Frameshift Mutations in Leukemia-Associated Genes Correlate With Superior Outcomes in Patients Undergoing Allogeneic Stem Cell Transplant for De Novo Acute Myeloid Leukemia.

Background: Allogeneic stem cell transplant (allo-SCT) is a mainstay of treatment for acute myeloid leukemia (AML). Its success depends largely on response of donor T lymphocytes against leukemia cells, known as graft-vs-leukemia (GvL) effect. A key potential driver of GvL is immune response to mutation-derived neoantigens. Previous studies in solid tumors have demonstrated enhanced immunogenicity of frameshift (FS)-derived peptides vs. those from non-synonymous single nucleotide variants (SNVs). We therefore hypothesized that AML cases bearing FS mutations in leukemia-associated genes would be more immunogenic than those with only other types of mutations (non-FS), and thus benefit more from allo-SCT via more robust GvL. Methods: We identified AML patients who had undergone allo-SCT between 2010 and 2022 and had next-generation sequencing data available on diagnostic specimens using a 42-gene hot spot panel. We compared the impact of tumor mutations present at diagnosis on overall survival and relapse-free survival based on FS versus non-FS status. Results: Ninety-five AML allo-SCT patients were identified. We observed superior relapse-free survival (P = 0.038, hazard ratio (HR): 0.24) and borderline superior overall survival (P = 0.058, HR: 0.55) post-transplant in de novo AML patients, who had at least one FS mutation (other than NPM1) in one of the 42 assessed genes versus those with only non-FS mutations. Conclusions: Our findings suggest that FS-mutated AML cases may benefit more from allo-SCT than those with only non-FS mutations, possibly due to increased generation of immunogenic neoepitopes. If validated in an expanded study, incorporation of somatic FS mutation status in AML could improve patient selection algorithms for bone marrow transplant and thereby lead to superior outcomes.

Translational insights into the genetics and immunobiology of relapsed/refractory follicular lymphoma.

Although follicular lymphoma (FL) is traditionally classified as an indolent subtype of B cell non-Hodgkin lymphoma, clinical trajectories are often diverse based on unique disease biology, and many patients will eventually experience relapse of their disease. Furthermore, progression of disease within 24 months is associated with increased mortality rates for FL. In the last five years, we have witnessed an upsurge in the commercial availability of targeted therapies for relapsed/refractory (R/R) FL, including chimeric antigen receptor-T (CAR-T) products, bispecific T cell engagers (BiTEs), epigenetic modifier therapies, and next-generation Bruton tyrosine kinase (BTK) inhibitors. Furthermore, clinical trial options have increased tremendously and now include combinatorial strategies that exert synergy against malignant germinal center B cells. Here, we provide a 2024 update of novel therapeutic agents whose development has been informed by recent advances in the genetics and immunobiology of R/R FL. Specifically, we emphasize high-value targeted therapeutics, including anti-CD3 x anti-CD20 BiTEs and adoptive T cell therapies. We discuss prospects on selection and sequencing of BiTEs and CAR-T therapies for patients with R/R FL. We underscore the principles of FL pathobiology that are paving way for future drug discovery and shed insight into therapeutic targeting within nodal basins based on our increasing understanding of the FL microenvironment. Finally, we summarize how a greater knowledge of FL immunobiology can inform risk stratification and therapy selection on a personalized basis for R/R FL in 2025.

Natural history of clonal haematopoiesis seen in real-world haematology settings.

Recursive partitioning of healthy consortia led to the development of the Clonal Hematopoiesis Risk Score (CHRS) for clonal haematopoiesis (CH); however, in the practical setting, most cases of CH are diagnosed after patients present with cytopenias or related symptoms. To address this real-world population, we characterize the clinical trajectories of 94 patients with CH and distinguish CH harbouring canonical DNMT3A/TET2/ASXL1 mutations alone ('sole DTA') versus all other groups ('non-sole DTA'). TET2, rather than DNMT3A, was the most prevalent mutation in the real-world setting. Sole DTA patients did not progress to myeloid neoplasm (MN) in the absence of acquisition of other mutations. Contrastingly, 14 (20.1%) of 67 non-sole DTA patients progressed to MN. CHRS assessment showed a higher frequency of high-risk CH in non-sole DTA (vs. sole DTA) patients and in progressors (vs. non-progressors). RUNX1 mutation conferred the strongest risk for progression to MN (odds ratio [OR] 10.27, 95% CI 2.00-52.69, p = 0.0053). The mean variant allele frequency across all genes was higher in progressors than in non-progressors (36.9% ± 4.62% vs. 24.1% ± 1.67%, p = 0.0064). This analysis in the post-CHRS era underscores the natural history of CH, providing insight into patterns of progression to MN.

The heart of VIALE-A: Cardiac complications of hypomethylating agents and venetoclax in acute myeloid leukaemia.

As we commemorate 50 years since the introduction of classical 7 + 3 induction chemotherapy for acute myeloid leukaemia (AML), we also embark upon new territory with the advent of novel targeted therapeutics, including BH3 mimetics. To date, we do not have much large-scale longitudinal data regarding the toxicities of such novel therapies. Johnson et al. perform a comprehensive analysis of cardiac toxicities with hypomethylating agents and venetoclax and offer valuable insight into risk-benefit analysis when considering front-line therapy for AML. Commentary on: Johnson et al. Cardiac events in newly diagnosed acute myeloid leukaemia during treatment with venetoclax + hypomethylating agents. Br J Haematol 2024;204:1232-1237.

Revealing role of epigenetic modifiers and DNA oxidation in cell-autonomous regulation of Cancer stem cells.

BACKGROUND: Breast cancer cells (BCCs) can remain undetected for decades in dormancy. These quiescent cells are similar to cancer stem cells (CSCs); hence their ability to initiate tertiary metastasis. Dormancy can be regulated by components of the tissue microenvironment such as bone marrow mesenchymal stem cells (MSCs) that release exosomes to dedifferentiate BCCs into CSCs. The exosomes cargo includes histone 3, lysine 4 (H3K4) methyltransferases - KMT2B and KMT2D. A less studied mechanism of CSC maintenance is the process of cell-autonomous regulation, leading us to examine the roles for KMT2B and KMT2D in sustaining CSCs, and their potential as drug targets. METHODS: Use of pharmacological inhibitor of H3K4 (WDR5-0103), knockdown (KD) of KMT2B or KMT2D in BCCs, real time PCR, western blot, response to chemotherapy, RNA-seq, and flow cytometry for circulating markers of CSCs and DNA hydroxylases in BC patients. In vivo studies using a dormancy model studied the effects of KMT2B/D to chemotherapy. RESULTS: H3K4 methyltransferases sustain cell autonomous regulation of CSCs, impart chemoresistance, maintain cycling quiescence, and reduce migration and proliferation of BCCs. In vivo studies validated KMT2's role in dormancy and identified these genes as potential drug targets. DNA methylase (DNMT), predicted within a network with KMT2 to regulate CSCs, was determined to sustain circulating CSC-like in the blood of patients. CONCLUSION: H3K4 methyltransferases and DNA methylation mediate cell autonomous regulation to sustain CSC. The findings provide crucial insights into epigenetic regulatory mechanisms underlying BC dormancy with KMT2B and KMT2D as potential therapeutic targets, along with standard care. Stem cell and epigenetic markers in circulating BCCs could monitor treatment response and this could be significant for long BC remission to partly address health disparity.

Telehepatology Satisfaction Is Associated with Ethnicity: The Real-World Experience of a Vulnerable Population with Fatty Liver Disease.

BACKGROUND: Since the coronavirus disease 2019 (COVID-19) pandemic began, telemedicine use has transformed healthcare delivery. Yet there is concern that telemedicine may widen care disparities for vulnerable populations, and patient experience data are limited. AIMS: We aimed to assess patient satisfaction with hepatology-related telemedicine (telehepatology) for delivery of fatty liver disease (FLD) care in a safety-net healthcare system. METHODS: Adult patients with FLD were surveyed regarding satisfaction with telehepatology. Clinical, demographic, resources, and social determinants of health (SDoH) data were collected to identify factors associated with satisfaction through multivariable modeling. RESULTS: From June 2020 to March 2022, 220 participants were enrolled: the median age was 52 years, 37% were men, and 68% were Hispanic. One hundred nineteen (54%) had prior telehepatology experience. Overall, satisfaction was high; 70% reported being somewhat or very satisfied. On univariate analysis, Hispanic ethnicity (versus non-Hispanic, OR 0.34, 95% CI 0.1-0.9, p = 0.03) and limited access to personal cellphone/internet (OR 0.16, 95% CI 0.04-0.6, p = 0.01) were associated with lower satisfaction. On multivariable logistic regression modeling adjusted for pandemic duration, age, sex, severity of liver disease, and coexisting liver disease, Hispanic ethnicity and lack of personal cellphone/internet remained independently associated with lower telehepatology satisfaction (OR 0.24, 95% CI 0.07-0.9, p = 0.03 and OR 0.2, 95% CI 0.04-0.9, p = 0.04, respectively). The association remained statistically significant after inclusion of various SDoH in the multivariable model. CONCLUSIONS: Satisfaction with telehepatology among FLD patients in a safety-net clinical setting was high overall. However, Hispanic ethnicity and lack of personal cellphone/internet were independently associated with lower telehepatology satisfaction. A better understanding of patients' experience with telehepatology is needed to identify reasons for dissatisfaction, and in-person visits should remain an option for patients to ensure equitable care.

Individual- and Community-Level Socioeconomic Status and Deceased Donor Renal Transplant Outcomes.

BACKGROUND: This study examined the relationship between socioeconomic status (SES), race, and ethnicity and clinical outcomes following deceased donor kidney transplant (DDKT) at a high-volume transplant center. METHODS: This retrospective cohort study used regression models and survival analyses to examine the relationship between individual- and community-level SES, race, and ethnicity and DDKT outcomes (i.e., delayed graft function, graft failure, mortality) adjusting for potential confounders. RESULTS: The analytic sample included 3366 patients; 40.7% (n = 1370) were female, the mean age was 54.7 (SD = 13.3) years, 49.3% were non-Hispanic White, and the median follow-up time was 39.5 months (IQR = 24.2-68.1). Patients living in the most disadvantaged communities (using the US Census data) had a higher likelihood of delayed graft function (adjusted relative risk [RR] = 1.12, p = 0.042) and a higher hazard of mortality (adjusted hazard ratio [HR] = 1.32, p = 0.025) compared to patients living in the least disadvantaged communities. Patients without a high school diploma had a higher risk of delayed graft function compared to patients with an associate degree or more (RR = 1.37, p < 0.001). Patients with public insurance coverage had a higher risk of delayed graft function (RR = 1.24, p < 0.001) and a higher hazard of mortality (HR = 1.37, p < 0.001) and graft failure (HR = 1.71, p < 0.001) compared to patients without public insurance. There were no differences in graft failure or mortality by race and ethnicity. CONCLUSIONS: SES was not consistently associated with outcomes following DDKT; however, many of the predictors were associated with delayed graft function. With a large and diverse sample size, these findings further the heterogeneity of the present renal transplant research suggesting the need for further investigation to guide implementation of innovative strategies and interventions.

Atomistic mechanisms of water vapor-induced surface passivation.

The microscopic mechanisms underpinning the spontaneous surface passivation of metals from ubiquitous water have remained largely elusive. Here, using in situ environmental electron microscopy to atomically monitor the reaction dynamics between aluminum surfaces and water vapor, we provide direct experimental evidence that the surface passivation results in a bilayer oxide film consisting of a crystalline-like Al(OH)3 top layer and an inner layer of amorphous Al2O3. The Al(OH)3 layer maintains a constant thickness of ~5.0 Å, while the inner Al2O3 layer grows at the Al2O3/Al interface to a limiting thickness. On the basis of experimental data and atomistic modeling, we show the tunability of the dissociation pathways of H2O molecules with the Al, Al2O3, and Al(OH)3 surface terminations. The fundamental insights may have practical significance for the design of materials and reactions for two seemingly disparate but fundamentally related disciplines of surface passivation and catalytic H2 production from water.

Prognostic heterogeneity and clonal dynamics within distinct subgroups of myelodysplastic syndrome and acute myeloid leukemia with TP53 disruptions.

TP53 aberrations constitute the highest risk subset of myelodysplastic neoplasms (MDS) and acute myeloid leukemia (AML). The International Consensus Classification questions the blast threshold between MDS and AML. In this study, we assess the distinction between MDS and AML for 76 patients with TP53 aberrations. We observed no significant differences between MDS and AML regarding TP53 genomics. Median overall survival (OS) was 223 days for the entire group, but prognostic discrimination within subgroups showed the most inferior OS (46 days) for AML with multihit allelic state plus TP53 variant allele frequency (VAF) > 50%. In multivariate analysis, unadjusted Cox models revealed the following variables as independent risk factors for mortality: AML (vs. MDS) (hazard ratio [HR]: 2.50, confidence interval [CI]: 1.4-4.4, p = 0.001), complex karyotype (HR: 3.00, CI: 1.4-6.1, p = 0.003), multihit status (HR: 2.30, CI 1.3-4.2, p = 0.005), and absence of hematopoietic cell transplant (HCT) (HR: 3.90, CI: 1.8-8.9, p = 0.0009). Clonal dynamic modeling showed a significant reduction in TP53 VAF with front-line hypomethylating agents. These findings clarify the impact of specific covariates on outcomes of TP53-aberrant myeloid neoplasms, irrespective of the diagnosis of MDS versus AML, and may influence HCT decisions.

Clinico-Radio-Pathologic Correlation of Leukostasis in Acute Myeloid Leukemia with FLT3 Mutation.

The systemic complications of acute hematologic emergencies account for the high mortality rates seen during inpatient management. Perhaps the most challenging diagnostic entity among all hematologic emergencies is leukostasis. In acute myeloid leukemia, myeloid blasts are often highly adherent to the endothelial vasculature, and high peripheral blood blast count in excess of 100,000 cells per microliter can predispose patients to the pulmonary and neurologic complications, leading to rapid clinical deterioration even before a formal diagnosis of leukostasis is made. The mobilization of the appropriate healthcare personnel in the inpatient setting at inopportune times sometimes poses a major barrier to the successful treatment for patients with leukostasis, and patients often pass away quickly. In this report, we describe clinico-radio-pathologic correlations of leukostasis using pre- and post-mortem analysis in a patient with acute myeloid leukemia (AML) with a FLT3-TKD mutation, and we describe the current literature on best management approaches based on recent evidence.

The shifting therapeutic paradigm for relapsed/refractory mantle cell lymphoma.

Mantle cell lymphoma (MCL) is a heterogeneous subtype of non-Hodgkin lymphoma that has been historically associated with poor 5-year overall survival rates, especially for aggressive variants. Traditional cytotoxic chemotherapy had been a mainstay of therapy for relapsed/refractory (R/R) MCL for many years until the advent of molecularly targeted therapies and cell-based approaches. However, a significant concern is the lack of definitive consensus guidelines for management of R/R MCL. The managerial conundrum partly stems from the absence of head-to-head comparisons of novel therapies, with conclusions drawn from cross-trial comparisons. In this evidence-based review, we discuss the current therapeutic options for R/R MCL, including the most recent data from the BRUIN study that led to the approval of the first-in-class non-covalent reversible Bruton's tyrosine kinase (BTK) inhibitor pirtobrutinib in 2023, as well as the recent removal of ibrutinib from the market. We discuss outlooks for targeted therapy and tolerability considerations for novel agents, including unique considerations for the elderly population. We highlight emerging data that support the curative potential of chimeric antigen receptor-T (CAR-T) therapy from ZUMA-2, relative to other promising investigational agents in the pipeline, including glofitamab, epcoritamab, and zilovertamab vedotin. We summarize management recommendations based upon the most rigorous clinical evidence to date.

Evaluating the comparability of patient-level social risk data extracted from electronic health records: A systematic scoping review.

Objective: To evaluate how and from where social risk data are extracted from EHRs for research purposes, and how observed differences may impact study generalizability. Methods: Systematic scoping review of peer-reviewed literature that used patient-level EHR data to assess 1 ± 6 social risk domains: housing, transportation, food, utilities, safety, social support/isolation. Results: 111/9022 identified articles met inclusion criteria. By domain, social support/isolation was most often included (N = 68/111), predominantly defined by marital/partner status (N = 48/68) and extracted from structured sociodemographic data (N = 45/48). Housing risk was defined primarily by homelessness (N = 39/49). Structured housing data was extracted most from billing codes and screening tools (N = 15/30, 13/30, respectively). Across domains, data were predominantly sourced from structured fields (N = 89/111) versus unstructured free text (N = 32/111). Conclusion: We identified wide variability in how social domains are defined and extracted from EHRs for research. More consistency, particularly in how domains are operationalized, would enable greater insights across studies.

Harnessing autologous immune effector mechanisms in acute myeloid leukemia: 2023 update of trials and tribulations.

Numerous recent advances have been made in therapeutic approaches toward acute myeloid leukemia (AML). Since 2017, we have seen eleven novel Food & Drug Administration (FDA)-approved medications for AML, all of which extend beyond the classical cytarabine-based cytostatic chemotherapy. In the recent two decades, the role of immune surveillance in AML has been intensively investigated. The power of one's own innate and adaptive immunity has been harnessed pharmacologically toward the goal of clearance of AML cells. Specifically, pre-clinical studies have shown great promise for antibodies that disinhibit T cells and macrophages by blocking checkpoint receptors within the immunologic synapse, thereby resulting in the elimination of AML cells. Anti-CD33 CAR-T therapies and anti-CD3/CD123 bispecific antibodies have also exhibited encouraging results in pre-clinical and early clinical studies. However, despite these translational efforts, we currently have no immune-based therapies for AML on the market, with the exception of gemtuzumab ozogamicin. In this focused review, we discuss molecular target validation and the most relevant clinical updates for immune-based experimental therapeutics including anti-CD47 monoclonal antibodies, CAR-T therapies, and bispecific T cell engagers. We highlight barriers to the clinical translation of these therapies in AML, and we propose solutions to optimize the manufacturing and delivery of the most novel immune-based therapies in the pipeline.

Violence and Related Health Outcomes in Sexual and Gender Minority Communities: Introduction to the Special Issue.

Violence affects every community but is particularly prevalent among sexual and gender minority (SGM) people. Although research on violence within SGM populations is increasing, knowledge gaps remain that limit development of evidence-based policy, prevention, and intervention efforts to reduce the violence disparities the SGM community faces. In 2021, the National Institutes of Health (NIH) hosted a multiphase scientific workshop to identify and prioritize key research needs to further our understanding of violence affecting SGM communities and its health outcomes. In this perspective, we summarize the research needs identified. NIH supports this special issue as an outcome of the scientific workshop.

Diffuse large B-cell lymphoma presenting as an ileocaecal mass in a post-transplant patient.

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin's lymphoma. Extranodal involvement, including the gastrointestinal tract, occurs frequently. However, colorectal involvement is extremely rare. We present a case of a man in his 20s with prior renal transplantation on immunosuppression for 10 years who developed symptoms of gas and bloating associated with unintentional weight loss. Colonoscopy revealed a large fungating mass at the ileocaecal valve, and a biopsy of this lesion confirmed stage IV DLBCL. Endoscopy should be considered for early workup of vague gastrointestinal symptoms, even in younger patients, if they have been on long-standing immunosuppression.

Challenges and solutions to superior chimeric antigen receptor-T design and deployment for B-cell lymphomas.

Chimeric antigen receptor-T (CAR-T) therapies represent a major breakthrough in cancer medicine, given the ex vivo-based technology that harnesses the power of one's own immune system. These therapeutics have demonstrated remarkable success for relapsed/refractory B-cell lymphomas. Although more than a decade has passed since the initial introduction of CAR-T therapeutics for patients with leukaemia and lymphoma, there is still significant debate as to where CAR-T therapeutics fit into the management paradigm, as consensus guidelines are limited. Competing interventions deployed in subsequent lines of therapy for aggressive lymphoma include novel targeted agents, bispecific antibodies, and time-honoured stem cell transplant. In this focused review, we discuss the major obstacles to advancing the therapeutic reach for CAR-T products in early lines of therapy. Such barriers include antigen escape, "cold" tumour microenvironments, host inflammation and CAR-T cell exhaustion. We highlight solutions including point-of-care CAR-T manufacturing and early T lymphopheresis. We review the evidence basis for early CAR-T deployment for B-cell lymphomas in light of the recent Food and Drug Administration (FDA) approval of three first-in-class anti-CD3/CD20 bispecific antibodies-mosunetuzumab, epcoritamab and glofitamab. We propose practical recommendations for 2024.

Telehealth through the pandemic at a safety net hospital: observations and next steps for cancer care delivery.

The COVID-19 pandemic revolutionized cancer care delivery leading to rapid adoption of digital technology for telehealth in the United States. In this study, we describe telehealth utilization trends across the three largest waves of the pandemic at a safety net academic center. We also provide a perspective on lessons learnt and our vision for cancer care delivery using digital technology in the near future. The integration of interpreter services within the video platform and its integration within the electronic medical record system is crucial for safety net institutes that service a diverse patient population. Pay-parity for telehealth, especially ongoing support for audio-only visits, will be critical in overcoming health disparities for patients without access to smartphone technology. Use of telehealth in clinical trials, widespread adoption of hospital at home programs, electronic consults for rapid access, and structured telehealth slots in clinic templates will be crucial in making cancer care more equitable and efficient.

Precision and strategic targeting of novel mutation-specific vulnerabilities in acute myeloid leukemia: the semi-centennial of 7 + 3.

The year 2023 marks the semi-centennial of the introduction of classic '7 + 3' chemotherapy for acute myeloid leukemia (AML) in 1973. It also marks the decennial of the first comprehensive sequencing efforts from The Cancer Genome Atlas (TCGA), which revealed that dozens of unique genes are recurrently mutated in AML genomes. Although more than 30 distinct genes have been implicated in AML pathogenesis, the current therapeutic armamentarium that is commercially available only targets FLT3 and IDH1/2 mutations, with olutasidenib as the most recent addition. This focused review spotlights management approaches that exploit the exquisite molecular dependencies of specific subsets of AML, with an emphasis on emerging therapies in the pipeline, including agents targeting TP53-mutant cells. We summarize precision and strategic targeting of AML based on leveraging functional dependencies and explore how mechanisms involving critical gene products can inform rational therapeutic design in 2024.