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Olutasidenib, a potent, selective, oral, mutant isocitrate dehydrogenase 1 (mIDH1) inhibitor, is FDA-approved for relapsed/refractory (R/R) acute myeloid leukemia (AML). Here we report efficacy and safety of olutasidenib in 18 patients with mIDH1 AML who were relapsed (10), refractory (6) or had complete remission with incomplete hematologic recovery (CRi; 2) to a venetoclax combination. Of the 16 patients who were R/R, 4 (25%) achieved complete remission (CR), one (6.3%) achieved CR with partial hematologic recovery (CRh), and 7 (43.8%) achieved a composite complete remission (CRc). Median time to CRc was 1.9 months (range 1–2.8). As of data cutoff (18 June 2021), median duration of CRc was not reached (range, 1.2-NR, ongoing at 30.4+ months). Both patients with CRi at study entry achieved a CR. Safety was consistent with the overall profile of olutasidenib. Olutasidenib offers a valuable treatment option for patients with mIDH1 AML previously treated with venetoclax. [ABSTRACT FROM AUTHOR]

We use Google Trends data to identify hostile sexism and find that sexism negatively predicts Clinton's vote share in the 2016 general election and is associated with lower voter turnout among those more likely to vote for a Democrat. Although we find no evidence that hostile sexism was more prevalent in states in which Trump held more than 10 pre-election rallies, we find that sexism had a larger impact on votes in these areas. This shows that the marginal effect of sexism was not uniform across the country and links the differing magnitudes of the effect to Trump rallies. [ABSTRACT FROM AUTHOR]

Purpose: This study investigates the influence of corporate income tax on two corporate financial decisions — dividend and capital structure policies, particularly for Shariah compliant companies in Malaysia. Design/methodology/approach: The study considered data from a sample of 529 Malaysian listed companies from four industrial sectors from 2007–2021 (6,746 company-year observations, before eliminating outliers). Panel models such as Fixed Effect and Random effect models were used. The study specifically tested the effect of corporate income tax on dividend and capital structure policies for Shariah compliant companies (3,148 observations) and controlled for industrial sectors. Findings: (1) Firms are mostly Shariah-compliant, less liquid, less profitable and smaller in size, (2) Broadly when analysed together, tax has no impact on debt-equity ratio while it has an impact on dividend per share, (3) However, when tested separately for Shariah compliant companies, the influence of effective tax on capital structure is very evident but not for dividend and (4) influence of industrial sector on the relationship between corporate tax and capital structure and dividend policy is significant. Results indicate that Shariah firms might be raising debt to gain tax advantage. Companies in general pay dividends to avoid reputational damage. Research limitations/implications: This study assumes that leverage and dividend policy decisions are the main outcomes of the changing tax policies, while it seems that there could be other important outcomes that can be tested in future research. The study also shows the changing tax regimes of different ASEAN countries but they have not been tested to see the differences between countries. It will be indeed interesting for future researchers to focus on this aspect. Originality/value: The findings contribute to the literature on tax planning of the Shariah-compliant firms, a high growth business segment in the Asian context. The study discussed potential tax-based Islamic market product development. [ABSTRACT FROM AUTHOR]

Summary: In the phase 3 QUAZAR AML‐001 trial (NCT01757535) of patients with acute myeloid leukaemia (AML) in remission following intensive chemotherapy (IC) and ineligible for haematopoietic stem cell transplant (HSCT), oral azacitidine (Oral‐AZA) maintenance significantly prolonged overall survival (OS) versus placebo. The impact of subsequent treatment following maintenance has not been evaluated. In this post hoc analysis, OS was estimated for patients who received subsequent AML therapy, and by regimen received (IC or lower‐intensity therapy). First subsequent therapy (FST) was administered after treatment discontinuation in 134/238 Oral‐AZA and 173/234 placebo patients. OS from randomization in patients who received FST after Oral‐AZA versus placebo was 17.8 versus 12.9 months (HR: 0.82 [95% CI: 0.64–1.04], median follow‐up: 56.7 months); OS from FST was similar between arms. Among patients who received injectable hypomethylating agents as FST, median OS was 8.2 versus 4.9 months in the Oral‐AZA versus placebo groups (HR: 0.66 [95% CI: 0.41–1.06]). Forty‐eight patients (16/238 Oral‐AZA, 32/234 placebo) received HSCT following treatment discontinuation, including six Oral‐AZA patients still in first remission; Oral‐AZA OS benefit persisted when censoring these patients. Oral‐AZA maintenance can prolong AML remission duration without negatively impacting survival outcomes after salvage therapies. [ABSTRACT FROM AUTHOR]

High-dose cytarabine (HDAC) is conventionally delivered on days 1, 3 and 5 (HDAC-135) as acute myeloid leukemia (AML) post-remission therapy. Limited data is available on alternative HDAC schedules such as HDAC-123 (given consecutively for 3 days). We retrospectively compared the tolerability and efficacy of HDAC-135 and HDAC-123 delivered in sequential cohorts of adult AML patients. Seventy-three patients were included with 33% aged ≥60 years. HDAC-123 was associated with faster hematological recovery, reduced bacteremia and shorter hospitalization. No differences in safety profile or hematological recovery were seen between patients ≥60 years and <60 years receiving HDAC-123 except a shorter median time to neutrophil count recovery after cycle 1 in the latter group. Three patients (8%) receiving HDAC-123, all aged <60 years, required a change in schedule to HDAC-135 due to transient cytarabine-related side effects. HDAC-123 consolidation was well-tolerated by AML patients, including those ≥60 years, and associated with tangible reductions in resource utilization. [ABSTRACT FROM AUTHOR]

The burden of leukemia and related diseases is rapidly growing in Asia. Currently, there is a paucity of regional collaborative groups/initiatives that focus exclusively on the management of leukemia in the Asia‐Pacific (APAC) region. The Asia‐Pacific Leukemia Consortium (APLC) was established on the 8 September 2021 to understand the status quo, unmet needs, and ways to improve the management of leukemia and related diseases in the APAC region. The APLC working group set up a group of experts from various countries (Singapore, Malaysia, Thailand, Hong Kong, Japan, South Korea, Taiwan, China, and Australia) to discuss on the status of: (i) clinical trials; (ii) disease registry database; (iii) genetic and tissue repository; (iv) patient advocacy and care; and (v) disease prevention and education in the APAC region. Low levels of awareness about leukemia amongst the public, lack of financial support, and limited access to newly approved therapies were identified as barriers to the implementation of effective leukemia management in low‐ or mid‐income Asian countries. Patients often enroll in clinical trials to gain access to novel/approved therapies. The APLC group aims to address the growing threat of leukemia through a collaborative approach to advance disease prevention, research, clinical trials, and education. [ABSTRACT FROM AUTHOR]

Background: Emergency department (ED) visits are common at the end‐of‐life, but the identification of patients with life‐limiting illness remains a key challenge in providing timely and resource‐sensitive advance care planning (ACP) and palliative care services. To date, there are no validated, automatable instruments for ED end‐of‐life screening. Here, we developed a novel electronic health record (EHR) prognostic model to screen older ED patients at high risk for 6‐month mortality and compare its performance to validated comorbidity indices. Methods: This was a retrospective, observational cohort study of ED visits from adults aged ≥65 years who visited any of 9 EDs across a large regional health system between 2014 and 2019. Multivariable logistic regression that included clinical and demographic variables, vital signs, and laboratory data was used to develop a 6‐month mortality predictive model—the Geriatric End‐of‐life Screening Tool (GEST) using five‐fold cross‐validation on data from 8 EDs. Performance was compared to the Charlson and Elixhauser comorbidity indices using area under the receiver‐operating characteristic curve (AUROC), calibration, and decision curve analyses. Reproducibility was tested against data from the remaining independent ED within the health system. We then used GEST to investigate rates of ACP documentation availability and code status orders in the EHR across risk strata. Results: A total of 431,179 encounters by 123,128 adults were included in this study with a 6‐month mortality rate of 12.2%. Charlson (AUROC (95% CI): 0.65 (0.64–0.69)) and Elixhauser indices (0.69 (0.68–0.70)) were outperformed by GEST (0.82 (0.82–0.83)). GEST displayed robust performance across demographic subgroups and in our independent validation site. Among patients with a greater than 30% mortality risk using GEST, only 5.0% had ACP documentation; 79.0% had a code status previously ordered, of which 70.7% were full code. In decision curve analysis, GEST provided greater net benefit than the Charlson and Elixhauser scores. Conclusions: Prognostic models using EHR data robustly identify high mortality risk older adults in the ED for whom code status, ACP, or palliative care interventions may be of benefit. Although all tested methods identified patients approaching the end‐of‐life, GEST was most performant. These tools may enable resource‐sensitive end‐of‐life screening in the ED. See related Editorial by Goldberg et al. in this issue. [ABSTRACT FROM AUTHOR]

Purpose: Isocitrate dehydrogenase enzyme 1 (IDH1) mutations at 132nd amino acid residue (R132*) result in the cellular accumulation of the oncometabolite, 2-hydroxyglutarate (2-HG). IDH305 is an orally bioavailable, brain-penetrant, mutant-selective allosteric IDH1 inhibitor demonstrating target engagement in preclinical models. This first-in human study was designed to identify the recommended dose for expansion/maximum tolerated dose of IDH305 in patients with IDH1R132-mutant acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Methods: IDH305 was given at doses 75–750 mg twice daily in 41 patients with IDH1R132-mutant AML/MDS. Dose escalation was designed using Bayesian hierarchical model with overdose control principle and relationship with dose-limiting toxicity. Results: IDH305 exhibited rapid absorption with mean T1/2 approximately 4–10 h across doses. Interpatient variability was moderate and exposure increased with dose in a less than dose proportional manner. Most patients (35/41) demonstrated target engagement with reduction in 2-HG concentration at all doses. Complete remission (CR) or CR with incomplete count recovery occurred in 10/37 (27%) patients with AML and 1/ 4 patients with MDS. Adverse events (AEs) suspected to be related to study drug were reported in 53.7% of patients: increased blood bilirubin (14.6%), nausea (14.6%), increased alanine aminotransferase and aspartate aminotransferase (12.2%, each); most frequent grade 3 or 4 AEs were differentiation syndrome and tumor lysis syndrome (n = 3; 7.3%, each). Hepatotoxicity was manageable with dose modification. Conclusion: Due to potentially narrow therapeutic window, the study was prematurely halted and recommended phase 2 dose could not be declared. Trial registration: Clinicaltrials.gov identifier: NCT02381886. [ABSTRACT FROM AUTHOR]

TP53‐altered myelodysplastic syndrome with excess blasts and TP53‐altered acute myeloid leukemia should be considered under one unifying classification term for their study in clinical trials. Ultimately, such a unification would simplify the screening processes for clinical trials and allow a focus on treating the patient for a genetically defined disorder rather than one based on an arbitrary blast threshold. [ABSTRACT FROM AUTHOR]

Background: For patients with acute myeloid leukaemia (AML), the only potentially curative treatment is intensive chemotherapy (IC). This is highly toxic, particularly for patients > 60 years, potentially leading to prolonged hospitalisations requiring intensive supportive care, and sometimes treatment-related death. This also results in extensive healthcare costs and negatively impacts quality of life (QoL). Venetoclax with low-dose cytarabine (VEN + LDAC) is a novel, low-intensity treatment for AML patients who cannot receive IC. VEN + LDAC is given as an outpatient and toxicity appears significantly lower than with IC. Analysis of clinical trials performed to date are promising for patients with the genotype NPM1mutFLT3 ITDneg, where remission and survival rates appear comparable to those achieved with IC.Methods: VICTOR is an international, two-arm, open-label, multi-centre, non-inferiority, randomised-controlled phase II trial to assess VEN + LDAC compared to standard of care (IC) as first-line treatment in older patients (initially aged ≥ 60 years) with newly diagnosed AML. The trial will recruit patients with a NPM1mutFLT3 ITDneg genotype; those with a favourable risk in relation to the experimental treatment. University of Birmingham is the UK co-ordinating centre, with national hubs in Aarhus University Hospital, Denmark, and Auckland District Health Board, New Zealand. The primary outcome is molecular event-free survival time where an event is defined as failure to achieve morphological complete response (CR) or CR with incomplete blood count recovery after two cycles of therapy; molecular persistence, progression or relapse requiring treatment change; morphological relapse, or; death. Secondary outcomes include cumulative resource use at 12- and 24-months, and QoL as assessed by EORTCQLQ-C30 and EQ-5D-3L at 3-, 6-, 12-, 18- and 24-months. The trial employs an innovative Bayesian design with target sample size of 156 patients aged > 60 years.Discussion: The principle underpinning the VICTOR trial is that the chance of cure for patients in the experimental arm should not be compromised, therefore, an adaptive design with regular checks on accumulating data has been employed, which will allow for a staged expansion of the trial population to include younger patients if, and when, there is sufficient evidence of non-inferiority in older patients.Trial Registration: EudraCT: 2020-000,273-24; 21-Aug-2020.Isrctn: 15,567,173; 08-Dec-2020. [ABSTRACT FROM AUTHOR]

However, during the LD periods, leukapheresis was more commonly employed for patients with HL (31% in LD1.0/LD2.0 vs. 0% pre-LD, Table SV); the reason for this altered approach is unclear. During the COVID-19 pandemic, Melbourne has spent more time in civil lockdown (262 days) than any other city in the world [[1]]. We hypothesize that patients treated during LD in Melbourne may have benefited from the stricter barrier practices implemented during the pandemic; indirectly protecting vulnerable AL patients from being infected with COVID-19. [Extracted from the article]

A cancer diagnosis can have significant financial impacts for patients, often resulting from unexpected out‐of‐pocket expenses and a reduced capacity to work. These financial implications have been well characterised quantitatively in common cancers. However, less is known about the lived experience of financial stress, particularly outside the United States and in rarer cancers. This study aimed to explore the perceived financial impact of acute myeloid leukaemia (AML)—a rare haematological malignancy where patients may be particularly vulnerable to financial stress due to the lengthy, specialised and centralised care. The findings provide insight into the patients' lived experience of the personal financial impact of the disease. This Australian qualitative study was undertaken with 11 adults in remission from AML and recruited from their treating hospital. Semi‐structured interviews were transcribed, and data were managed using NVivo. Themes were identified through inductive and deductive analysis using open, axial and thematic coding. Four themes were identified: burden of AML‐attributable costs (e.g. out‐of‐pocket parking and medication expenses); accommodating the AML‐impact on paid work (e.g. early retirement and modifying job tasks); the consequence of financial strain from AML (e.g. using savings and accessing Government welfare) and concerns about the future and future familial financial burden (e.g. securing finances and worry about depleting financial resources). A reduction in or stopping work was perceived as the most burdensome to their current and future finances. The findings demonstrate people with AML experience financial difficulty even within a publically funded healthcare system. Opportunities exist for health services to alleviate some financial burden through reducing or abolishing parking fees for oncology patients and ensuring adequate access to social workers to facilitate access to Government welfare. Improving patients' financial difficulties contributes to improved quality of life, which is congruent to cancer survivorship. [ABSTRACT FROM AUTHOR]

Summary: Hypomethylating agents remain the current standard of care for patients with higher‐risk myelodysplastic syndromes. Adès et al. report outcomes from a randomised 'pick‐a‐winner' study design that examined the addition of either lenalidomide, valproic acid or idarubicin in combination with azacitidine, compared to azacitidine alone. Commentary on: Adès et al. A randomised phase II study of azacitidine (AZA) alone or with lenalidomide (LEN), valproic acid (VPA) or idarubicin (IDA) in higher‐risk MDS: GFM's 'pick a winner' trial, with the impact of somatic mutations. Br J Haematol 2022;198:535‐544. [ABSTRACT FROM AUTHOR]

Advances in scientific understanding have led to novel therapies and improved supportive care for many patients with haematological malignancies. However, these new drugs are often costly, only available at centralised health care facilities, require regular specialist reviews and lengthy treatment regimens. This leads to a significant financial burden. Understanding the impact of financial burden on haematological patients is important to appreciate the urgency of alleviating this systemic issue. Method: Eligible studies were identified by systematically searching Medline, PsycINFO, CINAHL and Embase. Self-reported data reported in both quantitative and qualitative studies that described the financial burden for patients with haematological malignancies were included. Quality appraisal of the included studies was undertaken using the Joanna Briggs Institute tools. A narrative synthesis was employed. For quantitative studies, outcomes were extracted, tabulated and categorised to find similarities and differences between the studies. For qualitative studies, quotations, codes and themes were extracted and then clustered. An inductive approach derived qualitative themes. Results: Twenty studies were identified for inclusion. Of the quantitative studies most (83%) employed un-validated researcher-generated measures to assess financial burden. Between 15–59% of patients experienced a financial burden. Out-of-pocket expenditure was frequent for clinical appointments, prescription and non-prescription medication, and travel. Financial burden was associated with a worsening quality of life and living in metropolitan areas, but there was no evidence for impact on survival. Patient-centred experiences from the qualitative inquiry complemented the quantitative findings and five themes were determined: familial or household impact; reliance on others; barriers to care due to cost; and barriers to accessing financial assistance and sources of out-of-pocket expenses. Conclusion: The impacts of financial burden are yet to be fully appreciated in haematological malignancies, exacerbated by the heterogeneous methods employed by researchers. Future work should focus on identifying the long-term ramifications of financial burden for patients and should trial interventions to reduce its prevalence and patient impacts. [ABSTRACT FROM AUTHOR]

Two oral hypomethylating agents, oral azacitidine (CC-486) and decitabine/cedazuridine (ASTX727), have recently entered the clinical domain. CC-486 has been shown to improve overall survival as maintenance therapy for older patients with acute myeloid leukemia in complete remission, whereas the combination of decitabine with cedazuridine, a cytidine deaminase inhibitor, is indicated for the treatment of adult patients with myelodysplastic syndromes and chronic myelomonocytic leukemia with intermediate-1, or higher, International Prognostic Scoring System risk. This article briefly summarizes the clinical development of both drugs, the pivotal studies that led to their approval and some of the issues faced in extending the use of these drugs to other indications. [ABSTRACT FROM AUTHOR]

Phase 3 trials Viale-A and Viale-C evaluated health-related quality of life (HRQoL) in patients with AML unfit for intensive chemotherapy who received venetoclax (VEN) + (AZA) (Viale-A) or low-dose cytarabine (LDAC) (Viale-C) or placebo (PBO) + AZA or LDAC. Patient-reported outcomes included: EORTC QLQ-C30 global health status (GHS/QoL) and physical functioning (PF), PROMIS Cancer Fatigue Short Form 7a (Fatigue), and EQ-5D-5L health status visual analog scale (HS-VAS). Time to deterioration (TTD), defined as worsening from baseline in meaningful change thresholds (MCT) of ≥10, 5, or 7 points for GHS/QoL or PF, fatigue, and HS-VAS, respectively, was assessed; differences between groups were analyzed using Kaplan-Meier and unadjusted log-rank analyses. VEN + AZA vs PBO + AZA patients had longer TTD in GHS/QoL (P = 0.066) and fatigue (P = 0.189), and significantly longer TTD in PF (P = 0.028) and HS-VAS (P < 0.001). VEN + LDAC vs PBO + LDAC patients had significantly longer TTD in GHS/QoL (P = 0.011), PF (P = 0.020), and fatigue (P = 0.004), and a trend in HS-VAS (P = 0.057). Approximately 43%, 35%, 32%, and 18% of patients treated with VEN + AZA, AZA + PBO, VEN + LDAC, or LDAC + PBO, respectively, saw improvements >MCT in GHS/QoL. Overall, VEN may positively impact HRQoL in patients with AML ineligible for intensive chemotherapy, leading to longer preservation of functioning and overall health status. [ABSTRACT FROM AUTHOR]

This study evaluated venetoclax population pharmacokinetics (popPK) in patients with treatment‐naïve acute myeloid leukemia and assessed the relationship between venetoclax exposure and clinical response for venetoclax in combination with either a hypomethylating agent (HMA) or low‐dose cytarabine (LDAC). A total of 771 patients who received venetoclax from 5 Phase 1–3 studies were included in the popPK model. Exposure‐response analyses included data from 575 patients for venetoclax/placebo plus HMA and 279 patients for venetoclax/placebo plus LDAC. The popPK model successfully characterized venetoclax plasma concentrations over time and confirmed venetoclax exposure did not vary significantly with age, weight, sex, mild to moderate hepatic impairment, or mild to severe renal impairment. Asian patients had 67% higher mean relative bioavailability than non‐Asian patients, however the range of exposures in Asian patients was similar to non‐Asian patients. For all efficacy endpoints with both treatment combinations, efficacy was higher in the venetoclax treatment groups compared with the respective control arm of placebo plus azacitidine or LDAC. Within patients who received venetoclax, no significant exposure‐efficacy relationships were identified for either treatment combination, indicating that the beneficial effects of venetoclax were already maximized in the dose ranges studied. There was no apparent effect of venetoclax exposure on treatment‐emergent Grade ≥3 thrombocytopenia or infections for either combination. Rates of treatment‐emergent Grade ≥3 neutropenia were higher in the venetoclax treatment arms compared with the respective control arms; however, within patients who received venetoclax, there was only a shallow relationship or no apparent relationship with venetoclax exposure for venetoclax plus HMA or LDAC, respectively. Along with the efficacy and safety data previously published, the exposure‐response analyses support the venetoclax dose regimens of 400 mg once daily (QD) plus HMA and 600 mg QD plus LDAC in treatment‐naïve AML patients who are ineligible for intensive chemotherapy. [ABSTRACT FROM AUTHOR]

Patient reported outcomes (PROs) are a pillar of modern-day patient-centered care and clinical trials. PROs complement clinical information with the patient's own report about their experiences of health, without influence or interpretation by other people. However, choosing an appropriate PRO measure from the many available remains challenging for clinicians and researchers. One of the common pitfalls in instrument selection is that the instrument is often developed with a different patient population than the group being cared for or researched. This difference can result in salient items of importance to the patients, being under-reported or missed altogether. We highlight, through the reporting of some of our own data, that PRO instrument development does not stop with a validation study and we provide suggestions for future research for further improvement in this space. [ABSTRACT FROM AUTHOR]

Two patients achieved a morphologic leukemia-free state at the 12 mg dose level and with GSK2879552 + ATRA combination therapy, and improvement in leukemia cutis was observed in one patient following treatment with GSK2879552 12 mg (Supplementary Figure 2). Among the 10 patients who received GSK2879552 + ATRA combination therapy, treatment-related Grade 2 pruritus led to treatment discontinuation due to investigator discretion in one patient. Outcomes remain poor for patients with advanced myelodysplastic syndrome (MDS) or relapsed/refractory acute myeloid leukemia (AML) [[1]] due to a lack of effective treatment regimens [[3]], highlighting an unmet clinical need for novel treatments for these patients. [Extracted from the article]

Although post-transplant maintenance therapy with sorafenib has been shown to significantly improve RFS in patients with I FLT3 i mutant AML, this study was conducted prior to the introduction of midostaurin in the frontline setting and so it is not known if post-transplant FLT3 targeting will have the same efficacy in the post-RATIFY era [[16]]. Many of the limitations of parenteral azacitidine in terms of patient and physician acceptance, ability to deliver maintenance therapy beyond 12 months and capacity to administer azacitidine for more than 5 days per cycle in the post-transplant setting may yet be overcome by the recent introduction of oral azacitidine into clinical AML practice. Allogeneic hematopoietic stem cell transplantation (HSCT) has been a cornerstone of post-remission therapy in AML, leveraging donor cell immunity to reduce relapse risk in patients with higher risk disease. Based on the established role of azacitidine in patients with higher risk myelodysplastic syndrome (MDS) and elderly AML [[6]], many investigators have explored the role of post-transplant hypomethylating agent-based maintenance therapy, aimed at mitigating relapse risk, particularly within the first 12 months after donor stem cell infusion. [Extracted from the article]

PURPOSE Acute myeloid leukemia (AML) is a rare hematologic malignancy accounting for 0.8% of new cancer diagnoses in Australia. High mortality and morbidity affect work productivity through workforce dropout and premature death. This study sought to estimate the productivity loss attributable to AML in the Australian population over 10 years and to estimate the costs of this productivity loss. Productivity was measured using productivity-adjusted life years (PALYs), a similar concept to quality-adjusted life years, but adjusts for the productivity loss attributable to disease, rather than impaired health. MATERIALS AND METHODS Dynamic life tables modeled the Australian working population (age 15-65 years) between 2020 and 2029. The model population had two cohorts: those with and without AML. Differences in life years, PALYs, and costs represented the health and productivity impact of AML. Secondary analyses evaluated the impact of different scenarios. RESULTS Over the next 10 years, there will be 7,600 years of life lost and 7,337 PALYs lost because of AML, amounting to Australian dollars (AU$) 1.43 billion in lost gross domestic product ($971 million in US dollars). Secondary analyses highlight potential savings of approximately AU$52 million if survival rates were improved by 20%and almost AU$118 million in savings if the return-to-work rates increased by 20%on the current estimates. CONCLUSION Our study demonstrates that even in low-incidence cancer, high mortality and morbidity translate to profound impacts on years of life, productivity, and the broader economy. Better treatment strategies are likely to result in significant economic gains. This highlights the value of investing in research for improved therapies. [ABSTRACT FROM AUTHOR]

The benefits of non-myeloablative stem cell transplant in older patients with acute myeloid leukaemia are unclear. We compare the long-term outcomes of this regimen in those aged 55–65 years in first remission with a chemotherapy only cohort that achieved durable morphologic remission. Five-year overall survival was similar (32% vs 33%, P = 0.90), as was relapse-free survival (23% vs 20%, P = 0.37). There was a trend for decreased relapse that was balanced against increased non-relapse mortality with transplantation. [ABSTRACT FROM AUTHOR]

VIALE-C compared the safety and efficacy of venetoclax or placebo plus low-dose cytarabine (+LDAC) in patients with untreated AML ineligible for intensive chemotherapy. Overall, 211 patients were enrolled (n = 143, venetoclax; n = 68, placebo). At the primary analysis, the study did not meet its primary endpoint of a statistically significant improvement in overall survival (OS), however, ~60% of patients had been on study for ≤6-months. Here, we present an additional 6-months of follow-up of VIALE-C (median follow-up 17.5 months; range 0.1–23.5). Median OS was (venetoclax +LDAC vs. placebo +LDAC) 8.4 vs. 4.1 months (HR = 0.70, 95% CI 0.50,0.99; P = 0.040); a 30% reduction in the risk of death with venetoclax. Complete response (CR)/CR with incomplete hematologic recovery (CRi) rates were 48.3% vs. 13.2%. Transfusion independence rates (RBC) were 43% vs.19% and median event-free survival was 4.9 vs. 2.1 months (HR = 0.61; 95% CI 0.44,0.84; P = 0.002). These results represent improved efficacy over the primary analysis. Incidence of grade ≥3 adverse events were similar between study arms and overall safety profiles were comparable to the primary analysis. These data support venetoclax +LDAC as a frontline treatment option for patients with AML ineligible for intensive chemotherapy. This trial was registered at www.clinicaltrials.gov as #NCT03069352. [ABSTRACT FROM AUTHOR]

Background: The present study evaluated the relative survival benefits associated with enasidenib and current standard of care (SoC) therapies for patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) and an isocitrate dehydrogenase 2 (IDH2) mutation who are ineligible for hematopoietic stem cell transplantation (HSCT). Methods: Propensity score matching (PSM) analysis compared survival outcomes observed with enasidenib 100 mg daily in the phase I/II AG221‐C‐001 trial and SoC outcomes obtained from a real‐world chart review of patients in France. Results: Before matching, enasidenib (n = 195) was associated with numerically improved overall survival (OS) relative to SoC (n = 80; hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.61–1.11). After matching and adjusting for covariates (n = 78 per group), mortality risk was significantly lower with enasidenib than with SoC (HR, 0.67; 95% CI, 0.47–0.97). The median OS was 9.26 months for enasidenib (95% CI, 7.72–13.24) and 4.76 months for SoC (95% CI, 3.81–8.21). Results remained robust across all sensitivity analyses conducted. Conclusions: PSM analyses indicate that enasidenib significantly prolongs survival relative to SoC among patients with R/R AML and an IDH2 mutation who are ineligible for HSCT. Future prospective studies are needed to validate these findings using other data sources and to assess the comparative efficacy of enasidenib for other treatment outcomes. [ABSTRACT FROM AUTHOR]

Background: Most older patients with acute myeloid leukemia (AML) who attain morphologic remission with intensive chemotherapy (IC) will eventually relapse and post-relapse prognosis is dismal. In the pivotal QUAZAR AML-001 trial, oral azacitidine maintenance therapy significantly prolonged overall survival by 9.9 months (P < 0.001) and relapse-free survival by 5.3 months (P < 0.001) compared with placebo in patients with AML in first remission after IC who were not candidates for transplant. Currently, the QUAZAR AML-001 trial provides the most comprehensive safety information associated with oral azacitidine maintenance therapy. Reviewed here are common adverse events (AEs) during oral azacitidine treatment in QUAZAR AML-001, and practical recommendations for AE management based on guidance from international cancer consortiums, regulatory authorities, and the authors' clinical experience treating patients in the trial. Methods: QUAZAR AML-001 is an international, placebo-controlled randomized phase 3 study. Patients aged ≥ 55 years with AML and intermediate- or poor-risk cytogenetics at diagnosis, who had attained first complete remission (CR) or CR with incomplete blood count recovery (CRi) within 4 months before study entry, were randomized 1:1 to receive oral azacitidine 300 mg or placebo once-daily for 14 days in repeated 28-day cycles. Safety was assessed in all patients who received ≥ 1 dose of study drug. Results: A total of 469 patients received oral azacitidine (n = 236) or placebo (n = 233). Median age was 68 years. Patients received a median of 12 (range 1–80) oral azacitidine treatment cycles or 6 (1–73) placebo cycles. Gastrointestinal AEs were common and typically low-grade. The most frequent grade 3–4 AEs during oral azacitidine therapy were hematologic events. AEs infrequently required permanent discontinuation of oral azacitidine (13%), suggesting they were effectively managed with use of concomitant medications and oral azacitidine dosing modifications. Conclusion: Oral azacitidine maintenance had a generally favorable safety profile. Prophylaxis with antiemetic agents, and blood count monitoring every other week, are recommended for at least the first 2 oral azacitidine treatment cycles, and as needed thereafter. Awareness of the type, onset, and duration of common AEs, and implementation of effective AE management, may maximize treatment adherence and optimize the survival benefits of oral azacitidine AML remission maintenance therapy. Trial registration This trial is registered on clinicaltrials.gov: NCT01757535 as of December 2012. [ABSTRACT FROM AUTHOR]

Summary: Based on promising results in older adults with acute myeloid leukaemia (AML), we treated patients with NPM1mut measurable residual disease (MRD) using off‐label venetoclax in combination with low‐dose cytarabine or azacitidine. Twelve consecutive patients were retrospectively identified, including five with molecular persistence and seven with molecular relapse/progression. All patients with molecular persistence achieved durable molecular complete remission (CRMRD‐) without transplantation. Six of seven patients with molecular relapse/progression achieved CRMRD‐ after 1–2 cycles of venetoclax. This paper highlights the promising efficacy of venetoclax‐based therapy to reduce the relapse risk in patients with persistent or rising NPM1mut MRD. [ABSTRACT FROM AUTHOR]

Conventional therapy for acute myeloid leukemia is composed of remission induction with cytarabine- and anthracycline-containing regimens, followed by consolidation therapy, including allogeneic stem cell transplantation, to prolong remission. In recent years, there has been a significant shift toward the use of novel and effective, target-directed therapies, including inhibitors of mutant FMS-like tyrosine kinase 3 (FLT3) and isocitrate dehydrogenase (IDH), the B-cell lymphoma 2 inhibitor venetoclax, and the hedgehog pathway inhibitor glasdegib. In older patients the combination of a hypomethylating agent or low-dose cytarabine, venetoclax achieved composite response rates that approximate those seen with standard induction regimens in similar populations, but with potentially less toxicity and early mortality. Preclinical data suggest synergy between venetoclax and FLT3- and IDH-targeted therapies, and doublets of venetoclax with inhibitors targeting these mutations have shown promising clinical activity in early stage trials. Triplet regimens involving the hypomethylating agent and venetoclax with FLT3 or IDH1/2 inhibitor, the TP53-modulating agent APR-246 and magrolimab, myeloid cell leukemia-1 inhibitors, or immune therapies such as CD123 antibody-drug conjugates and programmed cell death protein 1 inhibitors are currently being evaluated. It is hoped that such triplets, when applied in appropriate patient subsets, will further enhance remission rates, and more importantly remission durations and survival. [ABSTRACT FROM AUTHOR]

Background: Androgens function through DNA and non‐DNA binding‐dependent signalling of the androgen receptor (AR). How androgens promote erythropoiesis is not fully understood. Design and methods: To identify the androgen signalling pathway, we treated male mice lacking the second zinc finger of the DNA‐binding domain of the AR (ARΔZF2) with non‐aromatizable 5α‐dihydrotestosterone (5α‐DHT) or aromatizable testosterone. To distinguish direct hematopoietic and non‐hematopoietic mechanisms, we performed bone marrow reconstitution experiments. Results: In wild‐type mice, 5α‐DHT had greater erythroid activity than testosterone, which can be aromatized to estradiol. The erythroid response in wild‐type mice following 5α‐DHT treatment was associated with increased serum erythropoietin (EPO) and its downstream target erythroferrone, and hepcidin suppression. 5α‐DHT had no erythroid activity in ARΔZF2 mice, proving the importance of DNA binding by the AR. Paradoxically, testosterone, but not 5α‐DHT, suppressed EPO levels in ARΔZF2 mice, suggesting testosterone following aromatization may oppose the erythroid‐stimulating effects of androgens. Female wild‐type mice reconstituted with ARΔZF2 bone marrow cells remained responsive to 5α‐DHT. In contrast, ARΔZF2 mice reconstituted with female wild‐type bone marrow cells showed no response to 5α‐DHT. Conclusion: Erythroid promoting effects of androgens are mediated through DNA binding‐dependent actions of the AR in non‐hematopoietic cells, including stimulating EPO expression. [ABSTRACT FROM AUTHOR]

Patients with refractory or relapsed acute myeloid leukemia (R/R AML) have a poor prognosis, with a high unmet medical need. Idasanutlin is a small-molecule inhibitor of MDM2, a negative regulator of tumor suppressor p53. By preventing the p53-MDM2 interaction, idasanutlin allows for p53 activation, particularly in patients with TP53 wild-type (WT) status. MIRROS (NCT02545283) is a randomized Phase III trial evaluating idasanutlin + cytarabine versus placebo + cytarabine in R/R AML. The primary end point is overall survival in the TP53-WT population. Secondary end points include complete remission rate (cycle 1), overall remission rate (cycle 1) and event-free survival in the TP53-WT population. MIRROS has an innovative design that integrates a stringent interim analysis for futility; continuation criteria were met in mid-2017 and accrual is ongoing. Trial registration number: NCT02545283. [ABSTRACT FROM AUTHOR]

Recent regulatory approval of midostaurin, a FLT3 targeting small molecular inhibitor, will likely lead to increased use of midostaurin in combination with intensive chemotherapy for patients with FLT3-mutant AML. Translation of clinical trial results into everyday practice has its challenges. This study compared the relevance of the trial population and practices studied in the midostaurin registration study (RATIFY) with real-world practice in terms of patient factors, chemotherapy, mutation-specific frequencies and clinical outcomes among patients with FLT3-mutant AML in the pre-midostaurin era (2010–2015) in Australia. We observed substantial diversity of chemotherapy regimens used in the community and limitations of the generalizability of eligibility criteria used in RATIFY (such as age and hyperleukocytosis). This study provides real-world historical data that may be used for comparison with future trial cohorts incorporating FLT3 inhibitors into the management of FLT3-mutant AML and highlights the inherent difficulties in translating clinical trial data into routine practice. [ABSTRACT FROM AUTHOR]

Objectives: We examine how the supply and demand for news stories that reference an individualistic concept change in response to changes in inequality and the prevailing ideology. Methods: We use Google Trends data to construct an index of demand for individualistic news and a database of newspaper articles to construct an index of supply. We estimate fixed effects models on state and DMA‐level data from 1993 to 2017. Results: Demand for individualistic news is higher in more conservative areas and it is even stronger when inequality rises. Supply of individualistic news is higher when the share of income to the top 1 percent is higher. The supply effect is strongest in more liberal areas. Conclusion: These results provide evidence of both confirmation bias influencing demand and media capture influencing supply. Confirmation bias and media capture are distinct phenomenon, but provide reinforcing explanations for why consumption of individualistic news increases with inequality. [ABSTRACT FROM AUTHOR]