TP53 mutations are associated with unfavorable survival in many hematologic malignancies. However, the impact of TP53 mutations and their variant allele frequency (VAF) in acute lymphoblastic leukemia (ALL) remains unclear. We retrospectively analyzed TP53 mutations and their VAF in newly diagnosed ALL. The overall incidence of TP53 mutations was 17.2%; TP53 mutations were more common in older patients (median age, 61 vs 45 years; P< .001) and in those with Philadelphia chromosome-negative (Ph-) negative B-cell ALL (28% vs 3% in others; P< .001). The median TP53 VAF was 42% (range, 1-94). Patients aged ≥60 years with Ph- B-cell ALL and TP53 VAF ≥45% had poor outcomes, with 4-year event-free survival (EFS) and overall survival (OS) of 28%, driven primarily by increased relapse risk, even among patients treated with frontline inotuzumab ozogamicin (INO) and/or blinatumomab. Among patients aged <60 years who received frontline INO and/or blinatumomab, neither TP53 mutation nor VAF affected EFS or OS. However, younger patients with TP53 VAF ≥45% had higher 4-year cumulative incidence of relapse (35%) than those with VAF <45% (8%) or wild-type TP53 and no high-risk features (4%). In multivariate analysis, TP53 VAF ≥45% was independently associated with worse outcomes in patients aged ≥60 years, but neither TP53 status nor VAF predicted outcomes in younger patients. TP53 persistence at remission occurred in 44% of tested patients and was associated with increased ALL relapse risk. These results demonstrate that TP53 VAF is prognostic in older patients with Ph- B-cell ALL; high VAF may increase relapse risk but is not independently associated with survival in younger patients.

In this study, 108 pediatric patients with bone marrow (BM) failure and leukemia predisposition were evaluated for presence of clonal hematopoiesis in peripheral blood (PB) and BM. Robust PB-BM concordance for mutations but decreased sensitivity in PB for chromosomal abnormalities was found.

Advanced phases of Philadelphia chromosome-positive chronic myeloid leukemia (CML), classically encompassing de novo presentation of accelerated-phase disease and blast-phase disease (myeloid and lymphoid "blast crisis") and progression to these from antecedent chronic-phase disease, have diminished in incidence but remain a challenge. Despite continued development of additional and novel kinase inhibitors of BCR::ABL1, global limitations on access to diagnostics and therapy persist and account for continued incidence of advanced disease at initial presentation and progressive disease. Evolution in defining risk through clinical and molecular characterization should increase ability to identify emerging advanced disease, minimize progression, and improve treatment of resistant chronic-phase and blast-phase diseases. While BCR::ABL1 tyrosine kinase inhibition remains central in advanced disease, combination therapy with conventional and novel chemotherapy, immunotherapy, and allogeneic stem cell transplant provide best long-term outcomes.

Anaplastic large cell lymphomas (ALCLs) are CD30+ T-cell lymphomas that share pathologic features but differ in presentation, outcome, and genetics. Current classification incorporates clinical presentation and anaplastic lymphoma kinase (ALK) status but inadequately addresses molecular heterogeneity and therapeutic vulnerabilities. We studied 689 patients with ALCL in the LLMPP (Lymphoma/Leukemia Molecular Profiling Project) and performed expert consensus review, genetic subtyping (ALK, DUSP22, TP63, and triple negative), and immunohistochemistry for phosphorylated STAT3Tyr705. RNA sequencing with unsupervised gene expression profiling in 393 patients identified 2 main molecular types of ALCL that could be predicted with 91% accuracy based on the presence (type I) or absence (type II) of phosphorylated STAT3Y705 expression. Type I ALCLs included ALK+ ALCL and a subset of triple-negative ALCLs (TN-I); type II ALCLs included tumors with DUSP22 and/or TP63 rearrangements and the remaining triple-negative ALCLs (TN-II). Type I ALCLs were enriched for JAK-STAT3, whereas type II ALCLs were enriched for non-tyrosine kinase pathways, particularly epigenetic regulators such as EZH2. Immunohistochemistry showed overexpression of EZH2 and its trimethylated substrate H3K27. Prognosis in systemic ALCL was favorable for DUSP22-rearranged ALCL (5-year overall survival, 95%) and ALK+ ALCL (88%), intermediate for triple-negative ALCL (TN-I, 52% and TN-II, 37%), and poor for TP63-rearranged ALCL (0%). We introduce an integrated molecular classification that preserves currently diagnosed ALCL entities but identifies 4 molecularly distinct ALK- ALCL subtypes (DUSP22-rearranged, TP63-rearranged, TN-I, and TN-II). This classification can be easily implemented on paraffin tissue in routine practice or clinical trials, and stratifies ALCL into diagnostically, prognostically, biologically, and potentially therapeutically relevant subtypes.

Chronic granulomatous disease (CGD) is an inborn error of immunity associated with a 50% prevalence of inflammatory bowel disease (IBD) for which current treatments are suboptimal due to the increased risk of infections in this population. CGD results from defects in the nicotinamide adenine dinucleotide phosphate oxidase 2 complex, leading to minimal or absent phagocyte-derived reactive oxygen species production. Patients with CGD present with recurrent infections and severe inflammatory complications, especially in the gut. These inflammatory complications have been associated with the increased systemic activation of the nucleotide-binding domain and leucine-rich-repeat-containing protein 3 (NLRP3) inflammasome and dysregulation of the T-cell compartment. However, the role of the NLRP3 inflammasome at the intestinal barrier and whether it can be targeted to treat CGD-associated IBD (CGD-IBD) remain unclear. β-Hydroxybutyrate (βHB), a ketone body produced during fasting or adherence to a ketogenic diet, can inhibit the NLRP3 inflammasome and restore T-cell balance. In this preclinical study, we demonstrated that a ketogenic diet significantly improves colitis in CGD mice, to a greater extent than in wild-type mice, by reducing NLRP3 inflammasome activity, altering the microbiota, and inducing tolerogenic immune populations at the intestinal mucosal barrier. We also showed that βHB supplementation could significantly improve colitis in CGD mice and decrease systemic inflammation. We further confirmed that, in the blood cells of humans with CGD, βHB effectively reduces the levels of cytokines associated with inflammasome activation. In conclusion, our study identified that NLRP3 inflammasome blockade using a ketogenic diet or βHB supplementation is a potential novel and safer treatment for CGD-IBD.