bims-hemali Biomed News
on Hematologic malignancies
Issue of 2026–10–04
fifteen papers selected by
Alexandros Alexandropoulos, Γενικό Νοσοκομείο Αθηνών Λαϊκό
  1. Pembrolizumab-GVD in relapsed or refractory Hodgkin lymphoma: 5-year update of a multicenter phase 2 trial.
  2. Efficacy and safety of tirabrutinib monotherapy for relapsed/refractory primary CNS lymphoma: PROSPECT phase 2 trial.
  3. Integrating Asciminib into the Evolving Treatment Landscape of Chronic Myeloid Leukemia: A Canadian Perspective.
  4. BTK/BCL2 dual targeting enhances apoptosis in marginal zone lymphoma: preclinical activity of tacabrutideg (BGB-16673) and sonrotoclax.
  5. Liso-cel delivers: is the debate over for 3L FL?
  6. Rilzabrutinib, an oral Bruton tyrosine kinase inhibitor, in patients with warm autoimmune haemolytic anaemia: a prospective, single-arm, multicentre, phase 2b safety and clinical activity study (LUMINA 2).
  7. Phase 1/2 study of favezelimab plus pembrolizumab in anti-PD-1-naive relapsed or refractory classical Hodgkin lymphoma.
  8. Recent Advances in Chronic Myeloid Leukaemia (CML): Emerging Molecular and Immunotherapeutic Targets.
  9. Forimtamig, a GPRC5DxCD3 bispecific antibody with a novel 2:1 format, in relapsed/refractory multiple myeloma.
  10. Lu J, Xue S, Wang Y, et al. Venetoclax and decitabine vs intensive chemotherapy as induction for young patients with newly diagnosed AML. Blood. 2025;145(22):2645-2655.
  11. Systems reboot: a niche-based approach to AML.
  12. Primary central nervous system lymphoma in the molecular era: genomic drivers, liquid biopsy, and targeted therapeutic strategies.
  13. Functional Classification of Monoallelic TP53 Mutations Refines Prognostic Stratification in Myelodysplastic Neoplasms.
  14. DMT1 Facilitates Heme-iron Absorption in Rats and Mice.
  15. PIM1 in myeloproliferative neoplasms: potential pathogenic and therapeutic implications.
  1. Blood. 2026 Sep 08. pii: blood.2026035115. [Epub ahead of print]
    Pembrolizumab-GVD in relapsed or refractory Hodgkin lymphoma: 5-year update of a multicenter phase 2 trial.
    Kishan Patel, Gunjan L Shah, Heiko Schöder, Nivetha Ganesan, Esther Drill, Helen Hancock, Theresa Davey, Alayna Marie Santarosa, Natasha Galasso, Anita Kumar, Oscar B Lahoud, Paul A Hamlin, David J Straus, Colette N Owens, Philip C Caron, Andrew M Intlekofer, Steven M Horwitz, Lorenzo Falchi, M Lia Palomba, Ariela Noy, Matthew J Matasar, Gilles A Salles, Santosha A Vardhana, Beatriz Wills, Joachim Yahalom, Ahmet Dogan, Andrew D Zelenetz, Phillip Wong, Maho Toyomura, Laure Michaud, Filiz Sen, Kimon V Argyropoulos, Craig H Moskowitz, Alison J Moskowitz.
      A phase II trial assessed the safety and efficacy of pembrolizumab, gemcitabine, vinorelbine, and liposomal doxorubicin (pembrolizumab-GVD) in transplant-eligible patients with relapsed/refractory (rel/rel) cHL, and demonstrated a complete response (CR) rate of 95% and progression-free survival (PFS) of 100% at 13.5 months (NCT03618550). We present an updated analysis of this trial at 5 years. Eligible patients received pembrolizumab 200mg intravenous (IV) (day 1), gemcitabine 1,000mg/m2 IV (days 1 and 8), vinorelbine 20mg/m2 IV (days 1 and 8), and liposomal doxorubicin 15mg/m2 IV (days 1 and 8) in 21-day cycles, followed by high-dose chemotherapy and autologous stem cell rescue (HDT/ASCR). Of 39 enrolled patients, 41% had primary refractory disease and 38% relapsed within 1 year of first-line treatment. In 38 response-evaluable patients, the CR and overall response rates after up to 4 cycles of pembrolizumab-GVD were 95% and 100%, respectively, with 35 patients (92%) attaining CR after only 2 cycles of therapy. Thirty-six (95%) patients underwent HDT/ASCR. After a median follow-up of 57 months, 1 patient experienced disease recurrence after per-protocol therapy, and 2 patients died from non-relapse or treatment-related causes. Estimated 5-year PFS and OS were 91% and 94%, respectively. No new safety signals were identified with extended follow-up.
    DOI:  https://doi.org/10.1182/blood.2026035115
  2. Blood. 2026 Oct 01. pii: blood.2026034926. [Epub ahead of print]
    Efficacy and safety of tirabrutinib monotherapy for relapsed/refractory primary CNS lymphoma: PROSPECT phase 2 trial.
    Christian Grommes, Lakshmi Nayak, Avyakta Kallam, David Peereboom, Prakash Ambady, Joe S Mendez, Dawit Aregawi, Ashley Sumrall, Antonio Omuro, Fabio M Iwamoto, Jörg Dietrich, Yoshie Umemura, Reinhold Munker, Ugonma Nnenna Chukwueke, Lauren R Schaff, Andrew Ip, Neel K Gupta, Jan Drappatz, Vyshak A Venur, Katherine B Peters, Ka-Wai G Ho, Ryan Merrell, Sergio Prados, Akira Takazawa, Arata Aoi, Tracy T Batchelor.
      Primary central nervous system lymphoma (PCNSL) is an aggressive subtype of non-Hodgkin lymphoma with a poor prognosis, high rate of refractory or relapsed (R/R) disease, and no established standard of care for R/R PCNSL. This phase 2 study evaluated the efficacy and safety of tirabrutinib, a potent, highly selective, second-generation Bruton tyrosine kinase inhibitor, in patients with R/R PCNSL in the US. In the open-label PROSPECT study, adults with R/R PCNSL whose disease progressed on or after ≥1 high-dose methotrexate-based therapy received once-daily oral tirabrutinib 480 mg. The primary endpoint was overall response rate (ORR), and secondary endpoints included complete response (CR) rate, duration of response (DOR), and time to response (TTR), as assessed by independent review committee. Safety was assessed by frequency and severity of treatment-emergent adverse events (TEAEs). Among 48 enrolled patients, median follow-up was 11.5 months, ORR was 67% (95% confidence interval [CI], 52-80), and CR rate was 44% (95% CI, 29-59). Median DOR was 9.3 months (95% CI, 4.6-14.6), and median TTR was 1.0 month (range, 0.9-3.7). Treatment-related TEAEs occurred in 36 patients (75%), most commonly anemia (19%), maculopapular rash (17%), fatigue (15%), neutropenia (15%), lymphocytopenia (15%), pruritus (15%), and other rash (15%). Grade ≥3 treatment-related TEAEs occurred in 13 patients (27%), most commonly neutropenia (8%) and maculopapular rash (6%). One death (bronchopulmonary aspergillosis) was treatment related. In patients with R/R PCNSL, once-daily oral tirabrutinib monotherapy resulted in rapid and durable responses and demonstrated a favorable safety profile. This trial was registered at www.clinicaltrials.gov as NCT04947319.
    DOI:  https://doi.org/10.1182/blood.2026034926
  3. J Blood Med. 2026 ;17 627651
    Integrating Asciminib into the Evolving Treatment Landscape of Chronic Myeloid Leukemia: A Canadian Perspective.
    Dennis Dong Hwan Kim, Lambert Busque, Christopher Hillis, Pierre Laneuville, Mary Lynn Savoie.
      Five years after the first readout of the ASCEMBL trial, asciminib evidence has rapidly expanded across the chronic myeloid leukemia (CML) treatment landscape. Subsequent studies and growing real-world experience have also clarified its efficacy and tolerability in earlier treatment lines. As the first allosteric inhibitor targeting the BCR::ABL1 myristoyl pocket, asciminib provides a mechanistically distinct approach that may reduce cross-resistance and toxicity associated with ATP-competitive TKIs. At a time when treatment goals in CML emphasize long-term tolerability, quality of life, and the potential for treatment-free remission (TFR), asciminib's unique molecular and clinical profile justify its inclusion in CML treatment considerations. In this expert opinion review, we synthesize emerging clinical and real-world evidence for asciminib and discuss practical considerations for its integration into contemporary CML management, including its potential im-plications for TFR eligibility. We also explore the role of next-generation sequencing in detecting salvageable resistance mutations, the prognostic significance of co-mutations such as ASXL1, and the concept of mutation-guided treatment sequencing. Collectively, these data position asciminib as an established later-line therapy and an emerging frontline option, with the potential to improve long-term treatment sustainability through favorable tolerability and early molecular response kinetics.
    Keywords:  ASXL1; CML; asciminib; combination strategies; mutational testing; sequencing; treatment-free remission
    DOI:  https://doi.org/10.2147/JBM.S627651
  4. Haematologica. 2026 Oct 01.
    BTK/BCL2 dual targeting enhances apoptosis in marginal zone lymphoma: preclinical activity of tacabrutideg (BGB-16673) and sonrotoclax.
    Alberto J Arribas, Alex Zadro, Elisa Civanelli, Giulio Sartori, Camilla Scalise, Luciano Cascione, Riccardo Moia, Nawar Maher, Laura Carosella, Stefano Raniolo, Andrea Rinaldi, Chiara Arrigoni, Davide Rossi, Emanuele Zucca, Gianluca Gaidano, Matteo Moretti, Vittorio Limongelli, Francesco Bertoni.
      Bruton tyrosine kinase (BTK) and BCL2 are key therapeutic targets in marginal zone lymphoma (MZL). We evaluated the novel BTK degrader tacabrutideg (BGB-16673) and the secondgeneration BCL2 inhibitor sonrotoclax, alone and in combination, in MZL models, including derivatives with acquired resistance to BTK, BCL2, and PI3K inhibitors. Tacabrutideg was evaluated for cytotoxicity, apoptosis, transcriptomic and protein changes, real-time cell growth, three-dimensional stromal co-culture, and activity in primary MZL samples. Combination studies included sonrotoclax, venetoclax, bendamustine, lenalidomide, rituximab, selinexor, and tazemetostat.Tacabrutideg showed single-agent activity in MZL cell lines, inducing BTK degradation and suppression of BCR signaling, MYC targets, and oxidative phosphorylation. Its biological effects largely overlapped with those of zanubrutinib while maintaining complete target degradation. Tacabrutideg inhibited PLCG2 and ERK phosphorylation, reduced cell growth in realtime assays, retained activity in three-dimensional stromal co-cultures, and suppressed growth and ERK phosphorylation in primary MZL samples. Combination studies identified the greatest benefit with sonrotoclax, venetoclax, bendamustine, lenalidomide, and rituximab. Sonrotoclax consistently outperformed venetoclax, exhibiting >10-fold greater potency in three MZL cell lines and synergizing with tacabrutideg across multiple models. The combination enhanced apoptosis through coordinated modulation of BCL2 family proteins, including BCL2, MCL1, and BCL-XL. Tacabrutideg demonstrates potent preclinical activity in MZL as a single agent and in combination regimens. Together with the superior activity of sonrotoclax, these findings provide a strong rationale for the clinical evaluation of dual BTK degradation and BCL2 inhibition in patients with MZL.
    DOI:  https://doi.org/10.3324/haematol.2026.300780
  5. Blood. 2026 Oct 01. 148(14): 1756-1758
    Liso-cel delivers: is the debate over for 3L FL?
    Karina N Ruiz-Esteves, Caron A Jacobson.
      
    DOI:  https://doi.org/10.1182/blood.2026035205
  6. Lancet Haematol. 2026 Oct;pii: S2352-3026(26)00218-8. [Epub ahead of print]13(10): e698-e709
    Rilzabrutinib, an oral Bruton tyrosine kinase inhibitor, in patients with warm autoimmune haemolytic anaemia: a prospective, single-arm, multicentre, phase 2b safety and clinical activity study (LUMINA 2).
    Nichola Cooper, David J Kuter, Henrik Frederiksen, Bing Han, Frederick Chen, Wilma Barcellini, Bruno Fattizzo, Joan Cid, Catherine M Broome, Miriam Vara Pampliega, Amitabha Mazumder, Alessandro Lucchesi, Xin Zhao, Antonio Risitano, Sumit Sawhney, Quentin A Hill, Deepthi Jayawardene, Heidi Krenz, Lei Wang, Jing Zhao, Ahmed Daak.
       BACKGROUND: Warm autoimmune haemolytic anaemia is a rare blood disorder characterised by haemolysis, anaemia, elevated thromboembolism risk, fatigue, and impaired quality of life. The selective Bruton tyrosine kinase inhibitor, rilzabrutinib, might increase haemoglobin through multi-immune modulatory mechanisms targeting key drivers of warm autoimmune haemolytic anaemia pathophysiology. The aim of the study was to report clinical safety and activity results for rilzabrutinib in patients with warm autoimmune haemolytic anaemia.
    METHODS: LUMINA 2, a multicentre, single-arm, open-label, phase 2b study, evaluated rilzabrutinib (with or without concomitant corticosteroids) in adults aged 18 years or older with primary or systemic lupus erythematosus-associated warm autoimmune haemolytic anaemia who were relapsed, refractory to, or dependent on corticosteroids. Patients were enrolled in 15 clinical research study centres from China, Denmark, Italy, Spain, the UK, and the USA. Patients in part A received oral rilzabrutinib at 400 mg twice a day for 24 weeks. The part A primary endpoint was overall haemoglobin response by week 24: response (haemoglobin increased by ≥2 g/dL from baseline without biochemical resolution of haemolysis) or complete response (haemoglobin ≥11 g/dL for women or ≥12 g/dL for men with no evidence of haemolysis). Responding patients in part A continued into part B with oral rilzabrutinib at 400 mg twice a day until the last patient completed 52 weeks (eligible patients could continue long-term extension for up to 253 weeks). The part B primary endpoint of durable response was haemoglobin at least 10 g/dL with an increase from baseline of at least 2 g/dL on three consecutive visits from after week 24 to week 50. Primary endpoints were without rescue medication or transfusion. The study is registered with ClinicalTrials.gov (NCT05002777) and EU Clinical Trials Register (2023-509441-13-00); enrolment is complete, analyses conducted at the 50-week data cutoff are provided per protocol, and the long-term extension is continuing.
    FINDINGS: From Jan 24, 2022, to Dec 6, 2023 (50-week data cutoff for ongoing trial was Nov 21, 2024), 22 patients enrolled in part A and 15 entered part B. 14 (64%; 95% CI 41-83) of 22 patients in part A had overall haemoglobin response (13 [59%; 36-79] response and three [14%; 3-35] complete response). 12 (80%) of 15 patients in part B had durable haemoglobin response. Treatment-related adverse events were observed in ten (45%) of 22 patients in part A and four (27%) of 15 patients in part B. The most common treatment-related adverse events in part A were nausea in three (14%) and diarrhoea in two (9%) of 22 patients. Four (18%) of 22 patients in part A had serious adverse events (ie, influenza, pneumonia, haemolytic anaemia, and tenosynovitis); none were treatment related. One patient in part B had severe anaemia considered related to treatment and one patient had a serious adverse event of decreased haemoglobin unrelated to treatment. There were no adverse events of special interest, leading to rilzabrutinib discontinuation, or deaths.
    INTERPRETATION: To our knowledge, this is first clinical study of a Bruton tyrosine kinase inhibitor, rilzabrutinib, in warm autoimmune haemolytic anaemia. Rilzabrutinib showed robust overall and durable haemoglobin response and favourable safety in patients with previously treated warm autoimmune haemolytic anaemia. Rilzabrutinib has the potential to treat the underlying pathophysiology of warm autoimmune haemolytic anaemia through multi-immune modulation, induce a robust and sustained haemoglobin response, and provides an opportunity to decrease or stop corticosteroid use.
    FUNDING: Sanofi.
    DOI:  https://doi.org/10.1016/S2352-3026(26)00218-8
  7. Blood Adv. 2026 Oct 02. pii: bloodadvances.2025018506. [Epub ahead of print]
    Phase 1/2 study of favezelimab plus pembrolizumab in anti-PD-1-naive relapsed or refractory classical Hodgkin lymphoma.
    Nathalie A Johnson, David Lavie, Peter Borchmann, Gareth P Gregory, Alex F Herrera, Leonard Minuk, Vladan Vucinic, Philippe Armand, Abraham Avigdor, Robin Gasiorowski, Yair Herishanu, Colm Keane, John Kuruvilla, Rachel Marceu West, Pallavi M Pillai, Patricia Marinello, John M Timmerman.
      The phase 1/2 MK-4280-003 study evaluated favezelimab plus pembrolizumab for relapsed or refractory (R/R) hematologic malignancies. We report results in anti-PD-1-naive R/R classical Hodgkin lymphoma (cHL; cohort 1). The study comprised a safety lead-in (across 4 cohorts) to establish the recommended phase 2 dose (RP2D) of favezelimab plus pembrolizumab and an efficacy expansion phase (pembrolizumab 200 mg plus favezelimab at RP2D intravenously [IV] every 3 weeks [Q3W]). Adults with anti-PD-1-naive R/R cHL were enrolled in cohort 1. Primary end point was safety (dose-limiting toxicity [DLT], adverse events [AEs], and AEs leading to discontinuation) to establish RP2D. Objective response rate (ORR) was secondary. Duration of response (DOR), progression-free survival (PFS), and overall survival (OS) were exploratory. RP2D was favezelimab 800 mg plus pembrolizumab 200 mg IV Q3W. DLT occurred in 1 of 21 participants in the safety lead-in (grade 4 autoimmune hepatitis). Cohort 1 enrolled 30 participants. Treatment-related AEs occurred in 27 participants (90%; grade 3 or 4 in 7 participants [23%]; no grade 5), and 5 participants (17%) discontinued treatment. ORR was 83% (95% CI, 65-94); complete response rate was 37% (95% CI, 20-56). Median DOR was 17.0 months (range, 2.6-33.3+); an estimated 44% of responders continued to have responses after ≥24 months. Median PFS was 19.4 months (95% CI, 9.5-28.5); 24-month PFS rate was 46%. Median OS was not reached (NR; 95% CI, 46.9-NR); 24-month OS rate was 93%. Favezelimab plus pembrolizumab showed antitumor activity and manageable safety in participants with anti-PD-1-naive R/R cHL. This trial was registered at www.ClinicalTrials.gov as NCT03598608.
    DOI:  https://doi.org/10.1182/bloodadvances.2025018506
  8. Front Biosci (Landmark Ed). 2026 Sep 18. 31(9): 48912
    Recent Advances in Chronic Myeloid Leukaemia (CML): Emerging Molecular and Immunotherapeutic Targets.
    Jingyi Dai, Panpan Zheng, Jian Liu, Linyan Cheng, Xiao Zheng, Lujun Chen, Jingting Jiang, Zhuojun Zheng.
      Chronic myeloid leukaemia (CML), a distinct myeloproliferative neoplasm, results from the malignant reprogramming of haematopoietic stem cells (HSCs) into leukaemia stem cells (LSCs), primarily driven by breakpoint cluster region and Abelson (BCR-ABL1) fusion oncogene. Although the advent of tyrosine kinase inhibitors (TKIs) has significantly transformed clinical management, leading to improved patient survival and quality of life, sustained treatment-free remission (TFR) remains achievable in only a minority of patients. This limitation is largely attributable to the persistence of LSCs and the development of resistance mechanisms. Emerging evidence indicates that LSCs evade TKI-induced apoptosis through aberrant expression of specific cell-surface markers, dysregulated intracellular signalling pathways, and extensive epigenetic alterations. This review examines recent advancements in CML therapy, with a focus on these novel therapeutic targets. It highlights the pivotal role of LSCs in disease progression and relapse, evaluates potential molecular and epigenetic regulators as new targets for intervention, and supports the development of combination treatment strategies to improve TFR rates and move towards curative outcomes.
    Keywords:  chronic myeloid leukaemia; epigenomics; leukaemia stem cell; molecular targeted therapy; signal transduction; treatment-free remission; tyrosine kinase inhibitor
    DOI:  https://doi.org/10.31083/FBL48912
  9. Blood Adv. 2026 Sep 30. pii: bloodadvances.2026020498. [Epub ahead of print]
    Forimtamig, a GPRC5DxCD3 bispecific antibody with a novel 2:1 format, in relapsed/refractory multiple myeloma.
    Anna Caroline Hasselbalch, Simon J Harrison, Salomon Manier, Sung-Soo Yoon, Cyrille Hulin, Francesco Volzone, Rakesh Popat, Paolo Corradini, Cyrille Touzeau, Enrique M Ocio, Fritz Offner, Elena Zamagni, Paula Rodriguez-Otero, Christopher Parrish, Maria-Victoria Mateos, Ida Bruun Kristensen, Rodger E Tiedemann, Chang-Ki Min, Kihyun Kim, Wolfgang Jacob, Ann-Marie E Bröske, Iryna Dekhtiarenko, Eva Rossmann, Georgina Meneses-Lorente, Emilie Schindler, Vu-Long Tran, Orwa Albitar, Hans-Joachim Helms, Nassim Sleimann, Natalie Dimier, Martin Weisser, Carmelo Carlo-Stella.
      We report the results from a Phase 1 study (NCT04557150) evaluating subcutaneous (SC) forimtamig, a novel GPRC5DxCD3 bispecific antibody with a 2:1 configuration, in relapsed/refractory multiple myeloma (RRMM). After dose-escalation, backfilling at optimized target doses in combination with weekly (step-up: Cycle [C] 1 Day [D] 1 and C1D8; target: C1D15) and condensed (step-up: C1D1 and C1D4; target: C1D8) step-up dosing was pursued for benefit-risk assessment. Primary objectives were evaluating safety/tolerability and determining the maximum tolerated dose (MTD) and recommended Phase 2 dose/schedule. Secondary objectives included pharmacokinetics, immunogenicity and anti-tumor activity. In total, 171 patients were enrolled (median age: 64.0 years; high-risk cytogenetics: 32.2%; triple-class refractory: 60.2%). The starting C1D1 dose was 0.05 mg. Dose-limiting toxicities occurred in 20 patients (11.7%). MTD was not identified. Dose-escalation concluded at 7.2 mg target dose due to accumulating toxicity. The most common adverse event (AE) was cytokine release syndrome (75.4%). Grade 5 AEs occurred in 11 patients (6.4%); two events were considered treatment-related. Across all cohorts, the overall response rate (ORR) was 59.6%. At the optimized target doses (0.75 mg/1.5 mg), ORR was 71.7% with the condensed schedule (n = 46) and 47.1% with the weekly schedule (n = 34). Early soluble B-cell maturation antigen reduction and minimal residual disease negativity were associated with improved progression-free survival. SC forimtamig demonstrated potent and durable activity in RRMM, which could be enhanced with a condensed step-up schedule. On-target, off-tumor toxicities were common, highlighting the narrow therapeutic window for GPRC5D as a target for T-cell-engaging bispecific antibodies.
    DOI:  https://doi.org/10.1182/bloodadvances.2026020498
  10. Blood. 2026 Oct 01. 148(14): 1854
    Lu J, Xue S, Wang Y, et al. Venetoclax and decitabine vs intensive chemotherapy as induction for young patients with newly diagnosed AML. Blood. 2025;145(22):2645-2655.
      
    DOI:  https://doi.org/10.1182/blood.2026035742
  11. Blood. 2026 Oct 01. 148(14): 1758-1759
    Systems reboot: a niche-based approach to AML.
    David T Scadden.
      
    DOI:  https://doi.org/10.1182/blood.2026035279
  12. Ann Hematol. 2026 Jul 29. pii: 434. [Epub ahead of print]105(10):
    Primary central nervous system lymphoma in the molecular era: genomic drivers, liquid biopsy, and targeted therapeutic strategies.
    Feng Yan, Yongzhi Shan, Xiaotong Fan, Yaming Wang, Penghu Wei, Yongrui Zhao, Yixian Guo.
      Primary central nervous system lymphoma (PCNSL) is an uncommon and aggressive extranodal non-Hodgkin lymphoma confined to the central nervous system, including the brain, leptomeninges, spinal cord, and eyes. Although high-dose methotrexate-based induction remains the backbone of first-line therapy, long-term disease control remains challenging, particularly in older or frail patients and in those with relapsed or refractory disease. Recent genomic and multi-omics studies have reshaped the biological understanding of PCNSL by identifying recurrent alterations in MYD88, CD79B, PIM1, PRDM1, CDKN2A/B, HLA-related genes, B2M, CIITA, and immune checkpoint loci, which converge on B-cell receptor/Toll-like receptor signaling, NF-κB activation, immune evasion, and microenvironmental adaptation. These molecular insights have accelerated minimally invasive diagnostics, including targeted mutation assays, multigene circulating tumor DNA profiling, methylation-based approaches, and cytokine analysis in cerebrospinal fluid, vitreous humor, and aqueous humor. Targeted and immune-based therapies, including Bruton tyrosine kinase inhibitors, immunomodulatory agents, immune checkpoint inhibitors, mTOR inhibitors, and CD19-directed chimeric antigen receptor T-cell therapy, have shown variable degrees of clinical activity, particularly in relapsed or refractory disease. However, most evidence remains derived from early-phase trials, single-arm studies, retrospective cohorts, or small series, and treatment selection is not yet routinely biomarker-defined. This review summarizes current advances in molecular taxonomy, pathogenesis, diagnostic work-up, liquid biopsy, prognostic stratification, and therapeutic management of PCNSL, emphasizing how molecular and longitudinal biomarker data may inform individualized treatment and future clinical trial design.
    Keywords:   MYD88 L265P; Bruton tyrosine kinase inhibitors; CAR-T-cell therapy; Immune evasion; Liquid biopsy; Primary central nervous system lymphoma
    DOI:  https://doi.org/10.1007/s00277-026-07216-5
  13. Blood. 2026 Oct 01. pii: blood.2026034224. [Epub ahead of print]
    Functional Classification of Monoallelic TP53 Mutations Refines Prognostic Stratification in Myelodysplastic Neoplasms.
    Alexander Streuer, Yotaro Ochi, Stephan Hutter, Vladimir Riabov, Yasuhito Nannya, Laurenz Steiner, Mohammed Abba, Georgia Metzgeroth, Eva Altrock, Felicitas Rapp, Verena Nowak, Edin Hepgülüm, Steffen Boettcher, Torsten Haferlach, Daniel Nowak, Wolf-Karsten Hofmann, Seishi Ogawa, Nanni Schmitt.
      TP53 mutations represent one of the strongest adverse prognostic factors in myelodysplastic neoplasms (MDS). While multi-hit TP53 (TP53multiHit) alterations uniformly lead to very poor outcomes, the prognostic relevance of monoallelic TP53 (TP53mono) mutations remains controversial. TP53 variants can cause dominant-negative, loss-of-function, or gain-of-function effects. We hypothesized that functional heterogeneity among TP53 variants contributes to the variable clinical behavior observed in TP53mono-mutated MDS. Therefore, we analyzed pretreatment samples from 4,505 patients with MDS from two independent cohorts (IWG: n=3,173; J-MDS: n=1,332), including 271 patients with TP53mono and 499 with TP53multiHit. Functional annotation of TP53 variants was performed using a previously published phenotype score (PS) derived from saturation mutagenesis screens, capturing dominant-negative and loss-of-function effects. Median leukemia-free survival (LFS) differed significantly by TP53 allelic state (TP53 wild-type (TP53wt) 37.2 months; TP53mono 19.2 months; TP53multiHit 7.8 months; p<0.001). Within the TP53mono subgroup, functional annotation identified marked heterogeneity. Patients with high PS (≥7) showed a significantly inferior median LFS compared with those with low PS (12.6 vs. 43.3 months; p<0.001), particularly for IPSS-R and IPSS-M low-risk cases. Combining PS and variant allele frequency (VAF) further improved risk stratification. TP53mono patients with PS ≥7 and VAF ≥22% had a median LFS comparable to TP53multiHit cases (9.2 vs. 7.8 months, p=0.3), whereas those with PS <7 and VAF <22% exhibited a median LFS similar to TP53wt cases (44.7 vs. 37.2 months, p=0.8). Overall, functional annotation of TP53 variants refines prognostication in TP53mono-mutated MDS and may enhance individualized risk assessment.
    DOI:  https://doi.org/10.1182/blood.2026034224
  14. Blood. 2026 Oct 02. pii: blood.2026034352. [Epub ahead of print]
    DMT1 Facilitates Heme-iron Absorption in Rats and Mice.
    Yue He, Jacob S Shine, Sitara Sriram, Li-Ying Kuo, Melissa Fraga, Laura M Garrick, Michael D Garrick, Iqbal Hamza, James F Collins.
      Mechanisms of heme-iron (HI) absorption remain uncertain. Heme is probably absorbed by receptor-mediated endocytosis; iron is then enzymatically liberated from heme within endosomes, or in the cytosol. If heme is catabolized in endosomes, a transporter, such as DMT1, would be required to export ionic iron into the cytosol. Here, we tested the hypothesis that intestinal DMT1 functions in the HI absorption pathway. The first experimental approach utilized Belgrade (b) rats, expressing dysfunctional DMT1 protein, and the second used conditional, intestine-specific DMT1 KO mice. HI absorption experiments were carried out with radiolabeled, donor rat RBCs, containing ~98% of iron as HI and with >94% of activity in 59Fe-heme. Iron-deficient, anemic +/b (control) rats absorbed 10.8% of a peroral dose of 59Fe-heme within 24 hours, while similarly anemic b/b rats absorbed 1.4% (an 8-fold reduction). Notably, serum hepcidin levels were invariable between both groups of rats (and 10x lower than controls). Moreover, ablation of intestinal DMT1 led to iron-restricted erythropoiesis and severe anemia in adolescent mice weaned on to nonheme iron (NHI) or HI diets. DMT1 was also required to upregulate 59Fe-heme absorption in iron-deficient, anemic mice. DMT1 thus facilitates the absorption of both main forms of dietary iron, NHI and HI.
    DOI:  https://doi.org/10.1182/blood.2026034352
  15. Leukemia. 2026 Sep 28.
    PIM1 in myeloproliferative neoplasms: potential pathogenic and therapeutic implications.
    Avik Dutta, Lilian Varricchio, Ronald Hoffman, Golam Mohi.
      Myeloproliferative neoplasms (MPNs) are clonal hematologic malignancies characterized by the overproduction of mature myeloid lineage cells. Although JAK2 inhibitors, such as ruxolitinib, can alleviate constitutional symptoms, they typically fail to eradicate malignant clones or reverse bone marrow fibrosis. Moreover, treatment failure and drug intolerance often limit their long-term use. Recent studies have identified PIM1 kinase as an important mediator of MPN pathogenesis. PIM1 expression is upregulated in MPN hematopoietic progenitors, which may contribute to aberrant proliferation and disease progression by regulating key downstream effectors, including mTORC1, BAD, MYC, HIF-1α, and TGF-β. Notably, PIM1 contributes to JAK2 inhibitor-persistent cell growth, and its inhibition restores ruxolitinib sensitivity in JAK2 mutant cells. Preclinical studies using genetic ablation and pharmacological inhibition of PIM1 have shown significant attenuation of the myelofibrosis phenotype in mouse models, providing a strong rationale for targeting this kinase. PIM kinase inhibitors are currently being evaluated in clinical trials for patients with myelofibrosis. This review summarizes the current understanding of PIM1 biology in the context of MPNs, details the molecular mechanisms underlying its pathogenic contributions, and evaluates the translational potential of PIM1-targeted therapies for MPNs.
    DOI:  https://doi.org/10.1038/s41375-026-03144-5
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