Blood

Transcriptional deregulation is a central event in the development of acute myeloid leukemia (AML). To identify potential disturbances in gene regulation, we conducted an unbiased screen of allele-specific expression (ASE) in 209 AML cases. The gene encoding GATA binding protein 2 (GATA2) displayed ASE more often than any other myeloid or cancer-related gene. GATA2 ASE was strongly associated with CEBPA double mutations (CEBPA DM), with 95% of cases presenting GATA2 ASE. In CEBPA DM AML with GATA2 mutations, the mutated allele was preferentially expressed...

This phase 1-2 study evaluated brentuximab vedotin (BV) combined with nivolumab (Nivo) as first salvage therapy in patients with relapsed or refractory classical Hodgkin lymphoma. In parts 1 and 2, patients received staggered dosing of BV and Nivo in cycle 1, followed by same-day dosing in cycles 2-4. In part 3, both study drugs were dosed same day for all 4 cycles. At end of study treatment, patients could undergo autologous stem cell transplantation (ASCT) per investigator discretion. The objective response rate (N=91) was 85%, with 67% achieving a complete response...

Approximately 80% of adult patients with immune thrombocytopenia (ITP) fail or become dependent on corticosteroids and require second-line therapy. Several new and effective therapies have been introduced during the last decade and our understanding of disease burden and its effect on quality of life has expanded. It is now recommended that splenectomy, the standard second-line therapy for decades, be delayed for at least 12-24 months allowing more patients to achieve remission on medical therapies before considering surgery...

GPVI, the platelet immunoreceptor tyrosine activating motif (ITAM) receptor for collagen plays a striking role on vascular integrity in animal models of inflammation and sepsis. Understanding ITAM-receptor signaling defects in humans suffering from sepsis may improve our understanding of the pathophysiology, especially during disease onset. In a pilot study, platelets from fifteen septic patients were assessed consecutively at day of admission, day 5-7 and the day of ICU-discharge, and subjected to comprehensive analyses by flow cytometry, aggregometry and immunoblotting...

Acetaminophen (APAP)-induced liver injury is associated with activation of coagulation and fibrinolysis. In mice, both tissue factor-dependent thrombin generation and plasmin activity have been shown to promote liver injury after APAP overdose. However, the contribution of the contact and intrinsic coagulation pathways has not been investigated in this model. Mice deficient in individual factors of the contact (FXII and PK) or intrinsic coagulation (FXI) pathway were administered a hepatotoxic dose of 400 mg/kg of APAP...

ZUMA-3 is a phase 1/2 study evaluating KTE-X19, an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, in adult relapsed/refractory (R/R) B-ALL. We report the phase 1 results. Following fludarabine/cyclophosphamide lymphodepletion, patients received a single infusion of KTE-X19 at 2, 1, or 0.5×106 cells/kg. The rate of dose-limiting toxicities (DLTs) within 28 days following KTE-X19 infusion was the primary endpoint. KTE-X19 was manufactured for 54 enrolled patients and administered to 45 (median age: 46 years [range, 18-77])...

Primary immunodeficiencies in the co-stimulatory molecule CD27 and its ligand CD70 predispose for pathologies of uncontrolled Epstein Barr virus (EBV) infection in nearly all affected patients. We demonstrate that both depletion of CD27 positive cells and antibody blocking of CD27 interaction with CD70 causes uncontrolled EBV infection in mice with reconstituted human immune system components. While overall CD8+ T cell expansion and composition is unaltered after antibody blocking of CD27, only some EBV specific CD8+ T cell responses, exemplified by early lytic EBV antigen BMLF1 specific CD8+ T cells are inhibited in their proliferation and killing of EBV transformed B cells...

Bortezomib, lenalidomide, dexamethasone plus transplant is a standard of care for eligible Multiple Myeloma patients. As responses can deepen with time, regimens with longer and more potent induction/consolidation phases are needed. In this phase II study, patients received eight 28-day cycles of carfilzomib (K) 20/36mg/m2 (D1-2,8-9,15-16), lenalidomide (R) 25 mg (D1-21), and dexamethasone (d) 20 mg (D1-2,8-9,15-16,22-23). All patients proceeded to transplant after 4 cycles and received 1-year lenalidomide maintenance (10 mg, D1-21)...

Selective targeting of BCL2 with the BH3-mimetic venetoclax is proving transformative for patients with various leukemias. TP53 controls apoptosis upstream from where BCL2 and its pro-survival relatives, such as MCL1, act. Therefore, targeting these pro-survival proteins could trigger apoptosis across diverse blood cancers, irrespective of TP53 mutation status. Indeed, targeting BCL2 has produced clinically relevant responses in blood cancers with aberrant TP53. However, we show that TP53 mutated or deficient myeloid and lymphoid leukemias outcompete isogenic controls with intact TP53, unless sufficient concentrations of BH3-mimetics targeting BCL2 or MCL1 are applied...

Neogenin (NEO1) is a ubiquitously expressed multi-functional transmembrane protein. It interacts with hemojuvelin (HJV), a BMP co-receptor that plays a pivotal role in hepatic hepcidin expression. Earlier studies suggest that the function of HJV relies on its interaction with NEO1. However, the role of NEO1 in iron homeostasis remains controversial because of the lack of an appropriate animal model. Here, we generated a hepatocyte-specific Neo1 knockout (Neo1fl/fl;Alb-Cre+) mouse model that circumvented the developmental and lethality issues of the global Neo1 mutant...

Thromboembolic events including venous thromboembolism (VTE), arterial thromboembolism (ATE), and mortality from sub-clinical thrombotic events occur frequently in COVID-19 inpatients. Whether the risk extends post-discharge has been controversial. Our prospective registry included consecutive COVID-19 patients hospitalized within our multihospital system from March 1st - May 31st 2020. We captured demographics, comorbidities, laboratory parameters, medications, post-discharge thromboprophylaxis, and 90-day outcomes...

Lymphoma survivors have a significantly higher risk of developing second primary lymphoma than the general population; however, bidirectional risks of developing B- and T-cell lymphomas (BCL; TCL) specifically are less well understood. We used population-based cancer registry data to estimate the subtype-specific risks of second primary lymphoma among patients with first BCL (n=288,478) or TCL (n=23,747). We observed nearly five-fold increased bidirectional risk between BCL and TCL overall (TCL following BCL: standardized incidence ratio [SIR]=4...

The core-binding factors (CBFs), composed of CBFβ and RUNX subunits, play critical roles in most hematopoietic lineages, and are deregulated in Acute myeloid leukemia (AML). The fusion oncogene CBFβ-SMMHC expressed in AML with the chromosome inversion inv(16)(p13q22) acts as a driver oncogene in hematopoietic stem cells and induces AML. This review focuses on novel insights on the molecular mechanisms involving CBFβ-SMMHC driven leukemogenesis and recent advances in therapeutic approaches to target CBFβ-SMMHC in inv(16) AML...

Angioimmunoblastic T-cell lymphoma (AITL) is a unique subtype of peripheral T-cell lymphoma (PTCL) with distinct clinicopathologic features and poor prognosis. We performed a subset analysis of 282 patients with AITL enrolled between 2006 and 2018 in the international prospective T-cell Project (NCT01142674). The primary and secondary endpoints were 5-year overall survival (OS) and progression-free survival (PFS), respectively. We analyzed the prognostic impact of clinical covariates and progression of disease within 24 months (POD24) and developed a novel prognostic score...

Acalabrutinib has demonstrated significant efficacy and safety in relapsed chronic lymphocytic leukemia (CLL). The efficacy and safety of acalabrutinib monotherapy was evaluated in a treatment-naïve CLL cohort of a single-arm phase 1/2 clinical trial (ACE-CL-001). Adults were eligible for enrollment if chemotherapy was declined or deemed inappropriate due to comorbidities (N = 99). Patient demographics included a median age of 64 years and 47% with Rai stage III/IV disease. Acalabrutinib was administered orally either 200 mg once daily (QD) or 100 mg twice daily (BID) until progression or intolerance...

The abundance of genetic abnormalities and phenotypic heterogeneities in AML pose significant challenges to developing improved treatments. Here we demonstrated that a key GAS6/AXL axis is highly activated in AML patient cells, particularly in stem/progenitor cells. We developed a potent, selective AXL inhibitor that has favorable pharmaceutical properties and efficacy against preclinical patient-derived xenotransplantation (PDX) models of AML. Importantly, inhibition of AXL sensitized AML stem/progenitor cells to venetoclax treatment, with strong synergistic effects in vitro and in PDX models...

Hematopoiesis is extrinsically controlled by cells of the bone marrow microenvironment, including skeletal lineage cells. The identification and subsequent studies of distinct subpopulations of maturing skeletal cells is currently limited due to a lack of methods to isolate these cells. We found that murine Lineage-CD31-Sca-1-CD51+ cells can be divided into four subpopulations using flow cytometry, based on their expression of the platelet derived growth factor receptors ⍺ and β (PDGFR⍺ and PDGFRβ). The use of different skeletal lineage reporters confirmed the skeletal origin of the four populations...

Chronic natural killer large granular lymphocyte (NK-LGL) leukemia, also referred to as chronic lymphoproliferative disorder of NK cells (CLPD-NK), is a rare disorder defined by prolonged expansion of clonal NK cells. Similar prevalence of STAT3 mutations in chronic T- and NK-LGL leukemia is suggestive of common pathogenesis. We undertook whole genome sequencing to identify mutations unique to NK-LGL leukemia. We analyzed the results to develop a resequencing panel and applied it to 58 patients. PI3K pathway gene mutations (PIK3CD/PIK3AP1) and TNFAIP3 mutations were seen in 5% and 10% of patients, respectively...

A small subset of cases of chronic lymphocytic leukemia undergoes transformation to diffuse large B-cell lymphoma, Richter's Syndrome (RS), which is associated with a poor prognosis. Conventional chemotherapy results in limited responses, underlining the need for novel therapeutic strategies. Here, we investigate the ex-vivo and in vivo efficacy of the dual PI3K-d/g inhibitor Duvelisib (Duv) and the Bcl-2 inhibitor Venetoclax (Ven) using four different RS-patient-derived xenograft (PDX) models. Ex-vivo exposure of RS cells to Duv, Ven or their combination results in variable apoptotic responses, in line with the expression levels of target proteins...

Loss-of-function mutations in KMT2D are a striking feature of the germinal centre (GC) lymphomas, resulting in decreased H3K4-methylation and altered gene expression. We hypothesised that inhibition of the KDM5 family, which demethylates H3K4me3/me2, would re-establish H3K4-methylation and restore the expression of genes repressed upon loss of KMT2D. KDM5-inhibition increased H3K4me3 levels and caused an anti-proliferative response in vitro, which was markedly greater in both endogenous and CRISPR-edited KMT2D mutant DLBCL cell lines, while tumour growth was inhibited in KMT2D mutant xenografts in vivo...