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2939 Interaction between Presenting Features, Co-Occurring Mutations, MRD and Induction Treatment Influences Outcome in Adults with NPM1 Mutated AML – an Analysis of 1357 Patients in the UK NCRI AML17 and AML19 Studies

Program: Oral and Poster Abstracts
Session: 617. Acute Myeloid Leukemias: Biomarkers, Molecular Markers and Minimal Residual Disease in Diagnosis and Prognosis: Poster II
Hematology Disease Topics & Pathways:
Research, clinical trials, Acute Myeloid Malignancies, AML, Clinical Research, Diseases, Myeloid Malignancies, Technology and Procedures, Minimal Residual Disease , molecular testing
Sunday, December 10, 2023, 6:00 PM-8:00 PM

Jad Othman, MBBS1,2,3, Nicola Potter, PhD1*, Adam Ivey4*, Yanis Tazi, MSc, BSc5*, Elli Papaemmanuil6, Jelena Jovanovic, PhD7*, Sylvie D Freeman8, Amanda Gilkes9*, Ian Thomas10*, Sean Johnson10*, Joanna Canham11*, Jamie Cavenagh12*, Panos Kottaridis13*, Claire Arnold14*, Ulrik Malthe Overgaard15*, Mike Dennis, MD, MRCP, FRCPath16, Charlotte Wilhelm-Benartzi9*, Brian Huntly, PhD17*, Alan K. Burnett, MD18*, Richard Dillon, PhD, MRCP, FRCPath1,2* and Nigel Russell19

1Department of Medical and Molecular Genetics, King's College London, London, United Kingdom
2Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom
3Faculty of Medicine and Health, University of Sydney, Sydney, Australia
4Alfred Health, Melbourne, AUS
5Memorial Sloan Kettering Cancer Center, New York
6Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY
7King’s College London, London, United Kingdom
8Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
9Cardiff University, Cardiff, GBR
10Cardiff University, Cardiff, United Kingdom
11Cardiff University, Cardiff, WAL, GBR
12Department of Haemato-Oncology, St Bartholomew's Hospital, Barts Health NHS Trust, London, GBR
13University College London Hospital NHS Foundation Trust, London, GBR
14Belfast City Hospital, Belfast, GBR
15Department of Hematology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
16The Christie, Manchester, GBR
17Cambridge Institute For Medical Research, University of Cambridge, Cambridge, GBR
18Paul O’Gorman Leukaemia Centre, Glasgow University, Glasgow, United Kingdom
19Guy's & St Thomas' NHS Foundation Trust, London, United Kingdom


NPM1 mutated (mut) AML is considered favourable risk unless associated with FLT3 internal tandem duplication (ITD) or adverse karyotype. However many other genetic and clinical risk factors have been identified, including high white cell count (WCC), secondary disease, co-mutations and presence of a “triple hit” genotype (NPM1mut, FLT3 ITD and DNMT3Amut). Although alternative classification systems have been proposed, few studies have been large enough to robustly evaluate clinical and molecular subgroups within NPM1mut, and none have incorporated the effects of measurable residual disease (MRD) status or treatment intensity. Therefore, clinical decision making remains challenging and inconsistent. Here, we performed comprehensive genotyping and molecular MRD assessment in two consecutive prospective randomised studies to clarify these issues.


NCRI AML17 (2009-2014) and AML19 (2015-2020) were large randomised trials for younger adults with newly diagnosed AML. Induction regimens included DA +/- etoposide (ADE) and FLAG-IDA, with or without Gemtuzumab. Patients underwent sequential MRD assessment by RT-qPCR, and diagnostic DNA samples were analysed by targeted NGS. Overall survival (OS) was calculated with the Kaplan-Meier method, while cumulative incidence of relapse (CIR) considered death as a competing risk. Relapse events included MRD relapse. All reported hazard/odds ratios are from multivariable analyses including age, prior haematological malignancy, prior chemo/radiotherapy, WCC (log transformed), cytogenetic risk and mutation profile (FLT3 ITD, DNMT3A, PTPN11, N/KRAS, TET2, IDH1, IDH2, WT1, TP53, MDS-related genes).


1357 patients with NPM1mut AML were identified, 888 in AML17 and 469 in AML19. 1100 patients had DNA available for panel sequencing, and 981 underwent MRD monitoring of whom 737 had an evaluable post course 2 (PC2) peripheral blood (PB) sample. Morphological remission (CR+CRi) was achieved in 1264/1357 patients (93%) and PC2 PB MRD negativity in 594/737 (81%). We confirmed the adverse impact of PB PC2 MRD positivity: 3y CIR was 65% vs 29% in those MRD- (p<0.001), and 3yr OS was 40% vs 79% (p<0.001). For PB PC2 MRD+ patients, CIR was >50% in all subgroups.

There was a lower rate of PC2 PB MRD negativity in patients with high presenting WCC (OR 1.14, p=0.05), FLT3 ITD (OR 2.58, p<0.001), DNMT3Amut (OR 2.2, p<0.001) and WT1mut (HR 2.04, p=0.02). There was no effect of FLT3 allelic ratio, while patients with both FLT3 ITD and DNMT3A mutations had the lowest rate of MRD- (64%, Figure A).

Of the 594 PC2 MRD– patients, we observed higher 3y CIR in patients with high WCC (HR 1.14, p=0.01), DNMT3Amut (HR 1.83, p=0.001), WT1mut (HR 1.96, p=0.01) and IDH1mut (HR 1.9, p=0.002), and lower CIR in patients with N/KRASmut (HR 0.53, p=0.01). Although presence of FLT3 ITD alone was not associated with CIR (HR 0.88, p=0.7), patients with both FLT3 ITD and DNMT3A mutations had 3y CIR from MRD- of 40% (HR 1.74, p=0.03). MDS-related gene mutations had no impact on achieving MRD-, nor relapse from MRD-.

Considering all patients, OS was poorer with increasing age (HR 1.03, p<0.001), WCC (HR 1.07, p<0.001), adverse karyotype (HR 2.48, p=0.01), FLT3 ITD (HR 1.34, p=0.01), DNMT3Amut (HR 1.56, p<0.001) and WT1mut (HR 1.71, p<0.001). 3y OS was 52% in patients with both FLT3 ITD and DNMT3Amut, 63% with FLT3 ITD only, 67% with DNMT3A only and 75% with neither.

Considering MRD– patients, only age (HR 1.02, p=0.04), DNMT3Amut (HR 1.75, p=0.007) and WT1mut (HR 1.8, p=0.048) remained associated with OS. There was no benefit to CR1 allogeneic transplant in MRD– patients (HR 0.83, 95%CI 0.51-1.34, p=0.4), including in any subgroups (heterogeneity p=0.9).

Compared with other treatments, FLAG-Ida increased MRD– (87% vs 79%, p=0.009), reduced relapse from MRD– (16% vs 34%, p<0.001) and improved 3y OS (79% vs 63%, HR 0.52, p<0.001). The OS benefit of FLAG-Ida was greatest in patients with at least one of the features associated with failure to achieve MRD– and relapse from MRD– (high WCC, triple hit or WT1mut, HR 0.39 95%CI 0.26-0.58, heterogeneity p<0.01).


The “triple hit” (NPM1, DNMT3A and FLT3 ITD) genotype, WT1mut and high WCC were associated with poor outcomes, due to a lower probability of achieving MRD–, and a higher relapse risk from MRD– remission. Survival was improved for patients receiving intensified induction with FLAG-Ida including patients in these high-risk groups.

Disclosures: Papaemmanuil: Isabl Inc.: Current equity holder in private company, Current holder of stock options in a privately-held company, Other: CEO, Patents & Royalties: Whole genome cancer analysis; TenSixteen Bio: Current equity holder in private company. Freeman: JAZZ: Research Funding, Speakers Bureau; BMS: Research Funding; MPAACT: Membership on an entity's Board of Directors or advisory committees; NOVARTIS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Dillon: Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Speakers Bureau; Jazz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AvenCell: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Honoraria, Speakers Bureau; Amgen: Research Funding; Shattuck labs: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Russell: Pfizer: Honoraria, Research Funding, Speakers Bureau; Jazz Pharma: Research Funding; Servier: Honoraria; Astellas: Honoraria.

*signifies non-member of ASH