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      Allogeneic hematopoietic cell transplantation improves outcome of adults with t(6;9) acute myeloid leukemia: results from an international collaborative study

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      1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 15 , 16 , 17 , 18 , 19 , * , 20 , 9 , 10 , 21 , 1 , 2 , 3 , 1 , 22 , 23 , 23 , 4 , 23 , 8 , 9 , 10 , 1 , 24 , 25 , 26
      Haematologica
      Ferrata Storti Foundation

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          Abstract

          Acute myeloid leukemia (AML) with t(6;9)(p22;q34) is a distinct entity accounting for 1-2% of AML cases. A substantial proportion of these patients have a concomitant FLT3-ITD. While outcomes are dismal with intensive chemotherapy, limited evidence suggests allogeneic hematopoietic cell transplantation (allo-HCT) may improve survival if performed early during first complete remission. We report on a cohort of 178 patients with t(6;9)(p22;q34) within an international, multicenter collaboration. Median age was 46 years (range: 16-76), AML was de novo in 88%, FLT3-ITD was present in 62%, and additional cytogenetic abnormalities in 21%. Complete remission was achieved in 81% (n=144), including 14 patients who received high-dose cytarabine after initial induction failure. With a median follow up of 5.43 years, estimated overall survival at five years was 38% (95%CI: 31-47%). Allo-HCT was performed in 117 (66%) patients, including 89 in first complete remission. Allo-HCT in first complete remission was associated with higher 5-year relapse-free and overall survival as compared to consolidation chemotherapy: 45% (95%CI: 35-59%) and 53% (95%CI: 42-66%) versus 7% (95%CI: 3-19%) and 23% (95%CI: 13-38%), respectively. For patients undergoing allo-HCT, there was no difference in overall survival rates at five years according to whether it was performed in first [53% (95%CI: 42-66%)], or second [58% (95%CI: 31-100%); n=10] complete remission or with active disease/relapse [54% (95%CI: 34-84%); n=18] ( P=0.67). Neither FLT3-ITD nor additional chromosomal abnormalities impacted survival. In conclusion, outcomes of t(6;9)(p22;q34) AML are poor with chemotherapy, and can be substantially improved with allo-HCT.

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          Most cited references37

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          Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis.

          C Thiede (2002)
          Constitutive activation of the FLT3 receptor tyrosine kinase, either by internal tandem duplication (ITD) of the juxtamembrane region or by point mutations in the second tyrosine kinase domain (TKD), has been described in patients with acute myelogenous leukemia (AML). We analyzed the prevalence and the potential prognostic impact of FLT3 mutations in 979 AML patients. Results were correlated with cytogenetic data and the clinical response. FLT3-ITD mutations were found in 20.4% and FLT3-TKD mutations in 7.7% of the patients. Each mutation was associated with similar clinical characteristics and was more prevalent in patients with normal karyotype. Significantly more FLT3 aberrations were found in patients with FAB M5, and fewer were found in patients with FAB M2 and M6. Although less frequent in patients with cytogenetic aberrations, FLT3-ITDs were found in 13 of 42 patients with t(15;17) and in 9 of 10 patients with t(6;9). The prevalence of the ITD allele on the DNA level was heterogeneous, ranging from faint mutant bands in some patients to predominant mutant bands in others. Based on quantitative analysis, the mutant-wild-type (wt) ratio ranged from 0.03 to 32.56 (median, 0.78). Patients with a high mutant/wt ratio (ie, greater than 0.78) had significantly shorter overall and disease-free survival, whereas survival in patients with ratios below 0.78 did not differ from those without FLT3 aberrations. Multivariate analysis confirmed a high mutant/wt ratio to be a strong independent prognostic factor. Taken together, these data confirm that FLT mutations represent a common alteration in adult AML. Constitutive activation may be associated with monocytoid differentiation. A high mutant/wt ratio in ITD-positive patients appears to have a major impact on the prognostic relevance.
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            Proposed revised criteria for the classification of acute myeloid leukemia. A report of the French-American-British Cooperative Group.

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              Regression models and life tables (with discussion)

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                Author and article information

                Journal
                Haematologica
                Haematologica
                haematol
                Haematologica
                Haematologica
                Ferrata Storti Foundation
                0390-6078
                1592-8721
                January 2020
                19 April 2019
                : 105
                : 1
                : 161-169
                Affiliations
                [1 ]Department of Internal Medicine V, University Hospital of Heidelberg, Heidelberg, Germany
                [2 ]German Cancer Research Center (DKFZ) and Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany
                [3 ]Cardiff University School of Medicine, Cardiff, UK
                [4 ]Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
                [5 ]Massachusetts General Hospital, Boston, MA, USA
                [6 ]Laboratory of Hematology, André Mignot Hospital, Le Chesnay, France
                [7 ]Department of Hematology, Oncology and Tumor Immunology, Charité-University Medical Center, Campus Virchow Clinic, Berlin, Germany
                [8 ]Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY, USA
                [9 ]Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
                [10 ]Division of Hematology/Department of Medicine, University of Washington, Seattle, WA, USA
                [11 ]University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, MD, USA
                [12 ]Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
                [13 ]Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA
                [14 ]Division of Hematology and Oncology, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
                [15 ]Department of Internal Medicine, Hematology and Oncology, Masaryk University and University Hospital Brno, Brno, Czech Republic
                [16 ]4 th Department of Internal Medicine-Hematology, Faculty of Medicine, Charles University and University Hospital Hradec Králové, Hradec Králové, Czech Republic
                [17 ]Department of Hemato-Oncology, Faculty of Medicine and Dentistry, Palacky University Olomouc and University Hospital Olomouc, Olomouc, Czech Republic
                [18 ]Université Paris-Saclay, Gustave Roussy Villejuif, France
                [19 ]Department of Medical & Molecular Genetics, King’s College London, Faculty of Life Sciences and Medicine, London, UK
                [20 ]Medical Clinic III for Oncology, Hematology and Rheumatology, University Hospital Bonn, Bonn, Germany
                [21 ]Department of Epidemiology, University of Washington, Seattle, WA, USA
                [22 ]Medical Clinic and Policlinic I, Hematology and Cellular Therapy, University Hospital Leipzig, Leipzig, Germany
                [23 ]Department of Internal Medicine I, University Hospital Carl-Gustav-Carus, Dresden, Germany
                [24 ]Department of Haematology, Nottingham University Hospitals NHS Trust, Nottingham, UK
                [25 ]NCT Trial Center, National Center for Tumor Diseases, Heidelberg, Germany
                [26 ]Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA
                Author notes
                Correspondence: SABINE KAYSER s.kayser@ 123456dkfz-heidelberg.de
                Article
                1050161
                10.3324/haematol.2018.208678
                6939530
                31004014
                2021a331-146e-475e-b7fd-b41f264516d8
                Copyright© 2020 Ferrata Storti Foundation

                Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions:

                https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or internal use. Sharing published material for non-commercial purposes is subject to the following conditions:

                https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for commercial purposes is not allowed without permission in writing from the publisher.

                History
                : 21 January 2019
                : 15 April 2019
                Categories
                Article
                Acute Myeloid Leukemia

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