Cytogenetic and molecular diagnostic characterization combined to postconsolidation minimal residual disease assessment by flow cytometry improves risk stratification in adult acute myeloid leukemia.

A total of 143 adult acute myeloid leukemia (AML) patients with available karyotype (K) and FLT3 gene mutational status were assessed for minimal residual disease (MRD) by flow cytometry. Twenty-two (16%) patients had favorable, 115 (80%) intermediate, and 6 (4%) poor risk K; 19 of 129 (15%) carried FLT3-ITD mutation. Considering postconsolidation MRD status, patients with good/intermediate-risk K who were MRD(-) had 4-year relapse-free survival (RFS) of 70% and 63%, and overall survival (OS) of 84% and 67%, respectively. Patients with good- and intermediate-risk K who were MRD(+) had 4-year RFS of 15% and 17%, and OS of 38% and 23%, respectively (P < .001 for all comparisons). FLT3 wild-type patients achieving an MRD(-) status, had a better outcome than those who remained MRD(+) (4-year RFS, 54% vs 17% P < .001; OS, 60% vs 23%, P = .002). Such an approach redefined cytogenetic/genetic categories in 2 groups: (1) low-risk, including good/intermediate K-MRD(-) with 4-year RFS and OS of 58% and 73%, respectively; and (2) high risk, including poor-risk K, FLT3-ITD mutated cases, good/intermediate K-MRD(+) categories, with RFS and OS of 22% and 17%, respectively (P < .001 for all comparisons). In AML, the integrated evaluation of baseline prognosticators and MRD improves risk-assessment and optimizes postremission therapy.

[1]  Adam J Mead,et al.  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. , 2008, Blood.

[2]  H. Kaneko,et al.  Internal tandem duplication of the flt3 gene found in acute myeloid leukemia. , 1996, Leukemia.

[3]  W. Hiddemann,et al.  1 KIT-D 816 mutations in AML 1-ETO positive AML are associated with impaired event-free and overall survival , 2005 .

[4]  B. Falini,et al.  Simultaneous detection of NPM1 and FLT3-ITD mutations by capillary electrophoresis in acute myeloid leukemia , 2005, Leukemia.

[5]  B. Falini,et al.  Quantitative assessment of minimal residual disease in acute myeloid leukemia carrying nucleophosmin (NPM1) gene mutations , 2006, Leukemia.

[6]  A. Órfão,et al.  Early immunophenotypical evaluation of minimal residual disease in acute myeloid leukemia identifies different patient risk groups and may contribute to postinduction treatment stratification. , 2001, Blood.

[7]  J. Esteve,et al.  Genomic polymorphisms provide prognostic information in intermediate-risk acute myeloblastic leukemia. , 2006, Blood.

[8]  J. Bourhis,et al.  Allogeneic compared with autologous stem cell transplantation in the treatment of patients younger than 46 years with acute myeloid leukemia (AML) in first complete remission (CR1): an intention-to-treat analysis of the EORTC/GIMEMAAML-10 trial. , 2003, Blood.

[9]  R. Gray,et al.  A simple, robust, validated and highly predictive index for the determination of risk‐directed therapy in acute myeloid leukaemia derived from the MRC AML 10 trial , 1999, British journal of haematology.

[10]  C. Bloomfield,et al.  Adverse prognostic significance of KIT mutations in adult acute myeloid leukemia with inv(16) and t(8;21): a Cancer and Leukemia Group B Study. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[11]  Paola Fazi,et al.  Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. , 2005, The New England journal of medicine.

[12]  F. Appelbaum Incorporating hematopoietic cell transplantation (HCT) into the management of adults aged under 60 years with acute myeloid leukemia (AML). , 2008, Best practice & research. Clinical haematology.

[13]  P. Chomczyński,et al.  Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. , 1987, Analytical biochemistry.

[14]  F. Lo‐Coco,et al.  The kinetics of reduction of minimal residual disease impacts on duration of response and survival of patients with acute myeloid leukemia , 2006, Leukemia.

[15]  Keith Wheatley,et al.  Randomised comparison of addition of autologous bone-marrow transplantation to intensive chemotherapy for acute myeloid leukaemia in first remission: results of MRC AML 10 trial , 1998, The Lancet.

[16]  Axel Benner,et al.  Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. , 2008, The New England journal of medicine.

[17]  C. Bloomfield,et al.  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. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[18]  C. Bloomfield,et al.  Cytogenetics in acute leukemia. , 2004, Blood reviews.

[19]  Stefan Fröhling,et al.  Mutant nucleophosmin (NPM1) predicts favorable prognosis in younger adults with acute myeloid leukemia and normal cytogenetics: interaction with other gene mutations. , 2005, Blood.

[20]  E. Kaplan,et al.  Nonparametric Estimation from Incomplete Observations , 1958 .

[21]  Marcos González,et al.  Immunophenotyping investigation of minimal residual disease is a useful approach for predicting relapse in acute myeloid leukemia patients , 1997 .

[22]  C. Bloomfield,et al.  High frequency of immunophenotype changes in acute myeloid leukemia at relapse: implications for residual disease detection (Cancer and Leukemia Group B Study 8361). , 2001, Blood.

[23]  K Wheatley,et al.  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. , 1998, Blood.

[24]  T. Haferlach,et al.  Gene-expression profiling in acute myeloid leukemia. , 2004, The New England journal of medicine.

[25]  F. Appelbaum,et al.  Chemotherapy compared with autologous or allogeneic bone marrow transplantation in the management of acute myeloid leukemia in first remission. , 1998, The New England journal of medicine.

[26]  N. Schmitz,et al.  Upfront Allogeneic Stem Cell Transplantation for Remission Induction in High-Risk Acute Myeloid Leukemia Patients within the Randomized Multi- Center Trial AML2003. , 2008 .

[27]  W. Hiddemann,et al.  Nucleophosmin gene mutations are predictors of favorable prognosis in acute myelogenous leukemia with a normal karyotype. , 2005, Blood.

[28]  C. Bloomfield,et al.  Clinical relevance of mutations and gene-expression changes in adult acute myeloid leukemia with normal cytogenetics: are we ready for a prognostically prioritized molecular classification? , 2007, Blood.

[29]  A. Venditti,et al.  Level of minimal residual disease after consolidation therapy predicts outcome in acute myeloid leukemia. , 2000, Blood.

[30]  M. Slovak,et al.  Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group study , 2000 .

[31]  Martin Dugas,et al.  Analysis of FLT3 length mutations in 1003 patients with acute myeloid leukemia: correlation to cytogenetics, FAB subtype, and prognosis in the AMLCG study and usefulness as a marker for the detection of minimal residual disease. , 2002 .

[32]  P. Hurteloup,et al.  Comparison of autologous bone marrow transplantation and intensive chemotherapy as postremission therapy in adult acute myeloid leukemia. The Groupe Ouest Est Leucémies Aiguës Myéloblastiques (GOELAM). , 1997, Blood.

[33]  W. Hiddemann,et al.  Prognostic impact of early response to induction therapy as assessed by multiparameter flow cytometry in acute myeloid leukemia. , 2004, Haematologica.

[34]  M. Vignetti,et al.  Daunorubicin versus mitoxantrone versus idarubicin as induction and consolidation chemotherapy for adults with acute myeloid leukemia: the EORTC and GIMEMA Groups Study AML-10. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[35]  Bob Löwenberg,et al.  Mutations in nucleophosmin (NPM1) in acute myeloid leukemia (AML): association with other gene abnormalities and previously established gene expression signatures and their favorable prognostic significance. , 2005, Blood.

[36]  F. Lo Coco,et al.  Toward optimization of postremission therapy for residual disease-positive patients with acute myeloid leukemia. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[37]  F. Lo‐Coco,et al.  The kinetics of reduction of minimal residual disease impacts on duration of response and survival of patients with acute myeloid leukemia. , 2006, Leukemia.

[38]  Torsten Hothorn,et al.  On the Exact Distribution of Maximally Selected Rank Statistics , 2002, Comput. Stat. Data Anal..

[39]  T. Haferlach,et al.  Prognostic relevance of FLT3-TKD mutations in AML: the combination matters--an analysis of 3082 patients. , 2008, Blood.

[40]  L. Shaffer,et al.  ISCN 2009 - An International System for Human Cytogenetic Nomenclature , 2009 .

[41]  Yi Ning,et al.  Pretreatment cytogenetics add to other prognostic factors predicting complete remission and long-term outcome in patients 60 years of age or older with acute myeloid leukemia: results from Cancer and Leukemia Group B 8461. , 2006, Blood.

[42]  C. Bloomfield,et al.  Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B (CALGB 8461). , 2002, Blood.

[43]  B. Löwenberg Strategies in the treatment of acute myeloid leukemia. , 2004 .

[44]  Iscn International System for Human Cytogenetic Nomenclature , 1978 .

[45]  E. Macintyre,et al.  Standardized RT-PCR analysis of fusion gene transcripts from chromosome aberrations in acute leukemia for detection of minimal residual disease , 1999, Leukemia.

[46]  E. Estey,et al.  Treatment of acute myeloid leukemia , 2009, Haematologica.

[47]  M. Vignetti,et al.  Use of glycosylated recombinant human G-CSF (lenograstim) during and/or after induction chemotherapy in patients 61 years of age and older with acute myeloid leukemia: final results of AML-13, a randomized phase-3 study. , 2005, Blood.

[48]  W. Hiddemann,et al.  Stability of leukemia‐associated aberrant immunophenotypes in patients with acute myeloid leukemia between diagnosis and relapse: Comparison with cytomorphologic, cytogenetic, and molecular genetic findings , 2004, Cytometry. Part B, Clinical cytometry.

[49]  T. Haferlach,et al.  Minimal residual disease levels assessed by NPM1 mutation-specific RQ-PCR provide important prognostic information in AML. , 2009, Blood.

[50]  R. Hills,et al.  Independent Prognostic Factors for Aml Outcome Pre-treatment Prognostic Factors , 2022 .

[51]  R. Frelick Cancer and leukemia group B (CALGB). , 1979, Delaware medical journal.

[52]  A. Venditti,et al.  Monitoring of minimal residual disease in adult acute myeloid leukemia using peripheral blood as an alternative source to bone marrow. , 2007, Haematologica.

[53]  C. Bloomfield,et al.  Chromosome aberrations, gene mutations and expression changes, and prognosis in adult acute myeloid leukemia. , 2006, Hematology. American Society of Hematology. Education Program.