bims-hemali Biomed News
on Hematologic malignancies
Issue of 2025–12–28
eight papers selected by
Alexandros Alexandropoulos, Γενικό Νοσοκομείο Αθηνών Λαϊκό
  1. Translocation t(11;14) and BCL2-inhibition in multiple myeloma.
  2. T-cell/histiocyte-rich large B-cell lymphoma in the era of novel immunotherapy: A focused review.
  3. Beyond PD-1: Mechanisms of Resistance to Checkpoint Blockade in Classical Hodgkin Lymphoma and Next-Generation Immune Strategies.
  4. Clinical significance of t(11;14) translocation in systemic AL amyloidosis in the era of daratumumab therapy.
  5. Chemotherapy-Sparing Strategies in Follicular Lymphoma: Emerging Targeted and Immune-Based Approaches.
  6. Efficacy and relapse profiles of Pola-R-CHP versus R-CHOP in previously untreated diffuse large B-cell lymphoma: A multicentre real-world study.
  7. How to drug a leukemic stem cell: deciphering heterogeneity for better specificity.
  8. Efficacy and safety of Pola-R-mini-CHP therapy in patients aged ≥80 years with CD5-positive diffuse large B-Cell lymphoma.
  1. Haematologica. 2025 Dec 24.
    Translocation t(11;14) and BCL2-inhibition in multiple myeloma.
    Shirlene Sim, Binod Dhakal, Hang Quach.
      Multiple myeloma is an increasingly treatable disease with improved survival, yet characterized by multiple subclones that drive heterogeneity and variable clinical outcomes between patients. A biomarker driven approach can help tailor treatment and improve patient outcomes. Translocation t(11;14), a primary cytogenetic abnormality present in 15-20% of myeloma patients at diagnosis, is currently the most prominent targetable lesion in myeloma. In the era of induction with proteasome inhibitor and/or immunomodulatory drugs, t(11;14) has been associated with poorer outcomes compared to other standard-risk subgroups, with shorter progression-free and overall survival. The presence of t(11;14) in myeloma cells confers increased dependence on the pro-survival BCL2 protein, thus driving its ability to evade apoptosis, and is the main biomarker predicting response to BCL2-inhibitors. This review will examine the pathogenesis and prognostic significance of t(11;14) in myeloma and the impact of concurrent high-risk cytogenetics, the mechanism of action of BCL2-inhibitors, cumulative evidence supporting its use, and proposed mechanisms of resistance. The review will also present potential future directions regarding BCL2-inhibitor based regimens and how best to position these drugs to optimize patient outcomes.
    DOI:  https://doi.org/10.3324/haematol.2025.289147
  2. Br J Haematol. 2025 Dec 23.
    T-cell/histiocyte-rich large B-cell lymphoma in the era of novel immunotherapy: A focused review.
    Joleen P Choy, Chan Y Cheah.
      T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) is an uncommon aggressive large B-cell lymphoma variant which can develop synchronously or following a diagnosis of nodular lymphocyte predominant Hodgkin lymphoma (NLPHL). There is morphological, immunophenotypic and molecular overlap between THRLBCL and NLPHL suggesting that these two entities may lie on the same spectrum. Due to the rarity of THRLBCL, accurate diagnosis can be challenging and there is a paucity of data on which to base treatment decisions. The management has largely followed diffuse large B-cell lymphoma (DLBCL) with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone established as the standard of care in the first line, with outcomes comparable to international prognostic index matched DLBCL. In the relapsed/refractory (R/R) setting, there is no standard of care. There is a move towards inclusion of THRLBCL patients in clinical trials evaluating novel agents, although historically they were commonly excluded. Due to the small numbers included in clinical trials, it has been difficult to discern the effect of novel agents in this cohort. Thus, we are reliant on larger real-world datasets to inform our understanding. This review will examine the data available in the first line and R/R setting with a focus on immunotherapeutic approaches.
    Keywords:  T‐cell histiocyte‐rich large B‐cell lymphoma; immunotherapy
    DOI:  https://doi.org/10.1111/bjh.70294
  3. Eur J Haematol. 2025 Dec 25.
    Beyond PD-1: Mechanisms of Resistance to Checkpoint Blockade in Classical Hodgkin Lymphoma and Next-Generation Immune Strategies.
    Santino Caserta, Enrica Antonia Martino, Mamdouh Skafi, Maria Eugenia Alvaro, Antonella Bruzzese, Nicola Amodio, Eugenio Lucia, Virginia Olivito, Caterina Labanca, Francesco Mendicino, Ernesto Vigna, Fortunato Morabito, Massimo Gentile.
      PD-1 inhibitors have reshaped the treatment landscape of classical Hodgkin lymphoma, yet a substantial proportion of patients exhibit primary or acquired resistance driven by tumor-intrinsic alterations, immunosuppressive microenvironmental signals, metabolic constraints, and EBV-mediated modulation. This review summarizes key mechanisms underlying PD-1 resistance and highlights emerging biomarkers-including early 18F-FDG PET response, circulating tumor DNA kinetics, molecular subtyping, and spatial immune profiling-that enable early identification of nonresponders and support precision immunotherapy. Novel therapeutic strategies such as macrophage-targeted agents, metabolic modulators, bispecific antibodies, low-dose PD-1 regimens, and CD30-directed CAR-T cells show promise in overcoming resistance, particularly when integrated into adaptive, biomarker-guided treatment algorithms. Early incorporation of PET and ctDNA monitoring may inform timely treatment adaptation, while combination approaches addressing macrophage-driven suppression or redundant immune checkpoints should be considered in biologically high-risk patients. Overall, a deeper mechanistic understanding coupled with biomarker-driven stratification is essential to optimize PD-1-based therapy and improve long-term outcomes in cHL.
    Keywords:  PD‐1; PET; classic Hodgkin lymphoma; ctDNA
    DOI:  https://doi.org/10.1111/ejh.70101
  4. Clin Exp Med. 2025 Dec 22.
    Clinical significance of t(11;14) translocation in systemic AL amyloidosis in the era of daratumumab therapy.
    Nao Nishimura, Yawara Kawano, Jun-Ichirou Yasunaga.
      The chromosomal translocation t(11;14)(q13;q32) is frequently observed in systemic light-chain (AL) amyloidosis, yet its clinical significance in the era of daratumumab-based therapy remains unclear. To compare clinical and cytogenetic characteristics, we retrospectively analyzed 68 patients with systemic AL amyloidosis and 107 patients with multiple myeloma (MM) newly diagnosed at Kumamoto University Hospital, with the MM cohort serving as a reference cohort. t(11;14) was detected in 55.9% of AL amyloidosis and 28.0% of MM cases. In both diseases, t(11;14) was associated with light chain-only M-protein and elevated CD20 expression on bone marrow plasma cells, suggesting a distinct phenotype. Notably, t(11;14)-positive AL amyloidosis patients exhibited a significantly lower incidence of renal dysfunction, a feature not observed in t(11;14)-positive MM. Among 47 AL amyloidosis patients treated with upfront daratumumab-containing regimens, overall survival did not differ significantly by t(11;14) status. However, event-free survival was significantly shorter in the t(11;14)-positive group (median 41.6 vs. 71.3 months, p = 0.037), accompanied by inferior 3 months hematological and cardiac responses. These findings suggest that t(11;14)-positive AL amyloidosis constitutes a distinct biological and clinical subtype characterized by delayed treatment response to daratumumab. Tailored therapeutic strategies targeting the unique biology of t(11;14)-positive AL amyloidosis is warranted.
    Keywords:  AL amyloidosis; CD38; Daratumumab; t(11;14)
    DOI:  https://doi.org/10.1007/s10238-025-02005-2
  5. Eur J Haematol. 2025 Dec 26.
    Chemotherapy-Sparing Strategies in Follicular Lymphoma: Emerging Targeted and Immune-Based Approaches.
    Enrica Antonia Martino, Santino Caserta, Mamdouh Skafi, Maria Eugenia Alvaro, Antonella Bruzzese, Nicola Amodio, Eugenio Lucia, Virginia Olivito, Caterina Labanca, Francesco Mendicino, Ernesto Vigna, Fortunato Morabito, Massimo Gentile.
      Follicular lymphoma (FL), traditionally considered an indolent yet incurable malignancy, is experiencing a substantial evolution in its therapeutic landscape with the emergence of chemo-free treatment strategies. These novel approaches challenge conventional chemotherapy-based paradigms and offer promising alternatives for both newly diagnosed and relapsed/refractory (RR) FL patients. Among these innovations, bispecific antibodies (BsAbs) have demonstrated compelling efficacy while providing practical advantages, including outpatient administration and generally manageable safety profiles. Chimeric antigen receptor (CAR) T-cell therapies have further expanded the therapeutic armamentarium, achieving unprecedented response rates in heavily pretreated and high-risk populations, although their implementation remains limited by logistical complexity and high associated costs. Additional targeted agents-such as Enhancer of zeste homolog 2 (EZH2) inhibitors, lenalidomide, and Bruton tyrosine kinase (BTK) inhibitors-also contribute meaningfully to chemo-free treatment options, particularly within combination regimens that may enhance clinical benefit. Despite these advances, several challenges persist. Early disease progression (POD24) remains one of the most powerful prognostic determinants in FL. The FLIPI-C model, incorporating machine-learning-derived risk stratification, has shown promise in identifying high-risk patients who may benefit most from innovative approaches. Introducing chemo-free therapies earlier in the treatment algorithm may improve outcomes for these patients while mitigating the long-term toxicities associated with conventional chemotherapy. Ongoing validation through prospective clinical trials and real-world evidence will be essential to define the optimal integration of these therapies. Overall, this evolving paradigm highlights the urgent need for continued innovation, multidisciplinary collaboration, and equitable access to ensure that the full potential of chemo-free strategies can be realized for patients with this complex disease.
    Keywords:  chemo‐free strategy; follicular lymphoma; target therapy
    DOI:  https://doi.org/10.1111/ejh.70105
  6. Br J Haematol. 2025 Dec 26.
    Efficacy and relapse profiles of Pola-R-CHP versus R-CHOP in previously untreated diffuse large B-cell lymphoma: A multicentre real-world study.
    Toshiki Terao, Isao Yoshida, Hiroki Kobayashi, Tomohiro Urata, Fuminari Fujii, Yusuke Meguri, Hiroyuki Sugiura, Takanori Yoshioka, Kyosuke Saeki, Daigo Niiya, Shoji Asakura, Hisakazu Nishimori, Daisuke Ikeda, Hideaki Fujiwara, Daisuke Ennishi, Yoshinobu Maeda.
      In this retrospective, multicentre cohort study, we compared the real-world efficacy of polatuzumab vedotin combined with rituximab, cyclophosphamide, doxorubicin and prednisone (Pola-R-CHP) versus the conventional rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) in 370 patients in the propensity score matching cohort from 1096 patients with previously untreated diffuse large B-cell lymphoma (DLBCL) (pola; n = 185 in the matched and 356 in the full cohort). The analysis focused on clinical efficacy, the prognostic performance of established risk models and the relapse profiles with the chemotherapies. The Pola-R-CHP group showed superior 1-year progression-free survival (PFS) compared to the R-CHOP group (86.7% vs. 73.5%, p = 0.027); however, the 1-year overall survival (OS) was similar (92.8% vs. 89.6%, p = 0.24). Within the Pola-R-CHP group, the Central Nervous System International Prognostic Index (CNS-IPI) effectively stratified the cumulative incidence of CNS relapse of 0%, 2.1% and 4.5% in the low, intermediate and high-risk groups respectively (p = 0.023). Additionally, the 1-year incidence of nodal relapse was significantly lower in the Pola-R-CHP group than in the R-CHOP group (2.1% vs. 10.9%, p = 0.013), whereas the incidence of extra-nodal relapse remained similar (3.8% vs. 5.2%, p = 0.57). These findings underscore the clinical efficacy of Pola-R-CHP over R-CHOP in first-line DLBCL treatment. However, early extra-nodal relapse and CNS relapse remained a therapeutic challenge.
    Keywords:  CNS relapse; DLBCL; early relapse; extra‐nodal relapse; polatuzumab vedotin
    DOI:  https://doi.org/10.1111/bjh.70280
  7. Blood Neoplasia. 2025 Nov;2(4): 100146
    How to drug a leukemic stem cell: deciphering heterogeneity for better specificity.
    Alice Worker, Nicholas Jinks, Peter Woodmancy, Claire Seedhouse, Sophie G Kellaway.
      Blood cancers, such as acute myeloid leukemia (AML), are becoming increasingly common due to an aging population but remain challenging to treat. Relapse is the most important singular cause of treatment failure in AML, and up to half of patients relapse after chemotherapy or bone marrow transplantation. Relapse in AML is primarily due to a population of quiescent leukemic stem cells (LSCs) that shelter in the bone marrow. Chemotherapy hits actively proliferating AML blasts, but LSCs escape and can later re-enter the cell cycle to regenerate the leukemia. LSCs resemble hematopoietic stem cells, but variable and unique differences may allow for LSC-specific treatment. In this review, we summarize the unique biology of LSCs, considering both global and subtype-specific traits. We describe how heterogeneity, both between different AML subtypes and within the LSC compartment, has impaired efforts to find drug targets so far and how this is being resolved with technological advances such as single-cell sequencing. We elucidate which aspects of LSC biology determine possibilities for targeted treatment and the progress so far made toward therapies to prevent or treat relapse.
    DOI:  https://doi.org/10.1016/j.bneo.2025.100146
  8. J Clin Exp Hematop. 2025 Dec 24.
    Efficacy and safety of Pola-R-mini-CHP therapy in patients aged ≥80 years with CD5-positive diffuse large B-Cell lymphoma.
    Kosuke Arai, Yasunobu Sekiguchi, Shizuka Hamano, Hiroki Tsutsumi, Masahisa Kudo, Nobuo Maseki, Yoshie Iizaki, Machiko Kawamura, Kazuhiko Kobayashi, Yu Nishimura, Hiroaki Kanda, Daisuke Takei, Tomoya Abe, Makoto Hanai, Sayaka Endo, Yu Kakusaka, Toshiaki Nakayama, Yasumasa Shimano, Hirofumi Kobayashi.
      
    Keywords:  CD5-positive DLBCL; CD79B; MYD88 L265P; Pola-R-mini-CHP; aged ≥80 years
    DOI:  https://doi.org/10.3960/jslrt.25066
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