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

Intermediate-risk cytogenetic acute myeloid leukemia with an internal tandem duplication of FLT3 (FLT3-ITD) is associated with a high risk of relapse, and is now a standard indication for allogeneic stem cell transplantation. Nevertheless, most studies supporting this strategy have been performed in young patients. To address the benefit of allogeneic transplantation in the elderly, we made a selection from the European Society for Blood and Marrow Transplantation registry of de novo intermediate-risk cytogenetic acute myeloid leukemia harboring FLT3-ITD in patients aged 60 or over and transplanted from a related or unrelated donor between January 2000 and December 2015. Two hundred and ninety-one patients were identified. Most patients received a reduced-intensity conditioning (82%), while donors consisted of an unrelated donor in 161 (55%) patients. Two hundred and twelve patients received their transplantation in first remission, 37 in second remission and 42 in a more advanced stage of the disease. The 2-year leukemia-free survival rate was 56% in patients in first remission, 22% in those in second remission and 10% in patients with active disease, respectively (P<0.005). Non-relapse mortality for the entire cohort was 20%. In multivariate analysis, disease status at transplantation was the most powerful predictor of worse leukemia-free survival, graft-versus-host disease and relapse-free survival, and overall survival. In this elderly population, age was not associated with outcome. Based on the current results, allogeneic transplantation translates into a favorable outcome in fit patients ≥ 60 with FLT3-ITD acute myeloid leukemia in first remission, similarly to current treatment recommendations for younger patients.

[1]  C. Bloomfield,et al.  Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 Mutation , 2017, The New England journal of medicine.

[2]  M. Andreeff,et al.  Relapse risk and survival in patients with FLT3 mutated acute myeloid leukemia undergoing stem cell transplantation , 2017, American journal of hematology.

[3]  M. Levis,et al.  How I treat FLT3-mutated AML. , 2017, Blood.

[4]  Bob Löwenberg,et al.  Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. , 2017, Blood.

[5]  C. Craddock,et al.  A comparison between allogeneic stem cell transplantation from unmanipulated haploidentical and unrelated donors in acute leukemia , 2017, Journal of Hematology & Oncology.

[6]  E. Vellenga,et al.  Comparative value of post-remission treatment in cytogenetically normal AML subclassified by NPM1 and FLT3-ITD allelic ratio , 2016, Leukemia.

[7]  B. Sandmaier,et al.  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 , 2016, Cancer.

[8]  W. Hiddemann,et al.  Spectrum and prognostic relevance of driver gene mutations in acute myeloid leukemia. , 2016, Blood.

[9]  S. Nikiforow,et al.  Haematopoietic cell transplantation with and without sorafenib maintenance for patients with FLT3‐ITD acute myeloid leukaemia in first complete remission , 2016, British journal of haematology.

[10]  H. Kantarjian,et al.  Allogeneic Transplantation in First Remission Improves Outcomes Irrespective of FLT3-ITD Allelic Ratio in FLT3-ITD-Positive Acute Myelogenous Leukemia. , 2016, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[11]  Nicola D. Roberts,et al.  Genomic Classification and Prognosis in Acute Myeloid Leukemia. , 2016, The New England journal of medicine.

[12]  N. Schmitz,et al.  Allogeneic Stem Cell Transplantation Improves Survival in Patients with Acute Myeloid Leukemia Characterized by a High Allelic Ratio of Mutant FLT3-ITD. , 2016, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[13]  Jong-Ho Won,et al.  DNMT3A R882 Mutation with FLT3-ITD Positivity Is an Extremely Poor Prognostic Factor in Patients with Normal-Karyotype Acute Myeloid Leukemia after Allogeneic Hematopoietic Cell Transplantation. , 2016, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[14]  S. Jhanwar,et al.  Stem cell transplantation in adults with acute myelogenous leukemia, normal cytogenetics, and the FLT3-ITD mutation. , 2016, Leukemia research.

[15]  S. Miyano,et al.  Profiling of somatic mutations in acute myeloid leukemia with FLT3-ITD at diagnosis and relapse. , 2015, Blood.

[16]  J. Esteve,et al.  Outcome of patients with distinct molecular genotypes and cytogenetically normal AML after allogeneic transplantation. , 2015, Blood.

[17]  M. Aljurf,et al.  HLA Mismatch Is Associated with Worse Outcomes after Unrelated Donor Reduced-Intensity Conditioning Hematopoietic Cell Transplantation: An Analysis from the Center for International Blood and Marrow Transplant Research. , 2015, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[18]  R. Mahfouz,et al.  Sorafenib Maintenance Appears Safe and Improves Clinical Outcomes in FLT3-ITD Acute Myeloid Leukemia After Allogeneic Hematopoietic Cell Transplantation. , 2015, Clinical lymphoma, myeloma & leukemia.

[19]  C. Meisner,et al.  Influence of age on outcome after allogeneic hematopoietic cell transplantation: a single center study in patients aged ⩾60 , 2015, Bone Marrow Transplantation.

[20]  E. Estey,et al.  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. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[21]  M. Sorror,et al.  Number of courses of induction therapy independently predicts outcome after allogeneic transplantation for acute myeloid leukemia in first morphological remission. , 2015, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[22]  A. Lane,et al.  Phase I trial of maintenance sorafenib after allogeneic hematopoietic stem cell transplantation for fms-like tyrosine kinase 3 internal tandem duplication acute myeloid leukemia. , 2014, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[23]  L. Bullinger,et al.  Differential impact of allelic ratio and insertion site in FLT3-ITD-positive AML with respect to allogeneic transplantation. , 2014, Blood.

[24]  E. Estey,et al.  Comorbidity-age index: a clinical measure of biologic age before allogeneic hematopoietic cell transplantation. , 2014, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[25]  R. Larson,et al.  Geriatric assessment to predict survival in older allogeneic hematopoietic cell transplantation recipients , 2014, Haematologica.

[26]  R. Hills,et al.  Impact of FLT3(ITD) mutant allele level on relapse risk in intermediate-risk acute myeloid leukemia. , 2014, Blood.

[27]  J. Lipton,et al.  Benefit of allogeneic transplantation in patients age ≥ 60 years with acute myeloid leukemia is limited to those in first complete remission at time of transplant. , 2014, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[28]  R. Hills,et al.  The prognostic relevance of flt3 and npm1 mutations on older patients treated intensively or non-intensively: a study of 1312 patients in the UK NCRI AML16 trial , 2014, Leukemia.

[29]  P. Armand,et al.  Outcomes in patients age 70 or older undergoing allogeneic hematopoietic stem cell transplantation for hematologic malignancies. , 2013, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[30]  Benjamin J. Raphael,et al.  Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. , 2013, The New England journal of medicine.

[31]  J. Esteve,et al.  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. , 2013, Blood.

[32]  R. Hills,et al.  Curability of patients with acute myeloid leukemia who did not undergo transplantation in first remission. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[33]  M. Perales,et al.  Who is the better donor for older hematopoietic transplant recipients: an older-aged sibling or a young, matched unrelated volunteer? , 2013, Blood.

[34]  Hwai I. Yang,et al.  Prognostic impact of allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia patients with internal tandem duplication of FLT3. , 2013, Leukemia research.

[35]  K. van Besien,et al.  Pilot study of comprehensive geriatric assessment (CGA) in allogeneic transplant: CGA captures a high prevalence of vulnerabilities in older transplant recipients. , 2013, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[36]  N. Kröger,et al.  Allogeneic stem cell transplantation for older advanced MDS patients: improved survival with young unrelated donor in comparison with HLA-identical siblings , 2013, Leukemia.

[37]  J. Rowe,et al.  The myth of the second remission of acute leukemia in the adult. , 2013, Blood.

[38]  J. Williamson,et al.  Geriatric assessment predicts survival for older adults receiving induction chemotherapy for acute myelogenous leukemia. , 2010, Blood.

[39]  M. Labopin,et al.  Potent graft-versus-leukemia effect after reduced-intensity allogeneic SCT for intermediate-risk AML with FLT3-ITD or wild-type NPM1 and CEBPA without FLT3-ITD. , 2012, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[40]  K. Götze,et al.  High activity of sorafenib in FLT3-ITD-positive acute myeloid leukemia synergizes with allo-immune effects to induce sustained responses , 2012, Leukemia.

[41]  J. Esteve,et al.  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. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[42]  D. Neuberg,et al.  Outcome of older adults with cytogenetically normal AML (CN-AML) and FLT3 mutations. , 2011, Leukemia research.

[43]  P. Hari,et al.  Long-term outcomes among older patients following nonmyeloablative conditioning and allogeneic hematopoietic cell transplantation for advanced hematologic malignancies. , 2011, JAMA.

[44]  M. McDevitt,et al.  Role of allogeneic transplantation for FLT3/ITD acute myeloid leukemia: outcomes from 133 consecutive newly diagnosed patients from a single institution. , 2011, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[45]  E. Vellenga,et al.  Original Articles Design and Methods Prognostic Impact of White Blood Cell Count in Intermediate Risk Acute Myeloid Leukemia: Relevance of Mutated Npm1 and Flt3-itd , 2022 .

[46]  T. Haferlach,et al.  Prognostic impact of FLT3-ITD load in NPM1 mutated acute myeloid leukemia , 2011, Leukemia.

[47]  Michael Boeckh,et al.  Reduced mortality after allogeneic hematopoietic-cell transplantation. , 2010, The New England journal of medicine.

[48]  M. Caligiuri,et al.  FLT3 internal tandem duplication associates with adverse outcome and gene- and microRNA-expression signatures in patients 60 years of age or older with primary cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study. , 2010, Blood.

[49]  Bob Löwenberg,et al.  Review Articles (434 articles) , 2008 .

[50]  G. Mufti,et al.  Allogeneic hematopoietic stem-cell transplantation for patients 50 years or older with myelodysplastic syndromes or secondary acute myeloid leukemia. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[51]  B. Sandmaier,et al.  Defining the intensity of conditioning regimens: working definitions. , 2009, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

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

[53]  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.

[54]  J. Radich,et al.  Role of allogeneic stem cell transplantation in FLT3/ITD-positive AML. , 2006, Blood.

[55]  R. Hills,et al.  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. , 2005, Blood.

[56]  G. Ledderose,et al.  Sequential regimen of chemotherapy, reduced-intensity conditioning for allogeneic stem-cell transplantation, and prophylactic donor lymphocyte transfusion in high-risk acute myeloid leukemia and myelodysplastic syndrome. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[57]  C Anasetti,et al.  Donor characteristics as risk factors in recipients after transplantation of bone marrow from unrelated donors: the effect of donor age. , 2001, Blood.