Haematologica

Hematopoietic cell transplants for acute leukemias

Robert Peter Gale — 2025-04-01

Putting the brakes on cyclin C: a promising strategy to cure B-cell acute lymphoblastic leukemia?

Siva Sai Naga Anurag Muddineni — 2025-01-02

Primary myelofibrosis progression: a game of cellular telephone

Lucas Wadley — 2025-01-02

Prevention, diagnosis and management of myeloproliferative neoplasms: an introduction to a review series

Yin Yuan — 2025-03-19

Prevention and treatment of transformation of myeloproliferative neoplasms to acute myeloid leukemia

Anand A. Patel — 2024-10-24

Philadelphia-chromosome negative myeloproliferative neoplasms (MPN) are hematopoietic stem disorders with a risk of progression to an accelerated phase (AP) or blast phase (BP) that is influenced by clinical, pathological, cytogenetic, and molecular variables. Overall survival of patients with MPN-AP/BP is limited with current treatment approaches, particularly in those patients who cannot receive an allogeneic hematopoietic stem cell transplant (allo-HCT). In addition, long-term survival with allo-HCT is predominantly seen in chronic-phase MPN, which suggests that the ideal time for intervention may be before the MPN evolves to AP/BP. In this review we focus on the risk factors for progression to MPN-AP/BP, identification of high-risk chronic-phase MPN, potential early-intervention strategies, and considerations around the timing of allo-HCT. We also summarize current survival outcomes of patients with MPN-AP/BP, discuss the uncertainty around how to best gauge response to therapy, and outline clinical trial considerations for this population of patients. Lastly, we highlight future directions in the management of high-risk MPN.

Evolution of myeloproliferative neoplasms from normal blood stem cells

Sahand Hormoz — 2024-12-05

Over the course of the last decade, genomic studies in the context of normal human hematopoiesis have provided new insights into the early pathogenesis of myeloproliferative neoplasms (MPN). A preclinical phase of MPN, termed clonal hematopoiesis was identified and subsequent lineage tracing studies revealed a multi-decade long time interval from acquisition of an MPN phenotypic driver mutation in a hematopoietic stem cell to the development of overt MPN. Multiple germline variants associated with MPN risk have been identified through genome-wide association studies and in some cases functional interrogation of the impact of the variant has uncovered new insights into hematopoietic stem cell biology and MPN development. Increasingly sophisticated methods to study clonal contributions to human hematopoiesis and measure hematopoietic stem cell fitness have helped to discern the biology underlying the tremendous clinical heterogeneity observed in MPN. Despite these advances, significant knowledge gaps remain, particularly with respect to germline genetic contributors to both MPN pathogenesis and phenotypic diversity, as well as limitations in the ability to prospectively quantify rates of clonal expansion in individual MPN patients. Ultimately, we envisage a personalized approach to MPN care in the future, in which an individualized genetic assessment can predict MPN trajectory and this information will be used to inform and guide therapy. MPN is particularly amenable to precision medicine strategies and our increased understanding of the evolution of MPN from normal blood stem cells provides a unique opportunity for early therapeutic intervention approaches and potentially MPN prevention strategies.

New approaches to standard of care in early-phase myeloproliferative neoplasms: can interferon-α alter the natural history of the disease?

Florence Pasquier — 2024-10-24

The classical BCR::ABL-negative myeloproliferative neoplasms (MPN) include polycythemia vera, essential thrombocythemia, and primary myelofibrosis. They are acquired clonal disorders of hematopoietic stem cells leading to hyperplasia of one or several myeloid lineages. MPN are caused by three main recurrent mutations, JAK2^V617F and mutations in the calreticulin (CALR) and thrombopoietin receptor (MPL) genes. Here, we review the general diagnosis, the complications, and the management of MPN. Second, we explain the physiopathology of the natural disease development and its regulation, which contributes to MPN heterogeneity. Thirdly, we describe the new paradigm of MPN development highlighting the early origin of driver mutations, decades before the onset of symptoms, and the consequence of early detection of MPN cases in the general population for prompt diagnosis and better medical management. Finally, we present interferon-α therapy as a potential, early disease-modifying drug after reporting its good hematologic and molecular efficacies in polycythemia vera, essential thrombocythemia, and early myelofibrosis in clinical trials as well as its mechanism of action in pre-clinical studies. As a result, we may expect that, in the future, MPN patients will be diagnosed very early during the course of disease and that new selective therapies under development, such as interferon-α, JAK2^V617F inhibitors and CALR^mut monoclonal antibodies, will be able to intercept the mutated clones.

Pathogenesis and management of high molecular risk myeloproliferative neoplasms

Victoria Y. Ling — 2024-12-05

Classical myeloproliferative neoplasms (MPN) are clonal stem cell disorders characterized by driver mutations that affect the constitutive activation of JAK-signaling. Mutations additional to an MPN-driver occur in a large number of patients and have been shown be associated with disease presentation and progression. In this review, we outline the current hypotheses regarding how clonal evolution in MPN is thought to occur and the functional mechanisms as to how concomitant somatic mutations (i.e., mutations in genes other than the ‘driver’ genes) contribute to disease progression. We discuss the definitions of high molecular risk MPN, provide an overview of how concomitant mutations influence the clinical management of MPN and suggest how the rapidly developing genetic risk stratification can be utilized to improve clinical outcomes.

Cyclin C promotes development and progression of B-cell acute lymphoblastic leukemia by counteracting p53-mediated stress responses

Jana Trifinopoulos — 2024-10-10

Despite major therapeutic advances in the treatment of acute lymphoblastic leukemia (ALL), resistances and long-term toxicities still pose significant challenges. Cyclins and their associated cyclin-dependent kinases are one focus of cancer research when looking for targeted therapies. We discovered cyclin C to be a key factor for B-cell ALL (B-ALL) development and maintenance. While cyclin C is not essential for normal hematopoiesis, CcncΔ/Δ BCR::ABL1+ B-ALL cells fail to elicit leukemia in mice. RNA sequencing experiments revealed a p53 pathway deregulation in CcncΔ/Δ BCR::ABL1+ cells resulting in the inability of the leukemic cells to adequately respond to stress. A genome-wide CRISPR/Cas9 loss-of-function screen supplemented with additional knock-outs unveiled a dependency of human B-lymphoid cell lines on CCNC. High cyclin C levels in B-cell precursor (BCP) ALL patients were associated with poor event-free survival and increased risk of early disease recurrence after remission. Our findings highlight cyclin C as a potential therapeutic target for B-ALL, particularly to enhance cancer cell sensitivity to stress and chemotherapy.

Acute myeloid leukemia drug-tolerant persister cells survive chemotherapy by transiently increasing plasma membrane rigidity, that also increases their sensitivity to immune cell killing

Yael Morgenstern — 2024-11-21

Resistance to chemotherapy remains a major hurdle to the cure of patients with acute myeloid leukemia (AML). Recent studies indicate that a minority of malignant cells, termed drug-tolerant persisters (DTP), stochastically upregulate stress pathways to evade cell death upon acute exposure to chemotherapy without acquiring new genetic mutations. This chemoresistant state is transient and the cells return to the baseline state after removal of chemotherapy. Nevertheless, the mechanisms employed by DTP to resist chemotherapy are not well understood and it is largely unknown whether these mechanisms are also seen in patients receiving chemotherapy. Here, we used leukemia cell lines, primary AML patients’ samples and samples from patients with AML receiving systemic chemotherapy to study the DTP state. We demonstrated that a subset of AML cells transiently increases membrane rigidity to resist killing due to acute exposure to daunorubicin and Ara-C. Upon removal of the chemotherapy, membrane rigidity returned to baseline and the cells regained chemosensitivity. Although resistant to chemotherapy, the increased membrane rigidity rendered AML cells more susceptible to T-cell-mediated killing. Thus, we identified a novel mechanism by which DTP leukemic cells evade chemotherapy and a strategy to eradicate these persistent cells.

Investigating the influence of germline ATM variants in chronic lymphocytic leukemia on cancer vulnerability

Roberta S. Azevedo — 2024-11-21

Chronic lymphocytic leukemia (CLL) patients have an increased risk of secondary cancers, along with predisposition to CLL in their relatives. We have previously identified germline ATM variants as associated with CLL risk. Here, we present their impact on predisposition to secondary neoplasms in CLL patients and their relatives. Patients enrolled in our tissue bank who had germline ATM status available were mailed a questionnaire between April 2022 and May 2023. Of the 333 patients who replied to the questionnaire, 283 patients (85%) reported at least one relative with a cancer history. The prevalence of family history of B-cell lymphoproliferative disorders was significantly higher (P=0.02) in patients with germline ATM variants (32%) compared to those without germline ATM variants (21%) including familial CLL (25% vs. 18%) (P=0.04). No significant difference in the prevalence of secondary cancers was found between patients with and without germline ATM variants (P=0.73), although the role for individual ATM variants in other malignancies could not be excluded given the small sample size. Time to first CLL treatment (TTFT) was shorter in patients harboring somatic ATM events while no difference was observed in patients with germline ATM variants. In conclusion, we demonstrate a higher prevalence of B-cell lymphoproliferative disorders, including familial CLL, in relatives of CLL patients carrying germline ATM variants. The presence of these germline variants did not impact TTFT compared to patients harboring somatic ATM mutations.

Intracranial hemorrhage before start of prophylaxis in children with hemophilia: incidence, timing, and potential for prevention

Nadine G. Andersson — 2024-11-28

Children with hemophilia have a significantly higher risk of intracranial hemorrhage (ICH) compared to the normal population. Prophylaxis reduces the risk of ICH and earlier initiation of prophylaxis may now be feasible, especially in hemophilia A (HA). The aim of the study is to explore the potential for preventing ICH by earlier start of prophylaxis by assessing the natural course of ICH before the initiation of prophylaxis and describe timing and incidence (clinicaltrials gov. Identifier: NCT02979119). In total, 2,727 children (2,275 with HA; 452 with hemophilia B [HB]) were included from the PedNet Registry, followed from 28 days until 36 months of life. ICH was observed in 61 children (incidence 2.2%; 10 per 1,000 patient years), with 75% of cases occurring before 1 year of age. Cumulative incidence was significantly lower in HB (0.9%) compared to HA (2.5%) and in non-severe HA (0.7%) compared to severe HA (3.5%). ICH occurred early, with a rise at 3 months, and a median age of 7.0 months in severe HA and 5.4 months in severe HB. In 40% of children, ICH occurred before the diagnosis of hemophilia was established, underscoring the importance of early diagnosis. Assuming that prophylaxis would have been started at the time of diagnosis and preventing all ICH in children with severe HA, the number needed to treat with prophylaxis would be 44 patients to prevent one ICH. Hopefully, prophylaxis options allowing initiation early in life, ideally before 3 months of age for children with severe HA, will reduce the incidence of ICH in the future.

A fully humanized von Willebrand disease type 1 mouse model as unique platform to investigate novel therapeutic options

Genevieve McCluskey — 2024-11-28

Patients suffering from von Willebrand disease (VWD) have reduced quality-of-life despite current treatment options. Moreover, innovation in VWD therapeutic strategies has essentially stalled, and available treatments have remained unchanged for decades. Therefore, there is an unmet need to develop new therapeutic strategies for VWD patients, especially for the large portion of those with VWD-type 1. Due to species differences, the available VWD murine models are not suitable for preclinical studies, making it difficult to test new therapeutic approaches in vivo. With this in mind, we generated mice selectively expressing human von Willebrand factor (VWF) and human GPIbα. Because this fully humanized model was found to express low VWF (12%) and factor VIII (FVIII) (40%) levels with normal multimer profile and activity/antigen ratio, we repositioned it as a VWD-type 1 model (hVWD1 mice). In depth characterization of this model confirmed VWD-type 1 features with a decrease in platelet adhesion and thrombus formation in vitro. In vivo, a moderate bleeding phenotype was observed which was corrected upon the administration of recombinant-VWF or upon histamine-induced release of endothelial VWF. In search of new therapeutic options for VWD, we designed a bispecific single-domain antibody that bridges VWF to albumin (KB-V13A12). Remarkably, a single subcutaneous administration of KB-V13A12 coincided with a sustained 2-fold increase in VWF antigen levels for up to ten days and normalized hemostasis in a tail-clip model in hVWD1 mice. Here, we describe the development of our unique humanized mouse model for VWD-type 1 and a promising new therapeutic that corrected hemostasis in these mice.

Different inflammatory, fibrotic, and immunological signatures between pre-fibrotic and overt primary myelofibrosis

Seung-Hyun Jung — 2024-10-10

Primary myelofibrosis (PMF) is a myeloid proliferative neoplasm (MPN) characterized by bone marrow fibrosis. Pre-fibrotic PMF (pre-PMF) progresses to overt PMF. Megakaryocytes play a primary role in PMF; however, the functions of megakaryocyte subsets and those of other hematopoietic cells during PMF progression remain unclear. We, therefore, analyzed bone marrow aspirates in cases of pre-PMF, overt PMF, and other MPN using single-cell RNA sequencing. We identified 14 cell types with subsets, including hematopoietic stem and progenitor cells (HSPC) and megakaryocytes. HSPC in overt PMF were megakaryocyte-biased and inflammation/fibrosis-enriched. Among megakaryocytes, the epithelial-mesenchymal transition (EMT)-enriched subset was abruptly increased in overt PMF. Megakaryocytes in non-fibrotic/non-PMF MPN were megakaryocyte differentiation-enriched, whereas those in fibrotic/non-PMF MPN were inflammation/fibrosis-enriched. Overall, the inflammation/fibrosis signatures of the HSPC, megakaryocyte, and CD14+ monocyte subsets increased from pre-PMF to overt PMF. Cytotoxic and dysfunctional scores also increased in T and NK cells. Clinically, megakaryocyte and HSPC subsets with high inflammation/fibrosis signatures were frequent in the patients with peripheral blood blasts ≥1%. Single-cell RNA-sequencing predicted higher cellular communication of megakaryocyte differentiation, inflammation/fibrosis, immunological effector/dysfunction, and tumor-associated signaling in overt PMF than in pre-PMF. However, no decisive subset emerged during PMF progression. Our study demonstrated that HSPC, monocytes, and lymphoid cells contribute to the progression of PMF, and subset specificity existed regarding inflammation/fibrosis and immunological dysfunction. PMF progression may depend on alterations of multiple cell types, and EMT-enriched megakaryocytes may be potential targets for diagnosing and treating the progression.

A novel CCL3-HMGB1 signaling axis regulating osteocyte RANKL expression in multiple myeloma

Aric Anloague — 2024-11-28

Multiple myeloma (MM) is a clonal plasma cell proliferative malignancy characterized by a debilitating bone disease. Osteolytic destruction, a hallmark of MM, is driven by increased osteoclast number and exacerbated bone resorption, primarily fueled by the excessive production of RANKL, the master regulator of osteoclast formation, within the tumor niche. We previously reported that osteocytes, the most abundant cells in the bone niche, promote tumor progression and support MM bone disease by overproducing RANKL. However, the molecular mechanisms underlying RANKL dysregulation in osteocytes in the context of MM bone disease are not entirely understood. Here, we present evidence that MM-derived CCL3 induces upregulation of RANKL expression in both human and murine osteocytes. Through a combination of in vitro, ex vivo, and in vivo models and clinical data, we demonstrate that genetic or pharmacologic inhibition of CCL3 prevents RANKL upregulation in osteocytes and attenuates the bone loss induced by MM cells. Mechanistic studies revealed that MM-derived CCL3 triggers the secretion of HMGB1 by osteocytes, a process required for osteocytic RANKL upregulation by MM cells. These findings identify a previously unknown CCL3-HMGB1 signaling axis in the MM tumor niche that drives bone resorption by promoting RANKL overproduction in osteocytes.

Terminal complement inhibition and control of hemolysis in patients with paroxysmal nocturnal hemoglobinuria who switched from high-dose eculizumab to ravulizumab: a phase IV, single-arm clinical trial

Morag Griffin — 2024-11-28

Depletion of the RNA binding protein QKI and circular RNA dysregulation in T-cell acute lymphoblastic leukemia

Alessia Buratin — 2024-12-05

FLT3 ligand kinetic profile predicts response to treatment in patients with high-risk myelodysplastic syndrome/chronic myelomonocytic leukemia receiving CPX-351: a study from the Groupe Francophone des Myélodysplasies

Pierre Peterlin — 2024-11-21

Donor cytomegalovirus serology impacts overall survival in children receiving first unrelated hematopoietic stem cell transplant for acute leukemia: European Society of Bone Marrow Transplantation Pediatric Diseases Working Party Study

Elif Ince — 2024-11-28

Teclistamab in relapsed refractory multiple myeloma: a multi-institutional real-world study from the French early access program

Aurore Perrot — 2024-11-21

Short-course subcutaneous alemtuzumab induces clinical responses in relapsed T-cell large granular leukemia

Miguel Ruiz — 2024-11-14

Dexamethasone is associated with reduced frequency and intensity of cytokine release syndrome compared with alternative corticosteroid regimens as premedication for glofitamab in patients with relapsed/refractory large B-cell lymphoma

Lorenzo Falchi — 2024-11-28

Letermovir prophylaxis for cytomegalovirus is associated with risk of post-transplant lymphoproliferative disorders after haploidentical stem cell transplantation

Xu-Ying Pei — 2024-11-28

Germline genetics, disease, and exposure to medication influence longitudinal dynamics of clonal hematopoiesis

Taralynn Mack — 2024-11-14

Calaspargase pegol and pegaspargase cause similar hepatosteatosis in mice

Veronica Ruiz-Torres — 2024-11-21

Identification of a clinicopathologic prognostic index for newly diagnosed large B-cell lymphoma patients treated with R-CHOP

Vincent Ni — 2024-11-28

Isatuximab, pomalidomide, and dexamethasone as salvage therapy for patients with multiple myeloma: the Italian, multicenter, retrospective clinical experience with 270 cases outside of controlled clinical trials

Enrica Antonia Martino — 2024-11-28

Incidental changes in hemoglobin levels in patients with myelofibrosis receiving treatment with sodium-glucose co-transporter-2 inhibitors

Fnu Aperna — 2024-11-28

Intestinal perforation following allogeneic stem cell transplantation caused by Epstein-Barr virus-positive mucocutaneous ulcer

Klaus Hirschbühl — 2024-12-05

Complete remission of NUP98 fusion-positive acute myeloid leukemia with the covalent menin inhibitor BMF-219, icovamenib

Hetty E. Carraway — 2024-12-05

Erratum to: Quercetin-mediated Mcl-1 and survivin downregulation restores TRAIL-induced apoptosis in non-Hodgkin’s lymphoma B cells

Guillaume Jacquemin — 2025-04-01

Erratum to: Bendamustine and rituximab as first-line treatment for symptomatic splenic marginal zone lymphoma: long-term outcome and impact of early unmeasurable minimal residual disease attainment from the BRISMA/IELSG36 phase II study

Emilio Iannitto — 2025-04-01