Article, 2024
Molecular, clinical and therapeutic determinants of outcome in NPM1 mutated AML
Blood,
ISSN
0006-4971,
1528-0020,
10.1182/blood.2024024310
Contributors
Othman, Jad
0000-0002-4971-3576
[1]
Potter, Nicola
[2]
Ivey, Adam
[3]
Tazi, Yanis
0000-0002-1595-9631
[4]
Papaemmanuil, Elli
[5]
Jovanovic, Jelena
[2]
Freeman, Sylvie D
0000-0003-1869-180X
[6]
Gilkes, Amanda Frances
[7]
Gale, Rosemary E
[8]
Rapoz-D'Silva, Tanya
[8]
Runglall, Manohursingh
0000-0002-0549-9029
[2]
Kleeman, Michelle
0000-0002-6984-9454
[9]
Dhami, Pawan
0000-0002-5408-1833
[9]
Thomas, Ian
[7]
Johnson, Sean
[7]
Canham, Joanna
[7]
Cavenagh, James Durrell
[10]
Kottaridis, Panagiotis D
[11]
Arnold, Claire
[12]
Ommen, Hans Beier
0000-0001-7628-8694
[13]
Overgaard, Ulrik Malthe
[14]
Dennis, Mike
[15]
Burnett, Alan Kenneth
0000-0003-3772-6625
[7]
Wilhelm-Benartzi, Charlotte S M
0000-0003-4927-6158
[7]
Huntly, Brian J P
0000-0003-0312-161X
[16]
Russell, Nigel H
0000-0003-1893-8155
[9]
Dillon, Richard James
(Corresponding author)
[2]
Affiliations
- [1]
The University of Sydney
[NORA names:
Australia; Oceania; OECD];
- [2]
King's College London
[NORA names:
United Kingdom; Europe, Non-EU; OECD];
- [3]
The Alfred Hospital
[NORA names:
Australia; Oceania; OECD];
- [4]
Rockefeller University
[NORA names:
United States; America, North; OECD];
- [5]
MSKCC, NYC, United Kingdom.
[NORA names:
United Kingdom; Europe, Non-EU; OECD];
(... more)
- [6]
University of Birmingham
[NORA names:
United Kingdom; Europe, Non-EU; OECD];
- [7]
Cardiff University
[NORA names:
United Kingdom; Europe, Non-EU; OECD];
- [8]
University College London
[NORA names:
United Kingdom; Europe, Non-EU; OECD];
- [9]
Guy's and St Thomas' NHS Foundation Trust
[NORA names:
United Kingdom; Europe, Non-EU; OECD];
- [10]
St Bartholomew's Hospital
[NORA names:
United Kingdom; Europe, Non-EU; OECD];
- [11]
University College Hospital
[NORA names:
United Kingdom; Europe, Non-EU; OECD];
- [12]
Belfast City Hospital
[NORA names:
United Kingdom; Europe, Non-EU; OECD];
- [13]
Aarhus University Hospital
[NORA names:
Central Denmark Region;
Hospital; Denmark; Europe, EU; Nordic; OECD];
- [14]
Copenhagen University Hospital
[NORA names:
Capital Region of Denmark;
Hospital; Denmark; Europe, EU; Nordic; OECD];
- [15]
The Christie NHS Foundation Trust
[NORA names:
United Kingdom; Europe, Non-EU; OECD];
- [16]
University of Cambridge
[NORA names:
United Kingdom; Europe, Non-EU; OECD]
(less)
Abstract
Although NPM1-mutated acute myeloid leukemia (AML) carries a generally favorable prognosis, many patients still relapse and die. Previous studies identified several molecular and clinical features associated with poor outcome, however only FLT3-ITD mutation and adverse karyotype are currently used for risk stratification due to inconsistent results and uncertainty around how other factors should influence treatment, particularly given the strong prognostic impact of post-induction measurable residual disease (MRD). Here we analyzed a large group of patients with NPM1mut AML enrolled in prospective trials (NCRI AML17 and AML19, n=1357) to delineate the impact of baseline molecular and clinical features, post induction MRD status and treatment intensity on outcome. FLT3-ITD (HR 1.28, 95%CI 1.01-1.63), DNMT3A (HR 1.65, 95%CI 1.32-2.05), WT1 (HR 1.74, 95%CI 1272-2.38) and non-ABD NPM1 mutations (HR 1.64, 95%CI 1.22-2.21) were independently associated with poorer overall survival (OS). These factors were also strongly associated with MRD positivity. For patients achieving MRD negativity, these mutations (except FLT3-ITD) were associated with an increased cumulative incidence of relapse (CIR) and poorer OS. However, apart from the few patients with adverse cytogenetics, we could not identify any group of MRD negative patients with a CIR >40% or with benefit from allograft in first remission. Intensified chemotherapy with the FLAG-Ida regimen was associated with improved outcomes in all subgroups, with greater benefits observed in the highest risk molecular subgroups.
Keywords
DNMT3A,
FLAG-IDA regimen,
FLAG-Ida,
FLT3-ITD,
FLT3-ITD mutation,
MRD negativity,
MRD status,
MRD-negative patients,
MRD-positive,
NPM1,
NPM1 mutations,
NPM1-mutated acute myeloid leukemia,
NPM1mut,
WT1,
acute myeloid leukemia,
adverse cytogenetics,
adverse karyotype,
allograft,
associated with poor overall survival,
baseline,
benefits,
chemotherapy,
clinical features,
cumulative incidence of relapse,
cytogenetics,
determination,
disease,
factors,
favorable prognosis,
features,
features associated with poor outcome,
group,
group of patients,
impact,
impact of baseline,
incidence of relapse,
inconsistent results,
increased cumulative incidence,
increased cumulative incidence of relapse,
influence treatment,
intensified chemotherapy,
intensity,
karyotype,
leukemia,
measurable residual disease,
molecular subgroups,
mutated acute myeloid leukemia,
mutations,
myeloid leukemia,
negative patients,
negatively,
outcomes,
overall survival,
patients,
poor OS,
poor outcome,
poor overall survival,
position,
post,
prognosis,
prognostic impact,
prospective trials,
regimens,
relapse,
remission,
residual disease,
results,
risk,
status,
study,
subgroups,
survival,
therapeutic determinants,
treatment,
treatment intensity,
trials,
uncertainty
Data Provider: Digital Science