Citations

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned coprimary or secondary analyses are not yet available. Clinical trial updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. Metformin has been associated with lower cancer risk in epidemiologic and preclinical research. In the MA.32 randomized adjuvant breast cancer trial, metformin ( v placebo) did not affect invasive disease-free or overall survival. Here, we report metformin effects on the risk of new cancer. Between 2010 and 2013, 3,649 patients with breast cancer younger than 75 years without diabetes with high-risk T1-3, N0-3 M0 breast cancer (any estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2) were randomly assigned to metformin 850 mg orally twice a day or placebo twice a day for 5 years. New primary invasive cancers (outside the ipsilateral breast) developing as a first event were identified. Time to events was described by the competing risks method; two-sided likelihood ratio tests adjusting for age, BMI, smoking, and alcohol intake were used to compare metformin versus placebo arms. A total of 184 patients developed new invasive cancers: 102 metformin and 82 placebo, hazard ratio (HR), 1.25; 95% CI, 0.94 to 1.68; P = .13. These included 48 contralateral invasive breast cancers (27 metformin v 21 placebo), HR, 1.29; 95% CI, 0.72 to 2.27; P = .40 and 136 new nonbreast primary cancers (75 metformin v 61 placebo), HR, 1.24; 95% CI, 0.88 to 1.74; P = .21. Metformin did not reduce the risk of new cancer development in these nondiabetic patients with breast cancer.

Abstract Acute myeloid leukemia (AML), an aggressive malignancy with unmet medical need, lacks immunotherapeutic options. CD123, the cellular receptor for interleukin-3, expressed in AML is an attractive target for tumor-specific therapy. Vibecotamab (XmAb14045), a humanized bispecific antibody, monovalently binds both CD3 and CD123 to recruit cytotoxic T cells to kill CD123+ tumor cells. This phase 1 study’s primary objectives were safety and tolerability and identification of a maximum tolerated dose/recommended dose for use as monotherapy in patients with relapsed/refractory AML. Identification of a recommended phase 2 vibecotamab dose comprised 3 step-up doses (Week 1), which were noted to reduce cytokine response syndrome (CRS), followed by weekly dosing (1.7 μg/kg, Cohort -1D). In 16 of 120 patients, at least 1 treatment-emergent adverse event was classified as a dose-limiting toxicity. CRS, the most common adverse event (59.2%), managed with premedication, were mostly ≤grade 2. A secondary objective was assessment of efficacy in patients with CD123-expressing leukemias. A total of 10 of 111 (9.0%) efficacy-evaluable patients with AML achieved an overall response of morphologic leukemia-free state or better with an overall objective response rate (ORR) of 9.0%. Response was only observed in patients receiving a target dose of 0.75 μg/kg or higher (n = 87) in which the efficacy-evaluable ORR was 11.5%. Response was associated with lower baseline blast counts in blood and bone marrow (<25%) suggesting potential benefit. This trial was registered at www.clinicaltrials.gov as #NCT02730312.

The NCCN Guidelines for Survivorship are intended to help healthcare professionals address the complex and varied needs of cancer survivors. The NCCN Guidelines provide screening, evaluation, and treatment recommendations for psychosocial and physical problems resulting from adult-onset cancer and its treatment; recommendations to help promote healthy behaviors and immunizations in survivors; and a framework for care coordination. These NCCN Guidelines Insights summarize recent guideline updates and panel discussions pertaining to sleep disorders, fatigue, and cognitive function in cancer survivors.

This selection from the NCCN Guidelines for Adolescent and Young Adult (AYA) Oncology focuses on considerations for the comprehensive care of AYA patients with cancer. Compared with older adults with cancer, AYA patients have unique needs regarding treatment, fertility counseling, psychosocial and behavioral issues, and supportive care services. The complete version of the NCCN Guidelines for Adolescent and Young Adult (AYA) Oncology addresses additional aspects of caring for AYA patients, including risk factors, screening, diagnosis, and survivorship.

Background and Aims: Fatty liver disease is a major public health threat due to its very high prevalence and related morbidity and mortality. Focused and dedicated interventions are urgently needed to target disease prevention, treatment, and care. Approach and Results: We developed an aligned, prioritized action agenda for the global fatty liver disease community of practice. Following a Delphi methodology over 2 rounds, a large panel (R1 n = 344, R2 n = 288) reviewed the action priorities using Qualtrics XM, indicating agreement using a 4-point Likert-scale and providing written feedback. Priorities were revised between rounds, and in R2, panelists also ranked the priorities within 6 domains: epidemiology, treatment and care, models of care, education and awareness, patient and community perspectives, and leadership and public health policy. The consensus fatty liver disease action agenda encompasses 29 priorities. In R2, the mean percentage of “agree” responses was 82.4%, with all individual priorities having at least a super-majority of agreement (> 66.7% “agree”). The highest-ranked action priorities included collaboration between liver specialists and primary care doctors on early diagnosis, action to address the needs of people living with multiple morbidities, and the incorporation of fatty liver disease into relevant non-communicable disease strategies and guidance. Conclusions: This consensus-driven multidisciplinary fatty liver disease action agenda developed by care providers, clinical researchers, and public health and policy experts provides a path to reduce the prevalence of fatty liver disease and improve health outcomes. To implement this agenda, concerted efforts will be needed at the global, regional, and national levels.

Apart from ancestry, personal or environmental covariates may contribute to differences in polygenic score (PGS) performance. We analyzed the effects of covariate stratification and interaction on body mass index (BMI) PGS (PGS BMI ) across four cohorts of European (N = 491,111) and African (N = 21,612) ancestry. Stratifying on binary covariates and quintiles for continuous covariates, 18/62 covariates had significant and replicable R 2 differences among strata. Covariates with the largest differences included age, sex, blood lipids, physical activity, and alcohol consumption, with R 2 being nearly double between best- and worst-performing quintiles for certain covariates. Twenty-eight covariates had significant PGS BMI –covariate interaction effects, modifying PGS BMI effects by nearly 20% per standard deviation change. We observed overlap between covariates that had significant R 2 differences among strata and interaction effects – across all covariates, their main effects on BMI were correlated with their maximum R 2 differences and interaction effects (0.56 and 0.58, respectively), suggesting high-PGS BMI individuals have highest R 2 and increase in PGS effect. Using quantile regression, we show the effect of PGS BMI increases as BMI itself increases, and that these differences in effects are directly related to differences in R 2 when stratifying by different covariates. Given significant and replicable evidence for context-specific PGS BMI performance and effects, we investigated ways to increase model performance taking into account nonlinear effects. Machine learning models (neural networks) increased relative model R 2 (mean 23%) across datasets. Finally, creating PGS BMI directly from GxAge genome-wide association studies effects increased relative R 2 by 7.8%. These results demonstrate that certain covariates, especially those most associated with BMI, significantly affect both PGS BMI performance and effects across diverse cohorts and ancestries, and we provide avenues to improve model performance that consider these effects.

Abstract Objectives We investigated coronavirus disease 2019 (COVID-19) vaccine safety in pregnant and breastfeeding women with autoimmune diseases (AID) in the COVID-19 Vaccination in Autoimmune Diseases (COVAD) study. Methods Delayed-onset (>7 days) vaccine-related adverse events (AE), disease flares and AID-related treatment modifications were analysed upon diagnosis of AID vs healthy controls (HC) and the pregnancy/breastfeeding status at the time of at least one dose of vaccine. Results Among the 9201 participants to the self-administered online survey, 6787 (73.8%) were women. Forty pregnant and 52 breastfeeding patients with AID were identified, of whom the majority had received at least one dose of COVID-19 vaccine (100% and 96.2%, respectively). AE were reported significantly more frequently in pregnant than in non-pregnant patients (overall AE 45% vs 26%, P = 0.01; minor AE 40% vs 25.9%, P = 0.03; major AE 17.5% vs 4.6%, P < 0.01), but no difference was found in comparison with pregnant HC. No difference was observed between breastfeeding patients and HC with respect to AE. Post-vaccination disease flares were reported by 17.5% of pregnant and 20% of breastfeeding patients, and by 18.3% of age- and disease-matched non-pregnant and non-breastfeeding patients (n = 262). All pregnant/breastfeeding patients who experienced a disease flare were managed with glucocorticoids; 28.6% and 20% of them required initiation or change in immunosuppressants, respectively. Conclusion This study provides reassuring insights into the safety of COVID-19 vaccines administered to women with AID during the gestational and post-partum periods, helping overcome hesitant attitudes, as the benefits for the mother and for the fetus by passive immunization appear to outweigh potential risks.

AbstractNext-generation sequencing (NGS) to identify pathogenic mutations is an integral part of acute myeloid leukemia (AML) therapeutic decision-making. The concordance in identifying pathogenic mutations among different NGS platforms at different diagnostic laboratories has been studied in solid tumors but not in myeloid malignancies to date. To determine this interlaboratory concordance, we collected a total of 194 AML bone marrow or peripheral blood samples from newly diagnosed patients with AML enrolled in the Beat AML Master Trial (BAMT) at 2 academic institutions. We analyzed the diagnostic samples from patients with AML for the detection of pathogenic myeloid mutations in 8 genes (DNMT3A, FLT3, IDH1, IDH2, NPM1, TET2, TP53, and WT1) locally using the Hematologic Neoplasm Mutation Panel (50-gene myeloid indication filter) (site 1) or the GeneTrails Comprehensive Heme Panel (site 2) at the 2 institutions and compared them with the central results from the diagnostic laboratory for the BAMT, Foundation Medicine, Inc. The overall percent agreement was over 95% each in all 8 genes, with almost perfect agreement (κ > 0.906) in all but WT1, which had substantial agreement (κ = 0.848) when controlling for site. The minimal discrepancies were due to reporting variants of unknown significance (VUS) for the WT1 and TP53 genes. These results indicate that the various NGS methods used to analyze samples from patients with AML enrolled in the BAMT show high concordance, a reassuring finding given the wide use of NGS for therapeutic decision-making in AML.