Prognostic impact of genetic characterization in the GIMEMA LAM99P multicenter study for newly diagnosed acute myeloid leukemia

The findings of this study reiterate the prognostic relevance of combining cytogenetic and mutational analysis (NPM1, FTT3) in the diagnostic work up of acute myeloid leukemia. See related perspective on page 976. Background Recent advances in genetic characterization of acute myeloid leukemia indicate that combined cytogenetic and molecular analyses provide better definition of prognostic groups. The aim of this study was to verify this prospectively in a large group of patients. Design and Methods Genetic characterization was prospectively carried out in 397 patients with acute myeloid leukemia (median age, 46 years) receiving uniform treatment according to the LAM99P protocol of the Italian GIMEMA group. The impact of genetic markers on response to therapy and outcome was assessed by univariate and multivariate analyses. Results For induction response, conventional karyotyping identified three groups with complete remission rates of 92%, 67% and 39% (p<0.0001). Complete remission rates in NPM1 mutated (NPM1+) and wild-type (NPM1-) groups were 76% and 60%, respectively, for the whole population and 81% and 61% in the group with normal karyotype (p<0.001 and p=0.026, respectively). Multivariate analysis indicated that low risk karyotype and NPM1+ were independent factors favorably affecting complete remission. Multivariate analysis of overall and disease-free survival among 269 patients who achieved complete remission showed a significant impact of karyotype on both estimates and of FLT3 status on disease free-survival (FLT3-ITD vs. FLT3 wild-type, p=0.0001). NPM1 status did not significantly influence disease free-survival in either the whole population or in the patients with a normal karyotype in this series, probably due to the low number of cases analyzed. Conclusions These results reiterate the prognostic relevance of combining cytogenetic and mutational analysis in the diagnostic work up of patients with acute myeloid leukemia.

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

[2]  B. Falini,et al.  Denaturing high-performance liquid chromatography: a valid approach for identifying NPM1 mutations in acute myeloid leukemia. , 2006, The Journal of molecular diagnostics : JMD.

[3]  M. Mancini,et al.  Incidence and significance of cryptic chromosome aberrations detected by fluorescence in situ hybridization in acute myeloid leukemia with normal karyotype , 2002, Leukemia.

[4]  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.

[5]  H. Mitsuya,et al.  Mutations in the receptor tyrosine kinase pathway are associated with clinical outcome in patients with acute myeloblastic leukemia harboring t(8;21)(q22;q22) , 2005, Leukemia.

[6]  X Thomas,et al.  Prognostic significance of FLT3 internal tandem repeat in patients with de novo acute myeloid leukemia treated with reinforced courses of chemotherapy , 2002, Leukemia.

[7]  J. Cayuela,et al.  Prevalence, clinical profile, and prognosis of NPM mutations in AML with normal karyotype. , 2005, Blood.

[8]  D. Harnden,et al.  An international system for human cytogenetic nomenclature (1985) : ISCN (1985) : report of the Standing Committee on Human Cytogenetic Nomenclature , 1985 .

[9]  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.

[10]  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.

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

[12]  A. Hagemeijer,et al.  Validation of an interphase fluorescence in situ hybridization approach for the detection of MLL gene rearrangements and of the MLL/AF9 fusion in acute myeloid leukemia. , 2006, Haematologica.

[13]  J. Cayuela,et al.  Favorable prognostic significance of CEBPA mutations in patients with de novo acute myeloid leukemia: a study from the Acute Leukemia French Association (ALFA). , 2002, Blood.

[14]  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.

[15]  Gerhard Ehninger,et al.  Prevalence and prognostic impact of NPM 1 mutations in 1485 adult patients with acute myeloid leukemia ( AML ) , 2006 .

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

[17]  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.

[18]  H. Kantarjian,et al.  Acute myeloid leukemia , 2018, Methods in Molecular Biology.

[19]  Myriam Alcalay,et al.  Immunohistochemistry predicts nucleophosmin (NPM) mutations in acute myeloid leukemia. , 2006, Blood.

[20]  Hartmut Döhner,et al.  Acute myeloid leukaemia , 2006, The Lancet.

[21]  G. Ehninger,et al.  Analysis of Flt3-activating Mutations in 979 Patients with Acute Myelogenous Leukemia: Association with Fab Subtypes and Identification of Subgroups with Poor Prognosis , 2022 .

[22]  T. Naoe,et al.  Prognostic significance of FLT3 internal tandem duplication and tyrosine kinase domain mutations for acute myeloid leukemia: a meta-analysis , 2005, Leukemia.

[23]  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 .

[24]  A. Cuneo,et al.  Prognostic Impact of C-Kit Mutations in Core Binding Factor-Leukemia. , 2004 .

[25]  T. Naoe,et al.  Biology, Clinical Relevance, and Molecularly Targeted Therapy in Acute Leukemia with Flt3 Mutation , 2006, International journal of hematology.

[26]  F. Mandelli,et al.  Alterations of the FLT3 gene in acute promyelocytic leukemia: association with diagnostic characteristics and analysis of clinical outcome in patients treated with the Italian AIDA protocol , 2002, Leukemia.

[27]  T. Naoe,et al.  Clinical characteristics and prognostic implications of NPM1 mutations in acute myeloid leukemia. , 2005, Blood.

[28]  R. Foà,et al.  A comprehensive genetic classification of adult acute lymphoblastic leukemia (ALL): analysis of the GIMEMA 0496 protocol. , 2005, Blood.

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

[30]  C. Bloomfield,et al.  Frequency of prolonged remission duration after high-dose cytarabine intensification in acute myeloid leukemia varies by cytogenetic subtype. , 1998, Cancer research.

[31]  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.

[32]  Gerhard Ehninger,et al.  Prevalence and prognostic impact of NPM1 mutations in 1485 adult patients with acute myeloid leukemia (AML). , 2006, Blood.

[33]  D. Gilliland,et al.  Genetics of myeloid leukemias. , 2003, Annual review of genomics and human genetics.

[34]  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.

[35]  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 .

[36]  U. Francke.  An international system for human cytogenetic nomenclature--high-resolution banding (1981). ISCN (1981). Report of the Standing Committee on Human Cytogenetic Nomenclature. , 1981, Cytogenetics and cell genetics.

[37]  C. Bloomfield,et al.  Influence of new molecular prognostic markers in patients with karyotypically normal acute myeloid leukemia: recent advances , 2007, Current opinion in hematology.

[38]  Brunangelo Falini,et al.  Acute myeloid leukemia carrying cytoplasmic/mutated nucleophosmin (NPMc+ AML): biologic and clinical features. , 2007, Blood.

[39]  S. Meshinchi,et al.  Mutations in KIT and RAS are frequent events in pediatric core-binding factor acute myeloid leukemia , 2005, Leukemia.