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Acute Leukemia

FLT3 mutational status is an independent risk factor for adverse outcomes after allogeneic transplantation in AML

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Abstract

Allogeneic hematopoietic cell transplantation (HCT) has been increasingly used in the setting of FMS-like tyrosine kinase-3 (FLT3)-mutated AML. However, its role in conferring durable relapse-free intervals remains in question. Herein we sought to investigate FLT3 mutational status on transplant outcomes. We conducted a retrospective cohort study of 262 consecutive AML patients who underwent first-time allogeneic HCT (2008–2014), of whom 171 had undergone FLT3-ITD (internal tandem duplication) mutational testing. FLT3-mutated AML was associated with nearly twice the relapse risk (RR) compared with those without FLT3 mutation 3 years post-HCT (63% vs 37%, P<0.001) and with a shorter median time to relapse (100 vs 121 days). FLT3 mutational status remained significantly associated with this outcome after controlling for patient, disease and transplant-related risk factors (P<0.05). Multivariate analysis showed a significant association of FLT3 mutation with increased 3-year RR (hazard ratio (HR) 3.63, 95% confidence interval (CI): 2.13, 6.19, P<0.001) and inferior disease-free survival (HR 2.05, 95% CI: 1.29, 3.27, P<0.01) and overall survival (HR 1.92, 95% CI: 1.14, 3.24, P<0.05). These data demonstrate high risk of early relapse after allogeneic HCT for FLT3-mutated AML that translates into adverse disease-free and overall survival outcomes. Additional targeted and coordinated interventions are needed to maintain durable remission after allogeneic HCT in this high-risk population.

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References

  1. Schlenk RF, Pasquini MC, Perez WS, Zhang MJ, Krauter J, Antin JH et al. HLA-identical sibling allogeneic transplants versus chemotherapy in acute myelogenous leukemia with t(8;21) in first complete remission: collaborative study between the German AML Intergroup and CIBMTR. Biol Blood Marrow Transplant 2008; 14: 187–196.

    Article  Google Scholar 

  2. Schnittger S, Schoch C, Dugas M, Kern W, Staib P, Wuchter C 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. Blood 2002; 100: 59–66.

    Article  CAS  Google Scholar 

  3. Frohling S, Schlenk RF, Breitruck J, Benner A, Kreitmeier S, Tobis K et al. 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.

    Article  CAS  Google Scholar 

  4. Kottaridis PD, Gale RE, Frew ME, Harrison G, Langabeer SE, Belton AA et al. 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.

    Article  CAS  Google Scholar 

  5. Yamamoto Y, Kiyoi H, Nakano Y, Suzuki R, Kodera Y, Miyawaki S et al. Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies. Blood 2001; 97: 2434–2439.

    Article  CAS  Google Scholar 

  6. Whitman SP, Archer KJ, Feng L, Baldus C, Becknell B, Carlson BD et al. Absence of the wild-type allele predicts poor prognosis in adult de novo acute myeloid leukemia with normal cytogenetics and the internal tandem duplication of FLT3: a cancer and leukemia group B study. Cancer Res 2001; 61: 7233–7239.

    CAS  PubMed  Google Scholar 

  7. Pasquini MC, Wang Z. Current Use and Outcome of Hematopoietic Stem Cell Transplantation: CIBMTR Summary Slides. National Marrow Donor Program and the Center for International Bone Marrow Registry: Minneapolis, MN and Milwaukee, WI, 2013.

  8. Vyas P, Appelbaum FR, Craddock C . Allogeneic hematopoietic cell transplantation for acute myeloid leukemia. Biol Blood Marrow Transplant 2015; 21: 8–15.

    Article  Google Scholar 

  9. Gale RE, Hills R, Kottaridis PD, Srirangan S, Wheatley K, Burnett AK 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. Blood 2005; 106: 3658–3665.

    Article  CAS  Google Scholar 

  10. Bornhauser M, Illmer T, Schaich M, Soucek S, Ehninger G, Thiede C et al. Improved outcome after stem-cell transplantation in FLT3/ITD-positive AML. Blood 2007; 109: 2264–2265 author reply 2265.

    Article  Google Scholar 

  11. Doubek M, Muzik J, Szotkowski T, Koza V, Cetkovsky P, Kozak T et al. Is FLT3 internal tandem duplication significant indicator for allogeneic transplantation in acute myeloid leukemia? An analysis of patients from the Czech Acute Leukemia Clinical Register (ALERT). Neoplasma 2007; 54: 89–94.

    CAS  PubMed  Google Scholar 

  12. Schlenk RF, Dohner K, Krauter J, Frohling S, Corbacioglu A, Bullinger L et al. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med 2008; 358: 1909–1918.

    Article  CAS  Google Scholar 

  13. Kim YK, Kim HN, Lee SR, Ahn JS, Yang DH, Lee JJ et al. Prognostic significance of nucleophosmin mutations and FLT3 internal tandem duplication in adult patients with cytogenetically normal acute myeloid leukemia. Korean J Hematol 2010; 45: 36–45.

    Article  CAS  Google Scholar 

  14. DeZern AE, Sung A, Kim S, Smith BD, Karp JE, Gore SD et al. Role of allogeneic transplantation for FLT3/ITD acute myeloid leukemia: outcomes from 133 consecutive newly diagnosed patients from a single institution. Biol Blood Marrow Transplant 2011; 17: 1404–1409.

    Article  Google Scholar 

  15. Ehninger G, Bornhauser M, Kramer M, Rollig C, Wandt H, Hanel M et al. A strong immune effect by allogeneic stem cell transplantation may improve survival in AML patients with a high ratio of the FLT3-ITD mutation to the Wt-FLT3 allele: results from an analysis of 257 patients treated in the SAL AML-2003 trial. ASH Annu Meeting Abstr 2011; 118: 497.

    Google Scholar 

  16. Kayser S, Zucknick M, Dohner K, Krauter J, Kohne CH, Horst HA et al. Monosomal karyotype in adult acute myeloid leukemia: prognostic impact and outcome after different treatment strategies. Blood 2012; 119: 551–558.

    Article  CAS  Google Scholar 

  17. Brunet S, Labopin M, Esteve J, Cornelissen J, Socie G, Iori AP 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. J Clin Oncol 2012; 30: 735–741.

    Article  Google Scholar 

  18. Sengsayadeth SM, Jagasia M, Engelhardt BG, Kassim A, Strickland SA, Goodman S et al. Allo-SCT for high-risk AML-CR1 in the molecular era: impact of FLT3/ITD outweighs the conventional markers. Bone Marrow Transplant 2012; 47: 1535–1537.

    Article  CAS  Google Scholar 

  19. Laboure G, Dulucq S, Labopin M, Tabrizi R, Guerin E, Pigneux A 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. Biol Blood Marrow Transplant 2012; 18: 1845–1850.

    Article  Google Scholar 

  20. Guieze R, Cornillet-Lefebvre P, Lioure B, Blanchet O, Pigneux A, Recher C et al. Role of autologous hematopoietic stem cell transplantation according to the NPM1/FLT3-ITD molecular status for cytogenetically normal AML patients: a GOELAMS study. Am J Hematol 2012; 87: 1052–1056.

    Article  Google Scholar 

  21. Pfeiffer T, Schleuning M, Mayer J, Haude KH, Tischer J, Buchholz S et al. Influence of molecular subgroups on outcome of acute myeloid leukemia with normal karyotype in 141 patients undergoing salvage allogeneic stem cell transplantation in primary induction failure or beyond first relapse. Haematologica 2013; 98: 518–525.

    Article  Google Scholar 

  22. Lin PH, Lin CC, Yang HI, Li LY, Bai LY, Chiu CF et al. Prognostic impact of allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia patients with internal tandem duplication of FLT3. Leuk Res 2013; 37: 287–292.

    Article  CAS  Google Scholar 

  23. Pratcorona M, Brunet S, Nomdedeu J, Ribera JM, Tormo M, Duarte R 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. Blood 2013; 121: 2734–2738.

    Article  CAS  Google Scholar 

  24. Burke MJ, Wagner JE, Cao Q, Ustun C, Verneris MR . Allogeneic hematopoietic cell transplantation in first remission abrogates poor outcomes associated with high-risk pediatric acute myeloid leukemia. Biol Blood Marrow Transplant 2013; 19: 1021–1025.

    Article  Google Scholar 

  25. Liu YC, Hsiao HH, Lin PM, Yang WC, Chang CS, Liu TC et al. Prognostic implication of molecular aberrations in cytogenetically normal acute myeloid leukemia patients receiving allogeneic hematopoietic stem cell transplantation. Genet Mol Res 2013; 12: 5414–5423.

    Article  CAS  Google Scholar 

  26. Yang Z, Tian H, Xu Y, Qiu H, Chen S, Sun A et al. [Clinical outcome of FLT3-ITD (+) acute myeloid leukemia patients treated with allogeneic hematopoietic stem cell transplantation]. Zhonghua Nei Ke Za Zhi 2014; 53: 94–98.

    CAS  PubMed  Google Scholar 

  27. Chou SC, Tang JL, Hou HA, Chou WC, Hu FC, Chen CY et al. Prognostic implication of gene mutations on overall survival in the adult acute myeloid leukemia patients receiving or not receiving allogeneic hematopoietic stem cell transplantations. Leuk Res 2014; 38: 1278–1284.

    Article  CAS  Google Scholar 

  28. Locatelli F, Masetti R, Rondelli R, Zecca M, Fagioli F, Rovelli A et al. Outcome of children with high-risk acute myeloid leukemia given autologous or allogeneic hematopoietic cell transplantation in the aieop AML-2002/01 study. Bone Marrow Transplant 2014; 50: 181–188.

    Article  Google Scholar 

  29. Schlenk RF, Kayser S, Bullinger L, Kobbe G, Casper J, Ringhoffer M et al. Differential impact of allelic ratio and insertion site in FLT3-ITD-positive AML with respect to allogeneic transplantation. Blood 2014; 124: 3441–3449.

    Article  CAS  Google Scholar 

  30. Schetelig J, Schaich M, Schafer-Eckart K, Hanel M, Aulitzky WE, Einsele H et al. Hematopoietic cell transplantation in patients with intermediate and high-risk AML—results from the randomized study alliance leukemia (SAL) AML 2003 trial. Leukemia 2014; 29: 1060–1068.

    Article  Google Scholar 

  31. Schechter T, Gassas A, Chen H, Pollard J, Meshinchi S, Zaidman I et al. The outcome of allogeneic hematopoietic cell transplantation for children with FMS-like tyrosine kinase 3 internal tandem duplication-positive acute myelogenous leukemia. Biol Blood Marrow Transplant 2015; 21: 172–175.

    Article  Google Scholar 

  32. Hanauer DA . EMERSE: The Electronic Medical Record Search Engine. AMIA Annu Symp Proc 2006; 2006: 941.

    Google Scholar 

  33. Sorror ML, Maris MB, Storb R, Baron F, Sandmaier BM, Maloney DG et al. Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood 2005; 106: 2912–2919.

    Article  CAS  Google Scholar 

  34. Slovak ML, Kopecky KJ, Cassileth PA, Harrington DH, Theil KS, Mohamed A 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. Blood 2000; 96: 4075–4083.

    CAS  Google Scholar 

  35. Fine JP, Gray RJ . A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc 1999; 94: 496–509.

    Article  Google Scholar 

  36. Gray RJ . A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat 1988; 16: 1141–1154.

    Article  Google Scholar 

  37. Kaplan EL, Meier P . Nonparametric-estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457–481.

    Article  Google Scholar 

  38. Walter RB, Sandmaier BM, Storer BE, Godwin CD, Buckley SA, Pagel JM et al. Number of courses of induction therapy independently predicts outcome after allogeneic transplantation for acute myeloid leukemia in first morphological remission. Biol Blood Marrow Transplant 2015; 21: 373–378.

    Article  Google Scholar 

  39. Schroeder T, Rachlis E, Bug G, Stelljes M, Klein S, Steckel NK et al. Treatment of acute myeloid leukemia or myelodysplastic syndrome relapse after allogeneic stem cell transplantation with azacitidine and donor lymphocyte infusions-a retrospective multicenter analysis from the German Cooperative Transplant Study Group. Biol Blood Marrow Transplant 2014; 21: 653–660.

    Article  Google Scholar 

  40. Chen YB, Li S, Lane AA, Connolly C, Del Rio C, Valles B 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. Biol Blood Marrow Transplant 2014; 20: 2042–2048.

    Article  CAS  Google Scholar 

  41. Platzbecker U, Wermke M, Radke J, Oelschlaegel U, Seltmann F, Kiani A et al. Azacitidine for treatment of imminent relapse in MDS or AML patients after allogeneic HSCT: results of the RELAZA trial. Leukemia 2012; 26: 381–389.

    Article  CAS  Google Scholar 

  42. Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 2012; 366: 2455–2465.

    Article  CAS  Google Scholar 

  43. Federmann B, Faul C, Meisner C, Vogel W, Kanz L, Bethge WA . Influence of age on outcome after allogeneic hematopoietic cell transplantation: a single center study in patients aged 60. Bone Marrow Transplant 2015; 50: 427–431.

    Article  CAS  Google Scholar 

  44. Pavletic SZ, Kumar S, Mohty M, de Lima M, Foran JM, Pasquini M et al. NCI First International Workshop on the Biology, Prevention, and Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation: report from the Committee on the Epidemiology and Natural History of Relapse following Allogeneic Cell Transplantation. Biol Blood Marrow Transplant 2010; 16: 871–890.

    Article  Google Scholar 

  45. Walter RB, Gooley TA, Wood BL, Milano F, Fang M, Sorror ML et al. Impact of pretransplantation minimal residual disease, as detected by multiparametric flow cytometry, on outcome of myeloablative hematopoietic cell transplantation for acute myeloid leukemia. J Clin Oncol 2011; 29: 1190–1197.

    Article  Google Scholar 

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Acknowledgements

We are grateful to the patients, their families and the clinical personnel who participated in this study. We thank Tracey Churay and Ashley Crouch and the BMT Program Team at the University of Michigan Clinical Trials Office for data collection and management. SWC is an A Alfred Taubman Institute/Edith Briskin/SKS Foundation Emerging Scholar. SWC is supported by a grant from the National Institutes of Health (1K23AI091623).

Author contributions

YS collected and analyzed data and drafted and approved the manuscript; YL analyzed data and approved the manuscript; LC, DAH, KAC and EG collected data and approved the manuscript; DC, SG, AP, PR, MR, JC, AH, CK, JL and GY cared for patients and approved the manuscript; TB designed the study, analyzed data and approved the manuscript; JM, BP and DB designed the study, cared for patients and approved the manuscript. SWC designed the study, cared for patients, collected and analyzed data and drafted and approved the manuscript.

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Correspondence to S W Choi.

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Song, Y., Magenau, J., Li, Y. et al. FLT3 mutational status is an independent risk factor for adverse outcomes after allogeneic transplantation in AML. Bone Marrow Transplant 51, 511–520 (2016). https://doi.org/10.1038/bmt.2015.170

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