Combination of a mitogen‐activated protein kinase inhibitor with the tyrosine kinase inhibitor pacritinib combats cell adhesion‐based residual disease and prevents re‐expansion of FLT3 ‐ITD acute myeloid leukaemia

Minimal residual disease (MRD) in acute myeloid leukaemia (AML) poses a major challenge due to drug insensitivity and high risk of relapse. Intensification of chemotherapy and stem cell transplantation are often pivoted on MRD status. Relapse rates are high even with the integration of first‐generation FMS‐like tyrosine kinase 3 (FLT3) inhibitors in pre‐ and post‐transplant regimes and as maintenance in FLT3 ‐mutated AML. Pre‐clinical progress is hampered by the lack of suitable modelling of residual disease and post‐therapy relapse. In the present study, we investigated the nature of pro‐survival signalling in primary residual tyrosine kinase inhibitor (TKI)‐treated AML cells adherent to stroma and further determined their drug sensitivity in order to inform rational future therapy combinations. Using a primary human leukaemia‐human stroma model to mimic the cell–cell interactions occurring in patients, the ability of several TKIs in clinical use, to abrogate stroma‐driven leukaemic signalling was determined, and a synergistic combination with a mitogen‐activated protein kinase (MEK) inhibitor identified for potential therapeutic application in the MRD setting. The findings reveal a common mechanism of stroma‐mediated resistance that may be independent of mutational status but can be targeted through rational drug design, to eradicate MRD and reduce treatment‐related toxicity

Addition of the mammalian target of rapamycin inhibitor, Everolimus, to consolidation therapy in acute myeloid leukaemia: experience from the UK NCRI AML17 trial

As part of the UK NCRI AML17 trial, adult patients with acute myeloid leukemia in remission could be randomized to receive the mammalian target of rapamycin inhibitor everolimus, sequentially with post-induction chemotherapy. Three hundred and thirty-nine patients were randomised (2:1) to receive everolimus or not for a maximum of 84 days between chemotherapy courses. The primary endpoint was relapse-free survival. At 5 years there was no difference in relapse-free survival [29% versus 40%; odds ratio 1.19 (0.9-1.59) P=0.2], cumulative incidence of relapse [60% versus 54%: odds ratio 1.12 (0.82-1.52): P=0.5] or overall survival [45% versus 58%: odds ratio 1.3 (0.94-1.81): P=0.11]. The independent Data Monitoring Committee advised study termination after randomization of 339 of the intended 600 patients because of excess mortality in the everolimus arm without any evidence of beneficial disease control. The delivery of the everolimus dose was variable, but there was no evidence of clinical benefit in patients with adequate dose delivery compared with no treatment. This study suggests that the addition of mammalian target of rapamycin inhibition to chemotherapy provides no benefit

Nuclear factor I-C overexpression promotes monocytic development and cell survival in acute myeloid leukemia

Nuclear factor I-C (NFIC) belongs to a family of NFI transcription factors that binds to DNA through CAATT-boxes and are involved in cellular differentiation and stem cell maintenance. Here we show NFIC protein is significantly overexpressed in 69% of acute myeloid leukemia patients. Examination of the functional consequences of NFIC overexpression in HSPCs showed that this protein promoted monocytic differentiation. Single-cell RNA sequencing analysis further demonstrated that NFIC overexpressing monocytes had increased expression of growth and survival genes. In contrast, depletion of NFIC through shRNA decreased cell growth, increased cell cycle arrest and apoptosis in AML cell lines and AML patient blasts. Further, in AML cell lines (THP-1), bulk RNA sequencing of NFIC knockdown led to downregulation of genes involved in cell survival and oncogenic signaling pathways including mixed lineage leukemia-1 (MLL-1). Lastly, we show that NFIC knockdown in an ex vivo mouse MLL::AF9 pre-leukemic stem cell model, decreased their growth and colony formation and increased expression of myeloid differentiation markers Gr1 and Mac1. Collectively, our results suggest that NFIC is an important transcription factor in myeloid differentiation as well as AML cell survival and is a potential therapeutic target in AML

Venetoclax combined with low dose cytarabine compared to standard of care intensive chemotherapy for the treatment of favourable risk adult acute myeloid leukaemia (VICTOR): Study protocol for an international, open-label, multicentre, molecularly-guided randomised, phase II trial

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

Fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin with gemtuzumab ozogamicin improves event-free survival in younger patients with newly diagnosed aml and overall survival in patients with npm1 and flt3 mutations

Purpose To determine the optimal induction chemotherapy regimen for younger adults with newly diagnosed AML without known adverse risk cytogenetics. Patients and Methods One thousand thirty-three patients were randomly assigned to intensified (fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin [FLAG-Ida]) or standard (daunorubicin and Ara-C [DA]) induction chemotherapy, with one or two doses of gemtuzumab ozogamicin (GO). The primary end point was overall survival (OS). Results There was no difference in remission rate after two courses between FLAG-Ida + GO and DA + GO (complete remission [CR] + CR with incomplete hematologic recovery 93% v 91%) or in day 60 mortality (4.3% v 4.6%). There was no difference in OS (66% v 63%; P = .41); however, the risk of relapse was lower with FLAG-Ida + GO (24% v 41%; P < .001) and 3-year event-free survival was higher (57% v 45%; P < .001). In patients with an NPM1 mutation (30%), 3-year OS was significantly higher with FLAG-Ida + GO (82% v 64%; P = .005). NPM1 measurable residual disease (MRD) clearance was also greater, with 88% versus 77% becoming MRD-negative in peripheral blood after cycle 2 (P = .02). Three-year OS was also higher in patients with a FLT3 mutation (64% v 54%; P = .047). Fewer transplants were performed in patients receiving FLAG-Ida + GO (238 v 278; P = .02). There was no difference in outcome according to the number of GO doses, although NPM1 MRD clearance was higher with two doses in the DA arm. Patients with core binding factor AML treated with DA and one dose of GO had a 3-year OS of 96% with no survival benefit from FLAG-Ida + GO. Conclusion Overall, FLAG-Ida + GO significantly reduced relapse without improving OS. However, exploratory analyses show that patients with NPM1 and FLT3 mutations had substantial improvements in OS. By contrast, in patients with core binding factor AML, outcomes were excellent with DA + GO with no FLAG-Ida benefit

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK.

BACKGROUND: A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. METHODS: This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. FINDINGS: Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0-75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4-97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8-80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3-4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. INTERPRETATION: ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials. FUNDING: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, Bill & Melinda Gates Foundation, Lemann Foundation, Rede D'Or, Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK

Background A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. Methods This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. Findings Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0–75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4–97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8–80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3–4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. Interpretation ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials

A British Society for Haematology good practice paper: Recommendations for laboratory testing of <scp>UK</scp> patients with acute myeloid leukaemia

No abstract available

Genomic correlates of outcome in a randomised comparison of CPX-351 and FLAG-Ida in high-risk acute myeloid leukaemia and myelodysplastic syndrome: results from the UK NCRI AML19 Trial

Background Liposomal daunorubicin and cytarabine (CPX-351) improves survival compared to 3+7 chemotherapy in patients aged 60 years with secondary AML defined by clinical or cytogenetic criteria (Lancet JE, JCO 2018). It is increasingly recognised that secondary AML may be better defined by mutational profile than clinical history (Döhner, Blood 2022; Khoury, Leukemia 2022), however patients with molecularly defined secondary AML were not specifically included in previous studies. Moreover, no randomised data for CPX-351 in patients aged <60y were available prior to this study. Previous UK NCRI trials established the FLAG-Ida regimen as a preferred regimen in patients aged <60y with high-risk and secondary AML (Burnett AK, Leukemia 2018). The UK NCRI AML19 trial randomised patients with AML or high grade MDS between induction therapy with CPX-351 and FLAG-Ida. Initial results reporting similar event-free and overall survival (OS) have been previously presented (Russell NH, HemaSphere 2022). Here we present an exploratory analysis of outcomes stratified by genomic, cytogenetic and clinical definitions of secondary AML. Methods AML19 (ISRCTN78449203) enrolled patients with previously untreated AML, MDS-EB2, or MDS-EB1 with IPSS score >3.5, predominantly aged <60 years. Patients known to have an adverse karyotype at diagnosis according to MRC criteria were randomised between CPX-351 and FLAG-Ida. Treatment consisted of up to 4 courses of CPX-351 or 2 courses of FLAG-Ida followed by MACE/MidAC consolidation with allogeneic transplant recommended after 2 cycles if feasible. Of note, patients could also enter the FLAG-IDA vs CPX randomisation if they became high risk at other defined points after induction, the results of which will be reported separately. Cytogenetic testing was performed in local laboratories with results reviewed and coded centrally. Complex karyotype was defined as ≥4 unrelated abnormalities. Following the completion of the trial, banked diagnostic DNA was analysed for variants in 41 recurrently mutated myeloid genes, including the entire coding regions of all myelodysplasia-related genes according to 2022 WHO and ELN criteria (ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, ZRSR2) (Döhner, Blood 2022; Khoury, Leukemia 2022). Libraries were prepared using the Agilent SureSelect XT HS2 platform and sequenced on an Illumina NextSeq2000 to a depth of >1000x. Results In total, 195 patients entered were randomised at trial entry, and NGS was performed on 173. Of the whole cohort, 49% were classified by clinical features as de novo AML, 20% as secondary AML and 31% as high-risk MDS. Myelodysplasia-related cytogenetic abnormalities were present in 70% of patients, with a complex karyotype in 51%. TP53 was the most commonly mutated gene in 43% of patients, followed by DNMT3A in 19% and ASXL1 in 18% (Figure A). A mutation in at least one myelodysplasia-related gene was present in 75 (43%) patients, of whom 60 (35%) were categorised as secondary AML by mutational status, which by ELN 2022 criteria requires the absence of TP53 variants. As previously reported, OS did not differ between the two randomisation arms (Hazard Ratio [HR] for CPX-351 0.84, 95% confidence interval [95CI] 0.59 - 1.20). In patients with clinically defined secondary AML, there was no OS benefit for CPX-351 (HR 1.1, 95CI 0.53 - 2.30), while high-risk MDS had a trend to benefit (HR 0.54, 95CI 0.28 - 1.00) (Figure B). When secondary disease was defined by the presence of myelodysplasia-related cytogenetic abnormalities, CPX-351 did not provide benefit (HR 1.04, 95CI 0.77 - 1.55). However, in patients with mutationally defined secondary AML, there was an OS benefit from CPX-351 (HR 0.42, 95CI 0.21 - 0.84, p value for heterogeneity 0.05) (Figure B). Patients with TP53 mutations had an adverse prognosis, with median OS of 7 months compared to 28 months in those with wild-type TP53. CPX-351 did not provide benefit compared to FLAG-Ida in this group (HR 0.92, 95CI 0.57 - 1.49). Conclusion In this exploratory subgroup analysis, CPX-351 had a significant survival benefit over FLAG-Ida in young high-risk patients with secondary AML/MDS as defined by the presence of myelodysplasia-related gene mutations, but not by clinical criteria. We observed no significant difference in patients with TP53 mutations