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My ASH “Mix Tape”: The Best of ASH Nonmalignant Sessions

December 16, 2021
Patrick Ellsworth, MD

Dr. Patrick Ellsworth (@PEllsworthMD) is an Assistant Professor of Medicine in the Division of Hematology at the University of North Carolina at Chapel Hill. He specializes in adult and pediatric hematology with interests in nonmalignant hematology, especially sickle cell disease and bleeding disorders. His research interest lies in the interaction of endothelium with blood cells via coagulation proteins. Dr. Ellsworth hails from lovely Salmon, Idaho, and currently calls Cary, North Carolina, part of the famous Research Triangle, his home. Outside of his rigorous efforts to treat patients with nonmalignant blood diseases, Dr. Ellsworth enjoys hanging out with his wife and four children. 

Writing about the “best” of ASH, I feel like a teenager again, making mix tapes to fill limited pocket space for that custom listening experience on the go. No mix tape had all my favorite songs, and I can’t possibly claim to have all the “best of ASH” here. Like the magnetic tape with limited space, this list will reflect everything from my own tastes and interests, to my mood or the weather, and are subject to change. My list includes most of the abstracts presented by Dr. Benjamin Kile during the Best of ASH session, with modifications and additions worth checking out, especially ones I didn’t already cover. 

The pediatrician in me was excited to see the work in severe congenital neutropenia (abstract 433) showing that SERF1 downregulation enhances survival of myeloid precursors affected by proximal ELANE mutations typically resistant to granulocyte colony-stimulating factor (G-CSF). This offers a therapeutic target in severe congenital neutropenia for G-CSF–resistant cases. 

Anyone who has had the painful experience of treating cold-agglutinin disease was pleased to see the success of sutimlimab, a C1s antibody, in safely increasing hemoglobin and decreasing hemolysis in these patients (abstract 349). It will likely cost more than my med school student loan balance, but it works. 

In some lab work that aligns so closely with my own interests that I couldn’t help but get excited, authors showed the role of SARS-CoV-2 ORF3a-driven externalization of phosphatidylserine as having a key role in the endotheliopathy and coagulation dysregulation with the virus (abstract 1). 

In hemoglobinopathies, Dr. Kile highlighted two abstracts involving fetal hemoglobin regulation. The first (abstract 571) reported HIC2 as a novel repressor of BCL11A via CRISPR-based genetic screens. Another group identified von Hippel-Lindau and HIF1α complexes in the oxygen-sensing pathway as regulators of fetal hemoglobin (abstract 574). In fact, when inhibiting prolyl hydroxylase domain enzymes with roxadustat (a clinically available small-molecule therapeutic), thereby increasing HIF1α degradation, hemoglobin F was successfully increased in erythroblasts. This effect was synergistic with hydroxyurea as well, giving new mechanistic targets for sickle cell disease (SCD) and thalassemia therapy. 

Other standouts to me were the abstracts featuring IMR-261 (abstract 853) and ML-0207/ASP8731 (abstract 854). These novel drugs are one part alphabet soup and one part hemoglobin F inducers. I’m a believer in oral disease-modifying therapy for SCD; IMR-261, a novel Nrf2 activator, is showing promise in hemoglobin F induction in mouse models and human cells, while ML-0207, a BACH1 inhibitor, is another small molecule therapeutic that induced hemoglobin F production in vitro, even in erythrocytes not responsive to hydroxyurea. 

Pairing nicely with these abstracts, like a nice stout with a steak, is a poster (abstract 2022) reporting the use of machine learning with RNA sequencing maps — a platform that is poorly described in my limited word count but that can enable higher-throughput identification of transcriptional regulators targetable by small molecule therapeutics. Their algorithm aims to identify hemoglobin F inducers that can outperform BCL11A knockdown, a current gene therapy approach. All aboard the fetal hemoglobin train! 

Others worth a mention are the reduction of transfusion burden in Sub-Saharan Africa with the use of hydroxyurea (abstract 11), low rates of opioid-related deaths in patients with SCD (abstract 124) and more data from a pyruvate kinase activator (abstracts 8 and 9) in SCD.  

In hemostasis, use of the tissue factor pathway inhibitor concizumab (see my hemostasis highlights piece for more on that) made another showing in the poster hall, this time showing quality of life improvements in patients with hemophilia A and B without inhibitors (abstract 1041) This is especially promising for patients with hemophilia B with inhibitors, making this a good year for hemophilia B patients. 

Another talk (abstract 1025) showed in a mouse model that an antibody to the cytokine B-cell activating factor (BAFF), when introduced in addition to splenectomy, significantly reduced the risk of high-titer inhibitors to factor VIII. This establishes the extrasplenic activity of BAFF in the immune response to exogenous FVIII and paves the way for prevention of inhibitors in patients with hemophilia A. 

Speaking of inhibitors, one of the Late-Breaking Abstracts was another fantastic clinical demonstration of basic science (abstract LBA-5). Recently published data have shown that Fc-fusion FVIII activates natural killer cells, which are subsequently capable of lysing anti-FVIII B-cells (Lagassé et al. 2021). This would seem to predict the utility of Fc-fusion proteins for immune tolerance induction. The authors of the VerITI-8 study presented first-of-its kind data successfully using an extended half-life FVIII product (Fc fusion-recombinant FVIII) as initial immune tolerance induction. 

Moving on to clotting, coagulationists love their prediction models for data-driven decisions, right? Our Austrian colleagues (abstract 775) have taken clinical prediction scoring to identify patients at especially low risk for venous thromboembolism (VTE) recurrence. It’s an important question, is clinically valuable, and refines current risk stratification practice. It tends to underestimate long-term recurrence, but it is a reasonable start. 

In a win for women with blood clots, a strong analysis (abstract 776) shows that women who have a VTE associated with combined oral contraceptives have a lower risk of VTE recurrence than women with unprovoked VTE, though clinically, many end up on neverending anticoagulation. 

Finally, in one of my favorites, the authors of the iPLAT1 study (abstract 351) used platelets cultured from induced pluripotent stem cells to transfuse a patient who was alloimmunized to platelets and refractory to donated units. They worked. They were safe. I don’t want to think about the cost of these platelets yet; I just want to imagine a world without platelet shortages for a while. 

There you have it, a small selection, but curated with just as much love as a mix tape. 

Dr. Ellsworth indicated no relevant conflicts of interest. 


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