Citations

Abstract VEXAS (vacuoles, E1-ubiquitin-like modifier activating enzyme, X-linked, autoinflammatory, somatic) syndrome is a recently described autoinflammatory disorder caused by acquired UBA1 mutations in hematopoietic precursor cells. The prevalence, clinical significance, and genomic landscape of UBA1variants in patients with hematologic malignancies (HM) remains unexplored. We analyzed the genomic profiles of 86 patients carrying 17 different UBA1variants amongst an unbiased cohort of 8,976 HM patients. Specific genetic and clinical features seen more frequently in patients with UBA1 pathogenic variants (PV) versus those with variants of uncertain significance (VUS) included: marked male predominance (98% versus 80%, P=0.002), macrocytic anemia (MCV 105 ± 1.4 fl versus 96 ± 1.4 fl, p=0.01), frequent dominant clones without concurrent somatic variants (53% versus 15%, p=0.004), and association with molecularly distinct low-risk myelodysplastic syndrome (MDS; 13%) with superior overall survival (OS). Interestingly, while the genetic profiles of UBA1 PV patients resemble patients with clonal cytopenia of unknown significance (CCUS), rapid UBA1 clonal expansion predispose patients to convert to low-grade MDS with a notably hastened progression compared to UBA1 wild-type CCUS. This “clone surge to clinical stability” (CS) is a mechanism that emphasizes the unique pathobiology of UBA1mutations in VEXAS and supports it as a distinct entity.

Abstract The dismal outcome of acute leukemia undergoing immunophenotype-switch, compounded by the increased incidence in the era of immunotherapy, highlights the need for in-depth systemic studies. We investigated the clinicopathological, cytogenetic, and molecular features of 33 patients experiencing switch between acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). The median duration from the primary diagnosis to lineage switch was 7.8 months, with the subsequent median survival being < 3 months. The majority experienced a transition from B-ALL to AML. The AML cases demonstrated a spectrum of differentiation, ranging from minimal to erythroid, with monocytic being the most common. Cytogenetic analysis revealed 11q23/KMT2A fusions as the most recurrent abnormalities (n = 18); also observed were complex karyotype, 7/7q-, 9p-/CDKN2A deletion, t(5;14)/TCLX3::BCL11b, t(8;9)/PCM1::JAK2, t(9;22)/BCR::ABL1, and t(12;19)/TCF3::ZNF384. Remarkably, in 60% of patients lacking KMT2A fusions, a chronic myeloid neoplasm was observed preceding the first leukemia. In contrast, no prior hematological malignancies were observed in KMT2A cases. Deep mutational profiling reinforced the inherent clonal relationship between the initial and subsequent leukemias, evident from the overlapping mutational signatures. The presence of distinct additional mutations across the two phases supports the long-standing theory of lineage switch emerging via divergent evolution of a multipotential progenitor.

Background: Due to lacking evidence on surveillance for gastric cancer (GC), this study aimed to determine the optimal postsurgical surveillance strategy for pathological stage (pStage) II/III GC patients and compare its cost-effectiveness with traditional surveillance strategies. Methods: Prospectively collected data from stage II/III GC patients (n=1661) who underwent upfront surgery at a large-volume tertiary cancer center in China (FJMUUH cohort) between January 2010 and October 2015. For external validation, two independent cohorts were included, which were composed of 380 stage II/III GC patients at an tertiary cancer center in U.S.A (Mayo cohort) between July 1991 and July 2012 and 270 stage II/III GC patients at another tertiary cancer center in China (QUAH cohort) between May 2010 and October 2014. Random forest models were used to predict dynamic recurrence hazards and to construct individual surveillance strategies for stage II/III GC. Cost-effectiveness was assessed by the Markov model. Results: The median follow-up period of the FJMUUH, the Mayo, and QUAH cohorts were 55, 158, and 70 months, respectively. In the FJMUUH cohort, the 5-year recurrence risk was higher in pStage III compared with pStage II GC patients (P<0.001). Our novel individual surveillance strategy achieved optimal cost-effectiveness for pStage II GC patients (ICER =$490/QALY). The most intensive NCCN surveillance guideline was more cost-effective (ICER =$983/QALY) for pStage III GC patients. The external validations confirmed our results. Conclusion: For patients with pStage II GC, individualized risk-based surveillance outperformed the JGCTG and NCCN surveillance guidelines. However, the NCCN surveillance guideline may be more suitable for patients with pStage III GC. Even though our results are limited by the retrospective study design, the authors believe that our findings should be considered when recommending postoperative surveillance for stage II/III GC with upfront surgery in the absence of a randomized clinical trial.