Haematologica

Azacitidine for MDS and CMML

2026-04-01T20:02:40+00:00

All patients with AML and FLT3-ITD should be transplanted in first remission. Also in the era of tyrosine kinase inhibitors? – the PRO

2026-04-01T20:02:37+00:00

All patients with acute myeloid leukemia and FLT3-ITD should be transplanted in first remission. Also in the era of tyrosine kinase inhibitors? – the CON

2026-04-01T20:02:39+00:00

Gatekeepers of mitochondrial metabolism: the emerging role of the SLC25 family in leukemia

2026-04-01T20:01:29+00:00

An emerging triplet option for newly diagnosed FLT3-mutated acute myeloid leukemia

2026-04-01T09:16:08+00:00

Inflammation control in the bone marrow: HES1 at the helm

2026-04-01T20:02:32+00:00

Taming neutrophil extravasation: a promising therapeutic approach to dampen inflammation?

2026-04-01T20:01:36+00:00

Old methods, lasting impact in relapsed/refractory primary mediastinal B-cell lymphoma

2026-04-01T09:16:11+00:00

From myeloma to POEMS: extending the potential of T-cell redirecting therapies

2026-04-01T20:01:28+00:00

Mapping the immune orchestra of zamtocabtagene autoleucel in primary CNS lymphoma

2026-04-01T20:02:36+00:00

JAK inhibitor selection in challenging scenarios of myelofibrosis: a review

2026-04-01T20:02:21+00:00

Myelofibrosis is a progressive myeloproliferative neoplasm characterized by dysregulated Janus kinase (JAK)/signal transducer and activator of transcription signaling. Common clinical manifestations include constitutional symptoms, splenomegaly, and anemia, which can significantly impact quality of life and survival. Although hematopoietic stem cell transplant is the only curative treatment modality in myelofibrosis, JAK inhibitors have transformed management by providing symptom relief and reducing spleen size in many patients; newer JAK inhibitors also offer anemia-related benefits. Four JAK inhibitors – ruxolitinib, fedratinib, pacritinib, and momelotinib – are now available for the treatment of myelofibrosis, each with distinct profiles and safety considerations that may inform selection. However, head-to-head trial comparisons are limited, and real-world experience with most of these JAK inhibitors is only just emerging; therefore, first-line selection and optimal sequencing in particular patients can be challenging. This review summarizes the current data surrounding available JAK inhibitors for the treatment of patients with myelofibrosis and examines how individual patients’ characteristics can help guide selection among them. To illustrate the diverse clinical factors and key considerations associated with JAK inhibitor selection in practice, we discuss these data in the context of four hypothetical cases representing possible real-world scenarios, offering treatment recommendations based on our collective expertise in the field. As the myelofibrosis therapeutic landscape continues to evolve, a thorough understanding of the strengths and limitations of each JAK inhibitor relative to a given patient’s presentation will support individualized treatment decisions for optimal long-term outcomes.

Advances in biomarkers for mantle cell lymphoma in the era of targeted therapies

2026-04-01T20:02:13+00:00

Exciting therapeutic advances are transforming the mantle cell lymphoma (MCL) treatment landscape, with an expanding array of novel agents. Growing evidence demonstrates that MCL is a biologically heterogeneous disease ineffectively managed with historical uniform standard chemoimmunotherapy approaches. Furthermore, traditional prognosticators such as the MCL-International Prognostic index (MIPI), proliferation index Ki-67, and presence of TP53 aberrations remain valuable but are insufficient to fully capture disease complexity or guide personalized therapy. Biomarker technologies are evolving rapidly. Reflecting this technological renaissance, recent studies have identified a range of novel molecular and cytogenetic alterations that carry prognostic or therapeutic relevance in the context of both chemotherapy and novel agent delivery. Advances in measurable residual disease detection using polymerase chain reaction analysis, next-generation sequencing, and circulating tumor DNA are reshaping risk stratification and offer the potential to guide therapy intensity and duration. New information is emerging regarding the critical role of the tumor microenvironment and immune dysregulation in driving treatment resistance. Additionally, the expanding utility of fluorodeoxyglucose positron emission tomography by harnessing quantitative parameters and radiomic data offers new opportunities for multimodality risk stratification. Here, we comprehensively review the literature beyond established MCL prognosticators and provide an overview of these newer prognostic and predictive biomarkers for MCL in modern treatment paradigms, and their role in informing treatment decisions and future research directions.

The evolution of the complete blood count: have we gone too far?

2026-04-01T20:02:34+00:00

The complete blood count (CBC) began its evolution at the end of the 19th century with the development of the hemacytometer to count blood cells. Soon thereafter, the hematocrit, a method to determine the packed red cell volume, was described in Sweden. Subsequently, the mean volume and hemoglobin content of red cells were added. Stains that distinguished individual leukocyte types permitted differential white cell counts: the product of the total white cell count and the fraction of each white cell type. A reliable means to count platelets rounded out the manual CBC. In 1954, Wallace Coulter introduced the Model A electronic particle counter. Modifications and advancements evolved into the Model S, a rapid, accurate, electronic method to determine the standard variables in the CBC and an array of additional measurements. Electronic particle counting has undergone numerous further developments including the application of florescence technology, such that approximately 30 variables can be measured as part of a CBC. This evolution has led to a chaotic situation; a recent study showed that the CBC ranged from 12 to over 24 variables when measured in either a community or academic hospital hematology laboratory. Out-of-range values, frequent and often trivial, have to be reconciled for patient and physician. Redundant and very low value variables have accrued in the CBC. We propose a major change in the CBC depending on the reason for its measurement. These recommendations markedly decrease the variables measured and make the results more impactful, which will enhance the physician’s focus on the use of this key laboratory test to the benefit of the patient’s care.

SLC25A1 reprograms mitochondrial and fatty acid metabolism to promote the progression of acute myeloid leukemia

2026-04-01T20:01:26+00:00

Abnormal metabolic reprogramming is a hallmark of acute myeloid leukemia (AML), contributing to leukemia initiation, progression and drug resistance. The key mitochondrial citrate transporter SLC25A1 plays an essential role in regulating cellular energy metabolism and plays an important role in the regulation of lipid metabolism. However, the role of SLC25A1 in the pathogenesis and aberrant lipid metabolism in AML remain unexplored. In this study, our analysis of public datasets and patient samples revealed that SLC25A1 expression was markedly elevated in AML and was associated with poor prognosis. Knockdown or pharmacological inhibition of SLC25A1 significantly suppressed AML cell proliferation by inducing apoptosis, without affecting cell cycle progression or differentiation. Moreover, SLC25A1 proved vital for AML tumorigenesis in vivo. Mechanistically, we demonstrated that SLC25A1 inhibition disrupted citrate homeostasis, leading to mitochondrial dysfunction and reduced fatty acid metabolism. Notably, we developed a novel SLC25A1 inhibitor, CTPI3, which effectively inhibits the progression of AML in vivo, and synergizes with venetoclax to kill AML cells by mitochondrial and fatty acid metabolism regulation. In summary, our findings highlight that SLC25A1 plays a vital role in maintaining AML cell survival and regulating its drug sensitivity. Furthermore we developed a more effective novel drug targeting SLC25A1, providing additional therapeutic options for venetoclax-resistant patients and highlighting SLC25A1 as a promising biomarker and therapeutic target for AML.

Age-specific mutation profiles and their prognostic implications in pediatric KMT2A-rearranged acute myeloid leukemia

2026-04-01T20:01:50+00:00

Driver mutations in KMT2A-rearranged (KMT2A-r) have been identified in acute myeloid leukemia (AML); however, age-related differences in their frequency and prognostic factors remain unclear. In this study, we report age-specific mutation profiles and outcomes in pediatric patients with KMT2A-r AML. In 239 cases of KMT2A-r AML, infants (<1 year, N= 59) showed a significantly higher event-free survival (EFS) and overall survival (OS) compared with children (≥1 year, N=180). Conversely, in 538 cases of non-KMT2A-r AML, infants exhibited a significantly lower EFS and OS than children. KMT2A::MLLT4 was only detected in children with KMT2A-r AML and was associated with a poor prognosis. In KMT2A-r AML, mutations in signaling pathway genes, such as KRAS, were frequently detected in infants and children. However, the frequency of non-signaling pathway mutations was significantly higher in children. Moreover, non-signaling pathway mutations had no significant effect on the prognosis in infants and children, whereas KRAS mutations were associated with poor prognosis in both groups. Multivariate analysis identified older age, a high white blood cell count, KMT2A::MLLT4, and KRAS mutations as independent adverse prognostic factors for both EFS and OS. These age-specific mutation profiles suggest distinct disease mechanisms across age groups and may help to refine risk stratification and treatment strategies for pediatric KMT2A-r AML.

Long-term outcomes in FLT3-mutated acute myeloid leukemia after frontline hypomethylating agent, venetoclax and a FLT3 inhibitor

2026-04-01T20:01:34+00:00

Triplet regimens with a hypomethylating agent, venetoclax and a FLT3 inhibitor yield high rates of response in newly diagnosed FLT3-mutated acute myeloid leukemia (AML). However, the long-term outcomes and patterns of relapse with these triplet regimens are not well-established. In this retrospective analysis, 73 patients with newly diagnosed FLT3-mutated AML received a frontline FLT3 inhibitor-containing triplet regimen. The composite complete remission and complete remission with incomplete hematologic recovery rate was 93%. According to next-generation sequencing (sensitivity: 0.005%), FLT3-ITD minimal residual disease negativity was achieved in 60% of patients after cycle 2 and 90% after cycle 4. The estimated 3-year relapse-free survival for FLT3-ITD-mutated and FLT3 TKD-mutated AML was 38% and 76%, respectively, and the 3-year overall survival (OS) was 45% and 76%, respectively. Neither age, NPM1 co-mutation, European LeukemiaNet 2022 risk category, nor allogeneic stem cell transplantation in first remission significantly impacted OS. Baseline RAS pathway mutations were associated with poor long-term survival (3-year OS 22% vs. 63% in those without a RAS pathway mutation). FLT3 wild-type relapses accounted for 65% of relapses, and new RAS pathway mutations were observed in 24% of relapses. Outcomes were poor after relapse (median OS of 6.1 months), particularly for those with persistently detectable FLT3 mutations. Triplet combinations of a hypomethylating agent, venetoclax and a FLT3 inhibitor result in durable remission and encouraging long-term OS in older adults with newly diagnosed FLT3-mutated AML. However, better strategies to prevent FLT3 wild-type relapses and to overcome RAS pathway-mediated resistance are still needed.

The comprehensive landscape of TTMV::RARA fusiondriven acute myeloid leukemia: from viral integration mechanisms to clinical outcomes

2026-04-01T09:16:34+00:00

Acute myeloid leukemia (AML) with TTMV::RARA fusion represents a novel subtype driven by torque teno mini virus (TTMV) integration into the retinoic acid receptor α (RARA) locus, while current understanding of its molecular features and clinical presentation relies predominantly on isolated case observations. Here, we characterize a large and independent cohort (N=25) through integrative analysis of clinical-omics data, uncovering unique features that distinguish it from classic acute promyelocytic leukemia (APL) and other AML subtypes. Our findings reveal that TTMV integrates exclusively within intron 2 of the RARA gene via microhomology-mediated end joining, forming functional TTMV::RARA transcripts. Clinically, patients harboring this fusion were predominantly pediatric (72%, age <18 years) and often presented with extramedullary diseases (24% with myeloid sarcoma, 16% with central nervous system infiltration). Blasts displayed APL-like morphology and immunophenotype but lacked PML::RARA, instead harboring TTMV::RARA with recurrent i(17)(q10) abnormalities (24%). Unsupervised clustering revealed it as a molecularly distinct subgroup. Transcriptomic profiling identified a Wnt-activated/extracellular matrix-dysregulated signature, driving leukemogenesis via dual mechanisms of clonal expansion and metastatic pathways. Despite achieving a 96% complete remission rate with induction therapy, long-term outcomes were significantly inferior, with 2-year event-free survival and relapse-free survival rates of 53.6% and 53.8%, respectively. Hematopoietic stem cell transplantation achieved durable remission in nine of 11 patients, particularly those with extramedullary disease or i(17)(q10) abnormalities. Conclusively, this work establishes TTMV::RARA as a novel AML subtype, highlighting the need for viral screening in APL-like cases and hematopoietic stem cell transplantation prioritization for this subset.

Human cytomegalovirus control in allogeneic stem cell transplant recipients in the letermovir era – emerging humoral and cellular players

2026-04-01T20:02:27+00:00

Allogeneic hematopoietic stem cell transplant (alloSCT) recipients frequently experience late-onset human cytomegalovirus (HCMV) reactivations following termination of letermovir prophylaxis. Letermovir prophylaxis extends the window for protective B- and T-cell reconstitution; however, our understanding of humoral responses and their contribution to HCMV immune control remains limited. Combining serological and flow cytometric analyses in 42 HCMV-seropositive alloSCT recipients, we herein provide the first comprehensive longitudinal (days 90-270 after transplant) characterization of HCMV-specific humoral responses, natural killer (NK)-cell phenotypes, and γδ T cells in the letermovir era. HCMV controllers showed predominantly HCMV-specific IgG-driven responses, higher pre-reactivation Vδ1+ γδ T-cell frequencies, and stronger expansion of “memory-like” NK cells than patients with clinically significant CMV infection. In contrast, patients with clinically significant CMV infection showed delayed HCMV-specific IgG production, IgM-skewed responses, and stronger post-reactivation expansion of memory B cells and Vδ1+ γδ T cells. Early (day 90) γδ T-cell reconstitution was associated with subsequent HCMV control. HCMV-specific IgG levels correlated only weakly with γδ T cells but showed distinct associations with “memory-like” NK-cell reconstitution in HCMV controllers, suggesting synergisms between humoral and cellular immunity. Collectively, these findings highlight a need to study anti-HCMV immune protection beyond type 1 T cells and refine risk stratification models in alloSCT patients by inclusion of novel immune markers such as γδ T-cell frequencies and phenotypes. Leveraging the extended B-cell reconstitution window created by letermovir, novel immunotherapies (e.g., therapeutic antibodies) and future vaccines might boost humoral anti-HCMV immunity and benefit from synergisms with γδ T cells and “memory-like” NK cells in improving HCMV control.

Children with chronic-phase chronic myeloid leukemia: characteristics and outcomes from the International Registry of Childhood CML

2026-04-01T20:01:45+00:00

Five hundred and thirty-five patients (median age 12.2 years; range, 8 months to 18 years; N=303 males, N=232 females) diagnosed with chronic myeloid leukemia (CML) in chronic phase were registered in the International Registry of Childhood CML (clinicaltrials gov. Identifier: NCT01281735). Clinical signs of leukostasis or bleeding were observed in 16.5% and 20% of the patients, respectively. The spleen was palpable in 76% of patients with a median of 9 cm (range, 1-32) below the costal margin. The median leukocyte count was 222x109/L (interquartile range, 95-353). First-line therapy consisted of imatinib in 482 children. Among them, 40% remained on imatinib with a median follow-up 3.8 years (95% confidence interval [CI]: 3.2- 4.3 years); 3.1% died and 3.9% progressed to advanced-phase disease. The overall survival rate at 36 months was 97.4% (95% CI: 95-99%). Progression-free survival rate at 3-years was 97.1% (95% CI: 94.9-99.2%), 91.7% (95% CI:84.5-98.3%) and 72.0% (95% CI: 59-87.9%) in the Eutos Long-Term Survival (ELTS) low-, intermediate-, and high-risk group, respectively (P log rank <0.001). Pediatric CML is characterized by bulky disease (large splenomegaly, high leukocyte counts) and the ELTS score can identify children with the poorest outcome.

Divergent processing of FVIII light chain variants: secretory potential versus proteasomal retention

2026-04-01T20:02:31+00:00

In 20-30% of severe hemophilia A (HA) patients, FVIII replacement therapy is hindered by inhibitory antibodies. Nonsense mutations in the FVIII light chain (A3-C1-C2) carry a higher risk of inhibitor formation than those in the heavy chain (A1-A2-B). The underlying molecular mechanism remains unclear. Using induced pluripotent stem (iPS) cells from HA patients, we developed two types of endothelial cell models, induced lymphatic endothelial cells (iLEC) and induced liver sinusoidal endothelial cells (iLSEC), that mimic native F8 mRNA expression and protein synthesis. Immunoassays detected FVIII protein in wild-type, intron 22 inversions (I22I), and two high inhibitor risk light chain variants (R1960X, R2228X). Co-staining with ER markers (PDI, BiP) revealed differential processing: R1960X exhibit enhanced proteasomal degradation with SEL1L, essential for MHC-I peptide loading, possibly contributing to higher immunogenicity. In contrast, R2228X showed a pattern more similar to wild-type, suggesting partial secretory potential. Although a mild co-localization with SEL1L was observed, it was not significant. Clinically, this patient did not develop inhibitors. In addition, exploratory in silico peptide binding predictions suggested that R1960X may generate a higher number of FVIII-derived epitopes presented via patient-specific HLA alleles compared to R2228X, further supporting differential immunogenicity. The I22I variant also showed detectable FVIII protein, which was deglycosylated and retained in the ER but did not co-localize with SEL1L; no inhibitor was observed in this case either. This cellular model shows reduced variability compared to primary cells, enabling patient-specific FVIII variant analyses, including intracellular processing, within the genetic background of the individual patient.

HES1 regulates bone marrow mesenchymal stromal cell function by suppressing NFATc2-mediated inflammation

2026-04-01T20:01:33+00:00

The Notch target gene, Hairy and enhancer of split-1 (HES1), encodes a basic helix-loop-helix transcriptional repressor that influences cell proliferation and differentiation in embryogenesis. Our previous studies indicate that HES1 is required for hematopoiesis under stress conditions. However, the role of HES1 in bone marrow (BM) microenvironment remains to be elucidated. By employing a BM niche specific Hes1 knockout mouse model, here we have investigated the role of HES1 in regulating mesenchymal stromal cell (MSC) homeostasis and their hematopoiesis supportive function. We found that while HES1 is not essential in MSC in supporting steady-state hematopoiesis, Hes1fl/flPrx1Cre mice are hypersensitive to lipopolysaccharide (LPS) challenge. Deletion of Hes1 in the BM reduces MSC frequency and affects MSC self-renewal and proliferation. Hes1-deficient MSC are less functional in supporting hematopoiesis both in vitro and ex vivo. Transcriptome analysis reveals that disruption of Hes1 in the BM stroma alters the expression of genes critical for cellular metabolism and inflammation. Pharmacological blockage of inflammation rescues Hes1-KO MSC phenotype and improves their hematopoiesis supportive function. Mechanistically, we show that HES1 binds to the conserved E boxes in the promoter of NFATc2, a member of the AT-rich interaction domain superfamily of DNA binding protein, to suppress NFATc2-mediated inflammation. Taken together, our study unveils a pivotal role for HES1 in maintaining BM MSC hemostasis and regulating their hematopoiesis supportive function.

Protein phosphatase 2A orchestrates hematopoietic fate determination via modulation of lactate metabolism

2026-04-01T09:16:51+00:00

Abnormal hematopoiesis is inherently linked to metabolic reprogramming. Protein phosphatase 2A (PP2A), a master regulator of hematopoietic homeostasis, has been implicated in multiple hematological disorders. However, the precise mechanisms by which PP2A coordinates metabolic networks to govern hematopoietic fate decisions remain poorly defined. Herein, we identify lactate as a critical mediator of myeloid-biased differentiation triggered by PP2A inactivation. Genetic ablation of PPP2CA, the catalytic subunit of PP2A, results in aberrant myeloid proliferation and lymphoid depletion. Transcriptomic profiling reveals that Ppp2ca deficiency alters the expression of transcriptional regulators governing hematopoietic lineage commitment and energy metabolism. Metabolomic analyses further demonstrate enhanced lactate metabolism in Ppp2ca-deficient hematopoietic progenitors. Importantly, either haploinsufficiency or pharmacological inhibition of lactate dehydrogenase A (LDHA) in vivo effectively reverses the abnormal hematopoiesis induced by Ppp2ca deficiency. Mechanistically, Ppp2ca deletion directly promotes the transcriptional initiation of glycolytic genes (e.g., Ldha) via RNA polymerase II (Pol II). This leads to heightened lactylation of histone deacetylases (HDAC) at specific residues - lysine 412 in HDAC1 and lysine 451 in HDAC2 - impairing the assembly of the HDAC1/2/SIN3A co-repressor complex on chromatin, enhancing histone acetylation, and ultimately dysregulating hematopoietic gene expression. Collectively, our work establishes the “PP2A-lactate- HDAC lactylation” axis as a pivotal regulator of hematopoiesis and identifies LDHA as a promising therapeutic target for PP2A-associated hematological disorders.

Thrombin generation to predict breakthrough bleeding in patients with acquired hemophilia A under emicizumab prophylaxis

2026-04-01T09:16:56+00:00

Acquired hemophilia A (AHA) is a serious bleeding disorder due to neutralizing autoantibodies against factor VIII (FVIII). Emicizumab mimics the activity of FVIIIa restoring thrombin generation. It was shown to protect patients with AHA from bleeding, but some patients experience clinically relevant breakthrough bleeding. Therefore, monitoring the efficacy of emicizumab might be useful, potentially through thrombin generation assay (TGA). The aims of this study were to assess (i) how TGA is related to emicizumab levels, residual FVIII activity, and antigen concentration of other coagulation factors, and (ii) whether it can predict breakthrough bleeding during emicizumab prophylaxis. We used samples from patients enrolled in the GTH-AHA-EMI study that prospectively assessed the risk of bleeding in AHA patients receiving emicizumab for 12 weeks. Calibrated automated thrombogram assay was used with minute amounts of tissue factor (TF-TGA) or factor XIa (FXIa-TGA) to initiate coagulation. We observed that FXIa-TGA peak thrombin generation increased with emicizumab levels and FVIII activity. Higher peak thrombin values were associated with lower rates of bleeding as indicated by incident rate ratios (IRR) below 1 (IRR=0.40; 95% confidence interval: 0.17-0.84; P<0.05). TF-TGA was less sensitive to emicizumab and FVIII activity and was not associated with bleeding rate. FIX, FX and FXI antigen levels were not related to bleeding. In conclusion, FXIa-TGA was related to emicizumab levels and residual FVIII activity and to rates of clinically relevant bleeding. FXIa-TGA could be a useful biomarker to indicate increased risk of bleeding in patients with AHA emicizumab prophylaxis.

The dual non-competitive CXCR1/2 inhibitor ladarixin impairs neutrophil extravasation without altering intravascular adhesion

2026-04-01T20:01:21+00:00

In many acute and chronic inflammatory disorders, recruitment of neutrophils plays a critical role in preventing disease severity and ensuring survival. On the other hand, neutrophil accumulation during inflammation can also favor disease progression in conditions such as autoimmune disorders and cancer or during ischemia-reperfusion injury. Therefore, blocking neutrophil influx has been considered an interesting therapeutic concept in diseases with overwhelming neutrophil responses. Using several in vivo and in vitro approaches we investigated the mode of action of ladarixin, a dual non-competitive inhibitor of chemokine receptors CXCR1 and CXCR2, in blocking neutrophil recruitment during inflammation. Examining neutrophil recruitment both in vivo in the mouse cremaster muscle via intravital microscopy and in vitro via flow chamber assays, we investigated the biological significance of the functional selectivity of the allosteric inhibitor, showing that ladarixin blocks neutrophil extravasation selectively at the level of vascular basement membrane penetration, a prerequisite for neutrophils to reach the inflamed tissue, without impairing rolling and adhesion to the inflamed endothelium. Mechanistically, ladarixin abolished neutrophil elastase translocation to the neutrophil surface, indispensable for neutrophil vascular basement membrane penetration and extracellular matrix degradation, in a selective and specific CXCR1/2-dependent fashion leading to reduced neutrophil elastase surface activity in mouse and primary human neutrophils. In brief, the allosteric CXCR1/2 inhibitor ladarixin effectively blocks neutrophil recruitment at the level of neutrophil extravasation without affecting firm adhesion. Clinically, this mode of action has interesting therapeutic potential to prevent neutrophil extravasation in inflammatory diseases including inflammatory bowel disease, psoriasis and other neutrophil-driven disorders.

TGFβ-activated kinase-1 knockdown in hematopoietic stem-progenitor cells causes PANoptosis and myelodysplastic syndrome-like disease in mice

2026-04-01T20:01:56+00:00

Mutant SF3B1 (SF3B1^mut) in hematopoietic stem/progenitor cells (HSPC) primarily affects erythropoiesis, resulting in myelodysplastic syndromes (MDS) with refractory macrocytic anemia and ring sideroblasts. SF3B1^mut results in aberrant splicing of a large number of transcripts in HSPC due to the alternative use of cryptic splice sites. Aberrant splicing of Tmem14c and Abcb7 has been shown to be the cause of the ring sideroblasts. However, the key mis-spliced gene(s) that drive macrocytic anemia have not been well-determined. Mis-splicing and downregulation of TAK1 pre-mRNA was detected in SF3B- 1^mut-HSPC. We found that TAK1 is required for the survival of HSPC by restricting RIPK1-dependent and -independent PANoptosis. PANoptosis was increased in bone marrow samples from SF3B1^mut-MDS patients. To study whether TAK1-downregulation is the cause of anemia in SF3B1^mut-MDS, we knocked down Tak1 (Tak1KD) in mouse HSPC. We found that mice transplanted with Tak1KD-HSPC developed anemia and that Ripk1 inhibition could restore blood cell counts in such anemic mice. Tak1KD-HSPC are highly sensitive to TAK1 inhibitor- or cIAP inhibitor-induced PANoptosis. Furthermore, RIPK1 inhibition could also correct differentiation and survival defects of SF3B1^mut human erythroblasts. TAK1 inhibitor could also preferentially eliminate SF3B1^mut HSPC from MDS patient samples. Our study suggests that SF3B1^mut MDS can be treated by either inhibition of RIPK1-PANoptotic signaling to restore blood cell counts or activation of PANoptosis to eliminate the mutant HSPC.

Loss of KDEL function from a calreticulin frameshift mutation drives expression of an immature, mutant calreticulin-dependent form of the thrombopoietin receptor MPL

2026-04-01T20:02:08+00:00

Mutant calreticulin (CALR) activates the thrombopoietin (TPO) receptor MPL, thereby inducing the development of essential thrombocythemia and primary myelofibrosis. Mutant CALR, due to a frameshift mutation, loses the endoplasmic reticulum (ER) retention signal, the KDEL sequence and is released extracellularly. To examine the significance of the loss of the KDEL sequence in mutant CALR-induced MPL activation, a series of constructs were prepared, including mutant CALR plus KDEL (mutant CALR^KDEL), mutant CALR plus the Venus tag and KDEL (mutant CALR^Venus-KDEL), and wild-type (WT) CALR minus KDEL (CALR WT^ΔKDEL). UT-7/TPO cells expressing mutant CALRKDEL exhibited autonomous cell growth in the absence of TPO, accompanied by the extracellular secretion of mutant CALRKDEL and subsequent activation of MPL. In contrast, UT-7/TPO cells expressing mutant CALRVenus-KDEL did not exhibit autonomous cell growth or MPL activation without TPO as well as the reduced extracellular secretion of mutant CALR^Venus-KDEL. These results suggest that the loss of KDEL function in mutant CALR is closely linked to MPL activation and the extracellular secretion of mutant CALR. While UT-7/TPO cells expressing CALR WT^ΔKDEL did not exhibit autonomous cell growth, they were responsive to mutant CALR proteins added exogenously, as evidenced by STAT5 activity. Furthermore, CALR WT^ΔKDEL conferred mutant CALR sensitivity to MPL by recognizing the N-glycans of MPL while maintaining it in an immature form, which may bind to mutant CALR. In conclusion, deletion of the ER retention signal KDEL from CALR is a prerequisite for the expression of the immature form of MPL, which can interact with secreted mutant CALR.

Clonal megakaryocyte dysplasia with normal blood values: a covert, thrombosis-prone, early myeloproliferative neoplasm

2026-04-01T20:02:24+00:00

To improve our knowledge on the epidemiological, clinical and pathobiological profile of clonal megakaryocyte dysplasia with normal blood values (CMD-NBV), a BCR::ABL-negative myeloproliferative neoplasms clinical variant, we here report a series of 30 consecutive subjects with CMD-NBV. Sixteen subjects were men and the median age was 48 years (interquartile range [IQR], 39-53 years). A situation-driven diagnosis (70% of cases had the diagnosis triggered by an incidental or symptomatic venous or arterial thrombosis), high incidence of thrombotic events (6.5 events x 100 subject-years), and indolent disease (the 10-year CMD-NBV-specific survival was 100%) were common. Nineteen subjects had a high body mass index at diagnosis and 14 had ≥1 Charlson co-morbidities. In 21 the driver variant was JAK2V617F with a median variant allele frequency at diagnosis of 8.9% (IQR, 5.4–18.4%). Six of 24 (25%) subjects with data on next-generation sequencing for myeloid neoplasm-related genes had ≥1 pathogenic somatic variant in ASXL1, TET2, DNMT3A or SRSF2, a frequency in the lower range of values of chronic myeloproliferative neoplasms. Twelve putative germline, non-pathogenic, missense variants in ASXL1, TET2, DNMT3A, RUNX1, CUX1, ABL1, NF1, KIT and CSF3R or 5’ UTR in NF1 and 3’ UTR in ASXL1 were detected in ten of 24 (42%) subjects. These data further support identification of CMD-NBV as a distinct entity.

Outcomes of patients with relapsed or refractory primary mediastinal B-cell lymphoma after frontline DA-EPOCH-R

2026-04-01T20:01:58+00:00

Most patients diagnosed with primary mediastinal B-cell lymphoma (PMBCL) achieve cure following standard-of-care therapy with frontline DA-EPOCH-R (dose-adjusted etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, rituximab). However, treatment strategies following relapse after DA-EPOCH-R are not well defined. We, therefore, performed a retrospective review of PMBCL patients with relapsed/refractory (R/R) disease after frontline DA-EPOCH-R to obtain better insight into outcomes with salvage therapy and autologous stem cell transplant (SCT). Our cohort consisted of 107 patients with R/R PMBCL. Ninety patients qualified for the intention-to-treat salvage therapy analysis. With a median follow up of 48.9 months in the salvage therapy analysis, the median progression-free survival was 5.4 months (95% confidence interval [95% CI]: 2.3 months-not reached) with a 5-year overall survival rate of 78% (95% CI: 69-88). Compared to relapsed patients (relapsing >6 months after frontline DA-EPOCH-R, N=23), refractory patients (relapsing <6 months after frontline DA-EPOCH-R, N=67) had an inferior overall response rate (48% vs. 83%), complete remission rate (19% vs. 44%), and 2-year progression-free survival rate (30% vs. 69%) with initial salvage therapy. Forty-eight patients (53%) underwent autologous SCT after salvage therapy with estimated 5-year progression-free and overall survival rates of 85% (95% CI: 75-96) and 88% (95% CI: 79-99), respectively. There were no relapses among 29 patients in complete remission prior to autologous SCT. In conclusion, this analysis is the largest review of R/R PMBCL to date and demonstrates unfavorable outcomes for patients with refractory disease after frontline DA-EPOCH-R chemotherapy. Patients able to undergo autologous SCT, especially those in complete remission prior to the transplant, had excellent outcomes.

Novel cryptic ADAMTS13 epitopes uncover a distinct open ADAMTS13 conformation in immune-mediated TTP

2026-04-01T09:17:25+00:00

Open ADAMTS13 conformation is gaining clinical interest as a biomarker for diagnosing immune-mediated thrombotic thrombocytopenic purpura (iTTP) and monitoring patients in remission for increased risk of relapse. Nevertheless, little is known about how open the structure of ADAMTS13 is exactly in iTTP patients. In this study, we aimed to assess the uniformity of open ADAMTS13 across iTTP patients. To do this, we identified four monoclonal antibodies that recognize epitopes that are cryptic in closed ADAMTS13 from healthy donors but accessible upon antibody-mediated ADAMTS13 opening. Distributed across the D, T7, T8 and CUB1 domains, these cryptic epitopes indicate ADAMTS13 closure through multiple interdomain contacts extending beyond the well-described S-CUB interaction. Interestingly, all acute iTTP patients consistently present one distinct open ADAMTS13 in which all novel cryptic epitopes are accessible. During remission, closed ADAMTS13 with all epitopes being cryptic is predominantly found in patients with restored activity, whereas distinct open ADAMTS13 is present in patients with subclinical disease. Furthermore, IgG from iTTP patients opened the conformation of ADAMTS13, corroborating the role of pathogenic autoantibodies in opening ADAMTS13 in iTTP. These new cryptic epitope-recognizing monoclonal antibodies hold promise to further enhance our understanding of compactly closed conformation of ADAMTS13 and may support the prediction of early relapses in the future.

Role of donor regulatory T-cell adoptive immunotherapy in B-cell immunity after hematopoietic cell transplantation

2026-04-01T20:02:06+00:00

Talquetamab, a GPRC5D×CD3 bispecific antibody, in Chinese patients with relapsed/refractory multiple myeloma: efficacy and safety from the phase 1/2 MonumenTAL-1 study

2026-04-01T20:01:37+00:00

Recovery of spermatogenesis following bone marrow transplantation

2026-04-01T20:02:10+00:00

Clinical outcomes of WHO2022 and ICC MDS entities with risk stratification by IPSS-R and IPSS-M

2026-04-01T20:01:57+00:00

Identification of a novel MYO1F::MLLT10 fusion in adult acute monocytic leukemia

2026-04-01T09:17:40+00:00

Ixazomib maintenance therapy in transplant-eligible multiple myeloma: real-world evidence from three large German centers

2026-04-01T20:01:41+00:00

TNF-α signaling drives myeloid skewing and clonal expansion of stem and progenitor cells in RUNX1-familial platelet disorder

2026-04-01T20:02:14+00:00

The impact of daratumumab-containing induction on stem cell mobilization, collection and engraftment in newly diagnosed multiple myeloma: results of the prospective DILEMMA study

2026-04-01T20:01:48+00:00

Single-cell analysis unveils distinct transcriptional alterations and cellular origins in IgD multiple myeloma

2026-04-01T20:02:00+00:00

Expanded clinical, genetic, and biological spectrum of filaminopathies with hematological involvement

2026-04-01T20:01:39+00:00

Clinical and genomic features of macrofocal multiple myeloma: a distinct profile

2026-04-01T20:01:53+00:00

Patient-centered care strategies for Jehovah’s Witnesses with acute leukemia and high-grade myeloid neoplasms

2026-04-01T20:02:03+00:00

TE-1146, a novel anti-CD38-antibody-lenalidomide conjugate, demonstrates potent ex vivo anti-myeloma activity

2026-04-01T20:02:16+00:00

Clinical and germline risk factors for multiple treatmentrelated toxicities in pediatric acute lymphoblastic leukemia

2026-04-01T20:02:04+00:00

Proteomic analysis of pericardial effusions in hematopoietic stem cell transplant recipients

2026-04-01T09:18:04+00:00

Teclistamab for heavily pretreated relapsed/refractory POEMS syndrome

2026-04-01T20:01:18+00:00

CNS infiltration by zamtocabtagene autoleucel tandem CD20/CD19 CAR T cells leading to complete remission in a patient with primary CNS lymphoma

2026-04-01T20:01:43+00:00

Combined asciminib and olverembatinib in blast-phase chronic myeloid leukemia

2026-04-01T20:02:35+00:00

HBV infection in the era of T-cell engagers in multiple myeloma: unresolved challenges and unmet needs. Comment on: “Hepatitis B virus reactivation following T-cell engager therapy in multiple myeloma despite negative hepatitis B core antibody serology: implications for screening in patients with hematological malignancies”

2026-04-01T20:01:27+00:00

Response to Comment on: “Hepatitis B virus reactivation following T-cell engager therapy in multiple myeloma despite negative hepatitis B core antibody serology: implications for screening in patients with hematological malignancies”

2026-04-01T20:01:27+00:00

Erratum to: “Impact of hematopoietic cell transplantation and quizartinib in newly diagnosed patients with acute myeloid leukemia and FMS-like tyrosine kinase 3-internal tandem duplications in the QuANTUM-First trial”

2026-04-01T20:02:40+00:00