bims-hemali 2025-11-30 papers

bims-hemali

Biomed News

on Hematologic malignancies

Issue of 2025–11–30
twenty-two papers selected by
Alexandros Alexandropoulos, Γενικό Νοσοκομείο Αθηνών Λαϊκό

MRD-driven Initial Therapy of Acalabrutinib and Lenalidomide plus Rituximab (ALR) or Obinutuzumab (ALO) for Mantle Cell Lymphoma.
Metformin alleviates side effects and supports the resumption of interferon therapy in polycythemia vera and essential thrombocythemia.
The Development of Novel Therapies for Chronic Lymphocytic Leukaemia in the Era of Targeted Drugs.
Alternative 5-Azacitidine 5-Day 100 mg/m2 Dosage Shows Non-Inferiority to Classical Schedule for Myelodysplastic Neoplasm (MDS) and Chronic Myelomonocytic Leukaemia (CMML) Treatment.
Discovery and Characterization of Novel BLIMP-1 Heterobifunctional Ligand-Directed Degraders.
Tracking leukemic residuals: dissecting the inverse relationship between CD26+ stem cells and extracellular BCR::ABL1 transcript in Chronic Myeloid Leukemia (CML).
Explain the unexplained.
Optimizing lower intensity triplet therapy in acute myeloid leukemia: a practical guide.
Influence of Oxidation Resistance 1 on disease progression in chronic myeloid leukemia.
Selective Cytotoxicity in Chronic Myeloid Leukemia (K-562) Cells Induced by 532 nm LASER Irradiation Without Exogenous Photosensitizers.
Moderate-Severe Thrombocytopenia Portends Poor Outcomes in Multiple Myeloma.
Multi-hit TP53 confers the poorest survival in multiple myeloma in the era of novel therapies.
Death receptor 3 gives life to Tregs in GVHD.
Outcomes for Primary Central Nervous System Lymphoma from a Single Institution.
European LeukemiaNet criteria for safety and efficacy evaluation of new drugs for myelofibrosis.
Hairy Cell Leukemia: a chronic B-lymphoma with unique clinicopathological features and unresolved molecular mechanisms.
Genomic landscape and molecular subtypes of primary central nervous system lymphoma.
Efficacy and Limitations of Flow Cytometry for the Rapid Diagnosis of Primary Central Nervous System Lymphoma.
Luspatercept treatment affects immune-regulatory subsets in patients with MDS with ring sideroblasts.
Correlation between duration of first-line treatment with daratumumab, lenalidomide, and dexamethasone and overall survival in patients with transplant-ineligible multiple myeloma in Japan.
Iron deficiency treatment pathway in Italy: patients' perceptions of diagnosis and treatment.
TriLeukeVax: A CD80/IL-15/IL-15Rα Expressing Autologous AML Cell Vaccine Elicits Robust Anti-Leukemic Cytolytic Activity.

Blood Adv. 2025 Nov 25. pii: bloodadvances.2025017760. [Epub ahead of print]

MRD-driven Initial Therapy of Acalabrutinib and Lenalidomide plus Rituximab (ALR) or Obinutuzumab (ALO) for Mantle Cell Lymphoma.

Jia Ruan, David A Bond, Bijal D Shah, John N Allan, Sarah C Rutherford, Caitlin Gribbin, Zhengming Chen, Bhavneet Bhinder, Wayne Tam, Davide Rossi, Jenny Z Xiang, Brittany Hobbie, Melinda Harbhajan, Tejasvi K Sahni, Gui Zhen Chen, Michael Sigouros, Giorgio Ga Inghirami, Selina Chen-Kiang, Olivier Elemento, Kami J Maddocks, John P Leonard, Peter Martin.

This phase 2 study evaluated the efficacy and safety of combining acalabrutinib (A) and lenalidomide (L) with either rituximab (ALR) or obinutuzumab (ALO), with longitudinal minimal residual disease (MRD) monitoring in frontline MCL treatment (ClinicalTrials.gov - NCT03863184). The primary objective was molecular CR after 12 cycles of induction, defined by Lugano criteria and undetectable MRD <10-6 (uMRD6) by clonoSEQ. Secondary objectives included safety, responses and survival. Exploratory objectives included tumor mutation profiles and cell-free DNA (cfDNA) by CAPP-Seq. Patients in uMRD6 molecular CR were eligible for discontinuation of A+L after 24 cycles; all patients received a minimum of 36 cycles of anti-CD20 antibody treatment. In the ALR cohort, grade 3-4 hematologic toxicities included neutropenia (38%), thrombocytopenia (4%) and anemia (4%). Non-hematologic toxicities included rash (42%), fatigue (4%), nausea (4%), and vomiting (4%). The ORR was 100%, CR 83% and molecular CR 67% after 12 cycles of induction, with best molecular CR at 83%. At a median follow-up of 53 months (range 46-60), the 4-yr OS and PFS for ALR were 91% and 76%, respectively. TP53 mutations were adversely associated with PFS (p=0.026). For ALO, ORR, CR and molecular CR were 90% following induction, and 2-yr OS and PFS were both at 100%. Longitudinal cfDNA analysis in ALR revealed clonal evolution during response and progression. This safe and active regimen is feasible as a time-limited initial therapy for MCL patients and warrants further evaluation in response-adapted strategy.

DOI: https://doi.org/10.1182/bloodadvances.2025017760
Haematologica. 2025 Nov 27.

Metformin alleviates side effects and supports the resumption of interferon therapy in polycythemia vera and essential thrombocythemia.

Brandi N Reeves, Jihyun Song, André Leier, Amanda Smith, Soo J Kim, Sheh-Li Chen, Tsewang Tashi, Josef T Prchal.

Interferon-α is emerging as the preferential cytoreductive therapy for polycythemia vera (PV) and essential thrombocythemia (ET) due to improved long-term outcomes over alternatives such as hydroxyurea. Historically, interferon-α therapy has been marked by high rates of adverse events and subsequently poor adherence. Long-acting formulations of interferon-α, i.e., ropeginterferon-α-2b (ropeg), improve tolerability. However, nearly half of ropeg-treated patients experience fatigue, arthralgias, or myalgias and 10-20% discontinue treatment or cannot tolerate maximal ropeg doses, due to adverse events. Herein, we report our retrospective experience of adjunct metformin therapy in 11 PV and ET patients who were intolerant of ropeg. Metformin improved ropeg-related fatigue and/or myalgias in 10 of 11 patients. A complete hematologic response (CHR) was maintained in all 6 patients who had already achieved this prior to starting metformin, and a deepened hematologic response was observed in 3 of 4 patients after the addition of metformin. These encouraging results merit further evaluation in a randomized clinical study. Further, additional investigations are needed to elucidate the mechanism of interferon-α-mediated fatigue and myalgias and the mechanism of putative beneficial interaction between interferon-α and metformin.

DOI: https://doi.org/10.3324/haematol.2025.288404
J Clin Med. 2025 Nov 20. pii: 8247. [Epub ahead of print]14(22):

The Development of Novel Therapies for Chronic Lymphocytic Leukaemia in the Era of Targeted Drugs.

Tadeusz Robak, Elżbieta Iskierka-Jażdżewska, Anna Puła, Pawel Robak, Bartosz Puła.

  Over the past decade, chronic lymphocytic leukaemia (CLL) treatment has shifted from chemoimmunotherapy to targeted oral agents, predominantly Bruton's tyrosine kinase inhibitors (BTKis) and the BCL-2 inhibitor venetoclax. These therapies have significantly improved outcomes and are now established as first-line treatment options. However, CLL remains incurable, and resistance or intolerance to both drug classes (double-refractory disease) is an emerging challenge. This has driven the development of novel therapeutic strategies, including non-covalent BTKis such as pirtobrutinib and nemtabrutinib, which retain activity in BTK C481-mutated disease. Next-generation BCL-2 inhibitors (sonrotoclax, lisaftoclax) and BTK degraders are promising in early clinical trials. Immunotherapeutic approaches, such as bispecific T-cell engagers, CD20/CD3 antibodies, and CAR-T cell therapies, provide additional options for high-risk patients. Although PI3K inhibitors remain under investigation, their role is yet to be defined due to safety concerns. Minimal residual disease (MRD)-guided, fixed-duration regimens represent a significant paradigm shift toward personalised treatment and potentially deeper remissions. Ongoing clinical studies are expected to introduce new effective therapies that may further transform the management of CLL in the coming years.

Keywords:  BCL-2 inhibitors; BTK degraders; BTK inhibitors; CAR-T; PI3K inhibitors; T-cell engagers; chronic lymphocytic leukaemia

DOI:  https://doi.org/10.3390/jcm14228247
EJHaem. 2025 Dec;6(6): e70185

Alternative 5-Azacitidine 5-Day 100 mg/m2 Dosage Shows Non-Inferiority to Classical Schedule for Myelodysplastic Neoplasm (MDS) and Chronic Myelomonocytic Leukaemia (CMML) Treatment.

Gerasimos Tsilimidos, Filipe Martins, Mariangela Costanza, Mathilde Gavillet, Sabine Blum.

   Introduction: 5-Azacitidine (AZA) is a major treatment option for myelodysplastic neoplasms (MDS) and myelodysplastic/myeloproliferative neoplasms (MDS/MPN). Here we evaluate the efficacy and toxicity of an alternative AZA regimen (100 mg/m2/day for 5 days/28 days) in 68 patients (51 MDS, 17 MDS/MPN) treated between 2008 and 2018.
Results: Median patient age was 66 years, with most patients (98%) having intermediate or high-risk disease. Overall response rate (ORR) was 62% with 22% complete responses (CR). Median OS and median PFS were 22.5 and 18.2 months, respectively. Inferior response rates were calculated in therapy-related MDS (t-MDS) and MDS with excess blast II, with t-MDS having also statistically worse OS and PFS. MDS/MPN patients showed 73.6% ORR with 31.5% CR. Transfusion independence (TI) for red blood cells (RBC) was achieved in 45.9% of transfusion-dependent patients and in 30% for platelets. CR patients showed longer mOS and mPFS (70.6 and 64.7 months, respectively). Longer mOS was also correlated with allogeneic transplantation (48.8 vs. 16.9 months, p = 0.01) and RBC TI (25.4 vs. 13.3 months, p = 0.01). Grade 3/4 cytopenias occurred in 41.1% (neutropenia in 33.8%), and treatment-related mortality was 7.4%.
Conclusion: This study demonstrates that this alternative AZA regimen has comparable efficacy and safety to the standard regimen, compared with historical data.
Trial Registration: The authors have confirmed clinical trial registration is not needed for this submission.

Keywords:  CMML; MDS; azacitidine

DOI:  https://doi.org/10.1002/jha2.70185
J Med Chem. 2025 Nov 24.

Discovery and Characterization of Novel BLIMP-1 Heterobifunctional Ligand-Directed Degraders.

Bryan J Simmons, Lynda Groocock, Jesus Moreno, David S Peters, Meredith E Hughes, Vijay Veeravalli, Jennifer M Crawford, Matthew Chalkley, Mark Griffith, Melissa Plooster, Bo Hu, Jim Gamez, Jim Leisten, Michael J Barnes, Jason Chinn, Gauri Deb, Hardik Modi, Madhu Katepalli, Dahlia Weiss, Walter Won, Zhenghang Sun, Shan Yu, Cameron Reid, Andrew F Donnell, Ling Li, Edmond R Watson, Sophie Perrin-Ninkovic, Lihong Shi, Rama Krishna Narla, Christoph W Zapf, Neil Bence, Antonia Lopez-Girona, Jennifer R Riggs.

B-lymphocyte-induced maturation protein 1 (BLIMP-1/PRDM1) is a master transcriptional repressor essential for terminal differentiation of activated B-cells into bone-marrow resident plasma cells. Multiple myeloma (MM) is a plasma cell malignancy wherein the BLIMP-1 regulon remains critical to support basal cell functions, such as an elevated metabolic state and immunoglobulin production that underlie disease manifestation and tumor cell proliferation. It is predicted that perturbation of BLIMP-1 will significantly impact tumor cell homeostasis and ultimately reduce MM cell survival. Herein, we describe the discovery and optimization of the first orally bioavailable BLIMP-1 heterobifunctional ligand-directed degrader (LDD) and demonstration of the expected antitumor response and immunomodulatory biology following BLIMP-1 degradation using preclinical in vivo MM models.

DOI: https://doi.org/10.1021/acs.jmedchem.5c02363
Stem Cells Transl Med. 2025 Nov 24. pii: szaf062. [Epub ahead of print]14(12):

Tracking leukemic residuals: dissecting the inverse relationship between CD26+ stem cells and extracellular BCR::ABL1 transcript in Chronic Myeloid Leukemia (CML).

Silvia Mutti, Alessia Cavalleri, Anna Sicuranza, Paola Pacelli, Claudia Ielo, Lucia Paolini, Valentina Mangolini, Alessandro Leoni, Teresa Miracapillo, Camilla Turriziani, Elisabetta Abruzzese, Mirko Farina, Annalisa Radeghieri, Michele Malagola, Massimo Breccia, Monica Bocchia, Domenico Russo, Simona Bernardi.

  Chronic myeloid leukemia (CML) persists due to leukemic stem cells, notably the CD26+ subset. We investigated correlations between circulating CD26+ leukemic stem cells (LSCs) and BCR::ABL1 transcripts in an extracellular vesicle-enriched secretome (EVES) from plasma samples of 44 CML patients. EVES were characterized and BCR::ABL1 quantified via digital PCR. We observed an inverse correlation between CD26+LSC counts and EVES BCR::ABL1 levels, especially in deep molecular responders (DMR). CD26+LSCs were elevated in patients in treatment-free remission (TFR), while EVES BCR::ABL1 levels were higher in those receiving therapy. These findings suggest distinct dynamics between LSC populations and vesicle-mediated transcript release, with potential implications for CML monitoring and prognosis.

Keywords:  BCR::ABL1; CD26; EVES; chronic myeloid leukemia; leukemic stem cells

DOI:  https://doi.org/10.1093/stcltm/szaf062
Blood. 2025 Nov 27. 146(22): 2622-2623

Explain the unexplained.

Jill Corre.

DOI: https://doi.org/10.1182/blood.2025030944
Blood Cancer J. 2025 Nov 25.

Optimizing lower intensity triplet therapy in acute myeloid leukemia: a practical guide.

Wei-Ying Jen, Curtis A Lachowiez, Jennifer Marvin-Peek, Jessica K Altman, Musa Yilmaz, Jacqueline S Garcia, Yasmin Abaza, Nicholas J Short, Joshua F Zeidner, Naval G Daver, Andrew H Wei, Ghayas C Issa, Courtney D DiNardo.

Venetoclax-based doublets with azacitidine or low dose cytarabine are the standard of care for the treatment of acute myeloid leukemia (AML) in older patients or those unfit for intensive chemotherapy. However, some patients do not attain complete remission, and over time, most patients relapse. Frontline triplet therapy incorporating a targeted therapy (FLT3, IDH or menin inhibitor) is an emerging treatment concept under investigation for this population. Initial triplet regimens have yielded encouraging composite complete remission and measurable residual disease negativity rates, enabling the transition to allogeneic stem cell transplantation for eligible patients. While effective, triplets are associated with myelosuppression and cytopenia-related toxicities, which can affect treatment tolerability and quality of life. In this review, we summarize the available evidence for triplet therapy in AML and offer our recommendations on the practical application of triplets in clinical practice, with particular focus on adjustments to dosing schedules in induction and continuation cycles. We also outline drug-specific adverse effects and interactions based on emerging clinical data to help guide the clinician, given the increasing use of novel combination therapies.

DOI: https://doi.org/10.1038/s41408-025-01429-z
JCI Insight. 2025 Nov 25. pii: e190833. [Epub ahead of print]

Influence of Oxidation Resistance 1 on disease progression in chronic myeloid leukemia.

Weiqi Huang, Bin Liu, Liping Hu, Chi-Hao Luan, Priyam Patel, Elizabeth T Bartom, Elizabeth A Eklund.

  Survival in chronic myeloid leukemia (CML) was dramatically improved by development of tyrosine kinase inhibitors (TKIs) directed to the BCR::ABL1 oncogene. Unfortunately, ~30% of CML patients develop TKI-resistance during prolonged treatment, with enhanced blast crisis risk. Oxidation Resistance 1 (Oxr1) regulates anti-oxidant pathways that detoxify reactive oxygen species (ROS) generated by the phagocyte-NADPH oxidase. In the current studies, we found that Oxr1 expression increased in hematopoietic stem and progenitor cells (HSPCs) from CML mice versus controls; decreased during TKI-induced remission; and rose during chronic phase relapse. Oxr1 has long and short isoforms, and we found increased short, but decreased long, Oxr1 in mice or humans during CML relapse. We determined long Oxr1 prevents ROS accumulation in CML marrow, but short Oxr1 is a dominant negative. Previously, we found exaggerated and sustained emergency granulopoiesis in CML mice, with repeated episodes facilitating relapse during TKI-remission. In the current studies, we found knocking-down Oxr1 in murine marrow further accelerates CML progression during this physiologic stress. We found increased DNA-damage in HSPCs from these mice, including a BCR::ABL1 kinase-domain mutation found in TKI-resistant human CML. These studies suggest long Oxr1 detoxifies ROS to decrease mutagenesis in CML, but aberrant short Oxr1 expression enhances progression.

Keywords:  Hematology; Innate immunity; Leukemias; Oncology

DOI:  https://doi.org/10.1172/jci.insight.190833
Biomedicines. 2025 Oct 29. pii: 2649. [Epub ahead of print]13(11):

Selective Cytotoxicity in Chronic Myeloid Leukemia (K-562) Cells Induced by 532 nm LASER Irradiation Without Exogenous Photosensitizers.

Danielle Viviana Ochoa-Arbeláez, Efraín Solarte-Rodríguez, Yamil Liscano.

  Background and Objectives: The treatment of Chronic Myeloid Leukemia (CML) faces challenges such as resistance to Tyrosine Kinase Inhibitors (TKIs), necessitating new adjuvant therapies. This study aimed to evaluate the cytotoxic effect of direct, photosensitizer-free irradiation with LASER and LED light on the CML cell line K-562, hypothesizing that LASER light at a specific wavelength would be selectively effective. This work serves as a foundational in vitro study to establish the basis for a potential ex vivo therapeutic strategy. Methods: The human CML cell line K-562 was irradiated with LASER (405, 532, 629 nm) and LED (457, 517, 630 nm) sources at energy doses from 1 to 10 J/cm2. Cell viability was assessed 24 h post-irradiation using Trypan Blue exclusion, the MTT assay, and biophysical changes in the cell absorbance spectrum. Results: Irradiation with a 532 nm LASER was the only condition that induced massive, statistically significant, and dose-dependent cytotoxicity, reaching up to 67.8% cell death at 10 J/cm2 (p < 0.05). In contrast, other LASER wavelengths and all tested LED wavelengths failed to produce a significant cytotoxic effect. The superiority of the LASER over the LED of a similar wavelength highlights the critical role of the physical properties of light. Conclusions: Direct, photosensitizer-free irradiation with 532 nm LASER light is a potent and selective method for inducing cytotoxicity in K-562 cells in vitro. This effect is critically dependent on both the specific wavelength and the optical properties of the light source. These findings establish a solid foundation for the development of new ex vivo adjuvant therapies, such as extracorporeal photopheresis, for CML, pending further validation of its mechanism and selectivity.

Keywords:  Chronic Myeloid Leukemia; Direct Light Stimulation; K-562; LASER Therapy; biophotonics; cytotoxicity

DOI:  https://doi.org/10.3390/biomedicines13112649
EJHaem. 2025 Dec;6(6): e70153

Moderate-Severe Thrombocytopenia Portends Poor Outcomes in Multiple Myeloma.

Grace M Ferri, Cenk Yildirim, Nhan V Do, Mary T Brophy, Nikhil C Munshi, Camille V Edwards, Nathanael R Fillmore.

   Background: Malignant plasma cells in multiple myeloma (MM) reprogram the bone marrow microenvironment to support tumor expansion. This myeloma cell-hematopoietic stem cell interaction leads to fewer hematopoietic stem cells in the bone marrow and altered differentiation of megakaryocytes, which can contribute to MM disease-related thrombocytopenia. Given the development of novel therapies for MM and the need for biomarkers reflecting the bone marrow microenvironment, we evaluated peripheral blood platelet count at diagnosis and during treatment of MM.
Methods: We retrospectively evaluated 14,313 patients diagnosed with MM between 2000 and 2019 at Veterans Administration hospitals using platelet count obtained closest to diagnosis and up to 2.5 years thereafter. Patients were stratified into four categories: moderate-severe thrombocytopenia, mild thrombocytopenia, normal platelets, and thrombocytosis (< 100, 100-149, 150-349, and ≥ 350 per microliter, respectively).
Results: Thrombocytopenia, present in 25% of patients at diagnosis, corresponded to inferior overall survival (OS). During follow-up, persistent or new thrombocytopenia was also associated with inferior OS. Moreover, the negative prognostication afforded by baseline moderate-severe thrombocytopenia remained despite standard therapies (hazard ratio [HR] 1.83; 95% confidence interval [CI] 1.70-1.97) and stem cell transplant (HR 1.41; 95% CI 1.34-1.48).
Conclusion: Our findings support the use of platelet count in MM as an easily accessible prognostic marker.
Trial Registration: The authors have confirmed clinical trial registration is not needed for this submission.

Keywords:  bone marrow; multiple myeloma; platelets; prognostication; tumor microenvironment

DOI:  https://doi.org/10.1002/jha2.70153
Mol Med. 2025 Nov 29.

Multi-hit TP53 confers the poorest survival in multiple myeloma in the era of novel therapies.

Romana Nesnadna, Anna Petrackova, Jiri Minarik, Vojtech Latal, Jirina Manakova, Tomas Papajik, Eva Kriegova.

  Multiple myeloma (MM) with high-risk (HR) genetic abnormalities has poor prognosis, despite the use of novel therapeutic agents. However, the individual contribution of specific HR genetic abnormalities or their co-occurrence to poor outcomes, especially in the era of novel agents, remains unclear. This study evaluated the impact of multi-hit TP53 (del(17p) and TP53 mutation or ≥ 2 TP53 mutations) compared with other HR abnormalities on progression-free survival (PFS), overall survival (OS) and blood signature in a real-world cohort of 204 patients with MM treated with novel agents (median follow-up 28 months). Patients with multi-hit TP53 (10.4%) had the shortest PFS and OS compared with those with single HR abnormalities (p ≤ 0.011) or with co-occurrence of ≥ 2 other HR abnormalities (p ≤ 0.002), regardless of therapy line. The relative risk of early progression in patients with multi-hit TP53 was almost three times higher than that of patients with other HR abnormalities. The prevalence of TP53 alterations increased in later disease stages: multi-hit TP53 was detected in 7.6% of patients with ≤ 1 prior therapy line and in 36.4% of patients with ≥ 2 prior lines. Patients with multi-hit TP53 also differed in blood signature, particularly in counts of white blood cells, lymphocytes, serum creatinine and β2-microglobulin levels compared with those with other HR abnormalities. In conclusion, multi-hit TP53 is associated with the poorest survival among all HR subgroups in MM. Considering that TP53 alterations accumulate during MM progression and are associated with drug resistance even in the context of novel therapies, our study further emphasizes the need for routine evaluation of both del(17p) and TP53 mutations. Patients with multi-hit TP53 should be prioritized for inclusion in trials of novel therapeutic strategies.

Keywords:  High-risk Myeloma; Multi-hit TP53 ; Multiple Myeloma; Next-Generation Sequencing

DOI:  https://doi.org/10.1186/s10020-025-01392-2
Blood. 2025 Nov 27. 146(22): 2626-2627

Death receptor 3 gives life to Tregs in GVHD.

Haroon Shaikh.

DOI: https://doi.org/10.1182/blood.2025030671
Hematol Rep. 2025 Oct 24. pii: 55. [Epub ahead of print]17(6):

Outcomes for Primary Central Nervous System Lymphoma from a Single Institution.

Sruthi Dontu, Jacob Boccucci, Michael Chahin, Amany Keruakous, Anand Jillella, Jorge Cortes, Vamsi Kota, Locke Bryan, Ayushi Chauhan.

  Background: Primary central nervous lymphoma (PCNSL) is a rare, aggressive, non-Hodgkin's lymphoma. Outcomes are poor with standard induction of high-dose methotrexate (HD-MTX)-based regimens and consolidation. We present retrospective data from the Georgia Cancer Center. Methods: A single retrospective chart review was conducted on all PCNSL patients from 2013 to 2023 to assess for various factors influencing care. Results: Of a total of 38 PCNSL patients, 6 died and 2 were lost to follow-up prior to therapy initiation, leading to a total of 30 patients for analysis. The median age was 62.3 (21-82 years). One patient had HIV/AIDS. Two patients were on immunosuppression for either kidney transplant or multiple sclerosis (MS). The HIV and MS cases were Epstein-Barr Virus (EBV)-positive. Completion of ≥six cycles of induction was predictive of response. Conclusions: PCNSL remains an area of high unmet need. Recent studies have shown that HD-MTX-based therapy and autologous stem cell transplantation afterwards leads to improved outcomes regardless of age; however, non-relapse mortality is important to consider. Our data from a primarily elderly and sub-rural cohort reiterate the efficacy of combination chemoimmunotherapy and impact of induction cycle number on response, regardless of age. A multidisciplinary approach and targeted agent maintenance should be considered to improve outcomes in the elderly.

Keywords:  elderly patients; high-dose methotrexate-based combination chemotherapy; outcomes; primary CNS lymphoma

DOI:  https://doi.org/10.3390/hematolrep17060055
Blood Cancer J. 2025 Nov 24. 15(1): 207

European LeukemiaNet criteria for safety and efficacy evaluation of new drugs for myelofibrosis.

Monia Marchetti, Alessandro Maria Vannucchi, John O Mascarenhas, Alberto Alvarez-Larran, Prithviraj Bose, Robert Peter Gale, Claire Harrison, Rűdiger Hehlmann, Jean-Jacques Kiladjian, Steffen Koschmieder, Ruben Mesa, Francesco Passamonti, Alessandro Rambaldi, Ayalew Tefferi, Tiziano Barbui.

Most myelofibrosis (MF) drug approvals by Health Authorities are based on 1 or 2 outcome measures such as spleen volume reduction and/or improved quality of life. This 1-2 dimensional approach fails to capture the clinical complexity of MF. A European LeukemiaNet (ELN) task force developed a composite endpoint that allows multiple outcomes to be simultaneously measured. The panel used the Desirability Of Outcome Ranking (DOOR) method to assign 25 outcomes into 4 quartiles based on a multi-dimensional desirability score and build a 5-layer composite outcome named Desirability of Myelofibrosis Outcomes (DEMYO). Outcome operational definitions were tested by Delphi consensus, and correlations with survival were validated by a literature review. The outcomes assigned to the first two quartiles were negatively correlated with leukemia-free survival and survival. DEMYO comprehensively captures relevant MF clinical features and meaningful endpoints. Despite DEMYO requiring validation based on available trial data, it is expected to improve the quality of Health Authority approvals for new drugs for MF.

DOI: https://doi.org/10.1038/s41408-025-01381-y
Blood Adv. 2025 Nov 26. pii: bloodadvances.2025017165. [Epub ahead of print]

Hairy Cell Leukemia: a chronic B-lymphoma with unique clinicopathological features and unresolved molecular mechanisms.

Ge Zhang, Jiancheng Hu.

Hairy cell leukemia (HCL) is a chronic B-cell lymphoproliferative disorder that is characterized by pancytopenia, splenomegaly and hepatomegaly resulting from the organ-specific infiltration of 'hairy' leukemic cells. Despite tremendous therapeutic advances with purine analogues and interferon, approximately half of patients with HCL relapse after initial treatment. The discovery of the causal gene BRAF(V600E) of HCL, unsealing an aberrant MAPK signaling pathway that drives the proliferation and survival of HCL B cells, provides a promising and effective target for treating patients who have developed resistance to myelotoxic and immune-suppressive drugs. More recently, two BRAF(V600E)-based HCL mouse models have been developed that could be extremely useful both for functional studies and for testing the activity of new drugs. This review aims to summarize current understanding of key pathogenic mechanisms underlying HCL development and discusses major hurdles that need to be overcome in the context of other BRAF-mutated malignancies.

DOI: https://doi.org/10.1182/bloodadvances.2025017165
Blood Cancer J. 2025 Nov 26.

Genomic landscape and molecular subtypes of primary central nervous system lymphoma.

Shengjie Li, Danhui Li, Zuguang Xia, Jianing Wu, Jun Ren, Yingzhu Li, Jiazhen Cao, Ying Sun, Chengxun Li, Wenjun Cao, Ying Mao.

The genetic landscape and molecular subtypes of primary central nervous system lymphoma (PCNSL) remain inadequately characterized, presenting a major obstacle to the development of effective therapeutic strategies. We conducted a genomic study of 176 PCNSLs from five tertiary centers with long-term follow-up to expand the genomic landscape and identify new molecular subtypes. We first confirmed that the molecular subtyping of diffuse large B-cell lymphoma, as previously published, may not be fully applicable to Chinese PCNSL patients. We then identified (n = 58) and validated (n = 82) three prominent genetic subtypes related to different clinical and molecular features of PCNSL, and further confirmed by an independent external Chinese PCNSL cohort (n = 36). We called these BMIs (from the co-occurrence of mutations in two genes among BTG1, MYD88, and IRF4), which are associated with favorable outcomes; E3s (so-called EP300 mutations), which are associated with unfavorable outcomes; and UCs (unclassified, without characteristic mutations). Importantly, EP300 was mutated in more Asians (16.98%) than in Western PCNSLs (<4.53%), resulting in unfavorable outcomes independent of the specific mutation site. Our analysis comprehensively reveals the genomic landscape of Chinese PCNSL and emphasizes the clinical value of molecular classification for improving precision medicine strategies.

DOI: https://doi.org/10.1038/s41408-025-01421-7
Cancers (Basel). 2025 Nov 13. pii: 3646. [Epub ahead of print]17(22):

Efficacy and Limitations of Flow Cytometry for the Rapid Diagnosis of Primary Central Nervous System Lymphoma.

Hikaru Nakamura, Takeshi Hiu, Takeharu Kato, Nozomi Ueki, Ayaka Matsuo, Michiharu Yoshida, Shiro Baba, Kenta Ujifuku, Koichi Yoshida, Hirofumi Koike, Yukishige Hayashi, Hiroo Hasegawa, Koji Ando, Katsunori Yanagihara, Masahiro Nakashima, Yasushi Miyazaki, Takayuki Matsuo.

   BACKGROUND/OBJECTIVES: Primary central nervous system lymphoma (PCNSL) has a markedly high proliferation rate, making early diagnosis and prompt therapeutic intervention essential. To accelerate diagnosis, our institution adopted flow cytometry (FCM) in conjunction with conventional histopathology, and this study therefore evaluated the diagnostic performance of FCM for PCNSL.
METHODS: We retrospectively analyzed 67 consecutive patients with suspected PCNSL who underwent intraoperative FCM between 2010 and 2023 based on preoperative imaging. B-cell clonality was defined as ≥20% CD19/CD20-positive cells with a κ/λ ratio of >3.0 or <0.5.
RESULTS: Using histopathology, we confirmed the presence of PCNSL in 42 patients, all diagnosed as having diffuse large B-cell lymphoma. Six cases (14.3%) were discordant (FCM-D). The sensitivity, specificity, and positive predictive value of FCM were 85.7%, 100%, and 100%, respectively. T-cell markers were significantly elevated in FCM-D cases (p < 0.01), although these were pathologically diagnosed as diffuse large B-cell lymphoma based on histology and immunohistochemistry.
CONCLUSIONS: FCM yields reliable diagnostic information within hours of tissue collection and supports early therapeutic decisions in PCNSL. Discordant results may reflect reactive T-cell infiltration. This is the first study to present detailed subset analyses in PCNSL using FCM in correlation with pathology, underscoring its utility as a rapid diagnostic tool.

Keywords:  diffuse large B-cell lymphoma; flow cytometry; primary central nervous system lymphoma

DOI:  https://doi.org/10.3390/cancers17223646
Blood Neoplasia. 2025 Nov;2(4): 100170

Luspatercept treatment affects immune-regulatory subsets in patients with MDS with ring sideroblasts.

Stefania Leone, Francesco Grimaldi, Mara Memoli, Giulia Scalia, Annamaria Vincenzi, Maria Di Perna, Giuseppe Cerciello, Antonio Vassallo, Fabrizio Pane, Alessandra Picardi, Giuseppe Terrazzano, Giuseppina Ruggiero, Flavia Carriero, Valentina Rubino.

DOI: https://doi.org/10.1016/j.bneo.2025.100170
Curr Med Res Opin. 2025 Nov 26. 1-12

Correlation between duration of first-line treatment with daratumumab, lenalidomide, and dexamethasone and overall survival in patients with transplant-ineligible multiple myeloma in Japan.

Kazuhito Suzuki, Miku Ito, Chika Sakai, Hiroaki Tsuchiya, David Bin-Chia Wu, Yosuke Koroki.

   OBJECTIVE: Optimal management of multiple myeloma (MM) remains challenging, particularly among patients with transplant-ineligible newly diagnosed MM (TIE NDMM). Daratumumab + lenalidomide + dexamethasone (DRd) is approved in Japan for the treatment of TIE NDMM. A previously reported real-world, retrospective study of claims from the Japanese Medical Data Vision (MDV) database reported that first-line (1 L) DRd may improve outcomes versus second-line or later treatment in patients with TIE NDMM.
METHODS: Data from this study underwent further analysis to investigate the correlation between 1 L DRd duration of treatment (DoT) and overall survival (OS). DoT and OS outcomes were also assessed in subgroups defined by age (<75, ≥75 to <80, ≥80 years) and Charlson Comorbidity Index (CCI; low [score 0], medium [1 or 2], high [3 or 4] or very high [≥5]).
RESULTS: Of 35,581 patients in the MDV database with a diagnosis of MM between January 1, 2016 and October 31, 2023, 200 patients (median age 77 years, median time from MM diagnosis 16 days) were prescribed 1 L DRd and had baseline/demographic data available at the start of treatment. After a median follow-up of 12.8 months, 1 L DRd DoT (median 26.9 months) showed high-positive correlation with OS (not reached) using Pearson's (r = 0.832), Spearman's rank (rs=0.777), Kendall's Tau (τb=0.703), and Fleischer's (Corr [DoT, OS] = 0.789) coefficients in the overall population, and moderate- or high-positive correlation with OS across age and CCI score subgroups.
CONCLUSION: These findings suggest that 1 L DRd DoT is a potential predictor of OS when used in Japanese clinical practice.

Keywords:  Daratumumab; duration of treatment; lenalidomide; newly diagnosed multiple myeloma; overall survival; real-world evidence

DOI:  https://doi.org/10.1080/03007995.2025.2590840
J Comp Eff Res. 2025 Nov 28. e250011

Iron deficiency treatment pathway in Italy: patients' perceptions of diagnosis and treatment.

Ovidio Brignoli, Rose-Marie Carneiro, Cécile Fournier, Ettore Pinardi, Maurizio Serati.

  Aim: This 2023 online survey assessed the management of patients with iron deficiency anemia/iron deficiency without anemia (IDA/IDWA) in Italy. Materials & methods: The study used the patient's perspective to examine care pathways used to manage IDA/IDWA in Italy, to raise clinician awareness, improve patient care (earlier diagnosis, initiate appropriate treatment) and outcomes (reduce recurrence/progression). The survey questioned iron deficiency (ID) diagnoses of patients, their sources of information and influence, their knowledge of ID, perceptions and fears surrounding treatment, unmet needs and expectations, and underlying causes of treatment compliance and persistence. Results: Of the 404 respondents (102 males and 302 females) who completed the survey, all were aged between 18 and 80 years. Almost all respondents (97.0%) experienced ID symptoms, most frequently fatigue, weakness and tiredness (71.0% of the total cohort; 80.1% females vs 44.1% males); 76.8% of all respondents regarded symptoms as 'bothersome'. Most respondents (70.5%) consulted a physician as the first action to treat ID (79.8% females vs 43.1% males); general practitioners were the main healthcare providers, consulted by 55.6% of all respondents. Most respondents (94.1%) were aware of potential ID recurrence, and 75.0% reported recurrent ID episodes since their diagnosis. Satisfaction with ID treatment was rated as average (7-7.7/10); 56.4% of all respondents stayed on ID treatment for as long as prescribed, and 41.1% did not fully comply with tablet intake, primarily because they 'felt much better' (64.8%). Conclusion: This survey identified high rates of self-reported ID symptoms and recurrent ID episodes among respondents. It highlights the importance of increasing awareness of ID and its consequences among healthcare practitioners and individuals in the general population, of shortening the time before diagnosis, and ensuring that patients continue treatment for the prescribed duration to resaturate serum iron levels.

Keywords:  anemia; care pathway; iron deficiencies; patients; qualitative evaluation; quantitative evaluation; surveys

DOI:  https://doi.org/10.57264/cer-2025-0011
bioRxiv. 2025 Nov 13. pii: 2025.11.07.687000. [Epub ahead of print]

TriLeukeVax: A CD80/IL-15/IL-15Rα Expressing Autologous AML Cell Vaccine Elicits Robust Anti-Leukemic Cytolytic Activity.

Jacob Du, Uthpala N Wijayaratna, Xinyue Wang, Jeffrey P Fung, Belinda Huang, Farzin Farzaneh, Donald B Kohn, Alexis J Combes, Karin M L Gaensler.

Acute myeloid leukemia (AML) is the most common acute leukemia in adults and is associated with poor outcomes due to frequent relapse after remission induction. While hematopoietic stem cell transplantation (HSCT) can improve survival, many individuals, especially older patients, are ineligible. Prior immunotherapies have not reliably induced effective anti-leukemic immunity and have been associated with severe and unpredictable toxicities. Thus, there is a need for safe and effective therapies that reduce relapse and increase overall survival (OS). We have developed a universally applicable, patient-specific, lentivirally engineered autologous AML cell vaccine, TriLeukeVax (TLV), designed to stimulate leukemia-specific cytolytic immune responses in AML patients in remission. To generate TLV, AML cells are engineered to express the highly synergistic combination of the co-stimulatory protein CD80 and the IL-15/IL-15-receptor alpha (IL-15Rα) heterodimer. Prior proof-of-concept (POC) studies demonstrated eradication of disease in >80% of leukemic mice with serial administration of TLV. In the current studies, TLV was generated from 59/60 cryopreserved, diagnostic bone marrow-derived patient AML samples. Ex vivo priming of post-remission patient T-cells by ex vivo co-culture with autologous TLV stimulated robust proliferative and cytotoxic responses. In secondary co-cultures, T-cells previously primed by initial co-culture with TLV, showed greater clonal expansion and leukemia-specific cytolytic activity towards de novo autologous AML blasts than did control, unprimed T-cells. The enhanced anti-leukemic activity of TLV-primed T-cells against de novo AML confirms the potential for vaccine administration to effectively target minimal residual disease (MRD) persisting after chemotherapy and reduce relapse.
Key Points: TriLeukeVax induces proliferation, activation, and effective anti-leukemic cytolytic responses in remission T-cells.Primed T-cells show polyclonal expansion and transcription profiles associated with proliferation, memory, and cytotoxicity.
Abstract Figure:

DOI: https://doi.org/10.1101/2025.11.07.687000