Haematologica

The landmark contribution by Erik von Willebrand

Riitta Lassila, Erik Berntorp — Thu, 01 Jan 2026 00:00:00 +0000

One hundred years ago Professor Erik von Willebrand, working at the Deaconess Hospital in Helsinki, Finland, published his landmark paper on hereditary pseudohemophilia (the original paper, in Swedish, was entitled Hereditär pseudohemofili and was published in Finska Läkaresällskapets Handlingar). In 1924, a 5-year-old girl named Hjördis, living in Föglö in the Åland Island archipelago, was brought to Erik von Willebrand’s attention; his investigations of a large family living in the Åland Islands emerged in the 1926 publication in which a new hereditary bleeding disorder, distinct from classic hemophilia, was described. The index case was the ninth of 11 siblings of whom three had already bled to death. Hjördis herself had a history of serious bleeding, including nose bleeds, hematomas, anemia and, also, an ankle bleed. At the age of 14 years, she drastically bled to death during her fourth menstruation. Erik von Willebrand came close with his interpretation of the disorder, but it took several decades until other investigators could fully elucidate the pathophysiology underlying the bleeding diathesis which nowadays is known as von Willebrand disease. The index case had the most severe subtype 3. The structure, function and genetics of the factor named von Willebrand factor have now been revealed and the symptoms, epidemiology and treatment of the disorder thoroughly studied. The pioneering and visionary work of Erik von Willebrand, combining laboratory methods and clinical sharpness, set the stage for improving the lives of numerous people suffering from a generalized bleeding tendency or even life-threatening bleeds due to this most common hereditary bleeding disorder.

Introduction to the Review Series. A century after Erik von Willebrand

Pier Mannuccio Mannucci, Francesco Rodeghiero — Thu, 11 Dec 2025 00:00:00 +0000

Structure and multiple functions of von Willebrand factor

Sandra L. Haberichter, James S. O’Donnell — Thu, 11 Dec 2025 00:00:00 +0000

Since the first description of a patient with von Willebrand disease (VWD) back in 1926, significant advances have been made in understanding the biology of von Willebrand factor (VWF). Under normal conditions, in vivo biosynthesis of VWF is restricted to endothelial cells and megakaryocytes only. This biosynthesis involves complex post-translational modifications (including glycosylation and multimerization) which play a key role in enabling the hemostatic functions of VWF. As a result, VWF circulates in normal plasma as a series of heterogeneous multimers that can modulate tethering of platelets and primary hemostasis at sites of vascular injury. In addition, VWF also influences secondary hemostasis by serving as a chaperone molecule and protecting factor VIII from proteolysis and premature clearance. The molecular mechanisms underlying the pro-hemostatic functions of VWF have been comprehensively characterized. These insights serve to underpin the current classification of different VWD subtypes. Interestingly, accumulating evidence over the past decade has identified an array of new ligands that are able to bind to VWF. Consistent with these data, recent studies have further suggested a series of novel and non-hemostatic biological functions for VWF. These include potential roles for VWF in regulating inflammation, wound healing, angiogenesis and tumor cell metastasis. Further research in the coming years will be required to determine the clinical significance of these non-hemostatic roles of VWF. Defining the molecular mechanisms involved may offer exciting opportunities to develop novel anti-VWF targeted treatment approaches for important unmet clinical needs.

Von Willebrand disease: classification and epidemiology

Giancarlo Castaman, Augusto Bramante Federici — Thu, 11 Dec 2025 00:00:00 +0000

Von Willebrand disease (VWD) is a highly heterogeneous inherited bleeding disorder caused by reduced levels or activity of von Willebrand factor (VWF). VWD is associated with a wide spectrum of clinical and laboratory phenotypes, but diagnosis is based on three main criteria: a positive bleeding history, low levels of circulating VWF and autosomal inheritance patterns. VWD is classified into quantitative VWF deficiencies (type 1, partial and type 3, almost total) and peculiar qualitative defects (type 2 A, B, M, and N). The prevalence of VWD has been estimated by epidemiological investigations to be ~1%, but a clearcut diagnosis in clinical practice is often not possible because of several confounding factors influencing plasma VWF levels, especially in mild cases. The prevalence of clinically relevant VWD could range from 1/1,000-10,000 inhabitants based on patients referred to tertiary care centers. Recent genetic prevalence data however suggest that pathogenic VWF variants or putative disease alleles may be significantly more common than 1%.

Clinical and laboratory diagnosis of von Willebrand disease

Alberto Tosetto, Jeroen Eikenboom — Thu, 11 Dec 2025 00:00:00 +0000

von Willebrand disease (VWD) is a hereditary bleeding disorder first described by Erik von Willebrand in 1926. The disease is characterized by frequent bruising, bleeding from minor wounds, nosebleeds, heavy menstrual bleeding, bleeding after tooth extraction, gastrointestinal bleeding, and joint bleeds. The underlying cause of VWD was identified 45 years later as a deficiency of von Willebrand factor (VWF), a high-molecular-weight protein that circulates with factor VIII in plasma. The clinical diagnosis of VWD involves the presence of bleeding symptoms, detection of at least one abnormality of VWF function in laboratory tests, and demonstration of familial inheritance. VWD presents a broad spectrum of clinical and laboratory abnormalities, making the diagnostic process complex. Integrating clinical and laboratory data into the diagnostic pathway using a Bayesian approach can help build evidence for a diagnosis. Over the years, several diagnostic assays have been developed to measure the quantitative and qualitative properties of VWF. Automated laboratory assays for measuring VWF have been implemented in recent decades, and assessment tools for clinical evaluation of bleeding severity have been developed. Laboratory diagnosis involves screening and first-level diagnostic tests to measure VWF antigen, VWF-platelet binding activity, and factor VIII coagulant activity. Second-level subtyping tests are required to characterize the phenotypic defects of the type 2 variants and classify the patients. Proper diagnosis and classification of VWD are essential in order to recognize patients who may benefit from treatment, determine the optimal treatment modality, and prevent overdiagnosis.

Molecular genetic testing in von Willebrand disease: past, present, and beyond

Omid Seidizadeh, David Lillicrap — Thu, 11 Dec 2025 00:00:00 +0000

The gene for von Willebrand factor (VWF) was among the earliest genomic discoveries in the mid-1980s. It became feasible to use this new knowledge to better understand the genetic mechanisms responsible for von Willebrand disease (VWD) and to utilize the information to generate molecular genetic diagnostic testing strategies. Following initial studies demonstrating large structural variants in type 3 VWD patients, investigations focused on the genetic basis of the various type 2 forms of VWD, demonstrating that the pathogenic variants were localized to regions of the gene encoding functionally distinct domains of the VWF glycoprotein. These observations have resulted in increasing use of molecular genetic diagnosis as either the primary strategy for diagnosing type 2 forms of VWD or, more often, as confirmatory tests to substantiate the results of prior phenotypic analysis. In the meantime, genetic studies of type 3 were demonstrating that a wide range of pathogenic variants located throughout the VWF coding sequence were responsible for this severe phenotype. These studies also showed that ~15% of pathogenic variants responsible for type 3 were missense substitutions and that in ~25% of families this severe phenotype, classically thought to be recessive in nature, was transmitted as a semi-dominant trait. Finally, the most prevalent form of VWD, type 1/Low VWF, has proven to be the most challenging for routine molecular genetic testing, with VWF coding sequence variants identified in only ~65% of index cases. This review explores various aspects of molecular genetic testing for VWF, commemorating the 100th anniversary of VWD and the 40th anniversary of VWF cloning.

Historical, current and future treatments for von Willebrand disease

Caterina Casari, Frank W.G. Leebeek, Flora Peyvandi — Thu, 11 Dec 2025 00:00:00 +0000

Von Willebrand disease (VWD) is a heterogeneous group of defects characterized by a spectrum of bleeding symptoms ranging from mild to severe, which remain difficult to identify and assess quantitatively. Despite significant advances in our understanding of the pathophysiology of the disease, diagnosis and management remain challenging. This review examines the therapeutic landscape for VWD, discussing historical treatments, recent advancements and prospects. Decades of clinical evidence supporting the efficacy of replacement therapy will be critically presented, and preclinical data for emerging options will be examined. For many years, the standard of care for VWD has involved replacement therapy with blood-derived products and desmopressin. The introduction of recombinant von Willebrand factor represents a more recent development compared to other recombinant factors, and its use in certain populations of patients is still under investigation. Despite being relatively new, innovative therapeutic options are being explored and developed to address patients’ unmet needs. Some of these therapies are currently undergoing or nearing clinical evaluation, while others remain in the preclinical phase of development. After years of neglected attention, innovation in the treatment of VWD is now rapidly expanding.

Gynecologic and obstetric management of girls and women with von Willebrand disease

Rezan Abdul-Kadir, Margaret V. Ragni — Thu, 11 Dec 2025 00:00:00 +0000

Among the first patients with von Willebrand disease (VWD) described by Eric von Willebrand almost a century ago were young girls and women from a family in the Åland Islands who experienced “genital hemorrhage” so excessive that it led to exsanguination in five members.1 Only recently has attention focused on the risks and challenges that females with VWD face when experiencing heavy menstrual bleeding, conception, pregnancy, and delivery. The persistent monthly losses with heavy menstrual bleeding and increased demands during pregnancy commonly result in iron deficiency, but the lack of consensus regarding screening and treatment leads to underdiagnosis and undertreatment. While the genetics of VWD are known, female members of affected kindreds are infrequently screened and not considered at risk. Among girls and women with VWD in whom reproductive tract bleeding is the most common symptom, a diagnosis of VWD is often delayed up to a decade or more, leading to significant morbidity, fatigue, depression, iron deficiency, and poor quality of life. Furthermore, there is low certainty regarding effectiveness of current therapies and a lack of prospective trials to guide treatment. Novel therapeutics for inherited bleeding disorders are on the horizon, but women are excluded from studies and have poor access to care. While collaborative hematology-gynecology clinics have improved outcomes, females continue to be excluded from decision-making about their own care. Now, 100 years after the first cases of VWD were reported, it is timely to advocate for better care and management of females with reproductive tract bleeding to assure their future well-being.

Enhancing myeloablative fludarabine-busulfan conditioning with total marrow irradiation in high-risk myeloid disease

Fernando Molina, Alberto Mussetti, Anna Sureda — Thu, 25 Sep 2025 00:00:00 +0000

After CAR-T therapy for myeloma: challenge of persistent cytopenias and infections

Ofrat Beyar-Katz, Anat Stern — Thu, 21 Aug 2025 00:00:00 +0000

The age of fit-equity: ignoring age and fitness in treatment selection for chronic lymphocytic leukemia

Carolyn Owen — Thu, 28 Aug 2025 00:00:00 +0000

The French connection: extracranial internal carotid artery and cerebral infarction in pediatric sickle cell patients

Bart J. Biemond — Thu, 21 Aug 2025 00:00:00 +0000

Toward chemotherapy-reduced cure for TCF3::HLF B-cell acute lymphoblastic leukemia using CD19-directed immunotherapy

Aida Zeckanovic, André Baruchel, Jean-Pierre Bourquin — Thu, 21 Aug 2025 00:00:00 +0000

Metallothionein 1: the Achilles heel of Dnmt3a;Npm1-mutant acute myeloid leukemia

Bowen Yan, Olga A. Guryanova — Thu, 18 Sep 2025 00:00:00 +0000

Reporting blast percentage for response assessment in acute leukemias: recommendations from an EHA/ELN expert panel

Thu, 04 Sep 2025 00:00:00 +0000

Evaluation of bone marrow blast percentage is paramount to response criteria in acute leukemias. There is an identified need within the framework of updated laboratory practices to reduce inconsistencies in methodologies used by clinical laboratories to report blast values and clarify aspects of reporting. Representatives from international specialized working groups including the European Hematology Association (EHA) Diagnosis in Hematological Diseases Specialized Working Group and the European LeukemiaNet (ELN) produced consensus guidance for harmonized blast assessment to define response categories in patients with acute leukemia. This guidance addresses sampling best practice, key considerations for generating the most accurate blast enumeration and the limitations across the methodologies in acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML) and acute leukemia of ambiguous lineage. An integrated reporting scheme for deriving blast percentage is provided for ALL and AML. This incorporates results from appropriate measurable residual disease assays with morphological crosscheck. The practical guide and approach presented herein should facilitate uniform reporting standards both within clinical trials and in broader clinical practice.

PHF6 interacts with the LMO2 complex in T-cell acute lymphoblastic leukemia

Thu, 10 Jul 2025 00:00:00 +0000

The transcriptional mediator LIM domain only 2 (LMO2) forms a large multi-protein complex together with TAL1/LYL1, HEB/ E2A, LDB1 and GATA. This complex regulates transcription from the onset of hematopoietic development and during differentiation. Chromosomal re-arrangements involving LMO2 and TAL1 are causative for T-cell lymphoblastic leukemia (T-ALL). We have identified Plant Homeodomain (PHD)-like Finger 6 (PHF6) as a new LMO2-interacting factor. Somatic mutations in PHF6 have been found to occur in several types of leukemia. We show that PHF6 interacts with LMO2 as a part of the TAL1, GATA2, LDB1 complex in T-ALL and binds to the DNA. These findings show that PHF6 associates with the TAL1/LMO2/LDB1/ GATA2 complex and regulates genes that have a major role in blood development, such as SPI1 (PU.1).

Impact of minimal residual disease on the outcome of hematopoietic stem cell transplantation for childhood acute lymphoblastic leukemia within the FORUM trial

Thu, 07 Aug 2025 00:00:00 +0000

In the randomized cohort of the international phase-III FORUM trial, which showed the superiority of total-body irradiation (TBI) over chemotherapy-based conditioning prior to hematopoietic stem cell transplantation (HSCT) for pediatric acute lymphoblastic leukemia (ALL), type of conditioning and remission phase, but not pre-HSCT minimal residual disease (MRD), were associated with outcome. We report the impact of MRD within the extended FORUM cohort. Patients (N=1,014) aged 4-21 years old, transplanted from a matched donor who had ≥1 MRD measurement prior to and/or 100 days and/or one year after HSCT were eligible. A threshold of 0.01% defined MRD positivity versus negativity. Prior to HSCT, 21% of patients were MRDpos. Three-year event-free survival (EFS) was 0.73 and 0.59 (P<0.001), and 3-year cumulative incidence of relapse (CIR) was 0.20 and 0.33 (P<0.001) in MRDneg and MRDpos patients, respectively. The level of MRD positivity pre-HSCT (<0.1% vs. ≥0.1%) did not significantly affect outcome. Pre-HSCT MRDneg and TBI/etoposide conditioning were associated with a 2-fold lower risk of relapse, whereas MRDpos had a 2-fold higher risk of any failure and/or death. No detrimental effect of MRDpos pre-HSCT could be demonstrated in patients with T-cell ALL. MRDpos versus MRDneg patients at day 100 had an EFS of 0.47 versus 0.77 (P<0.001) and a CIR of 0.51 versus 0.17 (P<0.001), respectively, but post-HSCT MRDpos did not necessarily imply relapse. In conclusion, the MRD status pre-HSCT and at day 100 post-HSCT was a strong prognostic factor for children transplanted for ALL in the extended FORUM cohort.

The small GTPase ARF6 regulates sphingolipid homeostasis and supports proliferation in acute myeloid leukemia

Thu, 10 Jul 2025 00:00:00 +0000

Metabolic dependencies are emerging as promising therapeutic targets in cancer, including acute myeloid leukemia (AML). Several metabolic vulnerabilities have been identified in AML cells, including a requirement for balanced sphingolipid metabolism to maintain survival and proliferation. Here we describe a novel function of the RAS superfamily small GTPase ARF6 in maintaining sphingolipid homeostasis in AML. Genetic depletion of ARF6 inhibited the proliferation of AML cell lines and reduced colony formation of primary AML CD34+ cells. Mechanistically, ARF6 promotes conversion of ceramide to sphingomyelin by enhancing sphingomyelin synthase (SGMS1/2) expression, thereby preventing accumulation of cytotoxic ceramide levels. Accordingly, higher expression of ARF6 and its effectors SGMS1/2 in AML patients’ cells correlated with shorter survival in two independent AML cohorts, with ARF6 exhibiting an adverse prognostic effect independent of European LeukemiaNet genetic risk. Small molecule inhibitors of ARF6 suppressed colony formation by primary AML CD34+ cells, but not cord blood CD34+ cells and showed activity in xenograft models. The dependency of AML cells on ARF6 to regulate sphingolipid homeostasis may present a therapeutic opportunity.

Guadecitabine improved relapse-free survival in high-risk acute myeloid leukemia and myelodysplastic syndrome patients after transplant: phase II results from a single center

Thu, 24 Jul 2025 00:00:00 +0000

This phase II, single-center clinical trial evaluated the efficacy and safety of guadecitabine, with or without donor lymphocyte infusion, following allogeneic stem cell transplantation in adult patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). The study had three treatment cohorts based on post-transplant disease status. Cohort 1 included patients with hematologic relapse after transplant (N=13). Cohort 2 consisted of patients with minimal residual disease (MRD) detected after transplant (N=18). Cohort 3 compromised patients in remission without MRD within 100 days after transplant (N=24). The primary objectives were achievement of morphological complete remission in cohort 1 and MRD eradication in cohort 2 within six cycles of guadecitabine. Cohort 3 patients received 12 cycles to improve relapse-free survival (RFS). In cohort 1, 21.4% of patients achieved morphological complete remission. In cohort 2, 47.1% achieved MRD eradication. Those who cleared MRD had a 2-year RFS of 62.5%. Cohort 3 patients had a 2-year RFS rate of 62.5% with a median follow-up of 48 months. No unexpected adverse events occurred and no graft failures were observed. Guadecitabine demonstrated efficacy and a favorable safety profile across all cohorts, supporting the investigations of hypomethylating agents.

Longer time from diagnosis to initiation of hypomethylating agents plus venetoclax for acute myeloid leukemia does not worsen survival: results from the Consortium on Myeloid Malignancies and Neoplastic Diseases (COMMAND)

Thu, 24 Jul 2025 00:00:00 +0000

A diagnosis of acute myeloid leukemia (AML) has been considered an oncologic emergency. However, the prevailing wisdom to quickly administer AML-directed therapy is often in conflict with the time needed to complete the evaluation of actionable AML disease biology. Previous studies in intensively treated patients reported that time from date of diagnosis to treatment start date (TDT) did not impact survival outcomes. We conducted a US-based, multi-center, retrospective cohort study assessing the impact of TDT on overall survival (OS) in patients with newly diagnosed AML treated with hypomethylating agents (HMA) + venetoclax at eight participating academic centers. Four hundred and eighty-eight patients were included with a median age of 76 years. Patients had favorable (47.6%), intermediate (22.8%), and adverse (29.6%) risk disease by the 2024 European LeukemiaNet (ELN) 2024 less-intensive risk classification. Median TDT for the cohort was 9 days (interquartile range [IQR], 5-17). Those with TDT <14 days (median OS, 8.2 months; 95% confidence interval [CI]: 6.8-9.9) versus ≥14 days (median OS, 11.3 months; 95% CI: 9.5-15.4) had worse OS (P=0.007). TDT ≥14 days was associated with improved OS in multivariable analysis (hazard ratio =0.73, 95% CI: 0.54-0.97; P=0.033) adjusting for age, performance status, use of cytoreductive therapy, white blood cell count at presentation, ELN 2024 less-intensive risk classification, and presence of FLT3-ITD, TP53, and IDH1/2 mutations. These results suggest that stable patients with newly diagnosed AML eventually treated with HMA + venetoclax may await appraisal of disease biology and medical optimization before initiating induction therapy.

Hematopoietic stem cell transplantation is effective in achieving long-term survival for post-aplastic anemia myeloid neoplasms: the EBMT Severe Aplastic Anemia Report

Thu, 03 Jul 2025 00:00:00 +0000

Aplastic anemia (AA) transformation into myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) is associated with a dismal prognosis. Hematopoietic stem cell transplant offers the sole possibility of cure, but data on long-term survival are scarce. We retrospectively analyzed 270 patients transplanted for MDS, AML, or an isolated cytogenetic abnormality after a diagnosis of AA or paroxysmal nocturnal hemoglobinuria reported to the European Society for Blood and Marrow Transplantation (EBMT). The median age at transplantation was 39 years. The 5-year overall survival rate was 64%, and was unaffected by chromosome 7 abnormalities, age at transplant, sex, interval from clonal evolution to transplant, and intensity of conditioning regimen. The 5-year non-relapse mortality rates were 34% (95% Confidence Interval [CI]: 25-42%) for MDS patients and 19% (95% CI: 7-31%) for AML patients, and were higher following a myeloablative conditioning regimen. The 5-year relapse rate was 12% (95% CI: 6-19%) for MDS and 22% (95% CI: 9-35%) for AML. Our study’s survival estimates reflect a younger cohort of patients, considering the bimodal distribution of AA. Conditioning regimen intensity did not affect relapse. For MDS patients, pretreating before transplant did not improve survival nor reduce relapse. Transplantation is feasible and effective in achieving long-term survival for transplant-eligible post-AA myeloid neoplasm patients. MDS patients may benefit from upfront reduced intensity conditioning transplant, limiting toxicity without higher rates of relapse. Post-transplant maintenance therapies to reduce the relapse incidence among AML patients might be warranted.

Intensified conditioning with high-dose total marrow irradiation and myeloablative chemotherapy reduces risk of relapse without increasing toxicity in allogeneic hematopoietic stem cell transplant for high-risk myeloid malignancies: a phase II study

Thu, 19 Jun 2025 00:00:00 +0000

The intensity of the conditioning regimen in hematopoietic stem cell transplantation (HSCT) correlates with the risk of relapse, however its potential benefit may be outweighed by the associated risk of toxicity. The addition of total marrow irradiation (TMI) to myeloablative conditioning provides an opportunity to increase intensity with minimal additional toxicity. In this phase II clinical trial, 30 patients with high-risk myeloid malignancies underwent allogeneic HSCT using myeloablative TMI at 9 Gy in combination with standard myeloablative fludarabine/intravenous busulfan (FluBu4) chemotherapy. The study included patients with matched related donors (N=10) receiving TMI/FluBu4 and patients with matched unrelated (N=14) or one-antigen mismatched unrelated (N=6) donors receiving TMI/FluBu4 and rabbit anti-thymocyte globulin. All patients achieved sustained engraftment. Grade 3-4 extramedullary toxicities were mucositis in 59% (N=17), nausea/vomiting in 10% (N=3) and diarrhea in 7% (N=2) of the patients. Acute graft-versus-host disease (GvHD) grade 3 or 4 was seen in four patients (13.3%). Moderate/severe chronic GvHD was observed in 11 patients (36.7%). With a median follow-up of 1,483 days (range, 63-2,260 days) for patients alive, the overall survival and disease-free survival at 1 year were 72.4% and 65.5%, respectively. GvHD-free relapse-free survival at 1 year was 41.4%. Of 30 patients in the study, six relapsed/progressed (20%) and five of them died of the disease (16.7%), whereas six patients (20%) died of transplant-related causes. We conclude that a myeloablative regimen with TMI at 9 Gy and FluBu4 was well tolerated and achieved encouraging results in patients with myeloid malignancies at high risk of relapse (clinicaltrials.gov identifier: NCT03121014).

Cytopenias and infections following ciltacabtagene autoleucel in heavily pretreated relapsed or refractory multiple myeloma

Thu, 10 Jul 2025 00:00:00 +0000

Ciltacabtagene autoleucel (cilta-cel) was approved by the Food and Drug Administration in February 2022 for the treatment of relapsed/refractory multiple myeloma after four lines of therapy. On the CARTITUDE-1 trial, grade ≥3 cytopenias and infections were common. Herein, we sought to characterize cytopenias and infections after cilta-cel infusion in the standardof- care setting. This multicenter, retrospective study included 105 patients who received cilta-cel; 91 reached day 90 and 49 reached day 180 of follow-up. Grade ≥3 cytopenia was present among 52% of patients on day 30, and 24% of patients on day 90. Based on the newer immune effector cell-associated hematotoxicity (ICAHT) grading for neutropenia severity, 11 patients (10%) experienced grade ≥3 early ICAHT in the first 30 days, while only three (3.3%) experienced grade ≥3 late ICAHT after day 30. On univariate analysis, any grade thrombocytopenia at apheresis was associated with grade ≥3 cytopenia at both days 30 and 90. Granulocyte colony-stimulating factor was administered to 65%, transfusion support to 38%, thrombopoietin agonists to 10%, intravenous immunoglobulins to 52%, and CD34+ stem cell boosts to 9.5% of patients. Infections occurred in 49% of patients and were severe in 32%. Earlier infections in the first 30 days were equally bacterial (42%) and viral (42%). Later infections between days 31-100 and after day 100 were mostly viral (59% and 60%, respectively), with only 32% and 12% being grade ≥3 in each time period. On univariate analysis, worse Eastern Cooperative Oncology Group performance status at lymphodepletion, higher maximum grade of cytokine-release syndrome, delayed neurotoxicity, steroid and anakinra use, and lower IgA levels at day 90 were associated with severe infections.

CD6 expression is an independent predictor of time to first treatment in chronic lymphocytic leukemia

Thu, 03 Jul 2025 00:00:00 +0000

CD6 is a lymphocytic receptor expressed by all T cells and a subset of B and natural killer (NK) cells. It physically associates with the antigen-specific clonotypic receptor of T (TCR) cells, where it modulates the activation and differentiation signals delivered along lymphocyte development and upon peripheral antigen recognition. CD6 is also expressed in some B-cell malignancies (e.g., chronic lymphocytic leukemia [CLL]), though its biological role and clinical performance is largely unknown. To this end, we have evaluated the potential impact of CD6 differential expression in a CLL patient cohort. 270 CLL patient case histories from the CLL-ES project with available RNA-Seq data have been analyzed. High CD6 expression was found to be associated with mutated IGHV status and predictive of longer time to first treatment in a uni- and multi-variable model. Ten-year probability of receiving treatment was 33% vs. 55% in the CD6hi and CD6lo groups, respectively (P=0.0003), along with the lymphocyte count and the CLL International Prognostic Index. Further Gene Set Enrichment Analyses showed association of high CD6 expression with downregulation of MYC-regulated, mitotic spindle-related, and RNA splicing-associated genes, all positively related to cancer progression. Interestingly, CD38, a widely studied adverse prognostic marker in CLL, was significantly down-regulated in the CD6hi group, in agreement with flow cytometry data. These results reinforce the notion that CD6 may play a pivotal role in neoplastic B-cell biology and lay the ground to further explore CD6 expression in the context of CLL prognoses.

Rethinking the feasibility and safety of venetoclaxobinutuzumab in chronic lymphocytic leukemia: nontraditional factors may play a role in clinical practice

Thu, 26 Jun 2025 00:00:00 +0000

The concept of fitness to receive treatment with novel agents in chronic lymphocytic leukemia (CLL) remains debated. Comorbidities and treatment-related logistics are increasingly recognized as key factors in treatment feasibility. Venetoclax- obinutuzumab (VO) has demonstrated efficacy in both fit and unfit patients in clinical trials, yet real-world data remain limited. This retrospective, multicenter study analyzed disease- and patient-related factors affecting VO management and outcomes in 271 patients. Fitness was assessed using comorbidity indices (CLL-CI, CIRS, CCI), Eastern Cooperative Oncology Group performance status, and caregiver need. Adverse events (AE) and treatment modifications were evaluated across four treatment phases. The median age of the patients was 66 years (19% ≥75 years old); 83% had comorbidities, 34% required polypharmacy, and 10% needed caregiver support. Overall, 96% completed debulking, 89% the full regimen, while 11% discontinued due to toxicity (Tox-DTD). Grade ≥3 AE occurred in 55%, tumor lysis syndrome in 6%, severe infusion-related reactions in 5%. Overall, 3.3% of the patients died during treatment. Unfit patients did not show a significantly higher risk of treatment modifications due to AE. Dose adjustments were more frequent during debulking. None of the validated fitness scores predicted treatment feasibility or Tox-DTD. Global feasibility was impacted by age (P=0.002), prior malignancies (P=0.003), prolonged steroid pre-treatment (P<0.001), and baseline thrombocytopenia (P=0.013). Tox-DTD correlated with caregiver need (P=0.029), endocrine comorbidities (P=0.025), prior malignancies (P=0.002), hypogammaglobulinemia (P=0.003), high lymphocyte count (P=0.034), and prolonged steroid pre-treatment (P=0.006). In conclusion, this study confirms the feasibility of VO treatment in CLL clinical practice, highlighting the role of traditionally overlooked factors that ultimately do have an impact.

Mechanisms sensitive to different drugs mediate a proadhesive and pro-thrombotic platelet phenotype in antiphospholipid syndrome

Thu, 03 Jul 2025 00:00:00 +0000

Anti-phospholipid antibodies (aPL) mediate platelet- and leukocyte-interaction with damaged endothelium, contributing to anti-phospholipid syndrome (APS) vasculopathy. This study aimed to understand the mechanisms sustaining the pro-adhesive/- thrombotic platelet phenotype and the in vitro effects of different drugs. We included 34 primary APS (PAPS) patients and 12 healthy subjects (HS). All patients had medium/high aPL levels with vascular/obstetric symptoms according to the 2023 ACR/EULAR classification. In vivo, we evaluated by flowcytometry platelet activation markers (P-selectin, activated GPIIbIIIa [aGPIIbIII], tissue factor [TF], ApoER2 and β2GPI expression and platelet-monocyte and -granulocyte aggregates [PMA and PGA]). In vitro, the impact of antiplatelet and anti-inflammatory drugs on platelet activation induced by different aPL subpopulations was investigated. PAPS patients exhibited greater percentages of circulating ApoER2pos-, P-selectinpos-, aGPIIbIIIapos-, TFpos-platelets, and TFpos-platelet-leukocyte aggregates. In vitro, HS blood incubation with PAPS plasma fully reproduced the activation found in vivo. While anti-β2GPI-Domain(D)1, but not anti-D4,5, immunoglobulin (Ig)G upregulated platelet TF expression only, the addition of interleukin (IL)-6 also induced P-selectin and aGPIIbIIIa upregulation. An IL-6 receptor-blocking monoclonal antibody prevented the pro-adhesive/-coagulant platelet phenotype and the formation of platelet-leukocyte aggregates mediated by PAPS plasma or by total IgG plus exogenous IL-6. While aspirin and P2Y12 inhibitor fully inhibited platelet activation, hydroxychloroquine (HCQ) did not blunt TF expression. PAPS patients exhibit circulating pro-adhesive/-coagulant (TF-positive) platelets and platelet-leukocyte aggregates mediated by β2GPI-D1-dependent IgG and an inflammatory trigger. While aspirin and P2Y12 inhibitor significantly inhibited the aPL-mediated P-Selectin and TF upregulation, HCQ affected the adhesion phenotype only, and might not be adequate to prevent platelet-mediated thrombosis.

Single-cell RNA sequencing reveals heterogeneity of mucosaassociated invariant T cells in donor grafts and its diagnostic relevance in gastrointestinal graft-versus-host disease

Thu, 31 Jul 2025 00:00:00 +0000

Granulocyte colony-stimulating factor (G-CSF) enhances acute graft-versus-host disease (aGVHD) prophylaxis in allogeneic hematopoietic stem cell transplantation (allo-HSCT) by inducing T-cell tolerance and altering graft cell composition. Previous studies have shown that the number of mucosa-associated invariant T (MAIT) cells in G-CSF-induced graft was associated with a low incidence of gut aGVHD. However, the effect of G-CSF mobilization on MAIT cell and its role in MAIT-mediated protection against gut GVHD remain unclear. Here, using single-cell RNA sequencing, we found that the interaction of G-CSF with its receptor CSF3R enhances immunosuppression and tissue repair functions of MAIT cells, contributing to the anti-gut aGVHD effect. The chemokine receptor CXCR6 was identified as potentially crucial for recruiting these functional MAIT cells to gut tissues. Furthermore, we simulated the dynamic distribution of MAIT cells from donor G-CSF-mobilized peripheral blood stem cells (G-PBSC) grafts in recipient mouse, and further confirmed that the circulating MAIT cells migrated into gut tissue in a CXCR6-CXCL16-dependent manner. To further validate these findings, we developed a flow cytometry panel that effectively predicts the gut aGVHD occurrence following allo-HSCT by analyzing the frequency and functional markers of MAIT cells in G-PBSC. The predictive model shifts aGVHD prediction and intervention to the pre-transplant stage and offers a new strategy for the prevention and management of gut aGVHD in clinical practice.

Aging-declined RNA exportation impairs hematopoietic stem cells by inducing R-loop

Thu, 03 Jul 2025 00:00:00 +0000

Aging-related accumulation of DNA damage adversely affects hematopoietic stem cell (HSC). However, the mechanisms underlying this accumulation and strategies for its elimination to rejuvenate aged HSC remain largely obscure. This study uncovers a notable surge in R-Loop presence within aged HSC, notably co-localized with γH2AX and replication protein A (RPA), and correlated with RNA residency in the nucleus. Targeted induction of R-Loop impairs the function of HSC. Mechanistically, RNA exportation is compromised in aged HSC due to a decline in Alyref, the primary constituent of the transcription- export complex (TREX). Specifically, Alyref dysfunction results in RNA retention within the nucleus, mimicking the functional characteristics of aged HSC. The nuclear accumulation of RNA leads to the formation of RNA:DNA hybrids, known as R-Loop structures, consequently inducing replication stress and DNA damage. Introducing a quantitative boost of Alyref in aged HSC notably reinstates RNA transportation, diminishes R-Loop formation and replication stress, and ultimately enhances the performance of aged HSC. Taken together, our research demonstrates the initial revelation that aging-triggered replication stress stems from abnormal RNA transportation-propelled R-Loop configurations, hinting at the potential of quantitatively modulating RNA transportation to mitigate the physiological drawbacks of aging on HSC.

Safety and efficacy of the combination of copanlisib and nivolumab in patients with Richter’s transformation or transformed non-Hodgkin lymphoma: results from a phase I trial

Thu, 03 Jul 2025 00:00:00 +0000

Despite advances in targeted and cellular therapies, outcomes for patients with Richter’s transformation (RT) and transformed non-Hodgkin lymphoma (tNHL) remain dismal. In this report of a phase I multicenter investigator-sponsored study we describe the safety and efficacy of the combination of copanlisib, a selective, small molecule inhibitor of phosphoinositide- 3-kinase, and nivolumab, an antibody against programmed cell death protein 1. Twenty-seven adult patients with relapsed and/or refractory RT or tNHL were treated with escalating doses of copanlisib IV on days 1, 8, and 15 (dose level [DL] 1 - 45 mg, DL2 - 60 mg) combined with nivolumab 240 mg IV on days 1 and 15 of a 28-day cycle. Three dose-limiting toxicities occurred in two patients treated at DL2, hence 45 mg was determined to be the maximum tolerated dose and utilized in the expansion cohort. The most common treatment-related adverse events were diarrhea and anemia. All patients went off protocol, predominantly because of progressive disease and adverse events (67% and 26% of patients, respectively). The overall response rate (ORR) was 46%. Patients with transformed follicular lymphoma had an ORR of 67% (2 complete responses), with median progression-free survival of 4.4 months (95% confidence interval: 1.4-12.2). Patients with RT had an ORR of 31% (2 complete responses) with a median progression-free survival of 2.0 months (95% confidence interval: 0.7- 4.9). Treatment resulted in downregulation of MYC and NFκB pathways in malignant B cells. Responding RT patients exhibited sustained activation of interferon-α and interferon-γ signaling pathways in CD4⁺ and CD8⁺ T cells. Overall, treatment with copanlisib and nivolumab demonstrated manageable toxicity and promising clinical efficacy in tNHL patients.

Macrophages promote aberrant DNA repair in multiple myeloma via the CXCL5/8-CXCR2 axis

Thu, 26 Jun 2025 00:00:00 +0000

Multiple myeloma (MM) is closely associated with abnormal DNA repair and genome instability. The bone marrow microenvironment, particularly myeloma-associated macrophages (MΦ), is critical to the progression of MM. However, there is limited understanding on the role of MΦ in DNA repair in MM. Here, we found that MΦ regulated DNA repair in MM cells by the CXCL5/8-CXCR2 axis. By promoting non-homologous end joining rather than homology-directed repair, MΦ increased the probability of chromosomal translocations in MM cells. Furthermore, clinical data confirmed that MΦ are closely associated to the increased genetic variations of MM patients’ primary cells. The study elucidates a mechanism by which MΦ regulate DNA repair in MM in the microenvironment and provides a potentially new target to counter MM progression.

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

Thu, 31 Jul 2025 00:00:00 +0000

Despite the availability of novel agents, autologous hematopoietic cell transplantation (auto-HCT) remains the standard of care in newly diagnosed multiple myeloma (MM) patients. The impact of age on overall survival (OS), progression-free survival (PFS), relapse incidence, non-relapse mortality (NRM), and excess mortality (taking account of general population mortality) was investigated using information on 61,797 MM patients transplanted between 2013 and 2017. The median age at auto-HCT was 60.8 (range, 18.1-83.2) years of whom 2.0% were 18-39 years, 68.9% 40-64 years, 21.8% 65-69 years, 6.5% 70-74 years, and 0.8% ≥75 years of age, respectively. The corresponding OS probabilities at 3 years were 85.9%, 82.8%, 81.1%, 78.4%, and 74.8%, respectively (P<0.001). Excess mortality cumulative incidences were 13.1%, 15.0%, 14.6%, 15.0%, and 14.1% at 3 years, respectively (P=0.67). In multivariable analyses, older age was a significant risk factor for OS, PFS, and NRM but not for excess mortality or relapse risk. Our results indicate that advanced age alone should not preclude the use of auto- HCT in patients with MM.

Altered platelet lipidome in bleeding patients with unexplained platelet function defects

Thu, 24 Jul 2025 00:00:00 +0000

In patients with a mild to moderate bleeding disorder (MBD) and abnormal light transmission aggregometry (LTA), a platelet function defect (PFD) is suspected. However, in many patients with PFD, the underlying mechanism remains elusive. Given the essential role of lipids in platelet signaling, platelet lipid profiles in MBD patients with unexplained PFD may provide valuable diagnostic and mechanistic insights. This prospective cohort study investigated platelet lipidomes in patients with PFD of unknown cause from the Vienna Bleeding Biobank (VIBB). Using a standardized lipidomics workflow, we analyzed platelets from 27 patients and 19 age- and sex-matched controls and found that sex-specific lipid shifts emerged exclusively within the patient cohort, with greater deviations in females. Furthermore, lipid alterations correlated with impaired platelet aggregation and were predictive of responses to ADP and TRAP-6 stimuli in LTA experiments. Baseline and stimulated platelet analyses in a female subgroup showed intrinsic lipidomic changes, including upregulated polyunsaturated triacylglycerols (PUFA-TG), acylcarnitines (CAR), and reduced lysophosphatidylethanolamines (LPE). This study emphasizes lipidomic profiling as a promising diagnostic tool for unexplained platelet dysfunction and highlights TG, CAR, and LPE as potential therapeutic targets. Further research into lipid-driven platelet regulation may advance personalized treatments and improve clinical outcomes for patients with MBD.

Early detection and management of extracranial arteriopathy reduces the incidence of silent cerebral infarcts in sickle cell anemia: a long-term prospective cohort study

Thu, 26 Jun 2025 00:00:00 +0000

Previous reports about the Creteil newborn cohort (1988/April 2007) showed that the risk of silent cerebral infarcts (SCI) remained high (37.1%) at the age of 14 years in children with sickle cell anemia (SCA) and intracranial time-averaged mean maximum velocity (TAMMV) ≥200 cm/second (s), despite chronic transfusion. Systematic assessment of extracranial internal carotid artery (eICA) since June 2011 revealed that SCI risk is associated with chronic or acute anemia and eICA stenosis. Based on these results, SCA children with eICA TAMMV ≥200 cm/s or eICA stenosis were placed on chronic transfusion and considered for allogeneic stem cell transplantation (alloSCT). SCA children with 160-199 cm/s eICA TAMMV were maintained on hydroxyurea (HU). We hypothesized that detection/management of eICA arteriopathy and wider use of HU could reduce SCI incidence. Comparison between the new cohort (May 2007/December 2014; eICA-assessed before 4 years of age) with wider but not systematic use of HU and the earlier cohort (1988/April 2007; never eICA-assessed until the 2008 update) revealed a significant reduction in SCI risk (Log Rank: P=0.009) associated with eICA assessment but not with wider use of HU. eICA TAMMV ≥160 cm/s, even with no eICA stenosis, was a risk factor for SCI, suggesting that all SCA children with eICA TAMMV ≥160 cm/s should be placed on chronic transfusion. HU initiation at an early age was associated with lower intracranial arteriopathy incidence, but not with lower eICA arteriopathy or SCI incidence. In the overall cohort (1988-2014), including 332 SCA children, all assessed/managed for eICA arteriopathy after 2011, the cumulative SCI incidence by the age of 14 years was 25.0% (95%CI: 19.0-31.0%). SCI risk was associated with being older at first neck magnetic resonance angiography and having high mean corpuscular volume on HU. While the impact of HU on SCI incidence remains unclear, making controlled trials necessary, eICA arteriopathy management by intensive therapy is effective at improving SCI prevention.

Post-transplant maintenance with blinatumomab for children, adolescents, and young adults with relapsed and refractory B-cell acute lymphoblastic leukemia: results of phase I in SCT-ALL-BLIN21

Thu, 10 Jul 2025 00:00:00 +0000

Asparaginase-associated pancreatitis during therapy for pediatric acute lymphoblastic leukemia

Thu, 07 Aug 2025 00:00:00 +0000

Durable remission achieved in pediatric patients with TCF3-HLF-positive relapsed/refractory B-cell acute lymphoblastic leukemia by dual CD19- and CD22-targeted chimeric antigen receptor T-cell therapy

Thu, 22 May 2025 00:00:00 +0000

Two decades of single-institution data reveal rare longterm survivors of relapsed/refractory Burkitt lymphoma

Thu, 07 Aug 2025 00:00:00 +0000

Metronomic low-dose regimen of decitabine and venetoclax is safe and reduces monocyte burden in chronic myelomonocytic leukemia

Thu, 17 Jul 2025 00:00:00 +0000

Flow cytometric analysis of cerebrospinal fluid identifies patients with occult central nervous system involvement in relapsed pediatric acute lymphoblastic leukemia

Thu, 10 Jul 2025 00:00:00 +0000

Bortezomib-melphalan-prednisone versus lenalidomide-dexamethasone in elderly patients with multiple myeloma: the Real MM phase IV trial

Thu, 31 Jul 2025 00:00:00 +0000

Long non-coding RNA LINC00926 is a biomarker for naïve B-cells with prognostic value in advanced stage classic Hodgkin lymphoma

Thu, 17 Jul 2025 00:00:00 +0000

Metallothionein 1 mediates growth and survival of Dnmt3a;Npm1-mutant acute myeloid leukemia

Thu, 14 Aug 2025 00:00:00 +0000

Efficacy, safety, and health-related quality of life in transplant-ineligible newly diagnosed multiple myeloma patients receiving bortezomib maintenance therapy: a study of the Korean Multiple Myeloma Working Party KMMWP-174 study

Thu, 07 Aug 2025 00:00:00 +0000

FOXM1 down-regulation is a trigger of isatuximab-induced direct cell death in multiple myeloma cells with 1q+

Thu, 31 Jul 2025 00:00:00 +0000

Pregnancy and childbirth in women with thalassemia: past and present

Thu, 31 Jul 2025 00:00:00 +0000

Perioperative management of total hip arthroplasty in hemophilia A following gene therapy

Thu, 10 Jul 2025 00:00:00 +0000

Characteristics of patients with newly diagnosed acute myeloid leukemia not receiving treatment

Thu, 17 Jul 2025 00:00:00 +0000

Proteomic shifts post-plasma cell therapy in AL amyloid plaques and potential implications for light chaindirected anti-fibril monoclonal antibodies

Thu, 24 Jul 2025 00:00:00 +0000

Ibrutinib versus acalabrutinib in fixed-duration chronic lymphocytic leukemia therapy: a comparative analysis of efficacy

Stefano Molica, Tait D. Shanafelt, Diana Giannarelli, David Allsup — Thu, 03 Jul 2025 00:00:00 +0000

“Bridegroom of blood” - a biblical reference to hemophilia?

Joshua M. Kosowsky — Thu, 31 Jul 2025 00:00:00 +0000

Extensive non-clonal CAR T-cell expansion causing fatal hyperinflammatory syndrome with immune effector cell-associated hemophagocytic lymphohistiocytosis, cytokine release syndrome, and neurotoxicity syndrome

Thu, 28 Aug 2025 00:00:00 +0000

ALK-positive histiocytosis and a clonally related chronic myelomonocytic leukemia

Thu, 11 Sep 2025 00:00:00 +0000

Peripheral monoclonal plasmacytosis in infective endocarditis: a tangled web

Thu, 04 Sep 2025 00:00:00 +0000

Progressive multifocal leukoencephalopathy and BK virus-nephropathy with bispecific antibody therapy in multiple myeloma

Thu, 09 Oct 2025 00:00:00 +0000

Erratum to: “Optimizing CRISPR methodology for precise gene editing in the erythroid cell line BEL-A with high efficiency generation of a sickle cell anemia model”

Thu, 01 Jan 2026 00:00:00 +0000