Haematologica

Where would immune thrombocytopenia be without intravenous gammaglobulin?

James B. Bussel — 2026-10-01

Relapsed Hodgkin lymphoma: should all patients receive an autologous stem cell transplant? – the PRO

Chathuri Abeyakoon — 2026-04-02

Relapsed Hodgkin lymphoma: should all patients receive an autologous stem cell transplant? – the CON

Alison J. Moskowitz — 2026-04-02

ROCKing resistance: cytoskeletal mitochondrial synergy in acute myeloid leukemia

Weiwei Zheng — 2026-05-14

RNA methylation as a leukemia stem cell vulnerability

Fengbiao Zhou — 2026-04-30

FLT3 inhibition after transplantation: real-world evidence confirms common practice

Martin Bornhäuser — 2026-04-09

Disrupting adaptive proteostasis to overcome proteasome inhibitor resistance

Annamaria Brioli — 2026-03-26

Anticipating and overcoming resistance in blastic plasmacytoid dendritic cell neoplasm: new insights from pivekimab sunirine

Maria Rosaria Sapienza — 2026-03-12

Thrombopoietin agents and marrow fibrosis: fact or myth

James B. Bussel — 2026-06-25

The risks of delay?

Scott C. Kogan — 2026-07-02

An epigenetic Achilles’ heel in extranodal NK/T-cell lymphoma?

Matthew J. Ahearne — 2026-05-21

Immune checkpoint therapy in pediatric and adolescent lymphomas

David J. Hoogstra — 2026-06-04

Immune checkpoint therapy (ICT) is designed to unleash the anti-tumor activity of T-lymphocytes. Cytotoxic T-lymphocyte- associated antigen 4 (CTLA-4) inhibition and programmed death 1 (PD-1) inhibition are the most commonly utilized ICT in clinical cancer therapy, and they enhance anti-tumor immunity by interrupting the inhibitory signals CTLA-4 and programmed death ligand 1 (PD-L1), respectively. In pediatric Hodgkin lymphoma, ICT has demonstrated remarkable efficacy in both high-risk and relapsed disease, with investigation into the efficacy in low-risk disease ongoing. Pediatric mature B-cell lymphomas have variable expression of PD-L1 and there is very limited experience of incorporating ICT in their treatment. Primary mediastinal B-cell lymphoma (PMBCL), anaplastic large cell lymphoma, aggressive natural killer-cell lymphoma, and peripheral T-cell lymphoma, not otherwise specified all consistently express PD-L1, which provides a strong biological rationale for the use of ICT in these diseases. In PMBCL, the Children’s Oncology Group and the National Cancer Institute’s National Clinical Trials Network recently completed a randomized phase III trial of nivolumab in combination with chemo-immunotherapy in children and adults with newly diagnosed PMBCL. Results of this trial are expected in 2027. In anaplastic large cell lymphoma and aggressive natural killer-cell lymphoma, ongoing clinical trials are evaluating the efficacy of ICT. Given the transformational role of ICT in pediatric Hodgkin lymphoma, there is significant promise for the use of ICT in multiple subtypes of pediatric non-Hodgkin lymphoma with increased expression of PD-L1.

Emerging preclinical evidence supports a potential role for cannabidiol in the management of sickle cell disease

Arne M. de Kreuk — 2026-05-28

Sickle cell disease (SCD) imposes a substantial global health burden, with acute and chronic pain representing a major component of morbidity. Standard pain management, largely opioid-based, carries significant risks and often provides inadequate long-term relief, highlighting an unmet need for alternative analgesics as well as disease modifiers. Medicinal cannabinoids have analgesic and anti-inflammatory properties; most clinical studies so far have used Δ9-tetrahydrocannabinol (THC)-containing products with conflicting outcomes. In contrast, purified cannabidiol (CBD) has a broader spectrum of action beyond the endocannabinoid system, lacks psychoactive effects and associated long-term risks, allows safe dose optimization and can be prescribed legally in many settings. Here, we review evidence for CBD’s potential analgesic and disease-modifying properties for the management of SCD. Pain in SCD arises from local tissue inflammation and neuroinflammation, compounded by abnormal pain modulation and pro-nociceptive central nervous system alterations. CBD may attenuate the pathophysiological processes of SCD by modulating pro-inflammatory immune pathways, reducing oxidative stress and suppression of neurogenic inflammation. CBD also has a direct inhibitory effect on afferent nociceptive pathways. Furthermore, CBD has an important pain-modulating role by suppressing excitatory mechanisms in the dorsal root ganglia and central nervous system. Additionally, CBD may modulate pain-processing brain networks and attenuate opioid-induced reward-seeking behavior. Although human data are very limited, emerging preclinical findings and early reports on patients offer cautious optimism for CBD as a therapeutic option with potential disease-modifying properties in SCD. Clinically meaningful benefits may be expected in specific subgroups of patients, identifiable through well-designed clinical and mechanistic studies focused on pain processing and neuroinflammation.

Diagnostic and therapeutic challenges in rare hematologic entities: monoclonal gammopathy of thrombotic and bleeding significance

Despina Fotiou — 2026-04-02

Monoclonal gammopathies encompass a spectrum of clonal B-cell or plasma cell disorders characterized by the production of a monoclonal immunoglobulin. While most cases remain asymptomatic, certain clones can elicit organ or tissue injury through distinct pathogenic mechanisms, leading to the concept of monoclonal gammopathy of clinical significance (MGCS). Among the least recognized but clinically important MGCS entities are monoclonal gammopathy of thrombotic significance (MGTS) and monoclonal gammopathy of bleeding significance (MGBS), in which the M-protein directly interferes with hemostatic pathways, resulting in thrombosis or bleeding. These conditions remain underdiagnosed due to their heterogeneous clinical presentations and challenges in establishing causal relationships between the paraprotein and hemostatic abnormalities. MGTS and MGBS encompass diverse mechanisms, including cryoprotein formation, complement activation, coagulation factor inhibition, and von Willebrand factor or platelet dysfunction. Currently, there are no standardized diagnostic criteria or evidence-based treatment recommendations, and the role of anti-clonal therapy remains undefined. This perspective outlines an ongoing multinational initiative under the auspices of the International Society on Thrombosis and Haemostasis Scientific and Standardization Committee (ISTH SSC) Subcommittee on Cancer-Associated Thrombosis and Hemostasis, aiming to define diagnostic pathways, propose classification and treatment criteria, and identify patients who may benefit from targeted therapies. A unified framework will improve recognition, diagnosis, and management of these rare yet clinically significant entities.

Pharmacological blockade of rho kinase enhances venetoclax responses in translational models of acute myeloid leukemia

Upendarrao Golla — 2026-04-02

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy requiring concomitant targeting of critical cellular survival pathways due to resistance and frequent relapse with monotherapies. Venetoclax (VEN), a BCL-2 inhibitor, is one such promising clinical agent best utilized in combination therapies due to transient responses and acquired resistance. Given the involvement of the Rho/ROCK pathway in VEN activity, we combined Rho-associated coiled-coil–containing protein kinase inhibitors (ROCKi) with VEN to achieve superior antileukemic activity. The ROCKi (Fasudil, DJ4, GSK269962A) synergized with VEN to enhance cytotoxicity in both VEN-sensitive and VEN-resistant cell lines in vitro. Among the three ROCKi, GSK269962A (GSK) was best-tolerated in combination with VEN and effectively inhibited leukemia growth across multiple AML cell line-derived xenograft models in vivo. The GSK+VEN combination exhibited additive to synergistic cytotoxicity in primary AML patient cells ex vivo and enhanced antileukemic activity in a patient-derived xenograft model. Additionally, the GSK+VEN combination significantly decreased the clonogenicity of primary AML cells, relatively sparing normal cells. Functional assays demonstrated enhanced apoptosis (Annexin V, caspase-3/7), elevated reactive oxygen species, and mitochondrial depolarization in both VEN-sensitive and VEN-resistant AML cells following combination treatment. Mechanistically, GSK augmented venetoclax responses by down-regulating anti-apoptotic proteins (BCL2, MCL1) and inducing pro-apoptotic mediators (NOXA, MCL1 short isoforms), including in VEN-resistant AML cells. Together, these findings across multiple preclinical AML models demonstrate synergistic antileukemic activity and support combining VEN with ROCKi as a promising therapeutic strategy for AML.

NSUN2-FOSB reciprocity facilitates leukemogenesis in an m⁵C-dependent manner by increasing BCL2L1 expression

Bin Zhou — 2026-03-12

NOP2/Sun RNA methyltransferase family member 2 (NSUN2) catalyzes 5-methylcytosine (m5C) modifications on RNA to regulate mRNA stability. However, its roles in normal hematopoiesis and leukemogenesis remain poorly understood. Here, we show that NSUN2 is markedly upregulated in primary acute myeloid leukemia (AML) patients’ samples compared with normal hematopoietic cells. NSUN2 knockdown impaired AML cell proliferation, induced apoptosis, and reduced colony formation. Genetic ablation of Nsun2 in an MLL-AF9-transformed murine AML model substantially impaired leukemia stem cell self-renewal and prolonged overall survival, while sparing normal hematopoiesis, highlighting NSUN2 as a potential therapeutic target. Notably, wild-type NSUN2, but not catalytically inactive mutants, restored leukemia stem cell function and leukemogenesis in NSUN2-deficient AML cells, indicating that these effects are m⁵C-dependent. Mechanistically, NSUN2 stabilized FosB proto-oncogene (FOSB) mRNA via m⁵C modification at nucleotide 3656 in the 3′ untranslated region, thereby upregulating FOSB expression. In turn, FOSB transcriptionally activated NSUN2, forming a feedforward regulatory loop. Furthermore, FOSB promoted expression of the anti-apoptotic regulator B-cell lymphoma-2-like protein 1 (BCL2L1) by directly binding to its promoter. In conclusion, these findings uncover a novel NSUN2-FOSB-BCL2L1 axis that drives AML leukemogenesis in an m5C-dependent manner, suggesting the therapeutic potential of targeting this pathway.

Impact of FMS-like tyrosine kinase 3 inhibitor maintenance on post-transplant outcomes in acute myeloid leukemia with FMS-like tyrosine kinase 3 mutations: a real-world German registry analysis highlighting sorafenib

Radwan Massoud — 2026-03-05

FLT3-mutation occurs in 25-30% of acute myeloid leukemia (AML) and confers high relapse risk and inferior survival. Allogeneic hematopoietic cell transplantation (allo-HCT) offers curative potential, yet relapse remains a major post-transplant challenge. Maintenance therapy with FLT3 inhibitors (FLT3i) after allo-HCT has emerged as a promising strategy, but real- world evidence remains limited. This study aimed to assess the impact of FLT3i maintenance on transplant outcomes. We analyzed 523 adults with FLT3-internal tandem duplications (ITD) AML in first complete remission who underwent allo- HCT between 2011 and 2023 in 13 German transplant centers participating in the national German Registry for Hemato-poietic Stem Cell Transplantation and Cell Therapy registry; 22% received FLT3i maintenance (sorafenib 49%, midostaurin 37%, gilteritinib 5%, unknown 9%). In multivariable analyses, FLT3i maintenance improved overall survival (OS) (hazard ratio [HR]=2.25; 95% confidence interval [CI]: 1.28-3.95; P=0.005), relapse-free survival (RFS) (HR=1.72; 95% CI: 1.05- 2.81; P=0.030), non-relapse mortality (HR=3.62, 95% CI: 1.08-12.11; P=0.037), and graft-versus-host disease-free, relapse-free survival (GRFS) (HR=1.59; 95% CI: 1.06-2.40; P=0.025). The cumulative incidence of relapse did not differ. In univariate analyses (UVA), OS benefits were observed in MRD-positive (HR=2.35; 95% CI: 1.04-5.31; P=0.025) and MRD-negative patients (HR=2.64; 95% CI: 1.05-6.68; P=0.020. Sorafenib maintenance (N=50) demonstrated superior efficacy with 5-year OS of 85% versus 62% (HR=2.979; P=0.0045) and RFS of 84% versus 55% (HR=2.771; P=0.0043) compared to no maintenance. These real-world findings, while limited by the retrospective design and potential selection bias, align with randomized trial data and support the use of FLT3i maintenance as part of post-transplant care for FLT3.

Treatment of TP53-mutated myelodysplastic syndrome and acute myeloid leukemia with low-intensity metronomic decitabine and venetoclax

Mendel Goldfinger — 2026-04-02

Venetoclax (Ven) in combination with hypomethylating agents (HMA) (azacitidine or decitabine) is the standard of care for elderly or unfit patients with acute myeloid leukemia (AML) and is being explored in high-risk myelodysplastic syndrome (HR-MDS). However, currently approved dosing of HMA/Ven is associated with prolonged cytopenias, without a clear improvement in survival for TP53-mutated myeloid malignancies. In order to reduce hospitalizations during COVID, a once-weekly, metronomic schedule of decitabine (0.2 mg/Kg) and ven (400 mg) was developed for patients with MDS and AML. Based on the encouraging results, a phase II trial was performed. In the current study, we analyzed response rates and survival for all patients with TP53-mutated disease treated on the metronomic schedule. In total, 40 patients with TP53-mutated MDS and AML (26 in a prospective trial and 14 in the retrospective cohort) were included; 26 had HR-MDS and 14 had AML. The median age was 76.5 years, 70% had complex cytogenetics, and 82% had bi-allelic TP53 mutations. The overall response rate for AML (complete remission [CR] + CR with incomplete blood count recovery) was 70% and 57% (CR + marrow CR) for MDS. With a median follow-up of 12.9 months, the median overall survival for the entire cohort was 11.3 months (11.6 months for AML, 9.9 months for MDS), and median overall survival in the 31 patients with bi-allelic mutated TP53 was 10.4 months. Transfusion independence was achieved in 58%. Neutropenic fever occurred in 15%, there were no therapy-related fatalities, and the 100-day mortality was 7.5%. Results showed that a non-cytotoxic metronomic dosing schedule of decitabine/Ven has a low toxicity profile in TP53-mutated myeloid malignancies.

Predictive biomarkers of sustained treatment-free remission in chronic myeloid leukemia: gene expression analyses from the ENESTfreedom and ENESTop studies

Jerald P. Radich — 2026-03-26

Different primary thyroid B-cell lymphomas show overlapping mutation profiles, suggesting involvement of a common pathogenic process

Maria-Myrsini Tzioni — 2026-03-19

Primary thyroid lymphomas commonly originate from a background of Hashimoto’s thyroiditis and comprise largely extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (EMZL), diffuse large B-cell lymphoma (DLBCL), and follicular lymphoma (FL). Thyroid EMZL harbors a distinct mutation profile, but whether this discriminates them from thyroid FL and DLBCL is unknown. To investigate this, we have examined 42 EMZL (11 BCL6-translocation [tr]+ve), 21 FL (5 BCL2-tr+ve, 10 BCL6-tr+ve, 1 both BCL2/BCL6-tr+ve) and 34 DLBCL of the thyroid. Targeted next generation sequencing revealed a remarkable overlap in the mutation profile among thyroid EMZL, BCL2-tr-ve FL and DLBCL, all showing frequent mutations in TET2, IGLL5, TNFRSF14, CD274, GNA13, FAS, KLF2 and TNFAIP3. In contrast, BCL2-tr+ve FL of the thyroid showed frequent BCL2, KMT2D, CREBBP, EZH2, but not TET2 and CD274 mutations. Genomic analysis of BCL6 translocation by targeted locus capture next generation sequencing showed different genomic configurations between thyroid FL and EMZL. In thyroid FL, the majority of BCL6 translocations placed its coding exons under the transcriptional control of the IGH switch region super-enhancer or its partner genes, potentially resulting in BCL6 constitutive expression. In contrast, the majority of BCL6 translocations in thyroid EMZL juxtaposed the BCL6 gene to the IGHJ/D region without encompassing the Eμ enhancer or its partner genes in an opposite orientation, thus less likely to lead to constitutive BCL6 transactivation. The above genetic changes likely dysregulate B-cell maturation and peripheral tolerance, thus offer significant molecular insights into the pathogenesis of thyroid lymphomas, particularly underpinning autoimmunity in the lymphomagenesis and potentially explaining the overlap in histopathology between EMZL and FL.

Epcoritamab plus rituximab, dexamethasone, cytarabine, oxaliplatin/carboplatin induces deep and durable responses in transplant-eligible patients with relapsed or refractory diffuse large B-cell lymphoma: results from the EPCORE NHL-2 trial

Pau Abrisqueta — 2026-03-05

The treatment of relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) remains challenging, with inadequate responses to salvage chemoimmunotherapy limiting patients’ ability to receive potentially curative treatments such as autologous stem cell transplantation (ASCT). Epcoritamab, a subcutaneous CD3×CD20 bispecific antibody, has demonstrated antitumor activity in R/R DLBCL as a monotherapy and in combination with chemotherapy. In arm 4 of the EPCORE® NHL-2 phase IB/II trial (ClinicalTrials.gov identifier: NCT04663347), transplant-eligible patients with CD20+ R/R DLBCL received epcoritamab plus rituximab, dexamethasone, cytarabine, oxaliplatin/carboplatin (R-DHAX/C). Patients could continue epcoritamab until ASCT or progression. Twenty-nine patients received epcoritamab plus R-DHAX/C; 72% had stage IV disease; 66% had primary refractory disease. As of January 15, 2025 (median follow-up 40.4 months), the overall response rate (primary endpoint) was 79%, and complete response rate was 69%. Sixteen patients (55%) proceeded to ASCT and five remained on epcoritamab monotherapy. At 36 months, an estimated 70% of responses were ongoing, 59% of patients were progression-free, and 76% were alive. Common treatment-emergent adverse events (TEAE) were thrombocytopenia (90%), anemia (66%), and neutropenia (59%). Cytokine release syndrome occurred in 45% of patients; all were grade 1-2 and resolved after a median of 2 days. Immune effector cell-associated neurotoxicity syndrome occurred in one patient. No fatal TEAE or clinical tumor lysis syndrome were observed. Epcoritamab plus R-DHAX/C achieved deep, durable responses with manageable safety. Over half of patients proceeded to ASCT, a potentially curative treatment. These findings suggest the potential of epcoritamab combined with standard chemoimmunotherapy as an effective salvage treatment for patients with R/R DLBCL.

Ceritinib overcomes proteasome inhibitor resistance in multiple myeloma by suppressing the protein folding response

Andrej Besse — 2025-12-11

Proteasome inhibitor (PI) resistance remains a major therapeutic obstacle in the treatment of multiple myeloma (MM). MM cells demonstrate pronounced dependence on insulin and insulin-like growth factor-1 signaling via their cognate receptors, INSR and IGF-1R. In this study, we identify ceritinib, a clinically approved inhibitor of anaplastic lymphoma kinase, as a drug that can inhibit IGF-1R/INSR activity and downstream PI3K/AKT/mTORC1 signaling. Ceritinib can overcome PI-resistance in MM when used in combination with carfilzomib. This synergy was consistently observed across in vitro and in vivo models, and primary patient-derived MM cells. Mechanistically, MM cells exploit IGF-1R/INSR signaling to sustain expression of key molecular chaperones, including HSP70 and BiP, which are critical for maintaining proteostasis under conditions of high protein synthesis and turnover. Pharmacological inhibition of IGF-1R/INSR signaling by ceritinib abrogates this adaptive stress response, thereby preventing the upregulation of cytoprotective heat shock proteins upon proteasome inhibition. This disruption results in enhanced accumulation of protein aggregates, increased protein polyubiquitination, endoplasmic reticulum stress, and activation of apoptotic pathways. Collectively, our findings support the repurposing of ceritinib in combination with carfilzomib as a translationally relevant and safe strategy to circumvent PI resistance in MM, warranting further clinical investigation in the relapsed/refractory disease setting.

Oncolytic bovine herpesvirus type 1 induces immune microenvironment remodeling and enhances treatment responses in multiple myeloma

Vincenzo Raimondi — 2026-03-26

Despite therapeutic advances, multiple myeloma (MM) remains incurable due to the development of drug resistance by malignant plasma cells (PC) and a severe immunosuppressive bone marrow (BM) microenvironment. Oncolytic virotherapy offers the dual benefit of tumor cell lysis and immune activation, but the efficacy of human viruses is often hampered by pre-existing antiviral immunity. Here, we demonstrate that bovine herpesvirus type 1 (BoHV-1), a virus that is non-pathogenic to humans, efficiently infected MM cells, inducing mitochondrial apoptosis and suppressing pro-survival programs, including MYC targets, oxidative phosphorylation, and the unfolded protein response. Infected tumor cells up-regulated NK-activating ligands and down-regulated MHC class I, enhancing susceptibility to NK-mediated cytotoxicity. In patient-derived BM mononuclear cells (BMMC), BoHV-1 selectively reduced malignant PC and immunosuppressive myeloid subsets, while sparing lymphoid populations and hematopoietic progenitors. The infection promoted activation of CD8⁺ T cells, natural killer cells, and mono/macrophages, driving a shift toward a pro-inflammatory M1-like polarization. Monocyte depletion in BMMC attenuated the BoHV-1 anti-MM effect, confirming their functional contribution. This pronounced immune remodeling was accompanied by an inflammatory cytokine storm dominated by type I/II interferons and key innate immune mediators. Co-treatment of BoHV-1 with either bortezomib or lenalidomide increased anti-MM cytotoxicity. Finally, BoHV-1 up-regulated CD38 on both MM cells and immune effectors, thereby increasing sensitivity to the anti-CD38 daratumumab. These findings establish BoHV-1 as a promising immunovirotherapy agent, effective as a single agent and in combination strategies, by coupling direct oncolysis with broad immune remodeling of the BM microenvironment.

Phenotypic evolution of circulating plasma cells from early precursor stages to multiple myeloma

Martin Pietzsch — 2026-04-02

Circulating tumor plasma cells (CTPC) have emerged as valuable diagnostic and prognostic marker in multiple myeloma (MM), with their presence linked to progression from precursor stages and poorer outcomes in newly diagnosed MM (NDMM). While quantitative CTPC enumeration is increasingly validated, comprehensive phenotypic profiling across disease stages remains lacking. We applied 36-parameter spectral flow cytometry to 113 peripheral blood mononuclear cell samples of monoclonal gammopathy of undetermined significance (N=42), smouldering MM (N=22), NDMM (N=15), treated MM (N=24), and healthy controls (N=10), alongside paired bone marrow (BM) samples from six NDMM patients. CTPC were defined phenotypically as CD45-CD38highCD56+ events without assessment of clonality. Phenotypic profiling of the CD56+ CTPC-like subset across disease stages revealed alterations in canonical and lineage-atypical surface markers. Progression to NDMM was characterized by upregulation of CD38 and CD56 with concomitant loss of B- (CD19), myeloid- (CD14, CD16), and T-cell-associated (CD45RA) markers. In addition, HLA-ABC, interleukin receptor subunits (CD25, CD123), and chemokine receptors (CCR6, CCR7) were upregulated in NDMM. In treated MM, a reversed pattern was observed with lower CD25 and CD123 expression and increased levels of exhaustion markers (TIGIT, PD-1). Paired BM samples showed a different tissue-residency marker expression, characterized by higher CD69 and CCR6 and lower CD138, along with changes in cell-survival related markers, including increased CD25 and CD123. Both BCMA and CD307e were more highly expressed on BM plasma cells than CTPC. This study is among the first to provide a comprehensive phenotypic characterization of CD56+ CTPC across the MM spectrum, including checkpoint and chemokine receptors, treated disease cases, and paired BM samples for NDMM.

Therapeutic inhibition of myeloperoxidase with AZD5904 attenuates disease progression in mouse models of early stage and relapsed multiple myeloma

Connor M.D. Williams — 2026-04-02

Despite advances in therapeutic strategies for multiple myeloma (MM), long-term outcomes remain poor, largely due to inevitable relapse and acquired drug resistance. Reciprocal interactions between malignant MM plasma cells (PC) and the bone marrow microenvironment (BMME) drive disease progression, immune evasion, and therapeutic resistance, positioning the BM niche as a focus for targeted therapeutics. Myeloperoxidase (MPO) has recently emerged as a key regulator of MM progression via modification of the BMME. Here, we evaluate the efficacy of AZD5904, an orally bioavailable, irreversible MPO inhibitor, in preclinical models of MM. Initiation of MPO inhibition with AZD5904 during the early stages of MM tumor development significantly reduced tumor burden in the KaLwRij/5TGM1 and Vk*Myc murine models, however, had no effect when initiated in established disease. Furthermore, AZD5904 modulated immune responses by decreasing PD1+ T cells in vivo and restoring CD8+ T-cell cytotoxicity in vitro. While combining AZD5904 with the frontline agent bortezomib did not provide additional benefit in limiting disease progression, adjuvant AZD5904 following bortezomib treatment markedly delayed 5TGM1 tumor relapse. These findings suggest that while MPO inhibition may not enhance efficacy of bortezomib induction therapy, it holds promise as a maintenance strategy to improve long-term outcomes in MM. Collectively, our data support further investigation of AZD5904 as a novel maintenance therapy targeting the BM microenvironment, with potential to enhance and sustain the effectiveness of existing, standard of care regimens.

Thyroid hormones induce an acute platelet release mechanism via integrin αVβ3

Holly R. Foster — 2026-03-12

Understanding how mature megakaryocytes release their platelets and, crucially, what are the triggers that facilitate this process is of huge impact on human medicine. Controlling this biological process, as well as being able to utilize platelets produced in vitro will be a major therapeutic advancement. Unfortunately, the exact mechanism and mediators that drive thrombopoiesis remain elusive. Here, we seek to identify such mediators through studying the dynamics of platelet production after an acute loss of platelets. Analysis of plasma taken from 19 plateletpheresis donors at various timepoints before and after donation identified peak platelet production timepoints (4-8 hours). Analysis of these timepoints by proteomic and metabolomic techniques enabled the identification of triiodothyronine (T3), as well as its analogs, GC-1 (sobetirome), MGL-3196 (resmetirom) and KB2115 (eprotirome), as having a direct effect on in vitro platelet production in human cord blood (fold-change at 12 hours, mean ± standard deviation [SD]: T3 3 hours 100 nM, 1.26±0.24; GC-1 100 μM, 5.54±1.58; MGL-3196 300 μM, 6.92±1.38; KB2115 75 μM, 17.90±5.25) and induced pluripotent stem cell-derived megakaryocytes (foldchange, mean ± SD: viral A1ATD1 KB2115 36.1 μM, 3.36±0.38; inducible QOLG1.1H KB2115 75 μM, 1.85±0.46). Receptor-specific antagonists revealed that thyroid hormone-induced platelet production primarily signals via a non-genomic signaling pathway, integrin αVβ3 (CD51/61, vitronectin receptor), which megakaryocytes express highly. When combined with silk-based three-dimensional scaffold bioreactor technology, we observed a significant upscaling of platelets (fold-change, mean ± SD: KB2115, 2.8±0.79) that responded positively to agonist stimulation (P-selectin exposure). This shows the direct impact of thyroid hormones on platelet production through integrin αVβ3, which offers interesting therapeutic potential in the field of transfusion medicine.

Variations in mitochondrial genome as potential prognostic markers in sickle cell disease

Rudra Ray — 2026-03-19

Alterations in the mitochondrial genome integrity, including changes in mitochondrial DNA copy number (mtDNA-CN) and accumulation of mtDNA mutations, are associated with aging and diverse disorders, often linked to underlying systemic inflammation and metabolic stress. In sickle cell disease (SCD), inflammation drives the pathology, resulting in organ damage and early mortality. The prognostic role of mitochondrial genomic variation in SCD is largely unexplored. This study investigated whole blood-derived mtDNA alterations, including mtDNA-CN and mtDNA mutations, in adults with SCD, sickle trait, and healthy controls, and examined their associations with age and mortality in SCD. We also assessed mtDNA heteroplasmy distribution across tissues in a humanized mouse model of SCD. Elevated mtDNA-CN and mtDNA heteroplasmy burden were observed with increasing genotype severity across all cohorts (HbAA, HbAS < HbSB+ < HbSC < SCA [HbSS & HbSβ0]). In sickle cell anemia (SCA) patients, mtDNA mutation burden - including mtDNA heteroplasmy and mtDNA deletions increased with age, whereas mtDNA-CN level declined, indicating progressive deterioration of mtDNA integrity with age. In SCD patients, specific mtDNA variants showed strong positive correlations with mortality risk, lower mtDNA- CN correlated with higher National Institutes of Health (NIH) risk scores, and nuclear variants CYB5R3^T117S and PIEZO^1E756del influenced mtDNA mutation burden without affecting the NIH risk score. Consistent patterns of mutational load were observed across specific regions in mitochondrial genome in both humans and mice, suggesting potential mtDNA mutational hotspots. We conclude that variations in the mitochondrial genome are potential prognostic markers for SCD.

Pivekimab sunirine in blastic plasmacytoid dendritic cell neoplasm: assessing spatial response and unraveling resistance mechanisms

Margaux Poussard — 2026-02-05

Tumor flare pain reaction following bispecific T-cell engagers in multiple myeloma: a unique and underrecognized toxicity

Gaspard Jadot — 2026-03-26

Monitoring relapse in post-transplant acute myeloid leukemia requires integrated assessment, with flow cytometry showing the highest efficacy

Wei J. Wang — 2026-03-26

Outcomes of real-world complete responders after fixed duration glofitamab in relapsed/refractory large B-cell lymphoma

Evgenii Shumilov — 2026-04-02

CAR T therapy for relapsed/refractory large B-cell lymphoma in people living with HIV: efficacy, toxicity and treatment considerations

Angela Hwang — 2026-04-02

First-year results of the International Leukemia/ Lymphoma Target Board for pediatric relapsed and refractory hematological malignancies

Uri Ilan — 2026-04-02

Hypomethylating agents plus venetoclax versus intensive chemotherapy prior to transplant in high-risk acute myeloid leukemia

Guillaume Berton — 2026-04-02

Bedside treatment algorithm for safe administration of 24-hour high-dose methotrexate in adult acute lymphoblastic leukemia

Anna-Karin Hamberg — 2026-03-26

Inhibition of SUV39H1 as a potent therapeutic target in multiple myeloma

Laura Alibert — 2026-04-16

MLL-AF9 expression levels do not instruct lineage fate

Emmanouil Kyrloglou — 2026-03-26

Bipartite NUP98::RARA-E412* fusion with a cis-aligned ligand binding domain truncation mutation in atypical acute promyelocytic leukemia

Qinqin Liu — 2026-04-09

Preservation of adaptive immunity after nonmyeloablative hematopoietic cell transplantation in adults with sickle cell disease (PROTECT study)

Elisabeth Dovern — 2026-03-26

Disease course of FLT3 mutated extramedullary acute myeloid leukemia and efficacy of gilteritinib

Francesco Angotzi — 2026-04-09

Next generation sequencing panel for hereditary erythrocytosis in adults with otherwise unexplained erythrocytosis unveils additional genomic variants

Mahsa Rezasoltani — 2026-03-26

Overuse of thrombopoietin receptor agonists driven by suboptimal response is associated with myelofibrosis in pediatric immune thrombocytopenia

Jingyao Ma — 2026-05-07

Timing of microbial exposure and risk of infection-promoted acute lymphoblastic leukemia

Valeria Cazzaniga — 2026-04-16

CD20 re-emergence in a patient with diffuse large B-cell lymphoma who experienced a CD20-negative relapse after glofitamab treatment

Pranya Gaddipati — 2026-05-14

Azacitidine-induced remission enables allogeneic transplantation in TET2/BCOR-mutant relapsed extranodal natural killer/T-cell lymphoma: a case report

Carmen de Ramon Ortiz — 2026-04-02

Idiopathic multicentric Castleman - TAFRO syndrome can mimic sepsis and myeloid neoplasia

Ole Hudowenz — 2026-04-30

Erratum to: “The impact of age on survival and excess mortality after autologous hematopoietic cell transplantation in newly diagnosed multiple myeloma patients”

Shohei Mizuno — 2026-10-01

Erratum to: “Therapeutic targeting of mutant p53 in pediatric acute lymphoblastic leukemia”

Salih Demir — 2026-10-01