bims-hemali 2025-12-07 papers

bims-hemali

Biomed News

on Hematologic malignancies

Issue of 2025–12–07
forty papers selected by
Alexandros Alexandropoulos, Γενικό Νοσοκομείο Αθηνών Λαϊκό

Shifting treatment goals in myeloproliferative neoplasms: focusing on polycythemia vera.
[Incidence and associated factors of tyrosine kinase inhibitor withdrawal syndrome and psychological issues in patients with chronic-phase chronic myeloid leukemia after therapy discontinuation].
GIMEMA survey on the management of chronic myeloid leukemia patients in the third line and beyond: insights from Italian hematologists.
Chronic Myeloid Leukemia Harboring a Novel Four-Way Variant Translocation t(7;22;9;15)(p15;q11.2;q34.1;q22) With Cryptic Double Philadelphia Chromosomes.
JAK2 wild-type erythrocytosis: concept, differential diagnosis, diagnostic steps, and treatment approaches.
How I Treat Advanced Phases of CML.
Prognostic factors in chronic myeloid leukemia: at diagnosis and for treatment-free remission.
The secret to staying young: platelet factor 4.
Measurable residual disease assessment in multiple myeloma.
Clinical Outcomes in Patients With CLL Treated With BTKi at a Large US Cancer Center.
Maintenance Low-Dose BRAF Inhibition and Rituximab in Relapsed Hairy Cell Leukemia: A Therapeutic Alternative.
Choosing the optimal maintenance strategy in multiple myeloma.
Consensus Recommendations from the 2024 International Follicular Lymphoma Scientific Workshop.
Molecular subtypes of DLBCL: are we ready to translate our knowledge into the change of treatment paradigms?
The Evolving Therapeutic Landscape of Richter Transformation.
How to approach the high-risk myeloma from induction through relapse?
When immature plasma cells form lymphoma: how to improve on diagnostics and treatment of plasmablastic lymphoma?
ATTEC-mediated degradation of BCR-ABL in chronic myeloid leukemia cells.
Updates in the management of newly diagnosed chronic lymphocytic leukemia.
Outcomes of elranatamab in relapsed/refractory multiple myeloma: prognostic impact of monocyte count, MyCARe, and R2-ISS.
Fixed-duration ibrutinib-venetoclax with MRD-guided ibrutinib-obinutuzumab intensification in first-line chronic lymphocytic leukaemia (HOVON 158/NEXT STEP): primary analysis of a multicentre, open-label, phase 2 trial.
[A preliminary analysis of the efficacy and safety of homoharringtonine, venetoclax, and azacitidine for newly diagnosed acute myeloid leukemia].
Sweet stuff is dangerous in DLBCL.
Long-term outcomes and treatment patterns in Waldenström macroglobulinemia patients who discontinue Bruton tyrosine kinase inhibitor (BTKi) therapy.
Reversible Left Ventricular Dysfunction Related to Ropeginterferon Alfa-2b in Polycythemia Vera.
Multiple Myeloma with Hairy Cell-Like Plasma Cells.
On the CHOPping block? Rethinking initial therapy for PMBCL.
All shades of gray in the mediastinum: do we have bright ideas about how to diagnose and treat mediastinal gray zone lymphoma in the era of targeted agents?
Can I stop my treatment, doctor? Is MRD-guided therapy ready for prime time?
Triplet regimens for all: genomically agnostic approaches to improve on HMA + VEN in AML?
Diagnosis and management of cold agglutinin disease.
Anti-CD38 VLRB-Fc antibodies from transgenic tobacco exhibit potent anti-myeloma activity in vitro and in vivo.
Management of iron overload in adult myelodysplastic syndrome.
Zanubrutinib Combined With Rituximab in the Treatment of Bing-Neel Syndrome: A Case Report.
Final OS analyses from the TOURMALINE- MM3 and -MM4 RCTs of ixazomib maintenance in newly diagnosed multiple myeloma.
The untransfusable patient.
Updates in Treatment for Androgenetic Alopecia.
Capsaicin in the Management of Peripheral Neuropathy: A Review.
A High-Fiber Plant-Based Diet in Myeloma Precursor Disorders - Results from the NUTRIVENTION Clinical Trial and Preclinical Vk*MYC Model.
POEMS syndrome: diagnosis, treatments, and outcomes.

Int J Hematol. 2025 Nov 30.

Shifting treatment goals in myeloproliferative neoplasms: focusing on polycythemia vera.

Keita Kirito.

  JAK2V617F is the major driver mutation in polycythemia vera, and detection of this mutation is one of the most important keys for the diagnosis of this disease. In addition, JAK2V617F mutation is highlighted as a molecular marker for monitoring treatment. Clinical studies of the JAK inhibitor ruxolitinib and two recently introduced new forms of alfa interferon, pegylated interferon alfa 2b and ropeginterferon alfa 2b, demonstrated that treatment with these agents induced a molecular response, defined as a more than 50% reduction in the JAK2V617F allele burden from baseline, in approximately 60% of patients. In addition, some patients achieved a complete molecular response, defined as the disappearance of the mutation. More importantly, achievement of a molecular response was positively correlated with improved thrombosis-free and progression-free survival in PV patients. To date, controlling hematological parameters, especially maintaining hematocrit levels below 45%, has been the gold standard surrogate endpoint in PV treatment. With new treatment options and knowledge, molecular response should be incorporated as a new therapeutic surrogate endpoint in the management of PV.

Keywords:   JAK2V617F allele burden; Molecular response; Polycythemia vera; Ropeg interferon-alfa-2b; Ruxolitinib

DOI:  https://doi.org/10.1007/s12185-025-04119-5
Zhonghua Xue Ye Xue Za Zhi. 2025 Oct 14. 46(10): 929-936

[Incidence and associated factors of tyrosine kinase inhibitor withdrawal syndrome and psychological issues in patients with chronic-phase chronic myeloid leukemia after therapy discontinuation].

M Y Yuan, Z R Li, X S Zhang, S S Zhao, W W Li, C L Wang, Y Z Qin, Q Jiang.

  Objectives: To investigate the incidence of tyrosine kinase inhibitor (TKI) withdrawal syndrome and psychological issues, and their associated factors, in patients with chronic-phase chronic myeloid leukemia (CML-CP) after TKI discontinuation. Methods: We retrospectively analyzed the clinical data of CML-CP patients who discontinued TKI therapy at Peking University People's Hospital after September 2012. Logistic regression models were used to identify independent factors associated with the occurrence of TKI withdrawal syndrome and psychological issues. Results: A total of 158 patients were included, of whom 92 (58%) were female. The median age at discontinuation was 50 (IQR, 35-60) years. With a median follow-up of 25 (IQR, 11-49) months, the 4-year rate of sustained major molecular response (MMR) was 60% (95% CI: 51%-70%) . Fifty-one (32%) patients experienced TKI withdrawal syndrome at a median of 1.3 (IQR, 0.5-2.0) months after TKI discontinuation. Fifty-one (32%) patients reported psychological issues such as anxiety. These concerns stemmed from fears of fluctuating BCR::ABL1 levels or disease relapse, and, for those who discontinued TKI for pregnancy, worries about adverse fetal effects and/or the fetus inheriting CML. Multivariable analyses revealed that older age at discontinuation [P=0.003 when adjusting for TKI therapy duration; P=0.002 when adjusting for deep molecular response (DMR) duration], longer TKI therapy duration (P=0.010) , and longer DMR duration before discontinuation (P=0.005) were significantly associated with a higher risk of TKI withdrawal syndrome; a university degree or higher (P=0.010) and TKI discontinuation due to pregnancy or adverse events (P=0.001) were significantly associated with psychological issues after discontinuation. The occurrence of TKI withdrawal syndrome or psychological issues had no impact on the probability of major molecular response loss after discontinuation. Conclusion: TKI withdrawal syndrome and psychological issues are common in CML patients who discontinue TKI therapy. Older age at discontinuation and longer TKI therapy duration or DMR duration are significantly associated with TKI withdrawal syndrome. Higher education level and TKI discontinuation due to pregnancy or adverse events are significantly associated with psychological issues.

Keywords:  Leukemia, myeloid, chronic; Psychological issues; Treatment-free remission; Tyrosine kinase inhibitors; Withdrawal syndrome

DOI:  https://doi.org/10.3760/cma.j.cn121090-20250328-00155
Front Oncol. 2025 ;15 1697569

GIMEMA survey on the management of chronic myeloid leukemia patients in the third line and beyond: insights from Italian hematologists.

Massimo Breccia, Alfonso Piciocchi, Elisabetta Abruzzese, Daniela Cilloni, Fausto Castagnetti, Monica Messina, Stefano Soddu, Barbara Scappini, Uros Markovic, Mario Annunziata, Alessandra Malato, Gianni Binotto, Olga Mulas, Massimiliano Bonifacio, Paola Fazi, Fabrizio Pane.

   Background: Approximately one-third of chronic myeloid leukemia (CML) patients may develop resistance and/or intolerance to the current therapies and need to switch to later lines of treatment. However, how to choose a later line of therapy is still a matter of discussion.
Methods: A survey was performed by the Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) to understand how the scenario has changed after the introduction of the first allosteric inhibitor, asciminib, in later lines.
Results: The GIMEMA survey aimed to reassess the Italian approach to third-line or later-line treatments in CML. In the whole cohort of 1,637 patients, to treat resistance, ponatinib was used with a mean of 41% [standard deviation (SD) = 29] and a median of 50% (0-100), while asciminib was used with a mean of 27% (SD = 23) and a median of 25% (0-100). Indeed, to treat intolerance, asciminib was the most used with a mean of 32% (SD = 30) and a median of 30 (0-100), followed by bosutinib with a mean of 25% (SD = 25) and a median of 20 (0-90). Several possible treatment sequences were analyzed, and asciminib emerged as the best third-line treatment.
Conclusions: The survey attempted to understand the major reasons for treatment switch, how tyrosine kinase inhibitors (TKIs) were selected, and which drug was preferred based on patient and disease characteristics. The current algorithm of treatment seems to have changed in both resistant and intolerant CML patients in later lines. The reduction of TKI dose is a current practice to maintain efficacy while reducing the occurrence of side effects.

Keywords:  asciminib; chronic myeloid leukemia; later lines; prognosis; tyrosine kinase inhibitors

DOI:  https://doi.org/10.3389/fonc.2025.1697569
Cureus. 2025 Oct;17(10): e95633

Chronic Myeloid Leukemia Harboring a Novel Four-Way Variant Translocation t(7;22;9;15)(p15;q11.2;q34.1;q22) With Cryptic Double Philadelphia Chromosomes.

Shogo Kamigaki, Makoto Ito, Satsuki Nakano, Norio Takagi.

  Variant Philadelphia chromosomes are occasionally observed in chronic myeloid leukemia. Among them, four-way variant Philadelphia translocations are particularly rare. Double Philadelphia chromosomes, representing an additional Philadelphia chromosome, are also uncommon and have been reported to be associated with disease progression and therapeutic challenges. We report a case of chronic myeloid leukemia with a novel four-way variant translocation t(7;22;9;15)(p15;q11.2;q34.1;q22) accompanied by cryptic double Philadelphia chromosomes. Despite these unfavorable cytogenetic features, the patient was successfully treated with dasatinib and achieved a complete hematologic response.

Keywords:  chronic myeloid leukemia (cml); cytogenetics; dasatinib; double philadelphia chromosome; four-way translocation

DOI:  https://doi.org/10.7759/cureus.95633
Hematology Am Soc Hematol Educ Program. 2025 Dec 05. 2025(1): 183-190

JAK2 wild-type erythrocytosis: concept, differential diagnosis, diagnostic steps, and treatment approaches.

Natasha Szuber, Ayalew Tefferi, Naseema Gangat.

JAK2 unmutated/wild-type erythrocytosis is a prevalent condition encompassing a wide spectrum of hereditary and acquired entities. It is conventionally defined by the same hemoglobin/hematocrit thresholds as for polycythemia vera. Incidence has been reported to be between 0.13% and 4.1%. The most clinically relevant step in the workup of erythrocytosis is the exclusion of polycythemia vera through JAK2 mutation screening. Consideration of relative polycythemia, normal outliers, and the influence of erythropoietic drugs and comorbidities is also imperative. Distinguishing long-standing from newly acquired erythrocytosis further streamlines the diagnostic process. Hereditary erythrocytosis (HE) is lifelong and typically associated with a positive family history. Subnormal serum erythropoietin (EPO) suggests an EPO receptor mutation. Otherwise, oxygen tension at 50% hemoglobin saturation (p50) discerns between high oxygen-affinity hemoglobin variants, 3-bisphosphoglycerate deficiency, methemoglobinemia, and PIEZO1 mutations (low p50) and germline oxygen-sensing pathway/other rare mutations (normal p50). Acquired erythrocytosis results from hypoxia-driven factors (eg, cardiopulmonary, altitude, renal artery stenosis) and other mechanisms of EPO overproduction (eg, EPO-secreting tumors) or hypersensitivity, as well as EPO-independent mechanisms. Drugs (eg, sodium glucose co-transporter-2 inhibitors, testosterone) are also common causes. Idiopathic erythrocytosis is a diagnosis of exclusion, increasingly attributed to underlying genetic mutations/polymorphisms. There are currently no evidence-based treatment guidelines. Low-dose aspirin and/or phlebotomy (with frequency determined by symptom relief) might be considered on an individualized basis in the presence of hyperviscosity symptoms, cardiovascular comorbidities, and/or a history of thrombosis. Aggressive control of cardiovascular risk factors is recommended in all. A graphic abstract representation is provided in Figure 1.

DOI: https://doi.org/10.1182/hematology.2025000704
Blood. 2025 Dec 02. pii: blood.2024026510. [Epub ahead of print]

How I Treat Advanced Phases of CML.

Michael J Mauro.

Advanced phases of Philadelphia chromosome positive (Ph+) chronic myeloid leukemia, classically encompassing de novo presentation of accelerated phase disease and blast phase disease (myeloid and lymphoid 'blast crisis') as well as progression to these from antecedent chronic phase disease, have diminished in incidence but remain a challenge. Despite continued development of additional and novel kinase inhibitors of BCR::ABL1, global limitations on access to diagnostics and therapy persist and account for continued incidence of advanced disease at initial presentation as well as progressive disease. Evolution in defining risk through clinical and molecular characterization should increase ability to identify emerging advanced disease, minimize progression and improve treatment of resistant chronic phase and blast phase disease. While BCR::ABL1 tyrosine kinase inhibition remains central in advanced disease, combination therapy with conventional and novel chemotherapy, immunotherapy, and allogeneic stem cell transplantation provide best long-term outcomes.

DOI: https://doi.org/10.1182/blood.2024026510
Haematologica. 2025 Dec 04.

Prognostic factors in chronic myeloid leukemia: at diagnosis and for treatment-free remission.

Delphine Rea.

Although chronic myeloid leukemia (CML) is defined by the sole presence of the BCR::ABL1 fusion gene-the genetic event underlying the genesis of the disease-the diversity of clinical outcomes, even in the tyrosine kinase inhibitors (TKI) era, reveals that its apparent biological homogeneity is, in fact, misleading, both between and within individuals. Increasing knowledge of biological diversity through advances in cellular analytical tools and expansion of the TKI arsenal to address this heterogeneity are key factors in the path to a better disease control and ultimately cure. In this review, we focus on well-established and novel modifiable and non-modifiable prognostic factors of CML at diagnosis and for treatment-free remission, with particular emphasis on those that are easy to use in clinical practice. We will discuss how these factors may help shape therapeutic choices. Finally, we will highlight innovative research avenues aiming at improving prognostication of CML.

DOI: https://doi.org/10.3324/haematol.2025.287756
Blood. 2025 Dec 04. 146(23): 2734-2736

The secret to staying young: platelet factor 4.

James Ropa.

DOI: https://doi.org/10.1182/blood.2025031130
Leukemia. 2025 Dec 05.

Measurable residual disease assessment in multiple myeloma.

Saurabh Zanwar, S Vincent Rajkumar.

DOI: https://doi.org/10.1038/s41375-025-02830-0
Adv Hematol. 2025 ;2025 7492594

Clinical Outcomes in Patients With CLL Treated With BTKi at a Large US Cancer Center.

Kevin H Lin, Lynn Huynh, Xiaoqin Yang, Enrico Zanardo, Daria Liborski, Mikaela M McDonough, Mohammed Z H Farooqui, Enrico De Nigris, Shravanthi R Gandra, Mei Sheng Duh, Jennifer R Brown, Matthew S Davids.

  Patients with chronic lymphocytic leukemia (CLL) treated with covalent Bruton's tyrosine kinase inhibitors (BTKi) eventually discontinue treatment, but data on outcomes post-BTKi treatment discontinuation are limited. In this single-institution, retrospective chart review of 104 adult patients with CLL treated with a covalent BTKi between July 2011 and April 2019 and who subsequently discontinued for any reason, the majority of patients (59.9%) received the index BTKi in their first (27.5%) or second (32.4%) line of therapy. Median progression-free survival (PFS) from index BTKi initiation was 3.2 years, and median overall survival (OS) was 8.9 years. There was a notable correlation between PFS and OS (r = 0.79). Following the discontinuation of their last BTKi treatment, over half of these patients received subsequent therapies (80.6% of whom received regimens containing B-cell lymphoma 2 inhibitors [BCL2i]). Of the patients who received BCL2i-containing therapy after index BTKi treatment, 77.8% achieved an overall response to BCL2i at first clinical assessment. However, 73.8% of the patients exposed to BTKi and BCL2i eventually discontinued BCL2i treatment and 36.1% died, with a median follow-up of 2.6 years from BCL2i initiation. A subset of patients who were exposed to and were found to be relapsed, refractory, resistant, or intolerant to both BTKi and BCL2i-based regimens (n = 25) had high rates of progressive disease at first assessment (15.0%) and death (44.0%). These findings highlight an unmet clinical need for patients with CLL and underscore the urgency to develop effective new strategies to treat those patients who have already received covalent BTKi and BCL2i.

Keywords:  Bruton’s tyrosine kinase inhibitor (BTKi); chart review; chronic lymphocytic leukemia (CLL); overall survival; relapsed/refractory

DOI:  https://doi.org/10.1155/ah/7492594
Cureus. 2025 Oct;17(10): e95668

Maintenance Low-Dose BRAF Inhibition and Rituximab in Relapsed Hairy Cell Leukemia: A Therapeutic Alternative.

Anshul Patel, Sarina Koilpillai, Cassie Nguyen, Said Baidas.

  Hairy cell leukemia (HCL) is a rare, indolent B-cell neoplasm accounting for less than 2% of all leukemias. It is characterized by the presence of mature lymphocytes with typical hairy projections within the peripheral blood, bone marrow, and spleen, resulting in pancytopenia and splenomegaly. Purine analogs such as cladribine and pentostatin have been the mainstay of treatment for HCL. Despite high responsiveness to first-line therapy with purine analogs, almost half of the patients with HCL relapse and become progressively resistant to these medications. Treatment with a combination of BRAF V600E inhibitor and anti-CD20 monoclonal antibody has achieved durable responses in relapsed HCL. Here, we present a patient with relapsed and refractory HCL who achieved only partial response with three months of treatment with high-dose vemurafenib and rituximab, following which he was maintained on low-dose vemurafenib plus monthly rituximab for almost a year, after which he achieved complete morphologic and molecular response.

Keywords:  anti-cd20 monoclonal antibody; braf inhibitors; hairy cell leukemia (hcl); hairy cell leukemia relapse; vemurafenib

DOI:  https://doi.org/10.7759/cureus.95668
Hematology Am Soc Hematol Educ Program. 2025 Dec 05. 2025(1): 412-423

Choosing the optimal maintenance strategy in multiple myeloma.

Benjamin Puliafito, Diana Cirstea, Noopur Raje.

While lenalidomide has been the established standard of care for maintenance after autologous stem cell transplantation in newly diagnosed multiple myeloma, risk-adapted maintenance strategies with the addition of proteasome inhibitors can provide additional benefit in high-risk disease. The widespread use of anti-CD38 monoclonal antibodies (mAbs) in induction and consolidation has further disrupted this paradigm, offering the use of anti-CD38 mAbs in maintenance. Novel immunotherapeutic approaches and minimal residual disease-guided maintenance strategies are being actively investigated. The evolution of maintenance strategies provides a window to a future where maintenance therapy is not only more effective at sustaining deep and durable responses but also more dynamic with careful de-escalation strategies.

DOI: https://doi.org/10.1182/hematology.2025000732
Blood Adv. 2025 Dec 03. pii: bloodadvances.2025018079. [Epub ahead of print]

Consensus Recommendations from the 2024 International Follicular Lymphoma Scientific Workshop.

Reid W Merryman, Sarah C Rutherford, Stephen M Ansell, Philippe Armand, John P Leonard, Loretta Nastoupil, Sonali M Smith, John M Timmerman, Andrew D Zelenetz, Meghan Gutierrez, Wendy Béguelin, Carla Casulo, James R Cerhan, Michael R Green, Brad S Kahl, Robert Kridel, Brian K Link, Matthew J Maurer, Bertrand Nadel, Andrea Radtke, Efrat Luttwak, Gilles A Salles, Laurie H Sehn, Laura Pasqualucci, Ann S LaCasce.

Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma. Although patients with FL have high response rates to therapy, most develop increasingly resistant disease. In addition, transformation into an aggressive lymphoma is associated with unfavorable outcomes. Many novel agents are under investigation, and early clinical data are encouraging. Aligning treatment with the underlying tumor biology and sequencing of therapies remain key clinical challenges. At the Lymphoma Research Foundation's biannual 2024 Follicular Lymphoma Scientific Workshop, experts convened to discuss the role of chemotherapy in the context of new therapies, the impact of early progression on treatment sequencing, novel endpoints in clinical trials, disease biology and the tumor microenvironment, and new treatments on the horizon. This report focuses on updates in FL biology, first-line treatment, the role of progression of disease in 24 months (POD24), clinical trial design, and redefining cure in FL.

DOI: https://doi.org/10.1182/bloodadvances.2025018079
Hematology Am Soc Hematol Educ Program. 2025 Dec 05. 2025(1): 489-495

Molecular subtypes of DLBCL: are we ready to translate our knowledge into the change of treatment paradigms?

Sarah C Rutherford.

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease with disparate outcomes. While about two-thirds of patients have historically been cured with standard frontline chemoimmunotherapy, those who relapse or are refractory have typically had poor outcomes. Early efforts to tailor treatment based on molecular subtypes categorized by gene expression profiling (germinal center-like and activated B-cell-like) or approximation by immunochemistry algorithms did not substantially impact therapy in DLBCL. Genomic profiling led to the discovery of up to 7 subtypes with shared genetic alterations. The LymphGen and DLBclass are classifiers that assign patients to these subtypes. A clinical trial is under design to specifically treat subtypes of DLBCL in the frontline setting with targeted therapies in combination with standard treatment. Importantly, some of the most efficacious therapeutic approaches in relapsed/refractory DLBCL (chimeric antigen-receptor T cells and bispecific antibodies) appear to work independently of molecular subtype, although these agents' effectiveness may be impacted by the tumor microenvironment. Bispecific antibodies are being studied in newly diagnosed patients in combination with standard chemoimmunotherapy regimens. While future treatment may incorporate drugs with novel mechanisms and/or immunotherapies in the frontline setting, targeting by molecular subtype continues to hold promise as our treatment regimens evolve. Potential strategies could include escalation with specific therapies when response is inadequate, de-escalation of chemotherapy with continuation or addition of targeted agents in those with early complete responses, and refined algorithms to select appropriate treatment in high-risk or relapsed/refractory disease.

DOI: https://doi.org/10.1182/hematology.2025000741
Curr Hematol Malig Rep. 2025 Dec 03. 20(1): 21

The Evolving Therapeutic Landscape of Richter Transformation.

Henry Le, Grace Baek, Ivan Huang, Chloe Siu, Mazyar Shadman.

   PURPOSE OF REVIEW: Richter transformation (RT), the progression of chronic lymphocytic leukemia (CLL) to aggressive lymphomas, poses a significant therapeutic challenge with historically poor outcomes. Chemoimmunotherapy (CIT) regimens have demonstrated limited efficacy with short durations of response. This review aims to evaluate the evolving treatment landscape for RT, with a focus on recent advances in targeted therapies, immunotherapies, and cellular therapies that are redefining the current and future standards of care.
RECENT FINDINGS: The treatment paradigm for RT is rapidly shifting away from cytotoxic chemotherapy. The combination of the B-cell lymphoma 2 inhibitor venetoclax with CIT has emerged as a new first-line benchmark with promising response rates and overall survival. Covalent Bruton tyrosine kinase (BTK) inhibitors had modest activity as monotherapy but showed improved responses when given with an immune checkpoint inhibitor. Pirtobrutinib has demonstrated responses even in heavily pretreated patients. Furthermore, advancement in immunotherapy has expanded treatment options for this patient population with bispecific T-cell engagers achieving high response rates and chimeric antigen receptor T-cell therapy providing deep, durable responses and favorable median overall survival in the relapsed/refractory (R/R) setting. The therapeutic landscape for RT has broadened with the introduction of targeted agents and immunotherapy. Venetoclax-based regimens represent a new standard for chemotherapy-eligible patients, allowing for a more effective bridge to potentially curative consolidation with transplantation. For R/R disease, novel BTK inhibitors, bispecific antibodies, and cellular therapies are demonstrating substantial efficacy. Ongoing trials investigating combinations of these agents are poised to further transform RT management.

Keywords:  BTK inhibitors; CAR T-cell therapy; Chronic lymphocytic leukemia; Richter syndrome; Richter transformation; Venetoclax

DOI:  https://doi.org/10.1007/s11899-025-00765-y
Hematology Am Soc Hematol Educ Program. 2025 Dec 05. 2025(1): 652-658

How to approach the high-risk myeloma from induction through relapse?

Katja C Weisel, Christoph Schaefers, Lisa B Leypoldt.

Despite the enormous progress made in the treatment of multiple myeloma (MM) with various treatment choices in frontline and relapse settings, treatment of high-risk (HR)MM remains a therapeutic challenge. Definition of HR disease is dynamic and mainly based on cytogenetic assessment showing typical cytogenetic abnormalities. Most recently, the International Myeloma Society and the International Myeloma Working Group published a revision of HR criteria, IMS-IMWG Consensus Genomic Staging. Immediate identification of HRMM at primary diagnosis is crucial to refer the patients to optimal treatment. Emerging data, especially from clinical trials designed explicitly for HR patients, demonstrated that upfront quadruplet treatment followed by consolidation and continuous combination maintenance, including high dose melphalan and autologous stem cell transplantation for patients who qualify, is the current best approach leading to a markedly improved prognosis. The primary treatment goal is the rapid achievement of sustained minimal residual disease- negative response with treatment continuation beyond to avoid early relapses and evolvement of resistant clones. A distinct subgroup of patients, the so-called functional HR patients, are defined as relapsing between 12 and 18 months despite optimal frontline treatment. The unmet need for effective treatment options in this challenging situation is now partially mitigated by the introduction of B-cell maturation antigen-directed T-cell-engaging immunotherapies. Early data show favorable outcomes, with treatments with chimeric antigen receptor T-cells achieving durable responses.

DOI: https://doi.org/10.1182/hematology.2025000762
Hematology Am Soc Hematol Educ Program. 2025 Dec 05. 2025(1): 564-570

When immature plasma cells form lymphoma: how to improve on diagnostics and treatment of plasmablastic lymphoma?

Jorge J Castillo.

Plasmablastic lymphoma (PBL) is a rare and aggressive, usually CD20-negative, B-cell lymphoma with features between multiple myeloma and diffuse large B-cell lymphoma. Approximately 120 new cases are diagnosed annually in the United States, and there is a strong association with HIV infection and other immunosuppressive states. It affects mostly adult males, though PBL has been diagnosed in children and immunocompetent individuals. Epstein-Barr virus infection, MYC gene rearrangements, and other mechanisms appear to play a role in PBL lymphomagenesis. Given its rarity, PBL poses distinct diagnostic and therapeutic challenges. A timely diagnosis is essential and requires a high clinical suspicion and a thorough pathological evaluation. The clinical course is aggressive, with a high relapse rate and poor survival with standard therapies. More recently, better outcomes have been observed in patients with early-stage disease treated with combination chemotherapy followed by consolidative radiotherapy. Additionally, advanced disease outcomes may improve with the use of targeted agents, such as proteasome inhibitors and anti-CD38 monoclonal antibodies, when added to combination chemotherapy. Participation in clinical trials and multi-institutional collaboration will be essential to continue improving patient outcomes with PBL.

DOI: https://doi.org/10.1182/hematology.2025000750
Eur J Med Chem. 2025 Dec 01. pii: S0223-5234(25)01195-X. [Epub ahead of print]303 118430

ATTEC-mediated degradation of BCR-ABL in chronic myeloid leukemia cells.

Zhiyan Wang, Tingting Xu, Yiying Che, Jun-An Ma, Runqi Jin, Boao Mao, Xinru Lai, Kunrong Mei, Hongxia Zhao, Zhiguang Yuchi.

  Chronic myeloid leukemia (CML) is driven by the BCR-ABL oncoprotein, which exerts both kinase-dependent and kinase-independent oncogenic functions. However, current tyrosine kinase inhibitors (TKIs) fail to eliminate its non-catalytic activities. Here, we report the rational design and synthesis of autophagosome-tethering chimeras (ATTECs) that selectively degrade BCR-ABL via the autophagy-lysosome pathway. By conjugating the BCR-ABL inhibitor dasatinib with the LC3B-binding ligand GW5074, we engineered eight distinct ATTEC variants with diverse linkers. Among them, DS-PPE-GW, featuring a piperidine-based linker, exhibited the most potent antiproliferation activity in K562 CML cells, with an IC50 of 9.62 nM and a DC50 of 11.6 nM, achieving over 90 % BCR-ABL degradation. This degradation suppressed phosphorylation of STAT5, a downstream substrate of BCR-ABL, and significantly inhibited cell proliferation. The activity of DS-PPE-GW was further enhanced by the autophagy activator rapamycin, confirming its autophagy dependence. Notably, DS-PPE-GW did not increase global autophagic flux, suggesting selective engagement of pre-existing autophagosomes. These findings demonstrate that strategically designed ATTECs can efficiently degrade BCR-ABL, targeting both its catalytic and non-catalytic functions, and provide a promising strategy for next-generation CML therapy.

Keywords:  Autophagosome-tethering chimeras (ATTECs); BCR-ABL oncoprotein; Chronic myeloid leukemia (CML); Dasatinib; GW5074

DOI:  https://doi.org/10.1016/j.ejmech.2025.118430
Hematology Am Soc Hematol Educ Program. 2025 Dec 05. 2025(1): 45-51

Updates in the management of newly diagnosed chronic lymphocytic leukemia.

Kristen McClellan, Andrea Sitlinger.

The options for frontline chronic lymphocytic leukemia (CLL) treatment continue to expand. Therapies include monotherapy with a Bruton's tyrosine kinase inhibitor (BTKi), doublet therapies such as venetoclax with intravenous obinutuzmab or an oral BTKi, and triplet therapy combining BTKi, venetoclax, and CD20 antibody. Treatment duration also is increasingly variable, from fixed duration to utilization of undetectable minimal residual disease (uMRD) to determine optimal treatment completion. Currently, the best option for an individual patient requires a multifaceted approach considering the individual's cytogenetics, comorbidities, and personal preferences, including time-limited therapy vs continuous treatment. In this article, we outline the current state of frontline CLL including ongoing questions and future directions.

DOI: https://doi.org/10.1182/hematology.2025000686
Int J Hematol. 2025 Dec 03.

Outcomes of elranatamab in relapsed/refractory multiple myeloma: prognostic impact of monocyte count, MyCARe, and R2-ISS.

Taku Kikuchi, Shotaro Sugita, Ukyo Kondo, Miyu Watanabe, Chiaki Matsumoto, Moe Nomura-Yogo, Kodai Kunisada, Kota Sato, Tomomi Takei, Mizuki Ogura, Yu Abe, Osamu Hosoya, Tadao Ishida, Nobuhiro Tsukada.

   BACKGROUND: Elranatamab, a bispecific antibody targeting B-cell maturation antigen and CD3, has demonstrated efficacy in relapsed/refractory multiple myeloma (RRMM). However, real-world evidence is limited, and prognostic factors have not been sufficiently evaluated.
METHODS: We retrospectively analyzed patients with RRMM receiving elranatamab between June 2024 and July 2025. Responses were assessed using the International Myeloma Working Group criteria. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Prognostic factors were evaluated using univariate log-rank analysis, including R2-ISS at elranatamab initiation (dynamic R2-ISS) and modified MyCARe risk, with positivity defined as any detectable plasma cells in peripheral blood.
RESULTS: Thirty-seven patients were evaluated (median age, 67 years; prior lines, 5). Median follow-up was 7.5 (median PFS, 9.7) months. One-year OS was 66.3%. The overall response rate was 67.6%, and 45.9% achieved at least a very good partial response. Extramedullary disease, plasma cells in the peripheral blood, and high-risk cytogenetics were adverse features. A baseline monocyte count < 300/µL, high-risk classification by modified MyCARe, and dynamic R2-ISS stage IV were significantly associated with shorter PFS and OS.
CONCLUSION: Elranatamab was effective in real-world settings. Baseline monocyte count, modified MyCARe risk, and dynamic R2-ISS may serve as practical prognostic tools.

Keywords:  Elranatamab; Monocyte; Multiple myeloma; MyCARe; R2-ISS

DOI:  https://doi.org/10.1007/s12185-025-04127-5
Lancet Haematol. 2025 Dec;pii: S2352-3026(25)00288-1. [Epub ahead of print]12(12): e935-e945

Fixed-duration ibrutinib-venetoclax with MRD-guided ibrutinib-obinutuzumab intensification in first-line chronic lymphocytic leukaemia (HOVON 158/NEXT STEP): primary analysis of a multicentre, open-label, phase 2 trial.

Arnon P Kater, Sabina Kersting, Julie M Dubois, Bronno van der Holt, Caspar da Cunha-Bang, Doreen Te Raa, Cecile Idink, Fransien de Boer, Jolanda Droogendijk, Koen de Heer, Leonie van der Burg, Marten R Nijziel, Lidwien Tick, Henriette Levenga, Matthijs Silbermann, Inge Ludwig, Aart Beeker, Mar Bellido, Johan A Dobber, Ludo M Evers, Anne-Marie van der Kevie-Kersemaekers, Clemens Mellink, Ine Meulendijks, Sonia Cunha, Martine Abrahamse-Testroote, Gerben Zwezerijnen, Josée Zijlstra, Carsten U Niemann, Mark-David Levin.

BACKGROUND: Triplet regimens combining a Bruton's tyrosine kinase inhibitor, B-cell lymphoma 2 inhibitor, and anti-CD20 antibody are among the most effective first-line treatments for chronic lymphocytic leukaemia, but come with substantial toxicity. We investigated whether fixed-duration ibrutinib plus venetoclax, followed by ibrutinib plus obinutuzumab intensification for individuals with residual disease only, could offer a more tailored and less toxic alternative.
METHODS: HOVON158/NEXT STEP was an open-label, phase 2 study at 17 hospitals in the Netherlands and Denmark. Eligible participants were aged 18 years or older with previously untreated chronic lymphocytic leukaemia, requiring treatment according to the International Workshop on Chronic Lymphocytic Leukemia, with an Eastern Cooperative Oncology Group performance status of 0, 1, or 2. Participants with complete remission or complete remission with incomplete count recovery and undetectable measurable residual disease (<10-4 uMRD4) in bone marrow after 15 28-day cycles of oral ibrutinib (420 mg once daily) plus oral venetoclax (5-weekly ramp-up from cycle 4 up to 400 mg once daily) discontinued treatment; all other participants received an additional six cycles of ibrutinib plus obinutuzumab intravenously (1000 mg on days 1, 2, 8, and 15 of cycle 1 and day 1 of cycles 2-6). The primary endpoint was bone marrow uMRD4 complete remission or complete remission with incomplete count recovery 3 months after the end of intensification with ibrutinib plus obinutuzumab in participants who were not in complete remission or who had detectable measurable residual disease (MRD) on ibrutinib plus venetoclax, and analysed according to the modified intention-to-treat principle excluding participants retrospectively deemed ineligible. All participants who received at least one dose of the study drug were included in the safety assessment. This report is the primary endpoint analysis of this trial, which is registered at ClinicalTrials.gov, NCT04639362, and is ongoing.
FINDINGS: Between Dec 29, 2020, and Aug 20, 2021, 85 participants were enrolled, 84 of whom were eligible (56 male and 28 female). The intensification group consisted of 55 participants (37 male and 18 female) and the observation group consisted of 17 participants (11 male and six female). 3 months after the end of ibrutinib plus obinutuzumab treatment, 33 (60%; 90% CI 48-71) of 55 participants had bone marrow uMRD4 complete remission or complete remission with incomplete count recovery. The most common grade 3-4 adverse events during ibrutinib plus venetoclax treatment were neutropenia (36 [43%] of 84 participants) and infections (19 [23%] participants), and the most common during ibrutinib plus obinutuzumab treatment were neutropenia and thrombocytopenia (five [10%] of 52 participants) and nervous system disorders (4 [8%] participants). Serious adverse events occurred in 28 (33%) participants receiving ibrutinib plus venetoclax and seven (13%) participants receiving ibrutinib plus obinutuzumab. There were no treatment-related deaths.
INTERPRETATION: An intensification strategy guided by response and MRD deepened remissions in individuals with residual disease and spared early responders further treatment. This approach merits further study as an alternative to fixed-duration triplet therapy.
FUNDING: Janssen.
TRANSLATION: For the Dutch translation of the abstract see Supplementary Materials section.

DOI: https://doi.org/10.1016/S2352-3026(25)00288-1
Zhonghua Xue Ye Xue Za Zhi. 2025 Oct 14. 46(10): 937-942

[A preliminary analysis of the efficacy and safety of homoharringtonine, venetoclax, and azacitidine for newly diagnosed acute myeloid leukemia].

H Ai, Q Wang, H F Wu, Q S Yin.

  Objective: To compare the efficacy and safety of two induction regimens, homoharringtonine plus venetoclax and azacitidine (VHA) versus venetoclax and azacitidine (VA) , for newly diagnosed acute myeloid leukemia (AML) patients who are elderly or ineligible for intensive chemotherapy. Methods: We retrospectively analyzed the clinical data of 59 newly diagnosed AML patients treated with the VHA or VA regimen at Zhengzhou University Affiliated Cancer Hospital from September 2018 to July 2021. The cohort included 25 males and 34 females, with a median age of 63 years. The overall response rate (ORR) , composite complete remission (CRc) rate [CR+CR with incomplete hematologic recovery (CRi) ], minimal residual disease (MRD) negativity rate, overall survival (OS) , relapse-free survival (RFS) , and adverse events were compared between the two groups. Survival was estimated by the Kaplan-Meier method, and prognostic factors were evaluated using univariable and multivariable Cox regression. Results: At the end of the treatment, the ORR was 88.4% (23/26) in the VHA group [21 CR, 2 partial remissions (PR) ] and 90.9% (30/33) in the VA group (25 CR, 5 PR) , with no significant difference between the groups (P=0.458) . The MRD negativity rates after one cycle of induction were 73.1% (19/26) in the VHA group and 60.6% (20/33) in the VA group, respectively (P=0.315) . In the high-risk subgroup, the composite remission rates after one cycle were 78.6% (11/14) with VHA and 50.0% (5/10) with VA (P=0.143) ; MRD negativity rates were 64.3% (9/14) and 20.0% (2/10) , respectively (P=0.032) . The main adverse events were myelosuppression, gastrointestinal reactions, and infections during neutropenia. Rates of grade 3-4 neutropenia and decreased hemoglobin were similar between groups, whereas grade 3-4 thrombocytopenia was more frequent with VHA than with VA (76.9% vs 45.5%, P=0.015) . With a median follow-up of 13 months (range, 1-59) , 1 year RFS was 69.9% (95% CI: 53.1%-92.2%) with VHA and 55.6% (95% CI: 40.1%-77.1%) with VA (P=0.305) . The 1 year OS rates were 91.7% (95% CI: 77.3%-100.0%) and 58.2% (95% CI: 41.7%-81.4%) , respectively (P=0.024) . Among high risk patients, 1 year RFS and OS were higher with VHA than with VA (RFS: 66.2% vs 37.5%, P=0.046; OS: 85.7% vs 48.0%, P=0.011) . Undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) significantly improved RFS and OS (P=0.027 and 0.047, respectively) . On multivariable analysis, ELN risk classification and MRD negativity after the first cycle were independent prognostic factors for RFS. Treatment regimen (VHA vs VA) , MRD negativity after the first cycle, and receipt of transplantation were independent prognostic factors for OS. Conclusion: VHA provides clinical benefit in newly diagnosed AML patients who are unfit for intensive chemotherapy and in older adults, with particularly favorable outcomes in high risk patients; sequential allo-HSCT confers additional benefit, and associated adverse events are manageable.

Keywords:  Azacytidine; Homoharringtonine; Leukemia, myeloid, acute; Venetoclax

DOI:  https://doi.org/10.3760/cma.j.cn121090-20241111-00443
Blood. 2025 Dec 04. 146(23): 2739-2741

Sweet stuff is dangerous in DLBCL.

Falko Fend, Leticia Quintanilla-Martínez.

DOI: https://doi.org/10.1182/blood.2025031082
Blood Cancer J. 2025 Dec 03. 15(1): 211

Long-term outcomes and treatment patterns in Waldenström macroglobulinemia patients who discontinue Bruton tyrosine kinase inhibitor (BTKi) therapy.

Karan L Chohan, Lorenzo Gensini, Sherif Seif, Xiaowen Sun, Lei Feng, Melody R Becnel, Mahmoud M Gaballa, Hans C Lee, Oren Pasvolsky, Krina K Patel, J Christine Ye, Donna M Weber, Robert Z Orlowski, Sheeba K Thomas.

DOI: https://doi.org/10.1038/s41408-025-01415-5
Int Heart J. 2025 ;66(6): 1033-1035

Reversible Left Ventricular Dysfunction Related to Ropeginterferon Alfa-2b in Polycythemia Vera.

Mone Mukai, Tadao Aikawa, Yuya Matsue, Shuichi Shirane, Tohru Minamino.



Keywords:  Cardiac magnetic resonance imaging; Cardiotoxicity; Long-acting interferon-α

DOI:  https://doi.org/10.1536/ihj.25-382
Turk J Haematol. 2025 Dec 03.

Multiple Myeloma with Hairy Cell-Like Plasma Cells.

İrfan Yavaşoğlu, Yusufcan Aygül, Atakan Turgutkaya.

DOI: https://doi.org/10.4274/tjh.galenos.2025.2025.0327
Blood. 2025 Dec 04. 146(23): 2732-2734

On the CHOPping block? Rethinking initial therapy for PMBCL.

Nitya Gulati, Lisa Giulino-Roth.

DOI: https://doi.org/10.1182/blood.2025031030
Hematology Am Soc Hematol Educ Program. 2025 Dec 05. 2025(1): 547-554

All shades of gray in the mediastinum: do we have bright ideas about how to diagnose and treat mediastinal gray zone lymphoma in the era of targeted agents?

Clémentine Sarkozy, Alexandra Traverse-Glehen.

Mediastinal gray zone lymphoma (MGZL) is defined in the international World Health Organization classification as a B-cell lymphoma with overlapping clinical, morphological, immunophenotypic, and molecular features between primary mediastinal B-cell lymphoma (PMBL) and classical Hodgkin lymphoma (CHL), particularly nodular sclerosis CHL (NSCHL). Recent molecular studies have highlighted the similarities between these 3 entities, relying on immune escape, JAK-STAT, and nuclear factor-κB pathway alterations without specific features related to MGZL. These studies shed light on the different pathobiology of extramediastinal cases, leading to the conclusion that these cases are generally better classified as diffuse large B-cell lymphoma (DLBCL)-not otherwise specified. The absence of Epstein-Barr virus (EBV) on the biopsy is also a desirable criterion, leading to the differential diagnosis of EBV-positive DLBCL. Most studies reporting clinical and treatment data suggest that more intensive induction regimens provide greater disease control compared to standard regimens. Given the paucity of dedicated clinical trials, it remains unknown if, and when, the evolving therapeutic options of PMBL and NSCHL will become available to those with MGZL, offering novel immune-based treatments to these patients with a higher risk of primary chemorefractory disease.

DOI: https://doi.org/10.1182/hematology.2025000748C
Hematology Am Soc Hematol Educ Program. 2025 Dec 05. 2025(1): 645-651

Can I stop my treatment, doctor? Is MRD-guided therapy ready for prime time?

Benjamin A Derman.

Indefinite maintenance therapy, typically with lenalidomide, remains a standard of care for patients with multiple myeloma, largely based on studies that demonstrated improved progression-free and overall survival compared to observation or placebo. However, these early trials often did not incorporate modern induction regimens or measurable residual disease (MRD) assessments. Despite newer induction regimens leading to high rates of MRD negativity, further intensification of maintenance remains the focus rather than de-escalation. As treatment paradigms have evolved to include quadruplet induction regimens and sensitive MRD assays, clinicians and patients increasingly question whether maintenance therapy can be safely stopped in selected individuals. This review examines the rationale for maintenance therapy, the historical data supporting its use, and emerging evidence from prospective studies suggesting that maintenance may be safely discontinued in patients with sustained multimodal MRD negativity. Patient-centered considerations, such as treatment-related toxicity, quality of life, and financial burden, underscore the importance of individualized decision-making regarding maintenance cessation. Also explored are future directions in MRD-guided treatment strategies, including de-escalation in the context of deep and sustained response. As the evidence base evolves, the challenge remains to balance the risks of indefinite therapy with the potential benefits of personalized, response-adaptive care in multiple myeloma.

DOI: https://doi.org/10.1182/hematology.2025000761
Hematology Am Soc Hematol Educ Program. 2025 Dec 05. 2025(1): 607-613

Triplet regimens for all: genomically agnostic approaches to improve on HMA + VEN in AML?

William Nicol, Andrew H Wei.

Combined hypomethylating agent (HMA) plus venetoclax (Ven) therapy enables most older patients with acute myeloid leukemia (AML) to achieve clinical remission. Key objectives are now aimed at developing new triplet combinations to circumvent mechanisms of resistance and extend remission longevity and, by extension, survival. Genomically agnostic approaches combine hypomethylating agents and venetoclax (HMA-Ven) with novel agents directed at oncogenic pathways critical for leukemic cell survival, proliferation, metabolism, or differentiation. Challenges faced in the development of new HMA-Ven triplets include competition from targeted inhibitors, biological heterogeneity of AML, potential for additive toxicity, reduced efficacy from modifications to the HMA-Ven backbone, and the higher bar for success in older AML beyond the current standard of care.

DOI: https://doi.org/10.1182/hematology.2025000756
Hematology Am Soc Hematol Educ Program. 2025 Dec 05. 2025(1): 295-304

Diagnosis and management of cold agglutinin disease.

Sigbjørn Berentsen.

Cold agglutinin disease (CAD) is an autoimmune hemolytic anemia, a specific clonal B-cell disorder of the bone marrow, and a monoclonal gammopathy of clinical significance. Thus, CAD should be distinguished from cold agglutinin syndrome, a more heterogeneous cold hemolytic syndrome that occurs secondary to other clinical disease. Cold agglutinins in CAD are usually of the immunoglobulin M kappa class with a heavy chain variable region encoded by the IGHV4-34 gene segment. The hemolytic anemia is entirely mediated by classical complement activation, which also explains some additional clinical features, such as fatigue and acute exacerbations. Non-complement-mediated steps in pathogenesis are also essential, such as erythrocyte agglutination and, probably, coexistent cryoglobulin activity in some patients, resulting in cold-induced circulatory symptoms. Based on this heterogeneity, different clinical phenotypes can be defined and used to guide individualized treatment. Established therapies aim at targeting the pathogenic B-cell clone or the classical complement activation pathway. Novel and investigational therapies include Bruton's tyrosine kinase inhibitors, plasma cell-directed therapies, novel complement inhibitors, and entirely new approaches such as cytokine inhibitors and, possibly, antibodies specific for the VH4-34 protein sequence. Patients with CAD requiring therapy should be considered for clinical trials.

DOI: https://doi.org/10.1182/hematology.2025000718
Int J Biol Macromol. 2025 Nov 28. pii: S0141-8130(25)09786-7. [Epub ahead of print] 149229

Anti-CD38 VLRB-Fc antibodies from transgenic tobacco exhibit potent anti-myeloma activity in vitro and in vivo.

Caiquan Jin, Jun Li, Yerin Kim, Kibum Kim, Peter Hinterdorfer, Seonyoung Kang, Jae-Min Lim, Chang Ki Min, Mineui Hong, Kisung Ko.

  Multiple myeloma (MM) is an incurable hematological malignancy characterized by the abnormal proliferation of malignant plasma cells. While current therapies, particularly anti-CD38 monoclonal antibodies such as daratumumab, have improved patient outcomes, they are often associated with high costs and potential adverse effects. Therefore, there is a growing need for alternative, cost-effective therapeutic strategies. In this study, we report for the first time the successful generation of a plant-derived lamprey variable lymphocyte receptor B (VLRB) recombinant antibody, targeting CD38-expressing MM cells. Two versions of the plant-derived antibodies were engineered by fusing a lamprey-derived anti-CD38 VLRB domain to a human IgG Fc region (Fc) and an ER-retention KDEL signal (K). The first version, anti-CD38 VLRB-stalk-FcK, contains a stalk domain, whereas the second version, anti-CD38 VLRB-FcK, does not. Both antibodies were subsequently expressed in transgenic tobacco plants. Following purification, their binding affinity, cytotoxic effects, and immune effector functions were assessed in vitro using CD38+ MM cell lines. Anti-CD38 VLRB-stalk-FcK demonstrated superior CD38 binding, cytotoxicity, ADCC and inhibition of cell migration compared to anti-CD38 VLRB-FcK. In vivo experiments demonstrated that treatment with anti-CD38 VLRB-stalk-FcK significantly inhibited tumor growth in NOD/SCID mice implanted with multiple myeloma (MM) xenografts. The anti-tumor effect observed was comparable to that achieved with daratumumab, a clinically approved anti-CD38 monoclonal antibody. These findings highlight a novel plant-based platform for producing lamprey-derived therapeutic antibodies, and support the potential of anti-CD38 VLRB-stalk-FcK as a cost-effective, alternative therapeutic agent for the treatment of multiple myeloma.

Keywords:  Immunotherapetics; Multiple myeloma; Transgenic plant

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.149229
Hematology Am Soc Hematol Educ Program. 2025 Dec 05. 2025(1): 87-95

Management of iron overload in adult myelodysplastic syndrome.

Heather A Leitch, Rena Buckstein.

The clinical benefits of iron overload (IOL) management in hereditary anemias, including organ preservation and dramatically improved overall survival (OS), are widely accepted. Adult myelodysplastic syndrome (MDS) patients are older and may have comorbidities, treatments to extend OS are limited, and the clinical benefits of IOL management have been more challenging to demonstrate due to little prospective data in this population. However, current prognostic systems identify MDS patients with reasonable life expectancy who may benefit from IOL management. Half of MDS patients ultimately become dependent on red blood cell transfusion and develop transfusional IOL. Considerable preclinical and clinical data have accumulated indicating the adverse impact of IOL on multiple cellular and clinical end points and a clinical benefit to IOL management in MDS, which should be considered in some patients. Here we provide an overview of salient data in the usual (nonhematopoietic stem cell transplant) clinical MDS setting, summarize mechanisms of iron toxicity including increased radiologically detectable organ stores and redox-active iron-mediated tissue damage, furnish strategies for the identification of IOL, and suggest a framework for IOL severity and IOL reduction. We review which patients are appropriate for IOL management, recommend an appropriate time to intervene, discuss evidence supporting a clinical benefit to IOL management, and recommend how to off-load iron. We identify data gaps for future study and forecast future tools that may become available to minimize IOL toxicity in MDS.

DOI: https://doi.org/10.1182/hematology.2025000691
Clin Case Rep. 2025 Dec;13(12): e71504

Zanubrutinib Combined With Rituximab in the Treatment of Bing-Neel Syndrome: A Case Report.

Rongyao Zhang, Juan Chang, Yanqun Shen, Ping Hu, Lulu Zhang.

  Bing-Neel syndrome (BNS) is a rare complication of Waldenström macroglobulinemia, a condition with low incidence in clinical practice and prone to misdiagnosis. Vigilance is crucial for identifying this condition in patients with Waldenström macroglobulinemia presenting with neurological symptoms. In cases where a pathological biopsy is inconclusive, cerebrospinal fluid flow cytometry can be utilized to aid in diagnosis. Currently, there is no established standard treatment protocol for BNS, and treatment outcomes vary. In this study, a combination of zanubrutinib and R-CHOP regimen was administered, with zanubrutinib being continued for the management of BNS, resulting in a notably favorable response.

Keywords:  Bing–Neel syndrome; Waldenström macroglobulinemia; anti‐CD20 monoclonal antibody; flow cytometry; zanubrutinib

DOI:  https://doi.org/10.1002/ccr3.71504
Blood Cancer J. 2025 Dec 04.

Final OS analyses from the TOURMALINE- MM3 and -MM4 RCTs of ixazomib maintenance in newly diagnosed multiple myeloma.

Meletios A Dimopoulos, Sagar Lonial, Wee-Joo Chng, Shinsuke Iida, María-Victoria Mateos, Gareth J Morgan, Cong Li, Catriona Byrne, Kaveri Suryanarayan, Richard Labotka, S Vincent Rajkumar.

TOURMALINE-MM3 (NCT02181413) and -MM4 (NCT02312258) were phase 3 studies of fixed-duration, single-agent ixazomib maintenance in post-transplant (TOURMALINE-MM3)/transplant-ineligible (TOURMALINE-MM4) patients with newly diagnosed multiple myeloma (NDMM) that demonstrated improved median progression-free survival (PFS) for ixazomib vs placebo. We present the final overall survival (OS) analyses for each study separately. In both studies, eligible patients were randomized 3:2 to receive ixazomib maintenance (3 mg [cycles 1-4], 4 mg [from cycle 5 if tolerated]) or matching placebo for ≤26 cycles, or until progressive disease/unacceptable toxicity. At median follow-up of approximately 8 years (TOURMALINE-MM3) and 5 years (TOURMALINE-MM4), median OS was not reached in either arm in MM3 (hazard ratio [HR], 1.025; 95% confidence interval [CI], 0.789-1.332; p = 0.850), and was 64.8 (ixazomib) vs 69.5 (placebo) months in MM4 (HR, 1.090; 95% CI, 0.861-1.381; p = 0.473). No new safety signals were identified in either study; incidence of new primary malignancies was low. Despite meeting their primary endpoints (PFS), neither final OS analysis of TOURMALINE-MM3/-MM4 showed statistically significant differences between fixed-duration ixazomib maintenance and placebo in patients with NDMM. The growing number of available, highly effective salvage treatments with novel mechanisms of action make demonstrating an OS advantage in front-line myeloma studies increasingly challenging.

DOI: https://doi.org/10.1038/s41408-025-01411-9
Hematology Am Soc Hematol Educ Program. 2025 Dec 05. 2025(1): 191-198

The untransfusable patient.

Kathryn E Webert, Michelle P Zeller.

Red cell transfusions represent the main treatment of acute blood loss anemia; however, there are patients who are unable or refuse to receive blood products. Further, in all patients, it is essential to only transfuse when the benefits of transfusion outweigh the risks. In those patients who are unable to receive a blood transfusion, it is important to have a multidisciplinary treatment plan. Further, for those patients requiring surgery, it is important to consider the pre-, intra-, and postoperative periods. Many of the principles and strategies outlined in this article can be applied to patients across clinical contexts and are not exclusive to the surgical setting. Before any planned surgery or intervention, all patients should be screened for anemia at least 6 weeks prior to their anticipated surgical or delivery date. Anemia should be corrected, and the patient's bleeding history should be documented. Strategies to reduce blood loss intraoperatively should be discussed with the surgical and anesthetic team. A plan for emergency management of bleeding and treatment to reduce risk, both intraoperatively and postoperatively, should be developed. The patient's decisions about which, if any, blood products or fractions are acceptable should be documented. Intraoperatively, surgical and anesthetic techniques to minimize bleeding should be used along with appropriate medications. Postoperatively, considerations include the minimization of blood sampling, ongoing support of the patient's hemoglobin mass, and optimization of the physiologic tolerance of anemia. Options exist to allow for the safe and effective management of patients who refuse or are unable to receive blood transfusions. It is essential to have clear communication and documentation of the goals of therapy as well as acceptable interventions. The involvement of a multidisciplinary team to manage the patient is essential.

DOI: https://doi.org/10.1182/hematology.2025000705
Ann Dermatol. 2025 Dec;37(6): 327-335

Updates in Treatment for Androgenetic Alopecia.

Jung-Won Shin, Chang-Hun Huh.

  Androgenetic alopecia (AGA) is a common nonscarring hair loss condition that affects both men and women, often resulting in psychological distress and reduced quality of life. AGA pathogenesis involves genetic predisposition and androgen influence, primarily dihydrotestosterone (DHT), which leads to hair follicle miniaturization and progressive hair thinning. AGA remains challenging to manage due to its chronic progression and the combined influence of genetic and environmental factors. Topical minoxidil and oral finasteride are the most widely used treatments for AGA, addressing follicular miniaturization. However, their reliance on long-term use and potential for side effects or inconvenience has prompted increasing interest in alternative therapies. The mainstream of current AGA treatment can be categorized into androgen-targeting and non-androgen-targeting approaches. Finasteride and dutasteride, both 5-α-reductase inhibitors that reduce DHT levels in hair follicles, are key androgen-targeting treatments, with newer formulations like topical and injectable options emerging alongside traditional oral forms. Topical minoxidil remains central to non-androgen-targeted AGA treatments, though growing evidence supports the efficacy and safety of its low-dose oral form. Additionally, therapies like low-level light therapy, platelet-rich plasma, and exosome treatments are being explored. Recently, therapies targeting the androgen receptor, including small interfering RNA-based approaches, have been developed and are currently in clinical trial stages, offering innovative potential for AGA treatment. This review explores current and emerging treatments for AGA, addressing both androgen-targeted and non-androgen-targeted approaches with an emphasis on their mechanisms, efficacy, and safety. It ultimately aims to provide a comprehensive update on the latest advancements in AGA management.

Keywords:  Androgenetic alopecia; Dutasteride; Female androgenetic alopecia; Finasteride; Minoxidil

DOI:  https://doi.org/10.5021/ad.25.042
Curr Pain Headache Rep. 2025 Dec 05. 29(1): 121

Capsaicin in the Management of Peripheral Neuropathy: A Review.

Rabiul Ryan, Ramzan Judge, Jesse Lou, Andrew Ng.

   PURPOSE OF REVIEW: The purpose of this review is to provide an update on the efficacy and safety of capsaicin in the treatment of neuropathic pain.
RECENT FINDINGS: Capsaicin can provide prolonged relief from pain in various neuropathies. One proposed mechanism is the ability to cause degeneration of hypersensitized nerve tissue and incite regeneration of healthy nerve fibers. Capsaicin provides more significant relief than placebo and is non-inferior to pregabalin in the treatment of peripheral neuropathy. It is emerging as an alternative but effective and well-tolerated treatment for neuropathy due to diverse pathologic conditions. Capsaicin, a natural agonist at the TRPV1 receptor, has been studied for its therapeutic role in neuropathic pain. Capsaicin is an effective treatment with significant reduction in both diabetic and non-diabetic neuropathic pain. Due to its topical application, it is associated with fewer systemic adverse events and therefore, an attractive option in the treatment of peripheral neuropathy.

Keywords:  Capsaicin; Diabetic neuropathy; Peripheral neuropathy

DOI:  https://doi.org/10.1007/s11916-025-01423-x
Cancer Discov. 2025 Dec 04.

A High-Fiber Plant-Based Diet in Myeloma Precursor Disorders - Results from the NUTRIVENTION Clinical Trial and Preclinical Vk*MYC Model.

Urvi A Shah, Laura Lucia Cogrossi, Juan-Jose Garces, Anna Policastro, Francesca Castro, Andriy Derkach, Teng Fei, Susan DeWolf, Matteo Grioni, Sofia Sisti, Jenna Blaslov, Peter A Adintori, Kinga K Hosszu, Devin McAvoy, Mirae Baichoo, Justin R Cross, Jenny Paredes, Aishwarya Anuraj, Sandeep S Raj, Charlotte Pohl, Paola Zordan, Victoria Zinsmeyer, Ruben J Jesus Faustino Ramos, Marco Lorenzoni, Brianna Gipson, Kylee H Maclachlan, Ana Gradissimo, Leonardo Boiocchi, Nathan Aleynick, Camilla Marchigiani, Sara Pagani, Erica Salehi, Richard P Koche, Ronan Chaligne, Torin Block, Neha Korde, Carlyn R Tan, Malin Hultcrantz, Hani Hassoun, Gunjan L Shah, Michael Scordo, Oscar B Lahoud, David J Chung, Heather J Landau, Jonathan U Peled, Nicola Clementi, Marta Chesi, P Leif Bergsagel, Sham Mailankody, Michael N Pollak, Anita D'Souza, Ola Landgren, Susan Chimonas, Sergio A Giralt, Saad Z Usmani, Neil M Iyengar, Alexander M Lesokhin, Marcel R M van den Brink, Matteo Bellone.

Consumption of a western diet and high body mass index (BMI) are risk factors for progression from pre-malignant phenotypes to multiple myeloma, a hematologic cancer. In the NUTRIVENTION trial (NCT04920084), we administered a high-fiber, plant-based diet (meals for 12 weeks, coaching for 24 weeks) to 23 participants with myeloma precursor states and elevated BMI. The intervention was feasible, improved quality of life and modifiable risk factors: metabolic (BMI, insulin resistance), microbiome (diversity, composition), and immune (inflammation, monocyte subsets). Disease-progression trajectory improved (n=2) or was stable. Findings were translated to Vk*MYC mice modeling the myeloma-precursor state, in which a high-fiber diet delayed disease progression through improved metabolism and microbiome composition leading to increased short-chain fatty acid production that reinvigorated anti-tumor immunity and inhibited tumor growth. These effects from fiber consumption were independent of calorie restriction and weight loss. A high-fiber diet is a low-risk intervention that may delay progression to myeloma.

DOI: https://doi.org/10.1158/2159-8290.CD-25-1101
Hematology Am Soc Hematol Educ Program. 2025 Dec 05. 2025(1): 393-400

POEMS syndrome: diagnosis, treatments, and outcomes.

Angela Dispenzieri.

POEMS (polyneuropathy, organomegaly, endocrinopathy, M protein, skin changes) syndrome is a complex paraneoplastic syndrome related to a lambda-restricted low-tumor burden neoplasm. The diagnosis must be considered in the context of what might otherwise be believed to be a "monoclonal gammopathy of undetermined significance," with unusual features including, but not limited to, peripheral neuropathy, thrombocytosis, and extracellular volume overload. Once a diagnosis of POEMS syndrome is made, besides very specific supportive care, the treatments resemble those of multiple myeloma or solitary plasmacytoma of the bone. Based on case series, autologous stem cell transplant is still a favored therapy with durable remissions even without maintenance therapy. Even before the era of therapeutic monoclonal antibodies, bispecific T-cell engagers, and chimeric antigen receptor antibodies, 10-year overall survival approached 80%. Patients achieving a complete hematologic response have a progression-free survival of 88% even without maintenance therapy. Herein, a case of a patient with a less-than-average outcome is described to highlight some of the long-term challenges and complexities of managing patients with POEMS syndrome.

DOI: https://doi.org/10.1182/hematology.2025000729