Patti, Benedetta Puccini, Caterina Stelitano, Vittorio Zilioli, Stefano Luminari.

  Follicular lymphoma (FL) is an indolent disease characterized by multiple relapses and eventual refractoriness to therapy. Despite advancements in therapeutic approaches, FL treatment algorithm and management remain not well-established, necessitating both ongoing research into novel therapeutic strategies and in stating patient journey. We propose a comprehensive overview of current standard treatments for relapsed or refractory (R/R) FL, including chemoimmunotherapy and stem cell transplantation, and insights into emerging therapies such as chimeric antigen receptor (CAR) T-cell therapy and bispecific antibodies. We discuss the efficacy and safety profiles of these innovative treatments, their integration into the therapy armamentarium, and the potential they hold in altering the natural history of FL. Additionally, we propose a therapeutic flow depending on POD24 (i.e., progression of disease within 24 months), transformed disease, early relapse and fast/low progression, with the aim to provide a useful tool to all physicians dealing with this disease for achieving sustained remission and improving the quality of life in patients with R/R FL.

Keywords:  bispecific antibodies; follicular lymphoma; immunotherapy CAR T‐cells; management; relapsed/refractory

DOI:  https://doi.org/10.1002/hon.70140
Mayo Clin Proc. 2025 Oct 07. pii: S0025-6196(25)00504-X. [Epub ahead of print]

Icefish: Peculiar Creatures Without Hemoglobin or Red Blood Cells.

David P Steensma, William C Aird.

DOI: https://doi.org/10.1016/j.mayocp.2025.09.002
Blood Adv. 2025 Oct 08. pii: bloodadvances.2024015689. [Epub ahead of print]

Myeloid landscape profiling identifies DLBCL-specific suppressive macrophages colocalized with blood endothelial cells.

Juliette Ferrant, Simon Le Gallou, Francine Padonou, Charlotte Dubec-Fleury, Simon Léonard, Ilenia Papa, Charles Brottier, Celine Pangault, Anne Barthel, Vincent Launay, Guillaume Manson, Benedicte Hoareau, Laurent Deleurme, Celine Monvoisin, Benoit Alaud, Margaret A Shipp, Nathalie Van Acker, Camille Laurent, Francisco Llamas Gutierrez, Henri-Alexandre Michaud, Nathalie Bonnefoy, Thierry Pécot, Karin Tarte, Mikael Roussel.

Diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) are the two most common B-cell lymphomas and are characterized by a dynamic crosstalk between tumor B cells and a heterogeneous tumor-supportive microenvironment, including immune, endothelial, and stromal components. Despite their recognized impact on the pathogenesis and prognosis of B-cell lymphoma, tumor-associated macrophages (TAM) have not been extensively explored in these diseases. Herein, we investigated mononuclear phagocyte (MNP) heterogeneity at the single-cell level and the activation profile of MNP, stromal, and endothelial compartments in B-cell lymphoma lymph nodes compared to reactive secondary lymphoid organs. This was achieved using a combination of mass cytometry, single-cell RNA sequencing, in silico and spatial imaging approaches. Our findings revealed a lymphoma-specific pattern of TAM and blood endothelial cell (BEC) co-activation. Furthermore, we identified in DLBCL a spatial interaction between Annexin A1 (ANXA1)-expressing BEC and formyl-peptide receptor (FPR1/2) and S100A9-expressing monocytes/macrophages. This crosstalk is associated with an immunosuppressive tumor microenvironment and an adverse prognosis in two cohorts of DLBCL patients.

DOI: https://doi.org/10.1182/bloodadvances.2024015689