Issue Archive

The treatment of acute myeloid leukemia (AML) continues to be challenging as the prognosis remains poor despite recent advances in the molecular characterization of the disease. Chimeric antigen receptor (CAR) T-cell therapy has been effective for B-cell lineage leukemias but not for AML. In this review, Haubner and colleagues describe preclinical and clinical studies of CAR T cells for AML, outline the challenges that must be overcome to achieve durable antileukemic responses, and propose novel strategies to increase therapeutic efficacy.

Higher-risk myelodysplastic syndromes are a life-threatening diagnosis associated with poor survival despite standard therapy. Garcia et al present the results of a phase 1b study that investigated the safety of adding venetoclax to the current standard of care with the hypomethylating agent azacitidine. The regimen was well tolerated when venetoclax doses were adjusted due to toxicity, and higher response rates were observed when compared to prior azacitidine single-agent trials. These promising results set the basis for the ongoing phase 3 randomized trial that compares this combination with azacitidine monotherapy.

Immune effector cell–associated hematotoxicity (ICAHT) is the most common chimeric antigen receptor (CAR) T-cell–related adverse event. The existing CAR-HEMATOTOX (CAR-HT) model, designed to predict the development of ICAHT, has been validated for several diseases but not for B-cell acute lymphoblastic leukemia (B-ALL), a disease associated with bone marrow involvement and severe cytopenias. In this study, Nair and colleagues employed the CAR-HT score in a cohort of patients treated with CAR T-cell therapy for relapsed/refractory B-ALL and found the model has limited power to discriminate between high- vs low-risk patients. The authors developed ALL-Hematotox, a new refined score that is applicable to B-ALL with better accuracy.

Dysregulation of the redox state characterizes aging hematopoietic stem cells (HSCs). Using a mouse model, Aoyama et al identified that antioxidant selenoprotein deficiency disrupts redox homeostasis, leading to lipid peroxidation and ferroptosis, impaired HSC self-renewal, and B-cell development, all key features of aging-related hematopoietic decline. The addition of vitamin E, a potent ferroptosis inhibitor, partially restores HSC function and B-cell maturation in mice, shedding light into potential therapeutic strategies.

Immunomodulatory drugs (IMiDs) like lenalidomide are part of standard-of-care treatment for multiple myeloma (MM). Koh et al report a novel mechanism of resistance to lenalidomide involving adenosine deaminase acting on RNA1 (ADAR1). The study showed that lenalidomide triggered the double-stranded RNA (dsRNA)–sensing pathway in MM cells, inducing interferon-mediated cellular apoptosis. Loss of ADAR1 caused endogenous dsRNA accumulation and enhanced lenalidomide sensitivity, opening a therapeutic window for ADAR1 inhibition to potentially synergize with current IMiD treatment.

Inotuzumab ozogamicin (InO) is an antibody-drug conjugate approved for the treatment of relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) with substantial efficacy but large interpatient variability in response due to resistance. Escherich et al elucidate the DNA nucleotidylexotransferase (DNTT)–induced mechanisms of resistance to InO. The authors show that loss of DNTT diminishes the sensitivity of B-ALL to InO by modulating the cellular DNA damage response and that B-ALL blasts with low DNTT expression are resistant to treatment with InO in vivo.

Philadelphia chromosome–like B-cell acute lymphoblastic leukemia (Ph-like ALL) is associated with chemotherapy resistance and high relapse rates. In this article, Ding and colleagues describe mechanisms of therapeutic escape in patient-derived xenografts of Ph-like ALL. The authors show a specific MYC dependency in Ph-like ALL cells, defining a population of cells with senescence-associated stem cell–like features that can be successfully targeted by dual inhibition of JAK/STAT and BCL2 with ruxolitinib and venetoclax.

The epigenetic mechanisms underlying disease pathogenesis in pediatric acute myeloid leukemia (AML) are poorly understood. In this study, Cui and colleagues used mitochondrial single-cell assays for transposase-accessible chromatin with sequencing to determine the single-cell and clonally resolved chromatin accessibility in samples from 28 patients with AML, demonstrating specific AML subtype epigenetic patterns and upregulation of innate immune pathways. The combination of clonal tracing with chromatin accessibility profiling provides a rich resource and advances our understanding of the epigenetic landscapes of pediatric AML, with important implications for prognosis and treatment.