Translating recent advances in the pathogenesis of acute myeloid leukemia to the clinic.

Despite FDA approval of nine new drugs for patients with acute myeloid leukemia (AML) in the United States over the last 4 years, AML remains a major area of unmet medical need among hematologic malignancies. In this review, we discuss the development of promising new molecular targeted approaches for AML, including menin inhibition, novel IDH1/2 inhibitors, and preclinical means to target TET2, ASXL1, and RNA splicing factor mutations. In addition, we review progress in immune targeting of AML through anti-CD47, anti-SIRPα, and anti-TIM-3 antibodies; bispecific and trispecific antibodies; and new cellular therapies in development for AML.

Risk Prediction for Clonal Cytopenia: Multicenter Real-World Evidence.

Clonal cytopenia of undetermined significance (CCUS) represents a distinct disease entity characterized by myeloid-related somatic mutations with a variant allele fraction of ≥2% in individuals with unexplained cytopenia(s) but without a myeloid neoplasm (MN). Notably, CCUS carries a risk of progressing to MN, particularly in cases featuring high-risk mutations. Understanding CCUS requires dedicated studies to elucidate its risk factors and natural history. Our analysis of 357 CCUS patients investigated the interplay between clonality, cytopenia, and prognosis. Multivariate analysis identified 3 key adverse prognostic factors: the presence of splicing mutation(s) (score = 2 points), platelet count <100×109/L (score = 2.5), and ≥2 mutations (score = 3). Variable scores were based on the coefficients from the Cox proportional hazards model. This led to the development of the Clonal Cytopenia Risk Score (CCRS), which stratified patients into low- (score <2.5 points), intermediate- (score 2.5-<5), and high-risk (score ≥5) groups. The CCRS effectively predicted 2-year cumulative incidence of MN for low- (6.4%), intermediate- (14.1%), and high- (37.2%) risk groups, respectively, by Gray's test (P <.0001). We further validated the CCRS by applying it to an independent CCUS cohort of 104 patients, demonstrating a c-index of 0.64 (P =.005) in stratifying the cumulative incidence of MN. Our study underscores the importance of integrating clinical and molecular data to assess the risk of CCUS progression, making the CCRS a valuable tool that is practical and easily calculable. These findings are clinically relevant, shaping the management strategies for CCUS and informing future clinical trial designs.

Moving toward disease modification in polycythemia vera.

Polycythemia vera (PV) belongs to the BCR-ABL1-negative myeloproliferative neoplasms and is characterized by activating mutations in JAK2 and clinically presents with erythrocytosis, variable degrees of systemic and vasomotor symptoms, and an increased risk of both thromboembolic events and progression to myelofibrosis and acute myeloid leukemia (AML). Treatment selection is based on a patient's age and a history of thrombosis in patients with low-risk PV treated with therapeutic phlebotomy and aspirin alone, whereas cytoreductive therapy with either hydroxyurea or interferon alfa (IFN-α) is added for high-risk disease. However, other disease features such as significant disease-related symptoms and splenomegaly, concurrent thrombocytosis and leukocytosis, or intolerance of phlebotomy can constitute an indication for cytoreductive therapy in patients with otherwise low-risk disease. Additionally, recent studies demonstrating the safety and efficacy (ie, reduction in phlebotomy requirements and molecular responses) of ropegylated IFN-α2b support its use for patients with low-risk PV. Additionally, emerging data suggest that early treatment is associated with higher rates of molecular responses, which might eventually enable time-limited therapy. Nonetheless, longer follow-up is needed to assess whether molecular responses associate with clinically meaningful outcome measures such as thrombosis and progression to myelofibrosis or AML. In this article, we provide an overview of the current and evolving treatment landscape of PV and outline our vision for a patient-centered, phlebotomy-free, treatment approach using time-limited, disease-modifying treatment modalities early in the disease course, which could ultimately affect the natural history of the disease.

Consensus proposal for revised International Working Group 2023 response criteria for higher-risk myelodysplastic syndromes.

Myelodysplastic syndromes/myelodysplastic neoplasms (MDS) are associated with variable clinical presentations and outcomes. The initial response criteria developed by the International Working Group (IWG) in 2000 have been used in clinical practice, clinical trials, regulatory reviews, and drug labels. Although the IWG criteria were revised in 2006 and 2018 (the latter focusing on lower-risk disease), limitations persist in their application to higher-risk MDS (HR-MDS) and their ability to fully capture the clinical benefits of novel investigational drugs or serve as valid surrogates for longer-term clinical end points (eg, overall survival). Further, issues related to the ambiguity and practicality of some criteria lead to variability in interpretation and interobserver inconsistency in reporting results from the same sets of data. Thus, we convened an international panel of 36 MDS experts and used an established modified Delphi process to develop consensus recommendations for updated response criteria that would be more reflective of patient-centered and clinically relevant outcomes in HR-MDS. Among others, the IWG 2023 criteria include changes in the hemoglobin threshold for complete remission (CR), the introduction of CR with limited count recovery and CR with partial hematologic recovery as provisional response criteria, the elimination of marrow CR, and specific recommendations for the standardization of time-to-event end points and the derivation and reporting of responses. The updated criteria should lead to a better correlation between patient-centered outcomes and clinical trial results in an era of multiple emerging new agents with novel mechanisms of action.

A multicenter phase Ib trial of the histone deacetylase inhibitor entinostat in combination with pembrolizumab in patients with myelodysplastic syndromes/neoplasms or acute myeloid leukemia refractory to hypomethylating agents.

Patients with myelodysplastic syndromes/neoplasms (MDS) or acute myeloid leukemia (AML) with hypomethylating agent failure have a poor prognosis. Myeloid-derived suppressor cells (MDSCs) can contribute to MDS progression and mediate resistance to anti-PD1 therapy. As histone deacetylase inhibitors (HDACi) decrease MDSCs in preclinical models, we conducted an investigator-initiated, NCI-Cancer Therapy Evaluation Program-sponsored, multicenter, dose escalation, and expansion phase Ib trial (NCT02936752) of the HDACi entinostat and the anti-PD1 antibody pembrolizumab. Twenty-eight patients (25 MDS and 3 AML) were enrolled. During dose escalation (n=13 patients), there was one dose-limiting toxicity (DLT) on dose level (DL) 1 (G5 pneumonia/bronchoalveolar hemorrhage) and two DLTs at DL 2 (G3 pharyngeal mucositis and G3 anorexia). Per the 3 + 3 dose escalation design, DL 1 (entinostat 8 mg PO days 1 and 15 + pembrolizumab 200 mg IV day 1 every 21 days) was expanded and another 15 patients were enrolled. Hematologic adverse events (AEs) were common. The most common non-hematologic ≥G3 AEs were infection (32%), hypoxia/respiratory failure (11%), and dyspnea (11%). There were no protocol-defined responses among the 28 patients enrolled. Two patients achieved a marrow complete remission (mCR). Using a systems immunology approach with mass cytometry and machine learning analysis, mCR patients had increased classical monocytes and macrophages but there was no significant change of MDSCs. In conclusion, combining entinostat with pembrolizumab in patients with advanced MDS and AML was associated with limited clinical efficacy and substantial toxicity. Absence of an effect on MDSCs could be a potential explanation for the limited efficacy of this combination. ClinicalTrial.gov Identifier: NCT02936752.

Pericytes are protective in experimental pneumococcal meningitis through regulating leukocyte infiltration and blood-brain barrier function.

BACKGROUND: Brain pericytes participate in the regulation of cerebral blood flow and the maintenance of blood-brain barrier integrity. Because of their perivascular localization, their receptor repertoire, and their potential ability to respond to inflammatory and infectious stimuli by producing various cytokines and chemokines, these cells are also thought to play an active role in the immune response to brain infections. This assumption is mainly supported by in vitro studies, investigations in in vivo disease models are largely missing. Here, we analysed the role of brain pericytes in pneumococcal meningitis, in vitro and in vivo in two animal models of pneumococcal meningitis. METHODS: Primary murine and human pericytes were stimulated with increasing concentrations of different serotypes of Streptococcus pneumoniae in the presence or absence of Toll-like receptor inhibitors and their cell viability and cytokine production were monitored. To gain insight into the role of pericytes in brain infection in vivo, we performed studies in a zebrafish embryo model of pneumococcal meningitis in which pericytes were pharmacologically depleted. Furthermore, we analyzed the impact of genetically induced pericyte ablation on disease progression, intracranial complications, and brain inflammation in an adult mouse model of this disease. RESULTS: Both murine and human pericytes reacted to pneumococcal exposure with the release of selected cytokines. This cytokine release is pneumolysin-dependent, TLR-dependent in murine (but not human) pericytes and can be significantly increased by macrophage-derived IL-1b. Pharmacological depletion of pericytes in zebrafish embryos resulted in increased cerebral edema and mortality due to pneumococcal meningitis. Correspondingly, in an adult mouse meningitis model, a more pronounced blood-brain barrier disruption and leukocyte infiltration, resulting in an unfavorable disease course, was observed following genetic pericyte ablation. The degree of leukocyte infiltration positively correlated with an upregulation of chemokine expression in the brains of pericyte-depleted mice. CONCLUSIONS: Our findings show that pericytes play a protective role in pneumococcal meningitis by impeding leukocyte migration and preventing blood-brain barrier breaching. Thus, preserving the integrity of the pericyte population has the potential as a new therapeutic strategy in pneumococcal meningitis.

Plasma renalase levels are associated with the development of acute pancreatitis.

BACKGROUND/OBJECTIVES: Severe acute pancreatitis is associated with significant morbidity and mortality. Identifying factors that affect the risk of developing severe disease could influence management. Plasma levels of renalase, an anti-inflammatory secretory protein, dramatically decrease in a murine acute pancreatitis model. We assessed this response in hospitalized acute pancreatitis patients to determine if reduced plasma renalase levels occur in humans. METHODS: Plasma samples were prospectively and sequentially collected from patients hospitalized for acute pancreatitis. Two forms of plasma renalase, native (no acid) and acidified, were measured by ELISA and RNLS levels were compared between healthy controls and patients with mild and severe disease (defined as APACHE-II score ≥7) using nonparametric statistical analysis. RESULTS: Control (33) and acute pancreatitis (mild, 230 (76.7%) and severe, 70 (23.3%) patients were studied. Acidified RNLS levels were lower in pancreatitis patients: Control: 10.1 µg/ml, Mild 5.1 µg/ml, Severe 6.0 µg/ml; p < 0.001. Native RNLS levels were increased in AP: Control: 0.4 µg/ml, Mild 0.9 µg g/ml, Severe 1.2 µg/ml p < 0.001; those with severe AP trended to have higher native RNLS levels than those with mild disease (p = 0.056). In patients with severe AP, higher APACHE-II scores at 24 h after admission correlated with lower acid-sensitive RNLS levels on admission (r = -0.31, p = 0.023). CONCLUSION: Low plasma acidified RNLS levels, and increased native RNLS levels are associated with AP. Additional studies should assess the clinical correlation between plasma RNLS levels and AP severity and outcomes.

Cost-Effectiveness Analyses in AML: What Have We Learned, How Should This Impact Patient Care, and What Needs to Be Done in the Future?

Acute myeloid leukemia (AML) is the most common acute leukemia in adults in the United States and has seen the approval of several novel agents over the past decade. Similar to treatments for other hematologic and solid malignancies, these novel agents are costly. In the setting of finite financial resources in the healthcare system, the concept of cost-effectiveness analyses has been developed to compare the estimated costs and associated benefits expected with different interventions (eg, drugs, diagnostic tests, procedures). Although drug approvals in the United States are not based on budgetary considerations, cost-effectiveness analyses can inform health policy decisions, resource allocation, and societal debates. However, such analyses are only capturing parts of the costs and benefits to the healthcare system, payers, and consumers, and are based on modeling assumptions with inherent limitations. In addition, cost-effectiveness analyses for several of the novel agents approved for treatment of AML are limited and have reported conflicting results. This review uses cost-effectiveness analyses of azacitidine/venetoclax and liposomal cytarabine/daunorubicin as examples to review considerations and best practices when conducting and interpreting such studies. To ensure adequate interpretability of cost-effectiveness studies, transparency in the model inputs/assumptions, data sources, and funding is of great importance, as evidenced by the discrepant conclusions across studies. Furthermore, the perspective and the healthcare system from which a cost-effectiveness analysis is conducted are important to consider because practice patterns and drug prices between countries can be variable. However, with advances in health economic modeling techniques, adherence to best practices, and increasing public interest in these types of studies, cost-effectiveness analyses can become an important tool to inform various stakeholders in the healthcare system to allocate limited resources most efficiently.

Molecular predictors of immunophenotypic measurable residual disease clearance in acute myeloid leukemia.

Measurable residual disease (MRD) is a powerful prognostic factor in acute myeloid leukemia (AML). However, pre-treatment molecular predictors of immunophenotypic MRD clearance remain unclear. We analyzed a dataset of 211 patients with pre-treatment next-generation sequencing who received induction chemotherapy and had MRD assessed by serial immunophenotypic monitoring after induction, subsequent therapy, and allogeneic stem cell transplant (allo-SCT). Induction chemotherapy led to MRD- remission, MRD+ remission, and persistent disease in 35%, 27%, and 38% of patients, respectively. With subsequent therapy, 34% of patients with MRD+ and 26% of patients with persistent disease converted to MRD-. Mutations in CEBPA, NRAS, KRAS, and NPM1 predicted high rates of MRD- remission, while mutations in TP53, SF3B1, ASXL1, and RUNX1 and karyotypic abnormalities including inv (3), monosomy 5 or 7 predicted low rates of MRD- remission. Patients with fewer individual clones were more likely to achieve MRD- remission. Among 132 patients who underwent allo-SCT, outcomes were favorable whether patients achieved early MRD- after induction or later MRD- after subsequent therapy prior to allo-SCT. As MRD conversion with chemotherapy prior to allo-SCT is rarely achieved in patients with specific baseline mutational patterns and high clone numbers, upfront inclusion of these patients into clinical trials should be considered.

Azacitidine maintenance in AML post induction and posttransplant.

PURPOSE OF REVIEW: Disease relapse remains the most common cause of death among patients with acute myeloid leukemia (AML) following induction therapy and allogeneic hematopoietic cell transplant (allo-HCT). Prolonging the duration of remission with minimal nonrelapse mortality risk is an area of unmet need for AML patients. RECENT FINDINGS: In QUAZAR AML-001 study, the oral azacitidine analogue CC-486 demonstrated an overall survival (OS) benefit when given as postremission therapy (PRT) for patients in CR1 that were ineligible to proceed to allo-HCT. Used as maintenance post allo-HCT, CC-486 has also shown safety with encouraging disease-free survival (DFS). Although a recent randomized trial of parenteral azacitidine vs. placebo post allo-HCT failed to show relapse reduction, a subsequent meta-analysis of maintenance studies posttransplant has shown good utility with this approach. Such conflicting results emphasize the need for robust study designs to identify subsets of patients that derive maximal benefits using latest tools to risk stratify relapse risk. SUMMARY: PRT with hypomethylating agents is feasible and in select population, there is a survival advantage with CC-486. Better understanding of distinct epigenetic and immunomodulatory properties of azacitidine, holds significant promise to synergize pharmacologic and cellular drivers of disease control as PRT in future AML trials.

Phase 1 study of anti-CD47 monoclonal antibody CC-90002 in patients with relapsed/refractory acute myeloid leukemia and high-risk myelodysplastic syndromes.

CC-90002 is an anti-CD47 antibody that inhibits CD47-SIRPα interaction and enables macrophage-mediated killing of tumor cells in hematological cancer cell lines. In this first clinical, phase 1, dose-escalation and -expansion study (CC-90002-AML-001; NCT02641002), we evaluated CC-90002 in patients with relapsed/refractory acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS). CC-90002 was administered in escalating doses of 0.1-4.0 mg/kg, using a modified 3 + 3 design. Primary endpoints included dose-limiting toxicities (DLTs), non-tolerated dose (NTD), maximum tolerated dose (MTD), and recommended phase 2 dose. Secondary endpoints included preliminary efficacy, pharmacokinetics, and presence/frequency of anti-drug antibodies (ADAs). Between March 2016 and July 2018, 28 patients were enrolled (24 with AML and 4 with MDS) at 6 sites across the USA. As of July 18, 2018, all patients had discontinued, mainly due to death or progressive disease. The most common treatment-emergent adverse events were diarrhea (46.4%), thrombocytopenia (39.3%), febrile neutropenia (35.7%), and aspartate aminotransferase increase (35.7%). Four patients experienced DLTs (1 patient had grade 4 disseminated intravascular coagulation and grade 5 cerebral hemorrhage, 1 had grade 3 purpura, 1 had grade 4 congestive cardiac failure and grade 5 acute respiratory failure, and another had grade 5 sepsis). The NTD and MTD were not reached. No objective responses occurred. CC-90002 serum exposure was dose-dependent. ADAs were present across all doses, and the proportion of ADA-positive patients in cycle 1 increased over time. Despite no unexpected safety findings, the CC-90002-AML-001 study was discontinued in dose escalation for lack of monotherapy activity and evidence of ADAs. However, as other anti-CD47 agents in clinical trials are showing promising early results for AML and MDS, understanding preclinical and clinical differences between individual agents in this class will be of high importance.

Gilteritinib clinical activity in relapsed/refractory FLT3 mutated acute myeloid leukemia previously treated with FLT3 inhibitors.

Gilteritinib is approved for the treatment of relapsed/refractory (R/R) acute myeloid leukemia (AML) with an FLT3-mutation (FLT3mut+ ). However, the gilteritinib phase 3 ADMIRAL study (Perl et al NEJM 2019) was conducted prior to widespread adoption of either midostaurin as a component of standard intensive induction and consolidation or posttransplant FLT3 inhibitor maintenance. We performed a retrospective analysis using data from 11 US centers and where we identified 113 patients who received gilteritinib alone or as combination therapy for the treatment of R/R FLT3mut+ AML. The composite complete remission (CR) rate (CRc, defined as CR + CRi + CR with incomplete platelet recovery [CRp]) was 48.7% (n = 55). The CRc rate after treatment with gilteritinib in patients who were treated with only prior 7+3 and midostaurin with or without consolidation was 58% with a median survival of 7.8 months. Survival was longest in patients who obtained a CR, particularly a cMRD (clinical minimal or measurable residual disease) negative response; this remained significant after censoring at the time of stem cell transplant. The mitogen-activated protein kinase pathway activating mutations that are known for gilteritinib resistance (NRAS, KRAS, and PTPN11) had lower CRc (35% vs. 60.5%) and lower median overall survival than patients' whose leukemia did not express these mutations (4.9 months vs. 7.8 months) (HR 2.4; 95% CI 1. 5.4) p value <.01.

Maintenance therapies in acute myeloid leukemia: the renaissance of an old therapeutic concept.

PURPOSE OF REVIEW: Disease relapse remains the major cause of death in patients with acute myeloid leukemia (AML) and is driven by the persistence of leukemic cells following induction chemotherapy or allogeneic hematopoietic cell transplant (allo-HCT). Maintenance therapies to extend the duration of remission and to improve survival have been proposed for several years with mixed results but have experienced a renaissance recently. RECENT FINDINGS: The oral hypomethylating agent CC-486 has been the first agent to show an overall survival (OS) benefit compared with observation in AML patients in remission following intensive chemotherapy who are not proceeding to allo-HCT. In the realm of maintenance therapy following allo-HCT, the FLT3 inhibitor sorafenib has yielded superior results in terms of OS and relapse-free survival in randomized trials compared with observation. Several open questions remain regarding patient selection, timing, duration and safety of maintenance therapies. Various targeted agents are currently tested in clinical trials and could potentially enable an even more individualized therapeutic approach. SUMMARY: Maintenance therapies following intensive chemotherapy or allo-HCT offer a new therapeutic paradigm for an increasing number of AML patients and have been shown to result in an OS benefit in selected patients.

Clinical characteristics and outcomes of splenic infarction in cancer patients: a retrospective, single center report of 206 cases.

Cancer patients have a high risk of thromboembolic events including splenic infarct (SI). However, risk factors for SI in cancer patients are poorly understood, and the utility of systemic anticoagulation in such patients is uncertain. We performed a retrospective cohort study of all cancer patients with SI treated at Yale New Haven Hospital from 2008 to 2017. Central review of radiology imaging was performed to confirm the diagnosis of SI. Baseline differences in variables among patients with and without recurrent SI were compared using Fisher's exact test, Pearson's χ2 test, and t-test. Multivariable regression models were conducted to identify factors associated with recurrent SI. Of 206 patients with cancer and SI, 42 had a prior venous thromboembolic event, while 29 had atrial fibrillation/flutter. At a median follow-up of 11.4 months (range: 0-142.3 months), 152 patients underwent follow-up imaging, with only 6 having recurrent SI. The use of anticoagulation after initial SI was associated with a nonsignificant increase in recurrent SI (p = 0.054) and was not associated with development of venous thromboembolism after SI (p = 0.414). In bivariate analyses, the risk of recurrent SI showed a significant association with lower platelet counts (p < 0.001) and with atrial fibrillation/flutter (p = 0.036). In a multivariable logistic regression model, no variables were identified that were associated with a higher risk of recurrent SI. SI in cancer patients is typically an isolated event with low recurrence risk. Anticoagulation use should be guided by other thromboembolic risk factors.

Use of immunosuppressive therapy for management of myelodysplastic syndromes: a systematic review and meta-analysis.

Immunosuppressive therapy (IST) is one therapy option for treatment of patients with lower-risk myelodysplastic syndromes (MDS). However, the use of several different immunosuppressive regimens, the lack of high-quality studies, and the absence of validated predictive biomarkers pose important challenges. We conducted a systematic review and meta-analysis according to the Meta-Analysis of Observational Studies in Epidemiology (MOOSE) guidelines and searched MEDLINE via PubMed, Ovid EMBASE, COCHRANE registry of clinical trials (CENTRAL), and the Web of Science without language restriction from inception through September 2018, as well as relevant conference proceedings and abstracts, for prospective cohort studies or clinical trials investigating IST in MDS. Fixed and Random-effects models were used to pool response rates. We identified nine prospective cohort studies and 13 clinical trials with a total of 570 patients. Overall response rate was 42.5% [95% confidence interval (CI): 36.1-49.2%] including a complete remission rate of 12.5% (95%CI: 9.3-16.6%) and red blood cell transfusion independence rate of 33.4% (95% CI: 25.1-42.9%). The most commonly used forms of IST were anti-thymocyte globulin alone or in combination with cyclosporin A with a trend towards higher response rates with combination therapy. Progression rate to acute myeloid leukemia was 8.6% per patient year (95%CI: 3.3-13.9%). Overall survival and adverse events were only inconsistently reported. We were unable to validate any biomarkers predictive of a therapeutic response to IST. IST for treatment of lower-risk MDS patients can be successful to alleviate transfusion burden and associated sequelae.

Evolving therapies for lower-risk myelodysplastic syndromes.

The development in the therapeutic landscape of myelodysplastic syndromes (MDS) has substantially lagged behind other hematologic malignancies with no new drug approvals for MDS for 13 years since the approval of decitabine in the United States in 2006. While therapeutic concepts for MDS patients continue to be primarily defined by clinical-pathologic risk stratification tools such as the International Prognostic Scoring System (IPSS) and its revised version IPSS-R, our understanding of the genetic landscape and the molecular pathogenesis of MDS has greatly evolved over the last decade. It is expected that the therapeutic approach to MDS patients will become increasingly individualized based on prognostic and predictive genetic features and other biomarkers. Herein, we review the current treatment of lower-risk MDS patients and discuss promising agents in advanced clinical testing for the treatment of symptomatic anemia in lower-risk MDS patients such as luspatercept and imetelstat. Lastly, we review the clinical development of new agents and the implications of the wider availability of mutational analysis for the management of individual MDS patients.

Temporal patterns and predictors of receiving no active treatment among older patients with acute myeloid leukemia in the United States: A population-level analysis.

BACKGROUND: The majority of patients with acute myeloid leukemia (AML) are aged >65 years at the time of diagnosis and are not actively treated. The objective of the current study was to determine the prevalence, temporal trends, and factors associated with no active treatment (NAT) among older patients with AML in the United States. METHODS: A retrospective analysis was performed of Surveillance, Epidemiology, and End Results (SEER)-Medicare data from 14,089 patients with AML residing in the United States who were diagnosed with AML at age ≥66 years during 2001 through 2013. NAT was defined as not receiving any chemotherapy, including hypomethylating agents. Multivariable logistic regression models were used to analyze sociodemographic, clinical, and provider characteristics associated with NAT. RESULTS: The percentage of patients with NAT decreased over time from 59.7% among patients diagnosed in 2001 to 42.8% among those diagnosed in 2013. The median overall survival for the entire cohort was 82 days from the time of diagnosis. Patients treated with NAT had worse survival compared with those receiving active treatment. Variables found to be associated with higher odds of NAT included older age, certain sociodemographic characteristics (household income within the lowest quartile, residence outside the Northeast region of the United States, and being unmarried), and clinical factors (≥3 comorbidities, the presence of mental disorders, recent hospitalization, and disability). CONCLUSIONS: Greater than one-half of older patients with AML residing in the United States do not receive any active leukemia-directed therapy despite the availability of lower intensity therapies such as hypomethylating agents. Lack of active therapy receipt is associated with inferior survival. Identifying predictors of NAT might improve the quality of care and survival in this patient population, especially as novel therapeutic options with lower toxicity are becoming available.