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HemaBites showcase hematology news and short commentaries on recent high-impact articles published in international journals. This blog will keep you up to date with the latest developments and discoveries in the field of hematology.

Thursday, May 28, 2020

Roger EG Schutgens: Van Creveldkliniek, Benign Hematology Center, University Medical Center Utrecht and University Utrecht, Utrecht, The Netherlands

Emicizumab (Hemlibra®) is a recombinant humanized bispecific monoclonal antibody which facilitates FXa generation by forming a ternary complex with FIXa and FX on platelet surfaces (see Figure B within the article). It was developed to improve hemostasis in patients lacking FVIII (congenital hemophilia A) and its efficiency in prevention of bleeding episodes in these patients is well established. As compared to FVIII, emicizumab has several characteristics making it quite different from FVIII: (1) it is unselective toward FIX versus FIXa, (2) it does not need activation by thrombin, and (3) it is not inactivated by activated protein C (APC). On the other hand, emicizumab-mediated coagulation is regulated by APC, tissue factor pathway inhibitor, and antithrombin. Fibrin formation, followed by fibrinolysis, appears to be similar between emicizumab- and FVIIIa-mediated hemostasis. Due to its molecular and hemostatic characteristics, it might be applicable to diseases other than severe hemophilia A1. There are reports on its efficacy in mild/moderate hemophilia A, mild hemophilia B, FXI deficiency, von Willebrand disease (VWD), and acquired hemophilia A (AHA). However, a small amount of FIXa plays a key role in initiating emicizumab-mediated hemostasis. Therefore its hemostatic effect would be limited due to absence of feedback FIX-activation by FXIa in patients with FXI-deficiency and hemophilia B. Furthermore, thrombin height enhancement was modest in VWD type 1 compared with type 2 N VWD. In the near future, emicizumab will be part of the daily treatment arsenal of hemophilia treaters. It is of utmost importance that the use of tailored-based treatment with emicizumab for patients other than those with severe hemophilia A will be monitored very closely.

1. Yada K, et al. Arterioscler Thromb Vasc Biol. 2020;40(5):1148-1154.

Tuesday, May 12, 2020

Jessica Mastrodomenico: EHA/HemaSphere, The Hague, The Netherlands

HemaSphere publishes results of highly relevant basic, translational, and clinical research in hematology. We are especially interested in strong studies reporting high impact novel findings as well as hot hematology-focused topics such as CAR-T/immunotherapy, gene therapy, guidelines, EU policy, and more. Recently, we compiled a list of the top 10 most cited HemaSphere manuscripts to date. We encourage you to take a look below, starting with the most cited article to date, CAR-T Cell Therapy: Practical Considerations for Implementation in Europe. We hope you find this information useful.

Monday, May 4, 2020

David Kent: York Biomedical Research Institute, Department of Biology, University of York, York, United Kingdom

A recent study published in Nature Medicine out of Daniel Bauer's lab has explored the potential of using ribonucleoprotein (RNP) base editing for specifically targeting genes for therapy using hematopoietic stem cell transplantation.  Unlike methods that edit the genome through the non-homologous end-joining (NHEJ) repair process (as typically engaged using Cas9/guide RNA RNP complexes), this paper takes a homology-directed repair (HDR) approach by purifying and using a base editor to achieve gene delivery in blood stem cells.  HDR is more precise, but generally considered to be less efficient than NHEJ and this study essentially makes the case for being "efficient enough" to achieve a durable graft of blood stem cells with a corrected genome.  Importantly, they demonstrate this efficiency by serial transplantation of gene edited mobilized CD34+ cells in a xenograft model, showing reasonable donor cell engraftment in Figure 4.  That said, levels of engraftment in secondary transplantations were quite small compared to the primary animals suggesting that functional long-term HSCs may not be in high numbers in the donor cell suspension.  The ratio of edited to non-edited cells was fairly similar though, which indicates that low chimerism may not be specific to cells undergoing base editing.  Clearly, there remains an enormous hill to climb from a technological perspective, but this study still represents a significant step toward the overall goal of achieving precise gene editing in human patients.

Zeng J, Wu Y, Ren C, et al. Nat Med. 2020;26(4):535-541.

Thursday, April 23, 2020

Francesca Vinchi: Iron Research Program, Lindsley Kimball Research Institute, New York Blood Center, New York, New York, United States

The current coronavirus disease COVID-19 outbreak has posed a threat to global health and has turned into a major pandemic in the last decades. While COVID-19 has no effective treatment yet, it is emerging that convalescent plasma obtained from the blood of patients who recovered from COVID-19 and which contains antibodies against its causative virus SARS-CoV-2 may provide passive immunity for COVID-19 patients.

Transfusing plasma from patients who have recovered from infections has been already proven successful in the past. For COVID-19, this approach is supported by early scientific evidence and studies mainly conducted in China during the recent pandemic. Multiple works now show the beneficial effects of convalescent plasma therapy in the recovery of acute respiratory distress syndrome (ARDS) symptoms in COVID-19 patients. One of these studies authored by Duan et al shows that 10 severe COVID-19 patients transfused with a single 200 ml dose of convalescent plasma from recovered donors (with high antibody titer > 1:640) increased or maintained elevated circulating levels of neutralizing antibodies. Severe pneumonia caused by human coronavirus is hallmarked by rapid viral replication, massive inflammatory cell infiltration and elevated proinflammatory cytokines in the lungs, resulting in ARDS and pulmonary injury. Importantly, clinical symptoms were significantly improved by convalescent plasma transfusion. Oxyhemoglobin saturation was increased within 3 days, together with improved lymphocyte count and decreased C-reactive protein levels. Lung lesions, monitored radiologically, were strongly reduced by day 7. Finally, viremia became undetectable after convalescent plasma transfusion in most patients. Patients who received convalescent plasma transfusion before day 14 post infection showed more relevant improvement, suggesting that timing of plasma administration is critical for better recovery. Overall, this and parallel studies demonstrate that convalescent plasma therapy is safe and well tolerated and improves the clinical outcomes of severe pneumonia cases caused by SARS-CoV-2.

While optimal dose as well as clinical benefits require further investigation in larger cohorts, convalescent plasma therapy is easily accessible and truly promising for COVID-19 patients as it can be made widely available in short term thanks to the valuable support of blood services across the world. In the attempt to respond to the unprecedented challenge of fighting COVID-19, a worldwide effort is underway from the entire blood community to collect and provide convalescent plasma to COVID-19 patients in need. To whoever has recovered from COVID-19, please donate blood to your closest blood bank in a joint effort to help defeat the pandemic!

Duan K, Liu B, Zhang H, et al. Proc Natl Acad Sci U S A. 2020 Apr 6. [Epub ahead of print].

Figure Legend:
Convalescent plasma therapy against COVID-19 infection. Convalescent plasma therapy is more than a century old. Early versions of this therapy have been used to treat patients during the Spanish flu pandemic (1918), the diphtheria epidemic in the U.S. (1920s), a flesh-eating bacteria outbreak (1930s) and more recently the Ebola outbreak (2014). Plasma is rich in antibodies that are produced by the immune system to help clearing bacteria and viruses upon infections. The use of convalescent plasma as source of antibodies against SARS-CoV-2 is showing promising results in the improvement of ARDS symptoms in severe COVID-19 patients.

Monday, April 6, 2020

Melania Tesio: Laboratory of Onco-Hematology, Institut Necker Enfants Malades (INEM), Institut National de Recherche Médicale (INSERM) U1151, Paris, France

Natural killer/T-cell lymphoma (NKTCL) is a rare non-Hodgkin lymphoma strongly associated to Epstein-Barr virus infection. This malignancy, which originates from either NK or γδ T-cells, is clinically aggressive and challenging to diagnose owing, among other reasons, to its genetic and phenotypical heterogeneity. 

By integrating genomic, transcriptomic and clinical data from 128 newly diagnosed samples, Jie Xiong and colleagues provided an impressive characterization of this disease (Figure). Based on genomic alterations, Epstein-Barr virus sequences and transcriptional profiles, the authors identified three distinct molecular subtypes in NKTCL: the TSIM subtype (mutations in JAK-STAT pathway and TP53), the MB subtype (MGA mutations and BRDT loss of heterozygosity) and the HEA subtype (HDAC9, EP300, and ARID1A mutations).

Remarkably, this molecular classification correlated with the cell of origin as well as with the clinical outcome following asparagine-based regiments. The MB and HEA subtypes, predominantly depicting a T-cell of origin, predicted the worst and the best prognoses, respectively. In contrast, the TSIM subtype, predominantly showing an NK-cell of origin, predicted an intermediate prognosis. Last, but not least, these three molecular subtypes showed sensitivity to distinct targeted drugs.

Hence, in addition to providing important criteria for risk-based stratification, the multiomics approach undertaken by Xiong et al may open the way to novel targeted therapies for a rare but aggressive disease.

Xiong J, Cui BW, Wang N, et al. Cancer Cell. 2020;37(3):403-419.e6. 

Figure legend:
Thanks to a multi-omic approach, Xiong et al identified three subtypes of NKTCL, which correlated to the cell of origin, clinical outcome and sensitivity to distinct targeted therapies.