Citations

Abstract Background: Acute myeloid leukemia (AML) with TP53 alteration (TP53alt), including deletion (TP53del) detected by cytogenetics (CG) (karyotype, FISH, or genomic microarray) and/or TP53 mutation (TP53mut) identified by next-generation sequencing, is associated with poor prognosis. However, a subset of patients may achieve long-term survival after allogeneic hematopoietic cell transplantation (allo-HCT). Patient-, disease-, and transplant-related variables may inform risk stratification and improve treatment decision-making in this high-risk population. We used the CIBMTR registry to investigate outcomes of patients with TP53alt AML undergoing allo-HCT. Methods: We included adult patients with 2017 ELN adverse-risk AML who underwent first allo-HCT between 2013–2019 and had available CG and molecular data. TP53del was centrally reviewed by expert cytogeneticist. Patients were stratified into three TP53alt groups: Group 1 (TP53mut+/ TP53del+), Group 2 (TP53mut −/ TP53del+), and Group 3 (TP53mut+/ TP53del −). The control group comprised patients with 2017 ELN adverse-risk AML negative for both TP53mut and TP53del. Patients from embargoed centers, lacking consent or comprehensive research data, or missing CG and molecular information were excluded. Results: Of 6,474 patients with adverse-risk AML, 703 patients with TP53alt met inclusion criteria: Group 1 (n=203), Group 2 (n=271), Group 3 (n=229). The control group included 2,763 patients. Median age was 58 years (44% ≥60); 44% were female; 16% had Karnofsky score <90, and 52% had HCT-CI ≥3. Secondary AML was more frequent in TP53alt groups (32%, 27%, 27%) versus control (21%) (p<.01). Complex and monosomal karyotypes were most common in Group 1 (61%), followed by Group 2 (54%), Group 3 (31%), and control (6%), p<.01. More patients in Groups 1 and 2 (28% each) underwent HCT in primary induction failure/relapse (PIF/Rel) versus Group 3 (19%) and control (19%), p<.01. Median time from diagnosis to transplant was 5 months (1-331). Donor type was matched related in 23%, matched or mismatched unrelated in 50%, haploidentical in 18%, and umbilical cord blood in 7%. Conditioning intensity was myeloablative (MA) in 51%; reduced-intensity (RIC) in 36% , and 13% non-MA (NMA). Post-transplant cyclophosphamide (PTCy) was used in 27%; and in vivo T-cell depletion (ATG or alemtuzumab) in 26%. After median follow-up of 66 months (3-130), 5-yr OS was 18% (Group 1), 18% (Group 2), 35% (Group 3) vs 46% in controls (p<0.001). 5-yr LFS was 14%, 15%, and 28%, respectively, vs 38% (p<0.001). 5-yr CIR was 69%, 66%, and 52% vs 43% (p<0.001). Transplant-related mortality (TRM) was similar across groups (1-year: 12–16%). On multivariate analysis, compared with controls, TP53del (with or without TP53mut) was independently associated with higher relapse risk: Group 1 HR 1.97, Group 2 HR 1.91, Group 3 HR 1.45 (all p<0.001). These findings translated into inferior OS (HR 1.94, 1.87, and 1.45, respectively, p<0.001). PIF/Rel and CR2+ were also associated with worse survival (HR 2.58 (p<0.001) and 1.18 (p<0.001, respectively). No significant difference was observed between MA and RIC for relapse, while non-myeloablative regimens (HR 1.65; p<0.001) were associated with higher CIR. In vivo T-cell depletion increased relapse risk (HR 1.22; p=0.004). TRM was not influenced by TP53alt status; it was impacted by age, KPS, time from diagnosis to HCT, and GVHD prophylaxis regiment (non-PTCy). Conclusions: This large, registry-based study with long term median follow-up showed that among patients with adverse-risk AML, TP53alt is a strong independent predictor of poor post-HCT outcomes in AML, particularly when TP53del is present. Patients with TP53del , with or without concurrent TP53mut, experienced the worst outcomes, followed by those with isolated TP53mut. Despite the limitations of registry data including lack of information on timing of TP53mut, variant allele frequency (VAF), number of mutations, or accurate information on measurable residual disease (MRD), these findings reinforce the adverse prognostic impact of TP53alt and support its inclusion in risk stratification frameworks. While some patients with TP53alt —particularly those with isolated mutations—may benefit from allo-HCT, relapse remains the dominant cause of failure. Future studies incorporating TP53 functional status, VAF, clonal architecture, specific CG, MRD, and novel transplant approaches are warranted.

ABSTRACT Objective Despite high stand‐alone performance, studies demonstrate that artificial intelligence (AI)‐supported endoscopic diagnostics often fall short in clinical applications due to human‐AI interaction factors. This video‐based trial on Barrett's esophagus aimed to investigate how examiner behavior, their levels of confidence, and system usability influence the diagnostic outcomes of AI‐assisted endoscopy. Methods The present analysis employed data from a multicenter randomized controlled tandem video trial involving 22 endoscopists with varying degrees of expertise. Participants were tasked with evaluating a set of 96 endoscopic videos of Barrett's esophagus in two distinct rounds, with and without AI assistance. Diagnostic confidence levels were recorded, and decision changes were categorized according to the AI prediction. Additional surveys assessed user experience and system usability ratings. Results AI assistance significantly increased examiner confidence levels ( p < 0.001) and accuracy. Withdrawing AI assistance decreased confidence ( p < 0.001), but not accuracy. Experts consistently reported higher confidence than non‐experts ( p < 0.001), regardless of performance. Despite improved confidence, correct AI guidance was disregarded in 16% of all cases, and 9% of initially correct diagnoses were changed to incorrect ones. Overreliance on AI, algorithm aversion, and uncertainty in AI predictions were identified as key factors influencing outcomes. The System Usability Scale questionnaire scores indicated good to excellent usability, with non‐experts scoring 73.5 and experts 85.6. Conclusions Our findings highlight the pivotal function of examiner behavior in AI‐assisted endoscopy. To fully realize the benefits of AI, implementing explainable AI, improving user interfaces, and providing targeted training are essential. Addressing these factors could enhance diagnostic accuracy and confidence in clinical practice.

Abstract ZUMA-8 evaluated the safety of brexucabtagene autoleucel (brexu-cel), a CD19-directed autologous chimeric antigen receptor (CAR) T-cell immunotherapy, for patients with relapsed/refractory chronic lymphocytic leukemia (R/R CLL). Patients with ≥2 prior lines of therapy (including a Bruton tyrosine kinase inhibitor) underwent leukapheresis, optional bridging therapy, and conditioning chemotherapy (fludarabine/cyclophosphamide) before infusion of 1 × 106 (cohort 1) or 2 × 106 (cohort 2) anti-CD19 CAR T cells per kg. Patients in cohort 3 (low tumor burden), and cohort 4A (postibrutinib) received 1 × 106 cells per kg. Fifteen patients, median age of 63 years (range, 52-79), were treated in cohorts 1 (n = 6), 2 (n = 3), 3 (n = 3), and 4A (n = 3). Median follow-up was 24.3 months. One dose-limiting toxicity was observed in cohort 3 (grade 4 cytokine release syndrome). Grade ≥3 neurologic events occurred in 3 patients (20%). Seven of 15 patients responded (overall response rate, 47%; complete response [CR], 7%), including all 3 patients in cohort 3 (1 with CR). CAR T-cell expansion occurred in 4 patients (27%), with an apparent weak inverse correlation with absolute lymphocyte count before apheresis. Brexu-cel had no new safety signals in R/R CLL. CAR T-cell expansion and responses occurred in patients with low tumor burden. This trial was registered at www.clinicaltrials.gov as #NCT03624036.

Abstract Background This study evaluated the effect of an artificial intelligence (AI)-based clinical decision support system on the performance and diagnostic confidence of endoscopists in their assessment of Barrett’s esophagus (BE). Methods 96 standardized endoscopy videos were assessed by 22 endoscopists with varying degrees of BE experience from 12 centers. Assessment was randomized into two video sets: group A (review first without AI and second with AI) and group B (review first with AI and second without AI). Endoscopists were required to evaluate each video for the presence of Barrett’s esophagus-related neoplasia (BERN) and then decide on a spot for a targeted biopsy. After the second assessment, they were allowed to change their clinical decision and confidence level. Results AI had a stand-alone sensitivity, specificity, and accuracy of 92.2%, 68.9%, and 81.3%, respectively. Without AI, BE experts had an overall sensitivity, specificity, and accuracy of 83.3%, 58.1%, and 71.5%, respectively. With AI, BE nonexperts showed a significant improvement in sensitivity and specificity when videos were assessed a second time with AI (sensitivity 69.8% [95%CI 65.2%–74.2%] to 78.0% [95%CI 74.0%–82.0%]; specificity 67.3% [95%CI 62.5%–72.2%] to 72.7% [95%CI 68.2%–77.3%]). In addition, the diagnostic confidence of BE nonexperts improved significantly with AI. Conclusion BE nonexperts benefitted significantly from additional AI. BE experts and nonexperts remained significantly below the stand-alone performance of AI, suggesting that there may be other factors influencing endoscopists’ decisions to follow or discard AI advice.

PURPOSE Allogeneic hematopoietic cell transplantation (HCT) improves outcomes for patients with AML harboring an internal tandem duplication mutation of FLT3 ( FLT3-ITD) AML. These patients are routinely treated with a FLT3 inhibitor after HCT, but there is limited evidence to support this. Accordingly, we conducted a randomized trial of post-HCT maintenance with the FLT3 inhibitor gilteritinib (ClinicalTrials.gov identifier: NCT02997202 ) to determine if all such patients benefit or if detection of measurable residual disease (MRD) could identify those who might benefit. METHODS Adults with FLT3-ITD AML in first remission underwent HCT and were randomly assigned to placebo or 120 mg once daily gilteritinib for 24 months after HCT. The primary end point was relapse-free survival (RFS). Secondary end points included overall survival (OS) and the effect of MRD pre- and post-HCT on RFS and OS. RESULTS Three hundred fifty-six participants were randomly assigned post-HCT to receive gilteritinib or placebo. Although RFS was higher in the gilteritinib arm, the difference was not statistically significant (hazard ratio [HR], 0.679 [95% CI, 0.459 to 1.005]; two-sided P = .0518). However, 50.5% of participants had MRD detectable pre- or post-HCT, and, in a prespecified subgroup analysis, gilteritinib was beneficial in this population (HR, 0.515 [95% CI, 0.316 to 0.838]; P = .0065). Those without detectable MRD showed no benefit (HR, 1.213 [95% CI, 0.616 to 2.387]; P = .575). CONCLUSION Although the overall improvement in RFS was not statistically significant, RFS was higher for participants with detectable FLT3-ITD MRD pre- or post-HCT who received gilteritinib treatment. To our knowledge, these data are among the first to support the effectiveness of MRD-based post-HCT therapy.

Abstract Purpose: Treatment options are limited beyond JAK inhibitors for patients with primary myelofibrosis (MF) or secondary MF. Preclinical studies have revealed that PI3Kδ inhibition cooperates with ruxolitinib, a JAK1/2 inhibitor, to reduce proliferation and induce apoptosis of JAK2V617F-mutant cell lines. Patients and Methods: In a phase I dose-escalation and -expansion study, we evaluated the safety and efficacy of a selective PI3Kδ inhibitor, umbralisib, in combination with ruxolitinib in patients with MF who had a suboptimal response or lost response to ruxolitinib. Enrolled subjects were required to be on a stable dose of ruxolitinib for ≥8 weeks and continue that MTD at study enrollment. The recommended dose of umbralisib in combination with ruxolitinib was determined using a modified 3+3 dose-escalation design. Safety, pharmacokinetics, and efficacy outcomes were evaluated, and spleen size was measured with a novel automated digital atlas. Results: Thirty-seven patients with MF (median age, 67 years) with prior exposure to ruxolitinib were enrolled. A total of 2 patients treated with 800 mg umbralisib experienced reversible grade 3 asymptomatic pancreatic enzyme elevation, but no dose-limiting toxicities were seen at lower umbralisib doses. Two patients (5%) achieved a durable complete response, and 12 patients (32%) met the International Working Group-Myeloproliferative Neoplasms Research and Treatment response criteria of clinical improvement. With a median follow-up of 50.3 months for censored patients, overall survival was greater than 70% after 3 years of follow-up. Conclusions: Adding umbralisib to ruxolitinib in patients was well tolerated and may resensitize patients with MF to ruxolitinib without unacceptable rates of adverse events seen with earlier generation PI3Kδ inhibitors. Randomized trials testing umbralisib in the treatment of MF should be pursued.

The number of artificial intelligence (AI) tools for colonoscopy on the market is increasing with supporting clinical evidence. Nevertheless, their implementation is not going smoothly for a variety of reasons, including lack of data on clinical benefits and cost‐effectiveness, lack of trustworthy guidelines, uncertain indications, and cost for implementation. To address this issue and better guide practitioners, the World Endoscopy Organization (WEO) has provided its perspective about the status of AI in colonoscopy as the position statement. WEO Position Statement: Statement 1.1: Computer‐aided detection (CADe) for colorectal polyps is likely to improve colonoscopy effectiveness by reducing adenoma miss rates and thus increase adenoma detection; Statement 1.2: In the short term, use of CADe is likely to increase health‐care costs by detecting more adenomas; Statement 1.3: In the long term, the increased cost by CADe could be balanced by savings in costs related to cancer treatment (surgery, chemotherapy, palliative care) due to CADe‐related cancer prevention; Statement 1.4: Health‐care delivery systems and authorities should evaluate the cost‐effectiveness of CADe to support its use in clinical practice; Statement 2.1: Computer‐aided diagnosis (CADx) for diminutive polyps (≤5 mm), when it has sufficient accuracy, is expected to reduce health‐care costs by reducing polypectomies, pathological examinations, or both; Statement 2.2: Health‐care delivery systems and authorities should evaluate the cost‐effectiveness of CADx to support its use in clinical practice; Statement 3: We recommend that a broad range of high‐quality cost‐effectiveness research should be undertaken to understand whether AI implementation benefits populations and societies in different health‐care systems.