Abstract
Background aims
The internal tandem duplication of FLT3 (FLT3ITD) and NPM1 mutations (NPM1mut) are well-established prognostic factors in cytogenetically intermediate-risk acute
myeloid leukemia (AML) when treated with chemotherapy alone. However, their prognostic
value in the setting of allogeneic hematopoietic cell transplantation (HCT) is controversial.
Methods
FLT3 and NPM1 mutational status was determined at diagnosis using single-gene polymerase chain
reaction or next-generation sequencing in 247 adult patients with cytogenetically
intermediate-risk AML who underwent myeloablative HCT. Multivariate Fine–Gray and
Cox regression was used to analyze the cumulative incidence of relapse (CIR), relapse-free
survival (RFS) and overall survival (OS).
Results
FLT3ITD and NPM1mut were present in 74 of 247 (30%) and 79 of 247 (32%) patients, respectively. There
was no significant difference between patients without a FLT3ITD or NPM1mut (FLT3NONITD/NPM1WT) and patients with a FLT3ITD mutation alone (FLT3ITD/NPM1WT) with regard to CIR (P = 0.60), RFS (P = 0.91) or OS (P = 0.66). Similarly, there was no significant difference between FLT3NONITD/NPM1WT and FLT3NONITD/NPM1mut patients with regard to CIR (P = 0.70), RFS (P = 0.75) or OS (P = 0.95). The presence of a concurrent mutation in NPM1 did not appear to modify the impact of having a FLT3ITD mutation.
Conclusions
In contrast to chemotherapy-only treatment, FLT3 and NPM1 mutational status does not appear to predict outcomes in patients with cytogenetically
intermediate-risk AML following HCT. These results suggest that HCT may ameliorate
the poor prognostic effect of FLT3ITD mutation and that HCT should be considered over chemotherapy-only treatment in FLT3ITD-mutated AML.
Key Words
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to CytotherapyAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel.Blood. 2017; 129: 424-447
- A disease risk index for patients undergoing allogeneic stem cell transplantation.Blood. 2012; 120: 905-913
- The importance of diagnostic cytogenetics on outcome in AML: analysis of 1,612 patients entered into the MRC AML 10 trial. The Medical Research Council Adult and Children's Leukaemia Working Parties.Blood. 1998; 92: 2322-2333
- Prognostic relevance of integrated genetic profiling in acute myeloid leukemia.The New England journal of medicine. 2012; 366: 1079-1089
- The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials.Blood. 2001; 98: 1752-1759
- Prognostic significance of activating FLT3 mutations in younger adults (16 to 60 years) with acute myeloid leukemia and normal cytogenetics: a study of the AML Study Group Ulm.Blood. 2002; 100: 4372-4380
- Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis.Blood. 2002; 99: 4326-4335
- The prognostic impact of FLT3-ITD, NPM1 and CEBPa in cytogenetically intermediate-risk AML after first relapse.International journal of hematology. 2020; 112: 200-209
- Prognostic significance of NPM1 mutations in the absence of FLT3-internal tandem duplication in older patients with acute myeloid leukemia: a SWOG and UK National Cancer Research Institute/Medical Research Council report.Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2015; 33: 1157-1164
- Nucleophosmin gene mutations are predictors of favorable prognosis in acute myelogenous leukemia with a normal karyotype.Blood. 2005; 106: 3733-3739
- The impact of age, NPM1mut, and FLT3ITD allelic ratio in patients with acute myeloid leukemia.Blood. 2018; 131: 1148-1153
- The prognostic impact of FLT3-ITD and NPM1 mutation in adult AML is age-dependent in the population-based setting.Blood advances. 2020; 4: 1094-1101
- Favorable outcome of patients with acute myeloid leukemia harboring a low-allelic burden FLT3-ITD mutation and concomitant NPM1 mutation: relevance to post-remission therapy.Blood. 2013; 121: 2734-2738
- The impact of FLT3 internal tandem duplication mutant level, number, size, and interaction with NPM1 mutations in a large cohort of young adult patients with acute myeloid leukemia.Blood. 2008; 111: 2776-2784
- Differential impact of allelic ratio and insertion site in FLT3-ITD-positive AML with respect to allogeneic transplantation.Blood. 2014; 124: 3441-3449
- Allogeneic Stem Cell Transplantation Improves Survival in Patients with Acute Myeloid Leukemia Characterized by a High Allelic Ratio of Mutant FLT3-ITD.Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation. 2016; 22: 462-469
- Prognostic impact of FLT3-ITD load in NPM1 mutated acute myeloid leukemia.Leukemia. 2011; 25: 1297-1304
- Impact of NPM1/FLT3-ITD genotypes defined by the 2017 European LeukemiaNet in patients with acute myeloid leukemia.Blood. 2020; 135: 371-380
- Prevalence and prognostic impact of NPM1 mutations in 1485 adult patients with acute myeloid leukemia (AML).Blood. 2006; 107: 4011-4020
- Mutant nucleophosmin (NPM1) predicts favorable prognosis in younger adults with acute myeloid leukemia and normal cytogenetics: interaction with other gene mutations.Blood. 2005; 106: 3740-3746
- Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia.The New England journal of medicine. 2008; 358: 1909-1918
- Allogeneic Transplantation in First Remission Improves Outcomes Irrespective of FLT3-ITD Allelic Ratio in FLT3-ITD-Positive Acute Myelogenous Leukemia.Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation. 2016; 22: 1218-1226
- Impact of FLT3-ITD allele ratio and ITD length on therapeutic outcome in cytogenetically normal AML patients without NPM1 mutation.Bone marrow transplantation. 2020; 55: 740-748
- Improved outcome after stem-cell transplantation in FLT3/ITD-positive AML.Blood. 2007; 109: 2264-2265
- Role of allogeneic transplantation for FLT3/ITD acute myeloid leukemia: outcomes from 133 consecutive newly diagnosed patients from a single institution.Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation. 2011; 17: 1404-1409
- Indications for allo- and auto-SCT for haematological diseases, solid tumours and immune disorders: current practice in Europe, 2015.Bone marrow transplantation. 2015; 50: 1037-1056
- Indications for Autologous and Allogeneic Hematopoietic Cell Transplantation: Guidelines from the American Society for Blood and Marrow Transplantation.Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation. 2015; 21: 1863-1869
- Impact of FLT3 internal tandem duplication on the outcome of related and unrelated hematopoietic transplantation for adult acute myeloid leukemia in first remission: a retrospective analysis.Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2012; 30: 735-741
- Allo-SCT for high-risk AML-CR1 in the molecular era: impact of FLT3/ITD outweighs the conventional markers.Bone marrow transplantation. 2012; 47: 1535-1537
- Outcome of patients with distinct molecular genotypes and cytogenetically normal AML after allogeneic transplantation.Blood. 2015; 126: 2062-2069
- Does FLT3 mutation impact survival after hematopoietic stem cell transplantation for acute myeloid leukemia? A Center for International Blood and Marrow Transplant Research (CIBMTR) analysis.Cancer. 2016; 122: 3005-3014
- No evidence that FLT3 status should be considered as an indicator for transplantation in acute myeloid leukemia (AML): an analysis of 1135 patients, excluding acute promyelocytic leukemia, from the UK MRC AML10 and 12 trials.Blood. 2005; 106: 3658-3665
- Prognostic impact of allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia patients with internal tandem duplication of FLT3.Leukemia Research. 2013; 37: 287-292
- FLT3 internal tandem duplication does not impact prognosis after haploidentical allogeneic hematopoietic stem cell transplantation in AML patients.Bone marrow transplantation. 2019; 54: 1462-1470
- T-cell replete haploidentical stem cell transplantation attenuates the prognostic impact of FLT3-ITD in acute myeloid leukemia: A report from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.American journal of hematology. 2018; 93: 736-744
- Influence of FLT3-ITD and NPM1 status on allogeneic hematopoietic cell transplant outcomes in patients with cytogenetically normal AML.European journal of haematology. 2019; 102: 368-374
- Characteristics and prognostic significance of genetic mutations in acute myeloid leukemia based on a targeted next-generation sequencing technique.Cancer medicine. 2020; 9: 8457-8467
- Impact of FLT3-ITD mutation on post-transplant outcome of adult acute myeloid leukemia (AML) is modified by the concomitant NPM1 mutation and pre-transplant remission status: A report from Taiwan Bone Marrow Transplant Registry (TBMTR).Annals of Oncology. 2019; 30: v446
- Molecular MRD status and outcome after transplantation in NPM1-mutated AML.Blood. 2020; 135: 680-688
- Hematopoietic cell transplant outcomes after myeloablative conditioning with fludarabine, busulfan, low-dose total body irradiation, and rabbit antithymocyte globulin.Clinical transplantation. 2020; 34: e14018
- The addition of 400 cGY total body irradiation to a regimen incorporating once-daily intravenous busulfan, fludarabine, and antithymocyte globulin reduces relapse without affecting nonrelapse mortality in acute myelogenous leukemia.Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation. 2010; 16: 509-514
- Validation and refinement of the Disease Risk Index for allogeneic stem cell transplantation.Blood. 2014; 123: 3664-3671
- Minimal residual disease prior to allogeneic hematopoietic cell transplantation in acute myeloid leukemia: a meta-analysis.Haematologica. 2017; 102: 865-873
- Pre-transplant MRD predicts outcome following reduced-intensity and myeloablative allogeneic hemopoietic SCT in AML.Bone marrow transplantation. 2014; 49: 679-683
- Molecular MRD status and outcome after transplantation in NPM1-mutated AML.Blood. 2020; 135: 680-688
- FLT3 mutational status is an independent risk factor for adverse outcomes after allogeneic transplantation in AML.Bone marrow transplantation. 2016; 51: 511-520
- Differential Impact of Conditioning Intensity on Post-Transplant Outcome of FLT3 -Mutated and FLT3 Wild Type AML in First Remission, a Report from Taiwan Bone Marrow Transplant Registry (TBMTR).Blood. 2017; 130 (-3229): 3229
- Female donors contribute to a selective graft-versus-leukemia effect in male recipients of HLA-matched, related hematopoietic stem cell transplants.Blood. 2004; 103: 347-352
- Influence of donor/recipient sex matching on outcome of allogeneic hematopoietic stem cell transplantation for aplastic anemia.Transplantation. 2006; 82: 218-226
- Female donors contribute to a selective graft-versus-leukemia effect in male recipients of HLA-matched, related hematopoietic stem cell transplants.Blood. 2004; 103: 347-352
- Allogeneic HY antibodies detected 3 months after female-to-male HCT predict chronic GVHD and nonrelapse mortality in humans.Blood. 2015; 125: 3193-3201
- Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia.Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2003; 21: 4642-4649
- Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 Mutation.The New England journal of medicine. 2017; 377: 454-464
- The prognostic impact of FLT3-ITD and NPM1 mutation in adult AML is age-dependent in the population-based setting.Blood advances. 2020; 4: 1094-1101
- Allogeneic stem cell transplantation benefits for patients ≥ 60 years with acute myeloid leukemia and FLT3 internal tandem duplication: a study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.Haematologica. 2018; 103: 256-265
- Antithymocyte Globulin at Clinically Relevant Concentrations Kills Leukemic Blasts.Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation. 2016; 22: 815-824
- More acute lymphoid leukemia than acute myeloid leukemia blasts are killed by rabbit antithymocyte globulin.Cytotherapy. 2019; 21: 1161-1165
- Anti-thymocyte globulin's activity against acute myeloid leukemia stem cells.Bone marrow transplantation. 2019; 54: 549-559
- Antirelapse effect of pretransplant exposure to rabbit antithymocyte globulin.Blood advances. 2019; 3: 1394-1405
- Optimizing antithymocyte globulin dosing in haploidentical hematopoietic cell transplantation: long-term follow-up of a multicenter, randomized controlled trial.Science Bulletin. 2021; https://doi.org/10.1016/j.scib.2021.06.002
- Impact of FLT3(ITD) mutant allele level on relapse risk in intermediate-risk acute myeloid leukemia.Blood. 2014; 124: 273-276
- Quantitative fragment analysis of FLT3-ITD efficiently identifying poor prognostic group with high mutant allele burden or long ITD length.Blood cancer journal. 2015; 5: e336
- Comparative value of post-remission treatment in cytogenetically normal AML subclassified by NPM1 and FLT3-ITD allelic ratio.Leukemia. 2017; 31: 26-33
- Genomic and Epigenomic Landscapes of Adult De Novo Acute Myeloid Leukemia.New England Journal of Medicine. 2013; 368: 2059-2074
- Genomic Classification and Prognosis in Acute Myeloid Leukemia.New England Journal of Medicine. 2016; 374: 2209-2221
- Complex molecular genetic abnormalities involving three or more genetic mutations are important prognostic factors for acute myeloid leukemia.Leukemia. 2016; 30: 545-554
- Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT.Blood. 2005; 106: 2912-2919
Article info
Publication history
Published online: December 02, 2021
Accepted:
October 6,
2021
Received:
September 2,
2021
Identification
Copyright
© 2021 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.
