scholarly journals Examining the Usefulness of the Charlson Comorbidity Index to Predict Early Mortality in Patients with Acute Myeloid Leukaemia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1218-1218
Author(s):  
Mohamed Bakri Mohamed ◽  
Seán R Millar ◽  
Vitaliy Mykytiv ◽  
Rose McMorrow ◽  
Conan Donnelly ◽  
...  
Keyword(s):  
Acute Myeloid Leukaemia ◽  
Survival Time ◽  
Myeloid Leukaemia ◽  
Charlson Comorbidity Index ◽  
Median Survival Time ◽  
Research Funding ◽  
Cox Regression ◽  
Early Mortality ◽  
Comorbidity Index ◽  
Acute Myeloid

Abstract Background and aims: Acute myeloid leukaemia (AML) is a relatively rare haematological malignancy which is the most common acute leukaemia in adults. Patients with AML often have a substantial comorbidity burden. Consequently, different scores are used in clinical practice to predict outcomes in patients with multiple comorbidities. The Charlson Comorbidity Index (CCI), calculated based on 19 different medical conditions, weighs the comorbidities to measure a patient's burden of disease. Previous publications have suggested that the CCI may be useful in determining survival in AML patients. However, the CCI is not in routine use in Ireland for assessing patients with AML. In this study we examined the usefulness of the CCI to predict early mortality in AML patients, drawing on data from the Extended Blood Cancer Registration (EBCR) in Ireland. Methods: The EBCR was undertaken by National Cancer Registry Ireland registrars trained by consultant haematologists and deployed in national centres. Data collection began in 2017 and continued to 2019; 141 AML patients underwent extended data registration. Comorbidities were identified by ICD-9 codes and chart review. Kaplan Meier curves and Cox regression analyses were used to determine the usefulness of the CCI to predict early mortality in AML patients. Results: Of the 141 AML patients, 82% were between 50 and 70 years of age and 84 had died by 31/12/2019 (median survival time = 289.0 days). The median survival time for patients in the lowest tertile of the CCI was 498.5 days, compared to 246.0 and 116.5 days for subjects in tertiles 2 and 3, respectively (Figure 1. Log rank P-value <.001). In Cox regression analysis, a dose-response relationship was observed, with patients in the highest CCI tertile displaying a greater risk (HR = 4.90, 95% CI: 2.79-8.63) of mortality compared to subjects in tertile 2 (HR = 2.74, 95% CI: 1.64-4.57) and tertile 1 (reference). However, this relationship was attenuated, and non-significant, in analyses which adjusted for age at diagnosis and in a further multivariable model. Conclusions: Although results demonstrate a strong relationship between the CCI and early mortality in AML patients, our findings suggest that the CCI provides little or no additional prognostic information beyond that which is obtained from age at AML diagnosis alone. This study highlights the importance of validating risk assessment tools in order to determine their potential usefulness in a clinical setting and emphasise the importance of weighing in the treatment decision making paradigm. The Blood Cancer Network Ireland (BCNI) thank the Science Foundation of Ireland (SFI) and the Irish Cancer Society (ICS) for funding (2015-2021). We also thank our colleagues in the National Cancer Registry Ireland for assistance, advice and guidance. Figure 1 Figure 1. Disclosures Quinn: Takeda: Honoraria. O'Dwyer: Bristol Myers Squibb: Research Funding; Janssen: Consultancy; ONK Therapeutics: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Szegezdi: ONK Therapeutics: Research Funding.

Usefulness of Charlson Comorbidity Index to Predict Early Mortality and Overall Survival in Older Patients With Acute Myeloid Leukemia

2020 ◽  
Vol 20 (12) ◽  
pp. 804-812.e8 ◽  
Author(s):  
Prajwal Dhakal ◽  
Valerie Shostrom ◽  
Zaid S. Al-Kadhimi ◽  
Lori J. Maness ◽  
Krishna Gundabolu ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Charlson Comorbidity Index ◽  
Older Patients ◽  
Myeloid Leukemia ◽  
Early Mortality ◽  
Comorbidity Index ◽  
Acute Myeloid

scholarly journals Repressed Chromatin Drives Leukaemogenesis in Mutant IDH2 Acute Myeloid Leukaemia Via Inhibition of Granulocyte Differentiation and Cell Cycle Progression

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3467-3467
Author(s):  
Douglas RA Silveira ◽  
Prodromos Chatzikyriakou ◽  
Olena Yavorska ◽  
Sarah Mackie ◽  
Roan Hulks ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Research Funding ◽  
Differentially Expressed ◽  
Rna Seq ◽  
Induced Differentiation ◽  
Effector Genes ◽  
Acute Myeloid

Abstract Differentiation arrest in acute myeloid leukaemia (AML) results in accumulation of leukaemic progenitors (L-Prog) and bone marrow failure. Mutant isocitrate dehydrogenase enzyme produces d-2-hydroxyglutarate (2HG), which inhibits α-ketoglutarate-dependent dioxygenases, including Jumonji histone demethylases (JKDM) and TET2, but how this causes AML is unclear. Inhibitors of mutant IDH enzyme (mIDHi) restore differentiation in IDH-mutant (mIDH) AML (Amatangelo et al., 2018). Here, we studied transcriptional networks involved using single-cell (SC) gene expression (GEX) and transcription factor (TF) motif accessibility in primary AML treated with the mIDH2 inhibitor enasidenib (ENA) and found that ENA activates cell cycle (CC) and pro-differentiation programmes through increased promoter accessibility of granulocyte-monocyte (GM)-TF targets. We treated patient L-Prog in vitro with ENA or vehicle, and performed SC RNA-seq (Chromium 10x) in 4 responsive (R), and one non-responsive (NR) patient samples in early, mid and late timepoints. GEX signatures were used to annotate cells according to function (undifferentiated [U], early and late GM [EGM and LGM]) and CC states. In R samples, ENA yielded more dividing late-GM at mid-late timepoints than DMSO (18% vs 6.5%), and more terminally differentiated neutrophils at late timepoints (46% vs 16%). Using SCENIC (Aibar et al., 2017) to assign highly differentially-expressed genes to TF motifs, we computed regulatory networks (regulons, 'R'). Expression of the SP1 R was strongly correlated with active proliferation and ENA conditions led to generation of more cells that co-expressed CEBPA R or CEBPE R with SP1 R, emphasising simultaneous engagement of CC and GM programmes. SP1 function is associated with CC and GM differentiation, and silencing of its binding to its targets contributes to AML pathogenesis (Maiques-Diaz et al., 2012). Control and NR samples failed to produce neutrophils, had reduced co-expression of CEBPE/SP1 R and yielded more poorly differentiated cells expressing GATA2 R. At the individual gene level, ENA stimulated downregulation of GATA2, GFI1B, IKZF1/2, and RUNX3 together with upregulation of immediate early genes which respond to cytokine and mitogenic stimuli (EGR1, IER2, AP-1) in early-mid phase. Later there is upregulation of CEBP TFs and effector genes FUT4, ELANE, AZU1 and PRTN3. Interestingly, expression of some GM-TFs (RUNX1, SPI1/PU.1, GFI1) was similar between ENA and DMSO, indicating that gene expression alone was insufficient for GM differentiation. Given the effects of 2-HG on JKDM, we assessed chromatin accessibility and TF binding using SC ATAC-seq. Overall, we had 25% of differentially accessible (DA) peaks, from which 75% were more accessible in ENA than in DMSO. ENA DA peaks were highly enriched in promoters. Using ArchR (Granja et al., 2021), we clustered cells and used ELANE expression levels to compute trajectories in parallel with SC RNA-seq data. ENA peaks were sequentially enriched for CBF/RUNX and GATA families, followed by AP-1 (JUN/FOS) and EGR/CEBP/KLF motifs. Footprinting analysis showed sequential decrease and increase of TF binding for GATA2 and CEBPA/E respectively during ENA-induced differentiation. Although it did not cause higher expression of SPI1/PU.1, ENA induced increased accessibility of its target binding sites at promoters, which included CEBPA/E and GM effectors (MPO, FUT4, PRTN3). This provides a novel mechanism by which ENA induces differentiation of L-prog. Regulatory network analysis around active, differentially expressed TFs at different phases of ENA-induced differentiation showed a switch from a repressive transcriptional landscape driven by stem-progenitor TFs, to one where AP-1 and GM-TFs activate expression of GM-effector genes. We postulate a model where MYC, E2F8 and EGR1 upregulate the CEBP family in early-mid differentiation. In addition to stimulation of promoter accessibility of TFBS, we find that ENA increases accessibility of cis-regulatory elements of CEBP TFs, adding another mechanism by which differentiation of L-Prog occurs. Our data on the mechanism of action of ENA suggest that differentiation arrest in IDHm AML involves suppression of CC and GM differentiation programs in a repressive chromatin landscape, likely via inhibition of KDM6A and demethylation of repressive H3K27me3 marks. Disclosures Silveira: Astellas: Speakers Bureau; Abbvie: Speakers Bureau; Servier/Agios: Research Funding; BMS/Celgene: Research Funding. Hasan: Bristol Myers Squibb: Current Employment. Thakurta: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Vyas: Gilead: Honoraria; Astellas: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Takeda: Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Janssen: Honoraria; Daiichi Sankyo: Honoraria; Jazz: Honoraria; Pfizer: Honoraria; Novartis: Honoraria. Quek: BMS/Celgene: Research Funding; Servier/Agios: Research Funding.

scholarly journals A Mutation Pentad Defined Outcome of De Novo and Cytogenetically Normal Acute Myeloid Leukaemia in Young Adults

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1400-1400
Author(s):  
Sze Pui Tsui ◽  
Ip HW Alvin ◽  
Chunxiao Zhang ◽  
Tommy W.F. Tang ◽  
CH Lin ◽  
...  
Keyword(s):  
Young Adults ◽  
Hong Kong ◽  
Clinical Outcome ◽  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Research Funding ◽  
De Novo ◽  
Gene Mutations ◽  
Npm1 Mutation ◽  
Acute Myeloid

Background. Cytogenetically normal acute myeloid leukaemia (CN-AML) occurs in 50% adult AML and is a group of diseases with diverse mutations and distinct clinical outcome. CEBPα, NPM1 and FLT3 mutations that are commonly seen in CN-AML have been incorporated into risk stratification. However, prognostic impacts of other gene mutations and their combinations in this AML subtype have remained unclear. In this study, we examined a cohort of young adults with de novo CN-AML who have received uniform treatment protocol in Hong Kong and identified a mutation pentad that might define their clinical outcome. Methodology. Young adults (18-60 years old) with de novo CN-AML, diagnosed from 1st August 2003 to 7th August 2018 in 8 regional hospitals in Hong Kong, were included. They received standard "7+3" induction (Daunorubicin 60-90 mg/m2 and Cytarabine 100 mg/m2) followed by up to 4 courses of high dose cytarabine consolidation (Cytarabine 3 gram/m2 for 4-6 doses). Decision on allogeneic haematopoietic stem cell transplantation (HSCT) was based on clinical grounds and gene mutations according to ELN recommendations. Next generation sequencing (NGS) was performed in diagnostic bone marrow (BM) in 362 patients for 36 recurrent mutated genes and analyzed by in-house bioinformatics pipelines. Relapse-free survival (RFS) was defined by the time from first complete remission (CR) to relapse or death and overall survival (OS) by the time from diagnosis to death. Patients were censored at last follow up. Survivals were evaluated by Kaplan-Meier analysis and compared by log-rank test. Multivariate analyses of clinical and genetic parameters were analyzed by Cox-regression. P-values of <0.05 were considered statistically significant. Results. A total of 436 patients (Male=189; Female=247) were recruited. Their median age of onset was 49 years old (Range 18-60); median presenting white cell counts (WCC) was 21.85x109/L (range 0.25-411x109/L), median circulating blast % was 46% (range 1-99). 416 patients received induction of whom 90.1% achieved CR or CRi (N=375) after 1 (N=268), 2 (N=78) or ≥ 3 courses of induction (N=29). One hundred and sixty three patients received allogeneic HSCT at CR1 (N=102), CR2 (N=51), ≥ CR3 (N=2) and relapsed state (N=8). Eight mutations with ≥ 10% prevalence occurred in 79.8% patients (Figure 1). Univariate analyses showed that mutations of CEBPα, TET2, IDH2-R172K and RAS were not associated with treatment outcome and survival. Five genetic subgroups based on NPM1, FLT3 and DNMT3A mutations could be identified: NPM1 mutation only; NPM1 mutation and FLT3-ITD; All wildtype; FLT3-ITD only; DNMT3A irrespective of NPM1 and FLT3-ITD status. These subgroups showed distinct RFS and OS (Figure 2). Impacts of IDH1-R132 and IDH2-R140Q mutations were evaluated in these 5 subgroups. Interestingly, adverse impacts of IDH1-R132 on RFS and OS were only significant in the all wildtype subgroup and the adverse impact of IDH2-R140Q was only significant for RFS in the NPM1 mutation only subgroup. Conclusion. A mutation pentad comprising NPM1, FLT3, DNMT3A, IDH1-R132 and IDH2-R140Q seemed to define distinct prognostic subgroups in young adults with de novo CN-AML. A limited gene panel based on this pentad using conventional PCR may provide a practical and cost-effective means to guide post-remission therapy in these patients, especially in places where NGS may not be readily available. Acknowledgements: SK Yee Medical Foundation; Li Shu Fan Medical Foundation, LKS Faculty of Medicine, University of Hong Kong, Hong Kong Blood Cancer Foundation Disclosures Leung: Curegenix: Research Funding; Servier: Research Funding; Merck: Research Funding; Pfizer: Research Funding.

scholarly journals A Randomised Assessment of Ganetespib Combined with Low Dose Ara-C Versus Low Dose Ara-C in Older Patients with Acute Myeloid Leukaemia: Results of the LI-1 Trial

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2827-2827 ◽  
Author(s):  
Michael Dennis ◽  
Robert K Hills ◽  
Ian Thomas ◽  
Sunil Gupta ◽  
Nicki Panoskaltsis ◽  
...  
Keyword(s):  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Board Of Directors ◽  
Research Funding ◽  
Low Dose ◽  
Hazard Ratio ◽  
Significant Activity ◽  
Advisory Committees ◽  
Acute Myeloid

Abstract With a median age of 67 years, a significant proportion of patients with acute myeloid leukaemia (AML) are not considered suitable for conventional induction chemotherapy with "3+7" or related regimens. Such patients are typically treated with either demethylation agents or low-dose ara-C (LDAC). While demethylation agents appear to extend median survival, this does not convert into a greater long-term survival percentage, and 2 year survival is typically of the order of 10%. There is clearly a need to identify treatments which can offer the prospect of better long-term overall survival (OS). Heat shock protein 90 (HSP90) acts as a molecular chaperone in a diverse range of cellular functions, including kinase dependant signalling and chromatin/epigenetic remodelling. Overexpression of HSP90 is reported in AML and correlates with a worse outcome (Thomas etal Leuk Res 2005).Ganetespib is a novel triazolone heterocyclic compound with significant activity in downregulating HSP90 client protein levels. In preclinical testing ganetespib appeared to show promise when compared with LDAC (Lazenby etal Leuk Res 2015) and it was therefore included, combined with LDAC, as part of the LI-1 "pick-a-winner" trial. The "pick-a-winner" design assesses several treatments simultaneously in a randomised fashion, in this case versus LDAC. There are two interim assessment points. At the first, following the accrual of 50 patients to each arm of the comparison, remission rates must be increased by at least 2.5%; at the second, after approximately 170 deaths are observed, the hazard ratio in favour of the novel therapy must be less than 0.85. The ultimate aim is to double 2-year OS from 11% to 22%, equivalent to a hazard ratio of 0.70. Ganetespib was given at 120mg/m2 as a 1 hour intravenous infusion on days 1, 8, 15, 22 and 29 of each cycle of treatment. LDAC was given at 20mg bd subcutaneously on days 1-10. To access the ganetespib randomisation, patients had to fulfil specific cardiac entry criteria. Toxicities were defined as NCICTC v3. The study was closed prematurely after 218 patients had been accrued, because the drug company could no longer support ganetespib. Analyses shown here are presented based upon 162 events and a median follow-up of 24.8 months, and are therefore indicative of the decision that would have been taken at the second interim analysis had the trial continued. Results: Between 10/2012 and 3/2016, a total of 218 patients, median age 75.5 years (range 61-90) were recruited to the study. Overall 60% were male; 66% had de novo AML, 25% secondary AML, and 10% high risk MDS; 1% had favourable, 78% intermediate and 21% adverse cytogenetics. By validated Wheatley index, 1% were good risk, 43% standard risk and 56% poor risk. The median number of courses delivered was 2 (range 0-8) in either arm of the trial. Overall, a complete marrow response was seen in 17% of patients (ganetespib 18%; LDAC 16%, OR 0.85 (0.41-1.73) p=0.6). There was no increase in 30-day mortality with ganetespib (10% vs 14%, HR 0.65 (0.29-1.42) p=0.3), but OS was not significantly improved (2 year OS 19% vs 12%, HR 0.89 (0.65-1.21) p=0.5). There was no evidence of any difference in relapse-free survival (HR 0.97 (0.42-2.25) p=0.9). There was significantly greater toxicity seen with ganetespib in course 1, leading to significantly more inpatient days (median 11 vs 5, p=0.04). Causes of death were (LDAC+Ganetespib vs LDAC: resistant/recurrent disease 60 vs 60; infection 8 vs 14; haemorrhage 4 vs 3; pulmonary 1 vs 0; multiple 4 vs 5; other/unknown 1 vs 2). Conclusion: Despite promising data in vitro and acceptable tolerability we did not find evidence for ganetespib to deliver a significant survival benefit. On preliminary data after 162 events, the treatment effect is less than that required by the second continuation criterion for the study. Acknowledgments: We are grateful to Synta for providing drug and support for this Investigator Initiated Study. Figure Figure. Disclosures Hills: TEVA: Honoraria. Copland:Novartis: Research Funding; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Ariad: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; Ariad: Honoraria; Amgen: Honoraria; Shire: Honoraria. Burnett:CTI Life Sciences, London: Employment.

scholarly journals Characterization of Genomic Landscape and Risk Stratification of De Novo Cytogenetically Normal Acute Myeloid Leukaemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5267-5267
Author(s):  
Sze Pui Tsui ◽  
Tommy W.F. Tang ◽  
Ho-Wan Ip ◽  
Jason Chi Chiu So ◽  
Chun Hang Au ◽  
...  
Keyword(s):  
Hong Kong ◽  
Treatment Outcome ◽  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Research Funding ◽  
Gene Mutations ◽  
Haematopoietic Stem Cell ◽  
Patient Specific ◽  
Allogeneic Hsct ◽  
Acute Myeloid

Abstract Background. Acute myeloid leukaemia (AML) is a group of heterogeneous diseases with distinct clinicopathologic, cytogenetic and genetic features, sharing in common an abnormal increase in myeloblasts in blood or bone marrow (BM). Induction and consolidation chemotherapy as well as allogeneic haematopoietic stem cell transplantation (HSCT) are the mainstays of treatment. However, treatment outcome is unsatisfactory and only 30-40% patients achieve durable remission. Disease heterogeneity in AML may account for different treatment responses. In this study, we examined the mutation spectrum of cytogenetically normal AML (CN-AML) patients in Hong Kong, where AML treatment and indications for allogeneic HSCT are uniform, and evaluated their clinical outcome with respect to the specific gene mutations. Patients. Young adult patients (18-60 years old) with AML diagnosed between August 2003 to September 2017 in 8 regional hospitals in Hong Kong were included. Their clinicopathologic and cytogenetic features as well as treatment outcome were examined. Treatment and endpoints. Treatment comprised induction (daunorubicin 60-90 mg/m2 for 3 days; cytarabine 100 mg/m2 for 7 days) and consolidation (cytarabine 3 gram/m2 for 4-6 doses) for 3-4 courses. BM examination was performed on day 28 or until white cell and platelet counts recovered. Non-remission or relapsed cases were treated with salvage chemotherapy comprising combinations of cytarabine with idarubicin/etoposide, fludarabine, mitoxantrone or clofarabine. Complete remission (CR) was defined as circulating and BM blasts of ≤5% with neutrophil (≥1x109/L) and platelet count (≥100x109/L) recovery. CR with incomplete haematological recovery (CRi) was defined as circulating and BM blasts of ≤5% without complete neutrophil or platelet recovery. Mutation profiling. Next generation sequencing (NGS) for 36 recurrently mutated genes in AML was performed in diagnostic BM samples. Sequencing data were analyzed by in-house bioinformatics pipeline. Statistical evaluation. Patient survivals were calculated by Kaplan-Meier analysis and compared by log-rank test. P-values of <0.05 were considered statistically significant. Results. One hundred and seventy five patients were studied, with CR achieved in 150 cases after 1 (N=105, 70%), 2 (N=27, 18%) or ≥ 3 (N=18, 12%) courses of induction chemotherapy; and not achieved in 25 cases (primary refractory). Allogeneic HSCT was performed in 64 patients (at CR1,N=35; CR2, N=21; ≥ CR3, N=2; relapsed / persistent leukaemia, N=6). Relapse-free-survivals (RFS) at 1, 2 and 5 years were 41.3%, 27.3% and 9.3%; with median at 0.84 year. Overall survival (OS) at 1, 2 and 5 years were 69.1%, 38.3% and 15.4%, with median at 1.51 years. Mutations of ≥ 1 genes occurred in 169 cases (96%); involving with highest frequencies NPM1 (44%), FLT3-ITD (35.3%), DNMT3A (31%), IDH2 R140Q + R172K (14.3%) and CEBPA (bi-allelic, 13.7%). Individually these gene mutations had no impact on CR. However, FLT3-ITD + wildtype NPM1 and FLT3-ITD + mutated DNMT3A portended extremely poor RFS and OS. Bi-allelic CEBPA mutations portended significantly better OS but not RFS, suggesting that these cases were susceptible to relapse but were salvageable with re-induction and allogeneic HSCT. Co-existing mutations of NPM1, DNMT3A and FLT3 were common. Other mutations were mostly solitary, including bi-allelic CEBPA and IDH2 R172K mutations. NRAS and FLT3 mutations were mutually exclusive. Conclusion. CN-AMLs were intrinsically heterogeneous. Mutational profile might be useful for personalized treatment. The cooperativity and mutual exclusivity of gene mutations may be of pathogenetic significance and can inform patient-specific therapeutic strategies. Disclosures Kwong: Bayer: Consultancy, Honoraria; Beigene: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Leung:Daiichi: Research Funding; Novartis: Speakers Bureau.

Post-Transplant Flow Cytometry MRD Predicts Relapse in a Real World AML Cohort

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4566-4566
Author(s):  
Henry Wood ◽  
Katy Sanchez ◽  
Victoria Potter ◽  
Austin Kulasekararaj ◽  
Hugues de Lavallade ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Stem Cell ◽  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Genetic Risk ◽  
Research Funding ◽  
Post Transplant ◽  
Prevention Of Relapse ◽  
Active Disease ◽  
Acute Myeloid

Previous data indicate that pre-transplant flow cytometry measurable residual disease (MRD) in acute myeloid leukaemia (AML) patients in complete remission predicts relapse and survival. Diagnostic laboratories have started to report flow MRD (fMRD) at each AML disease assessment. We evaluated 83 consecutive patients with AML receiving allogeneic stem cell transplants at King's College Hospital (London, UK) in 2017-2018 to assess the significance of fMRD pre- and post-transplant. Flow MRD detection was based on leukaemia associated immunophenotype and 'difference from normal' strategies, reported at a sensitivity of 0.1%. Two timepoints were assessed: pre-transplant (post-induction) and day 100 post-transplant. Pre-transplant, 30 patients were excluded (9 active disease, 21 unknown fMRD) - of the remaining 53 patients in remission (<5% blasts by morphology), 15 were fMRD+ and 38 fMRD-. At day 100 post-transplant, 16 patients were excluded (14 died/relapsed, 2 no fMRD results) - of the remaining 67 patients, 7 were fMRD+ and 60 fMRD- at last assessment. Median follow up was 394 days (range 21-825) from transplant. Patient characteristics at each timepoint are listed in Tables 1 and 2. Outcome measures were overall survival (OS), relapse free survival (RFS), relapse and non-relapse mortality (NRM). Multivariate Cox regression analysis was performed using the parameters listed in the tables. Pre-transplant, the only predictor of OS was recipient CMV positivity - HR 0.07 (95% CI 0.01-0.79), p=0.03. RFS was predicted by age ≥65 - HR 0.18 (95% CI 0.05-0.65), p=0.01, secondary AML (sAML) - HR 0.19 (95% CI 0.05-0.77), p=0.02 and CMV positivity - HR 0.16 (95% CI 0.04-0.69), p=0.01. Relapse was predicted by age ≥65 - HR 10.98 (95% CI 1.68-71.73), p=0.01, genetic risk: favourable versus adverse - HR 0.02 (95% CI 0.001-0.04), p<0.01, sAML - HR 14.53 (95% CI 1.26-167.13), p=0.03, performance status <90% - HR 13.35 (95% CI 1.39-128.59), p=0.03, CMV positivity - HR 9.30 (95% CI 1.00-86.38), p=0.05 and fMRD+ - HR 4.75 (95% CI 1.25-18.08), p=0.02. No parameter predicted NRM. A separate pre-transplant analysis was performed to include molecular MRD (mMRD). Fifty three patients were excluded (9 active disease, 50 not assessed for mMRD, 1 no available result) - in the remaining 23 patients (21 NPM1 mutated, 2 KMT2A rearranged), mMRD was not predictive of any outcome. Eight patients remained mMRD+ in remission post-transplant; 3 were initially mMRD- post-transplant, but became mMRD+ later. Only 2/11 patients relapsed - the others responded to augmentation of the graft versus leukaemia (GVL) effect by reduction of immunosuppression or donor lymphocyte infusion (DLI). At day 100 post-transplant, OS was predicted by age ≥65 - HR 0.001 (95% CI 2×10-6-0.23), p=0.01 and sAML - HR 0.002 (95% CI 3.6×10-5-0.11), p<0.01. RFS was predicted by CMV positivity - HR 0.07 (95% CI 0.01-0.34), p<0.01, fMRD+ - HR 0.04 (95% CI 0.01-0.36), p<0.01 and DLI - HR 8.93 (95% CI 1.23-64.54), p=0.03. Relapse was predicted by therapy-related AML - HR 10744.98 (95% CI 1.63-71043020.5), p=0.04, CMV positivity - HR 2297.13 (95% CI 6.38-826805.30), p=0.01, fMRD+ - HR 5475.48 (95% CI 27.04-1108709.83), p<0.01 and DLI - HR 0.02 (95% CI 0.002-0.30), p<0.01. No parameter predicted NRM. In our cohort, recipient CMV positivity was strongly associated with poor outcomes. Age, genetic risk and secondary disease were also important. Pre-transplant fMRD was predictive of relapse but not survival. At day 100 post-transplant, fMRD predicted both relapse and RFS; DLI was associated with a protective effect. Median time to relapse from fMRD+ at day 100 post-transplant was 89 days - relapse occurred in 5/7 patients. This contrasts with the sensitivity of NPM1 mMRD+ disease to the GVL effect. Further work is required both to confirm our findings in a larger cohort and to determine how best to manage patients who are fMRD+ post-transplant. Disclosures Off Label Use: Azacitidine (Vidaza) - used for prevention of relapse after allogeneic stem cell transplantation for acute myeloid leukaemia. de Lavallade:Bristol Myers Squibb: Research Funding. Mufti:Celgene: Consultancy, Research Funding. OffLabel Disclosure: Azacitidine (Vidaza) - used for prevention of relapse after allogeneic stem cell transplantation for acute myeloid leukaemia

scholarly journals Early mortality and complications in hospitalized adult Californians with acute myeloid leukaemia

2017 ◽  
Vol 177 (5) ◽  
pp. 791-799 ◽  
Author(s):  
Gwendolyn Ho ◽  
Brian A. Jonas ◽  
Qian Li ◽  
Ann Brunson ◽  
Ted Wun ◽  
...  
Keyword(s):  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Early Mortality ◽  
Acute Myeloid

scholarly journals "Function First" Screen of Primary AML Cells Identifies Common and Personalised Therapeutic Targets

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1517-1517
Author(s):  
Jamshid S Khorashad ◽  
Carme Ripoll Fiol ◽  
Eva Yebra-Fernandez ◽  
Elisabet Nadal-Melsio ◽  
Mahroo Karimpoor ◽  
...  
Keyword(s):  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Research Funding ◽  
Therapeutic Targets ◽  
Signalling Pathway ◽  
Signalling Pathways ◽  
Library Screen ◽  
Shrna Library ◽  
Personalised Therapy ◽  
Acute Myeloid

Abstract Background Acute myeloid leukaemia (AML) is a tremendously heterogeneous clonal disorder of haemopoietic progenitor cells and is the most common malignant myeloid disorder in adults. Identified mutations from genomic data cannot provide information about their therapeutic significance without functional data. Hereby, we applied a pooled shRNA library screen to identify the activated signalling pathways essential for the survival of AML cells. Methods Mononuclear cells from seven karyotypically normal AML patients were separated from peripheral blood or bone marrow aspirate at diagnosis and transduced with a pooled shRNA library containing 27500 shRNAs targeting 5000 individual genes (Human Module 1, Decipher, Cellecta). The targeted genes were components of known signalling pathways. At 72h post transduction, 30% of the cells were stored for baseline measurements and the rest were co-cultured with HS-5 stromal cells for the selection period. DNA was then extracted and the shRNA barcodes were sequenced on the Illumina NextSeq platform. The frequency of barcode appearance after the selection period was compared to their prevalence at baseline to calculate the shRNA depletion. The shRNAs were filtered to identify those genes which had multiple shRNA meeting a threshold depletion. Results Our data analysis of the 7 AML samples identified various signalling pathways for each of these patients. These data support the notion of heterogeneity in AML. The top 100 depleted genes (with depletion in at least 3 shRNA per gene) in each patient were selected and compared. Our limited initial data showed there to be several activated signalling pathways for each AML sample indicating that inhibition of more than one gene or pathway might be required for efficiently suppressing these leukaemia cells. Common targets: NOX1 was the most commonly identified therapeutic target among the screened patients being significantly depleted in AML cells from 5/7 patients. This is an important finding as there are available NOX1 inhibitors for treatment of colon cancers and can be investigated as a therapeutic option for acute myeloid leukaemia. The other most common targets were CDK5R1, DISC1, FSCN3, and PSMB7 which were found to be significantly depleted among 3 of the 7 screened patients. The merged data also showed 58 essential genes for AML cell survival were common in at least 2/7 patients. Using Enrichr the activated signalling pathways based on the top selected genes were identified. Various signalling pathways were observed for each patient showcasing the heterogeneity among AML patients (Figure 1). However, some signalling pathways were indeed common among multiple patients - with different genes being responsible for the activation of those pathways among the patients. The most common pathway was the metabolic pathway which was observed among the top 20 essential pathways in 6/7 patients. The JAK-STAT5 signalling pathway, purine metabolism and cAMP signalling pathway were also among the top 20 essential pathways in 3/7 patients while the following pathways: FoxO, PI3K-AKT, HIF-1, P53, Glucagon, and proteasome were observed in 2/7 patients. Identification of several essential survival pathways provides the opportunity to develop personalised therapy through combined targeting of more than one pathway. Conclusion The signalling pathways analysis using candidate genes from a pooled shRNA library screen showed patient-specific signalling pathways and also common pathways among these screened patients. Absence of a common gene among the screened patients further highlights the significance of personalised therapy in AML and the necessity of developing diagnostic tools to identify potential targets at diagnosis. Identification of crucial genes such as NOX1 (a gene known to have a role in the survival of leukemic stem cells) and other genes with known significance in the pathogenesis of AML supports the application of this method for identifying therapeutic targets at diagnosis or relapse. Figure 1. Figure 1. Disclosures Knapper: Jazz: Other: Meeting and travel support; Daiichi Sankyo: Other: Meeting and travel support; Chroma Therapeutics: Research Funding; Celgene: Other: Meeting and travel support; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Apperley:Pfizer: Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Speakers Bureau.

scholarly journals A Randomised Evaluation of Low-Dose Ara-C Plus BCT-100 Versus Low Dose Ara-C in Older Patients with Acute Myeloid Leukaemia: Results from the LI-1 Trial

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2355-2355
Author(s):  
Francis J. Mussai ◽  
Ian Thomas ◽  
Cono Ariti ◽  
Laura Upton ◽  
Mia Sydenham ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Board Of Directors ◽  
Research Funding ◽  
Low Dose ◽  
Remission Induction ◽  
Significant Activity ◽  
Advisory Committees ◽  
Acute Myeloid

Abstract Background: Among patients with Acute Myeloid Leukaemia (AML) over the age of 60, a considerable number are not considered suitable for intensive remission-induction chemotherapy. Survival in these patients is poor, whether they are treated using hypomethylating agents or low-dose ara-C (LDAC). The possibility of combination therapy with additional agents represents an attractive option. Arginine metabolism plays a key role in AML pathogenesis (Mussai et al. Blood 2013); BCT-100 is a pegylated recombinant human arginase that leads to a rapid depletion in extracellular and intracellular arginine concentrations resulting in G0/G1 arrest, and subsequent death by necrosis. BCT-100 demonstrates significant activity as single-agent against AML cell lines, AML xenografts and primary AML blasts from newly diagnosed or relapsed patients (Mussai et al. Blood 2015). Importantly BCT-100 is synergistic in combination with cytarabine. Aims: To assess the efficacy of LDAC+BCT100 versus LDAC alone in patients aged 60+ unsuitable for intensive therapy, in a "pick a winner" design. This design allows several treatments to be assessed simultaneously in a randomised fashion, with the aim of doubling 2-year survival from 11% to 22% (HR 0.69), with interim assessments after 50 and 100 patients per arm are recruited. Methods: LDAC was given at 20mg BD SC on days 1-10 of each course. Patients randomised to the combination received LDAC as above with BCT-100 1600U/kg on Days 1, 8, 15 and 22 as a 1-hour intravenous infusion. Courses occurred at 4-6 week intervals. Toxicities were recorded using CTCAE version 3. Pharmacokinetic and biomarker samples were assessed in BCT-100 patients. Results here are based upon median follow-up of 3.8 months (range: 0.1 - 20.6 months) Results: Between September 2018 and December 2020, 83 patients were randomised. The trial was prematurely closed due to the COVID pandemic and did not reach the pre-planned first evaluation. Median age was 76.7 years (range 62-88). Overall, 65% were male; 70% de novo AML, 23% secondary AML, and 6% high risk MDS; 2% favourable, 59% intermediate, 23% adverse and 15% unknown/unreported cytogenetics. Median of 2 courses was delivered in either arm (mean 2 LDAC, 2 LDAC+BCT, range for both: 1-12). BCT-100 leads to a depletion of arginine from baseline in the majority of patients. Overall response (CR/CRi) was achieved in 12/81 patients (15%), (LDAC+BCT-100 15%, LDAC 15%, R 1.03 (0.30, 3.51),P=0.963). Thirty-day mortality was not significantly increased (18% vs 11%, HR 1.71 (0.50, 5.84), P=0.393; and 1-year survival showed no evidence of a difference (31% vs 30%, HR 1.28 (0.72, 2.25). Median overall survival time was 3.8 vs 6.4months; overall survival HR 1.11 (0.64, 1.90), P=0.715. The most common cause of death was resistant/recurrent disease: 12(46%) vs 16(59%). BCT-100 was not associated with any haematological toxicity; although rare grade 3/4 cardiac and hepatic events were reported, these were not significantly increased with BCT-100. Summary: The addition of BCT-100 to LDAC did not improve response rate or survival. BCT-100 was well tolerated with an acceptable toxicity profile. Further clinical evaluation of BCT-100 induced arginase depletion continues in a variety of malignancies. Acknowledgements: We are grateful to Blood Cancer UK for funding the trial and Bio-Cancer Treatment International for providing drug and additional support for this Investigator Initiated Study. Figure 1. OS All patients Figure 1 Figure 1. Disclosures Knapper: Jazz: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Astellas: Ended employment in the past 24 months, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau. McMullin: Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Other: clinical trial support, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AOP Orphan: Research Funding, Speakers Bureau. Copland: Incyte: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Cyclacel Ltd: Research Funding; Astellas: Honoraria, Speakers Bureau; Jazz: Honoraria, Speakers Bureau. Russell: Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Speakers Bureau; Astellas: Membership on an entity's Board of Directors or advisory committees; Jazz: Research Funding, Speakers Bureau.

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