Hematology:

Extramedullary disease (EMD) is a high-risk feature of multiple myeloma (MM) and remains a poor prognostic factor, even in the era of novel immunotherapies. Here, we applied spatial transcriptomics (RNA tomography for spatially resolved transcriptomics [tomo-seq] [n = 2] and 10x Visium [n = 12]) and single-cell RNA sequencing (n = 3) to a set of 14 EMD biopsies to dissect the 3-dimensional architecture of tumor cells and their microenvironment. Overall, infiltrating immune and stromal cells showed both intrapatient and interpatient variations, with no uniform distribution over the lesion. We observed substantial heterogeneity at the copy number level within plasma cells, including the emergence of new subclones in circumscribed areas of the tumor, which is consistent with genomic instability. We further identified the spatial expression differences between GPRC5D and TNFRSF17, 2 important antigens for bispecific antibody therapy. EMD masses were infiltrated by various immune cells, including T cells. Notably, exhausted TIM3+/PD-1+ T cells diffusely colocalized with MM cells, whereas functional and activated CD8+ T cells showed a focal infiltration pattern along with M1 macrophages in tumor-free regions. This segregation of fit and exhausted T cells was resolved in the case of response to T-cell-engaging bispecific antibodies. MM and microenvironment cells were embedded in a complex network that influenced immune activation and angiogenesis, and oxidative phosphorylation represented the major metabolic program within EMD lesions. In summary, spatial transcriptomics has revealed a multicellular ecosystem in EMD with checkpoint inhibition and dual targeting as potential new therapeutic avenues.

Venous thromboembolism (VTE) is common among older individuals, but provoking factors are not identified in many cases. Patients with myeloid malignancies, especially myeloproliferative neoplasms (MPNs), are at increased risk for venous thrombosis. Clonal hematopoiesis of indeterminate potential (CHIP), a precursor state to myeloid malignancies, is common among older individuals and may similarly predispose to venous thrombosis. We evaluated overall and genotype-specific associations between CHIP and prevalent and incident VTE in >400 000 samples from the UK Biobank. CHIP was modestly associated with incident VTE with a hazard ratio (HR) of 1.17 (95% confidence interval [CI], 1.09-1.3; P = .002) but was not significantly associated with prevalent VTE with an odds ratio (OR) of 1.02 (95% CI, 0.81-1.23; P = .81). TET2-mutant CHIP was associated with incident VTE with a HR of 1.33 (95% CI, 1.05-1.69; P = .02). JAK2 mutations were highly associated with both prevalent and incident VTE risk, with an OR of 6.58 (95% CI, 2.65-16.29; P = 4.7 × 10-5) and a HR of 4.2 (95% CI, 2.18-8.08; P = 1.7 × 10-5), respectively, consistent with the thrombophilia associated with JAK2-mutant MPN. The association between JAK2-mutant CHIP and VTE remained significant after excluding potential undiagnosed MPN based on laboratory parameters. JAK2-mutant CHIP was more strongly associated with VTE but was less common than heterozygous factor V Leiden and heterozygous prothrombin gene mutation. These results indicate that most individuals with CHIP do not have an altered risk of thrombosis, but individuals with JAK2-mutant CHIP have a significantly elevated risk of VTE.

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome characterized by aberrant immunological activity with a dismal prognosis. Epstein-Barr virus (EBV)-associated HLH (EBV-HLH) is the most common type among adults. Patients with EBV infection to B cells could benefit from rituximab, whereas lethal outcomes may occur in patients with EBV infection to T cells, nature killer cells, or multilineages. The necessity of allogeneic hematopoietic stem cell transplantation (HSCT) in adult patients with EBV-HLH remains controversial. A total of 356 adult patients with EBV-HLH entered this study. Eighty-eight received HSCT under medical recommendation. Four received salvage HSCT. The 5-year overall survival (OS) rate for patients who underwent HSCT was 48.7% (vs 16.2% in patients who did not undergo transplantation; P < .001). There was no difference in OS between patients who received transplantation at first complete response (CR1) and those at first partial response (PR1) nor between patients at CR1 and CR2. Patients who received transplantation at PR2 had inferior survival. The rate of reaching CR2 was significantly higher in patients with CR1 than PR1 (P = .014). Higher soluble CD25 levels, higher EBV-DNA loads in plasma after HSCT, poorer remission status, more advanced acute graft-versus-host disease (GVHD), and the absence of localized chronic GVHD were associated with inferior prognosis (P < .05). HSCT improved the survival of adult EBV-HLH significantly. For patients who achieved PR after initial treatment, HSCT was recommended. A wait-and-see strategy could be adopted for patients who achieved CR after initial treatment but with the risk of failing to achieve CR2.

Immune thrombocytopenia (ITP) is a complicated bleeding disease characterized by a sharp platelet reduction. As a dominating element involved in ITP, megakaryocytes (MKs) are responsible for thrombopoiesis. However, the mechanism underlying the dysregulation of thrombopoiesis that occurs in ITP remains unidentified. In this study, we examined the role of Yes-associated protein 1 (YAP1) in thrombopoiesis during ITP. We observed reduced YAP1 expression with cytoskeletal actin misalignment in MKs from patients with ITP. Using an experimental ITP mouse model, we showed that reduced YAP1 expression induced aberrant MK distribution, reduced the percentage of late MKs among the total MKs, and caused submaximal platelet recovery. Mechanistically, YAP1 upregulation by binding of GATA-binding protein 1 to its promoter promoted MK maturation. Phosphorylated YAP1 promoted cytoskeletal activation by binding its WW2 domain to myosin heavy chain 9, thereby facilitating thrombopoiesis. Targeting YAP1 with its activator XMU-MP-1 was sufficient to rescue cytoskeletal defects and thrombopoiesis dysregulation in YAP1+/- mice with ITP and patients. Taken together, these results demonstrate the crucial role of YAP1 in thrombopoiesis, providing potential for the development of diagnostic markers and therapeutic options for ITP.

Venoms have primarily been used to prepare antivenoms for the treatment of snake bites, but they have constituents that might serve other medical needs. These include metalloproteinases, serine proteases, phospholipases, and C-type lectin-like proteins. Some of the products that have been prepared from venoms are procoagulants employed as topical hemostatics, and either applied directly to bleeding wounds or used as adjuncts to surgical procedures to assist in controlling blood loss. Venoms are also a valuable source of laboratory reagents helpful in diagnosing specific coagulation factor deficiencies, identifying lupus anticoagulants, or managing therapeutic anticoagulation. In addition, the unique properties of certain venom components have led to their use as antithrombotic agents. This review describes how snake venoms have provided insight into coagulation mechanisms and generated products to improve human health. Venomous snakes are dangerous but we must learn to safely share our planet with them, not least because studies of their venoms might lead to the discovery of valuable biomolecules.

In 2022, leukemia ranked as the second most common hematological malignancy after non-Hodgkin lymphoma worldwide. However, updated global estimates of leukemia incidence by subtype are unavailable. We estimated leukemia incidences for different leukemia subtypes by country, world region, and human developmental index using data from the Cancer Incidence in Five Continents databases combined with the GLOBOCAN 2022 estimates of leukemia in 185 countries. We estimated sex-specific age-standardized rates (ASRs) per 100 000 for children (0-19 years) and adults (20+ years). In adults, the most common leukemia worldwide was AML (males: 38%, ASR = 3·1; females: 43%, ASR = 2·4), followed by CLL (males: 28%, ASR = 2·2; females: 24%, ASR = 1·3). In very high HDI countries, the ASR of CLL was higher than the ASR of AML among males (5·2 versus 4·3, respectively) and similar among females (2·9 and 3·0, respectively). In children, the most common leukemia was ALL (boys: 70%, ASR = 2·4; girls: 68%, ASR = 1·8) followed by AML (boys: 22%, ASR = 0·76; girls: 25%, ASR = 0·65). ALL proportions varied across world sub-regions from 57 to 78% among boys, and from 49 to 80% among girls. Our findings suggest clear geographical patterns of leukemia subtypes in adults and children. Further research into underlying causes that explain these variations is needed to support cancer control strategies for prevention and plan national healthcare needs.

In the central nervous system (CNS), neuronal function and dysfunction are critically dependent on mitochondrial integrity and activity. In damaged or diseased brains, mitochondrial dysfunction reduces adenosine triphosphate (ATP) levels and impairs ATP-dependent neural firing and neurotransmitter dynamics. Restoring mitochondrial capacity to generate ATP may be fundamental in restoring neuronal function. Recent studies in animals and humans have demonstrated that endogenous mitochondria may be released into the extracellular environment and transported or exchanged between cells in the CNS. Under pathological conditions in the CNS, intercellular mitochondria transfer contributes to new classes of signaling and multifunctional cellular activities, thereby triggering deleterious effects or promoting beneficial responses. Therefore, to take full advantage of the beneficial effects of mitochondria, it may be useful to transplant healthy and viable mitochondria into damaged tissues. In this review, we describe recent findings on the mechanisms of mitochondria transfer and provide an overview of experimental methodologies, including tissue sourcing, mitochondrial isolation, storage, and modification, aimed at optimizing mitochondria transplantation therapy for CNS disorders. Additionally, we examine the clinical relevance and potential strategies for the therapeutic application of mitochondria transplantation.

This narrative review seeks to summarize chemotherapeutic regimens commonly used for patients with newly diagnosed Philadelphia (Ph) chromosome-negative B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in the frontline setting and to describe the latest clinical research using the bispecific T-cell-engaging immunotherapy blinatumomab in the first-line treatment setting. Current standard-of-care chemotherapeutic backbones for newly diagnosed Ph-negative BCP-ALL are based on the same overarching treatment principle: to reduce disease burden to undetectable levels and maintain lasting remission. The adult treatment landscape has progressively evolved following the adoption of pediatric-inspired regimens. However, these intense regimens are not tolerated by all, and high-risk patients still have inferior outcomes. Therefore, designing more effective and less toxic strategies remains key to further improving efficacy and safety outcomes. Overall, the treatment landscape is evolving in the frontline, and integration of blinatumomab into different standard frontline regimens may improve overall outcomes with a favorable safety profile.

The outcomes of patients with acute myeloid leukemia (AML) and bone marrow fibrosis (MF) are not well defined. The study objectives were to evaluate the degrees of MF in AML, and corresponding response rates and outcomes. We performed a retrospective review of 2302 patients with AML. We annotated the clinical and molecular characteristics, response to therapy, and survival outcomes of patients with bone marrow fibrosis. Overall, 492 patients (21.4%) had a reported microscopic evaluation of MF: 344 (69.9%) had MF grade 0-1 and 148 (30.1%) had MF grade 2-3. Patients with MF 2-3 had a higher proportion of complex cytogenetics (39.2% vs. 24.7%, p = 0.002) JAK2 mutations (25.7% vs. 18%, p = 0.07) and lower proportion of IDH2 (16.9% vs. 25.9%, p = 0.03) and CEBPA (15.5% vs. 27.6%, p = 0.006) mutations. 64% were treated with low-intensity chemotherapy (LIT) and 36.1% with intensive chemotherapy (IT). The complete remission (CR)/CR with incomplete count recovery (CRi) rates were 63.5% with IC versus 37.9% with LIT (p = 0.007). In patients aged 60 or older 4-week mortality was 12.5% with IC vs. 9.3% with LIT (p = 0.8). The median overall survival (OS) was 14.2 with MF 0-1 versus 7.5 months with MF 2-3 (p < 0.005). In patients aged 60 or older with MF 2-3 median OS was 6.5 months with IT versus 7.0 months with LIT (p = 0.19). In a multivariate analysis, grade 2-3 MF (HR 2.0, 95%CI 1.59-2.51) was the strongest prognostic factor for survival. In summary, grade 2-3 MF in AML is associated with worse outcomes.

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of patients with relapsed or refractory hematologic malignancies, but it comes with unique toxicities, notably cytokine release syndrome and ICANS (immune effector cell-associated neurotoxicity syndrome). As experience with CAR T-cell therapy grows, distinct and infrequent neurologic complications are becoming increasingly evident. Recently, reports of acute myelopathy after the administration of CAR T-cell therapies have been accumulating. Despite the establishment of consensus guidelines for managing ICANS, there remains limited guidance on the appropriate investigations and treatments for this rare complication. In this manuscript, we delve into the clinical features, pathophysiology, and strategies for the optimal management of acute myelitis after CAR T-cell therapy and draw insights from reported cases in the literature.

Red blood cell (RBC) metabolism regulates hemolysis during aging in vivo and in the blood bank. However, the genetic underpinnings of RBC metabolic heterogeneity and extravascular hemolysis at population scale are incompletely understood. Based on the breeding of 8 founder strains with extreme genetic diversity, the Jackson laboratory diversity outbred population can capture the impact of genetic heterogeneity in like fashion to population-based studies. RBCs from 350 outbred mice, either fresh or stored for 7 days, were tested for post-transfusion recovery, as well as metabolomics and lipidomics analyses. Metabolite and lipid Quantitative Trait Loci (QTL) mapped >400 gene-metabolite associations, which we collated into an online interactive portal. Relevant to RBC storage, we identified a QTL hotspot on chromosome 1, mapping on the region coding for the ferrireductase Steap3, a transcriptional target to p53. Steap3 regulated post-transfusion recovery, contributing to a ferroptosis-like process of lipid peroxidation, as validated via genetic manipulation in mice. Translational validation of murine findings in humans, STEAP3 polymorphisms were associated with RBC iron content, lipid peroxidation and in vitro hemolysis in 13,091 blood donors from the Recipient Epidemiology and Donor Evaluation Study. QTL analyses in humans identified a network of gene products (FADS1/2, EPHX2, LPCAT3, SLC22A16, G6PD, ELOVL, PLA2G6) associated with lower levels of oxylipins. These polymorphisms were prevalent in donors of African descent and were linked to allele frequency of hemolysis-linked polymorphisms for Steap3 or p53. These genetic variants were also associated with lower hemoglobin increments in thousands of single-unit transfusion recipients from the vein-to-vein database.

Despite the introduction of JAK inhibitors, allogeneic hematopoietic cell transplant remains the only potentially curative treatment for patients with myelofibrosis but has considerable treatment-related complications. Whether the incorporation of JAK inhibition into the transplant algorithm leads to improved outcomes is still unclear. Here, we analyzed different transplant platforms in myelofibrosis patients undergoing a first transplant, comparing immune profiles and outcomes of (1) 33 patients continuing JAK inhibition at start of conditioning until stable engraftment (PERI-group), (2) 38 patients receiving JAK inhibition prior to transplant until start of conditioning (PRE-group), and (3) 38 patients that had never received JAK inhibition (NON-group). Patients in the PERI-group showed significantly higher early B-cell recovery as well as significantly increased late recovery of gamma-delta T cells and NK cells. We observed excellent neutrophil and platelet engraftment (100% for both) in the PERI-group and no hematotoxic effects or increased rates of infections following peri-transplant JAK inhibition. Cumulative incidence of acute graft-versus-host disease (GvHD) grade II-IV at day 100 after transplant was 15% in the PERI-group versus 29% in the PRE-group versus 34% in the NON-group. Cumulative incidence of relapse at 1 year after transplant was 9% in the PERI-group compared with 16% in the PRE-group and 18% in the NON-group. In conclusion, peri-transplant JAK inhibition was feasible with promising engraftment and acute GvHD rates, though deserves further investigation.

Many cases of venous thromboembolism (VTE) are idiopathic and clonal haemopoiesis, a risk factor for atherosclerotic vascular disease, may be a contributing factor to VTE. The report by Englisch and colleagues suggests that clonal haemopoiesis is a risk factor for recurrent VTE, especially in people without identifiable thrombotic predisposition. Commentary on: Englisch et al. Association of clonal hematopoiesis with recurrent venous thromboembolism: A case-control study. Br J Haematol 2024 (Online ahead of print). doi: 10.1111/bjh.19871.

CONCLUSIONS: Kidney lymphatic density was robustly increased in the mice. There were no changes in peritubular blood capillary density despite these endothelial cells also expressing VEGFR3. The model resulted in malformation of the lymphatic hilar plexus, resulting in severe hydronephrosis that resembled a human condition termed renal lymphangiectasia. This study defines the vascular consequences of augmenting VEGFC signaling during kidney development and provides new insight into human renal lymphatic malformations.

In REACH4, a phase 1/2, open-label, single-arm, multicenter study, the pharmacokinetics (PK), efficacy, and safety of ruxolitinib were evaluated in treatment-naïve and steroid-refractory pediatric patients with grade 2 to 4 acute graft-versus-host disease (aGVHD; n = 45). Ruxolitinib dosing was based on age and targeted the exposure in adults receiving 10 mg twice daily; group 1 (aged ≥12 to <18 years) received 10 mg twice daily and preliminary starting doses for groups 2 (aged ≥6 to <12 years) and 3 (aged ≥2 to <6 years) were 5 mg twice daily and 4 mg/m2 twice daily, respectively. The phase 1 primary objective was to assess ruxolitinib PK parameters and define an age-appropriate recommended phase 2 dose (RP2D) for patients aged <12 years. The phase 2 primary objective was to measure the activity of ruxolitinib as assessed by overall response rate (ORR) at day 28; the key secondary objective was to assess the durable ORR at day 56. Ruxolitinib exposure was comparable across age groups; starting doses were confirmed as the RP2D. The median duration of ruxolitinib exposure was 3.8 months (range, 0.3-11.2). ORR in all patients was 84.4% (90% confidence interval [CI], 72.8-92.5) at day 28, with a durable ORR at day 56 of 66.7% (90% CI, 53.4-78.2); high response rates were observed across age groups and in both treatment-naïve and steroid-refractory subgroups. Adverse events were consistent with those expected in patients with aGVHD (anemia, decreased neutrophil and leukocyte count) treated with ruxolitinib. In pediatric patients with aGVHD, ruxolitinib showed clinically meaningful efficacy with no new safety signals. This trial was registered at www.clinicaltrials.gov as #NCT03491215.

Atherosclerosis affects patients with systemic immune-mediated inflammatory diseases at an increased rate compared with the general population. In recent years, our understanding of the pathophysiology of atherosclerosis has advanced considerably. Nevertheless, cardiovascular imaging modalities that can adequately assess the biological background of atherosclerosis have not reached widespread clinical adoption. Novel developments in cardiac imaging have the potential to enhance the diagnostic yield of these modalities further while providing essential insights into the anatomy, composition, and biology of atherosclerotic lesions. In this review, we highlight some of the latest developments in the field for the evaluation of atherosclerosis using advances in echocardiography, computed tomography, positron emission tomography, and cardiovascular magnetic resonance. Additionally, we discuss evidence specifically in patients with immune-mediated inflammatory diseases and outline unmet research needs for future development.

Abstract: Relapse is the major cause of treatment failure in Philadelphia chromosome-positive (Ph) acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). This study aimed to evaluate the effect of a prophylactic tyrosine kinase inhibitor (TKI) strategy on relapse in this population. Patients were assigned to prophylactic or control groups based on measurable residual disease (MRD) pre-transplantation. The primary endpoint was the cumulative incidence of relapse. A total of 110 patients with Ph ALL undergoing allo-HSCT were enrolled in this prospective study. Thirty-eight patients with positive MRD pre-transplantation were included in the prophylactic group, and 72 with negative MRD pre-transplantation were included in the control group. The 4-year cumulative incidence of relapse was 25.3% (95% CI: 12.1%-41.0%) and 20.3% (11.6%-30.7%; HR = 1.272, 95% CI: 0.551-2.940, p = .549), and non-relapse mortality was 10.5% (3.3%-22.7%) and 9.7% (4.2%-17.9%; HR = 1.094, 95% CI: 0.320-3.738, p = .928) in the prophylactic and control groups. The 4-year overall survival was 71.8% (53.2%-84.1%) and 84.1% (72.9%-90.9%; HR = 1.746, 95% CI: 0.741-4.112, p = .196), and leukemia-free survival was 64.1% (45.8%-77.7%) and 70.0% (57.6%-79.4%; HR = 1.212, 95% CI: 0.607-2.421, p = .585) in the prophylactic and control groups. Our results suggest that prophylactic TKI post-HSCT in patients with positive MRD pre-transplantation can produce outcomes comparable to negative MRD pre-transplantation without TKI post-HSCT.

Patients with sickle cell disease (SCD) are at elevated risk of silent cerebral infarcts and strokes; however, they frequently lack established stroke risk factors (e.g., macrovascular arterial steno-occlusion) and as such the mechanisms underlying such events are incompletely characterized. This study evaluated cerebral metabolism with respect to imaging markers of vascular shunting in 143 SCD participants, including 73 pediatric (6-17 years) and 70 adult (18-40 years) participants. Participants completed clinical and cerebral imaging assessments using 3-Tesla brain MRI to quantify cerebral hemo-metabolic measures. Vascular shunting was assessed in each patient using a previously published ordinal venous hyperintensity score (VHS=0, 1, or 2) on cerebral blood flow-weighted MRI. Relationships between age group (pediatric versus adults) and hemo-metabolic measures for varying VHS were investigated using two-way ANOVA. Participants with VHS=2, indicative of the most rapid arterio-venous transit, had significantly reduced blood oxygen content (CaO2=10.90±1.69 ml O2/100ml blood), oxygen extraction fraction (OEF=33.52±5.54%), and cerebral metabolic rate of oxygen consumption (CMRO2=2.91±0.69 ml O2/100g tissue/min) compared to their counterparts with VHS=0 (CaO2=12.42±1.58 ml O2/100ml blood; OEF=39.03±3.80%; CMRO2=3.77±0.84 ml O2/100g tissue/min) or VHS=1 (CaO2=11.86±1.73 ml O2/100ml blood; OEF=36.37±5.11%; CMRO2=3.59±0.78 ml O2/100g tissue/min). Both pediatric and adult SCD patients presenting with greater imaging evidence of vascular shunting had mildly reduced OEF and CMRO2. These findings highlight that imaging markers of vascular shunting are associated with significant, albeit mild, evidence of reduced OEF and CMRO2 in patients with SCD.

In the central nervous system, cell-to-cell interaction is essential for brain plasticity and repair, and its alteration is critically involved in the development of neurodegenerative diseases. Neural stem cells are a plentiful source of biological signals promoting neuroplasticity and the maintenance of cognitive functions. Extracellular vesicles (EVs) represent an additional strategy for cells to release signals in the surrounding cellular environment or to exchange information among both neighboring and distant cells. In the last years, rising attention has been devoted to the ability of stem cell (SC)-derived EVs to counteract inflammatory and degenerative brain disorders taking advantage of their immunomodulatory capacities and regenerative potential. Here, we review the role of adult neurogenesis impairment in the cognitive decline associated with neurodegenerative diseases and describe the beneficial effects of SC-derived EVs on brain plasticity and repair also discussing the advantages of SC-derived EV administration versus SC transplantation in the treatment of neurodegenerative disorders.

Over the past decade, treatment recommendations for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) have shifted from traditional chemoimmunotherapy to targeted therapies. Multiple new therapies are commercially available, and in many cases a lack of randomized clinical trial data makes selection of the optimal treatment for each patient challenging. Additionally, many patients continue to receive chemoimmunotherapy in the US, suggesting a gap between guidelines and real-world practice. The Lymphoma Research Foundation convened a workshop comprised of a panel of CLL/SLL experts in the US to develop consensus recommendations for selection and sequencing of therapies for patients with CLL/SLL in the US. Herein, the recommendations are compiled for use as a practical clinical guide for treating providers caring for patients with CLL/SLL, which complement existing guidelines by providing a nuanced discussion relating how our panel of CLL/SLL experts in the US care for patients in a real-world environment.