Issue Archive

Abdominal aortic aneurysm (AAA) is associated with very high mortality if rupture occurs. In this Plenary Paper, Benson and colleagues use data from surgical specimens, 2 independent case-control studies, and 2 mouse models to define a critical role for platelets in AAA formation. The authors reveal that soluble glycoprotein VI (GPVI) is both a biomarker for AAA progression and a therapeutic target. This research should prompt pursuit of GPVI-targeted strategies to improve AAA management.

There is a high unmet need for new effective therapies for myelofibrosis (MF), a chronic, progressive myeloproliferative neoplasm, but the efficacy end points currently used in trials may not be the best for identifying natural history–altering novel agents. In this Perspective, Ross and colleagues challenge regulatory dogma and provide a clear and robust roadmap for advancing clinical trial design and end point validation in MF.

Recurrence after current standard-of-care CD19 chimeric antigen receptor (CAR) T-cell therapy for B-cell acute lymphoblastic leukemia (B-ALL) is generally due to either loss of CD19 expression by leukemic cells or CAR T-cell dysfunction. In this phase 1 trial, Srinagesh et al demonstrate the safety and feasibility of administering a polymer-conjugated recombinant interleukin-15 agonist known as NKTR-255 to patients with relapsed/refractory B-ALL after infusion of a dual CD19- and CD22-targeted CAR T-cell product. The authors’ data provide impetus for further exploration of combinatorial therapy.

Wiskott-Aldrich syndrome (WAS) is an X-linked disorder characterized by eczema, microthrombocytopenia, and immunodeficiency, with difficult-to-treat inflammatory symptoms. Borrowing from experience in arthritis and inflammasomopathies, Naviglio et al show that inflammatory complications of WAS can be effectively treated with interleukin-1 blockade as a bridge to definitive therapy (stem cell transplantation or gene therapy).

Grillone et al used an unbiased screening strategy in the search for noncoding elements in the multiple myeloma (MM) genome that may be vulnerabilities. The authors demonstrate that the long noncoding RNA (lncRNA) RP11-350G8.5 negatively regulates the protein kinase RNA–like endoplasmic reticulum kinase pathway in MM to prevent the induction of immunogenic cell death and provide experimental support for targeting this lncRNA for therapeutic gain.

Myelodysplastic syndrome with isolated 5q deletion [MDS-del(5q)] displays unique biology manifested by good prognosis and unique sensitivity to lenalidomide therapy. The impact of concurrent TP53 mutation on the natural history has not been understood, leading Montoro et al to study, in this month’s CME article, TP53 mutations and allelic burden in a large cohort of patients with MDS-del(5q) and mature follow-up. The authors found that TP53 was the most frequently mutated gene, occurring in 18.9% of cases, that risk of progression to acute myeloid leukemia was higher when TP53 was mutated, and that outcomes were considerably worse when either multiple TP53 mutations were present or the allelic burden exceeded 20%.

The cold storage lesion is a major barrier to the use of refrigerated platelet concentrates. Hegde and colleagues identified that the activation of the small GTPase RAS homolog family, member A (RHOA), is necessary for the signals responsible for this lesion and that the genetic loss of RHOA makes platelets insensitive to refrigeration-induced clearance. Inhibition of RHOA ex vivo during cold storage preserves platelet survival and clotting activity of transfused platelets at similar levels as conventional room temperature–stored platelets. This research should prompt further translational research aimed at testing this approach clinically.