Issue Archive

Despite well-defined genetic and phenotypic differences, do the roots of pediatric leukemias have a common transcriptional phenotype? This is the question asked by Chen and colleagues using single-cell genomics (expression and methylation) to investigate 96 primary acute leukemia samples of myeloid, lymphoid, or mixed phenotype. The authors identify a common transcriptional signature, reminiscent of hematopoietic stem cells, in chemotherapy-resistant cells from patients destined to relapse, explore its regulation, and suggest potential treatment targets for further investigation.

It is a common misperception that tyrosine kinase inhibitor (TKI) dosing in patients with chronic myeloid leukemia is very standard and straightforward. In this Perspective, Dalgetty and Cortes highlight what we know and do not know about optimal dosing and scheduling for the various TKIs. The authors make a robust case for a dynamic approach to dosing that starts with standard regimens and is adapted according to disease state, response markers, resistance mutations, and treatment goals. Specific guidance for practice is outlined.

If you mess with the actin cytoskeleton, you disrupt immune-cell function. Immunoactinopathies are rare monogenic disorders that result from mutations in 23 actin-related genes and manifest in a variety of clinical presentations, including thrombocytopenia, immune deficiency, and growth disturbance. Hiensch and colleagues categorize immunoactinopathies based on their most distinguishing symptoms and discuss the underlying biological pathways, with the aim of aiding in diagnosis and improving patient care.

Fixed-duration venetoclax-rituximab (VenR) is standard therapy for relapsed chronic lymphocytic leukemia (CLL) based on the initial results of the randomized MURANO trial. Kater and colleagues provide a final report of this trial, with the 7-year progression-free survival (PFS) being 23% and overall survival 70%. Among patients with relapse requiring further therapy, retreatment with VenR achieved a 72% overall response rate and a median second PFS of approximately 2 years. These long-term results reinforce the utility of this regimen and validate its reuse in selected patients.

We know that the tumor microenvironment can influence treatment responses in diffuse large B-cell lymphoma (DLBCL). Using a high-fidelity murine model of activated B-cell subtype DLBCL, Garcia-Lacarte et al identified autocrine and paracrine activities of lymphoma cell–derived interleukin-10 (IL-10). These important biological effects may be exploited for tailoring immunotherapy interventions.

Burkitt lymphoma (BL) is a rare but highly aggressive CD19 B-cell malignancy affecting both children and adults, and relapse portends a dismal prognosis. Samples and colleagues report real-world outcomes from CD19-directed chimeric antigen receptor (CAR) T-cell therapy in 31 patients with relapsed BL. Unfortunately, despite a 58% response rate, the data indicate that benefit is typically short-lived, and median survival is only 6 months. The authors conclude that current CAR T-cell therapy is not indicated for BL, even as a bridge to later allograft.

von Willebrand factor (VWF), which is deficient in von Willebrand disease, is a multimeric glycoprotein essential for primary hemostasis but prothrombotic when overly abundant or active; hence, its levels need to be tightly controlled. Byrne and colleagues reveal that recombinant VWF produced in Chinese hamster ovary (CHO) cells has a longer half-life than native VWF due to an alteration in its oligosaccharide structures. Switching of the end-sugar structure reduces the interaction of VWF with clearance receptors, thereby increasing its half-life. These findings open the door to targeted glycan engineering as a strategy to develop novel extended half-life VWF therapies.

The relationship between the gut microbiota, the metabolome, and graft-versus-host disease (GVHD) is an area of intense focus given the disappointing outcomes for steroid-refractory gastrointestinal GVHD (GI GVHD). Lauder et al used integrated multiomics to describe microbial and metabolite changes between syngeneic and allogeneic transplant recipients in well-established murine models, analyzing variations by specific location in the gut and time after transplantation. The authors also identified and experimentally validated phenyl lactate as a novel regulator of GI GVHD, shedding additional light on the regulation of inflammation in the gut.

Distinct from other chimeric antigen receptor (CAR) therapies, B-cell maturation antigen–targeted CAR T-cell therapy can cause non-immune effector cell–associated neurotoxicity syndrome neurotoxicities (NINTs), typically associated with high CAR T-cell expansion that manifests as movement disorder or cranial nerve palsies and a variety of other neurological disturbances. Blumenberg et al present 13 cases of NINT, including 6 patients receiving cyclophosphamide for steroid-refractory symptoms. While steroids appear sufficient for isolated cranial nerve palsies, cyclophosphamide provides major benefits in more complex cases. This finding requires formal validation, ideally in prospective trials.