Skip to main content
Top
Published in: Annals of Hematology 8/2020

Open Access 01-08-2020 | Acute Myeloid Leukemia | Original Article

Pre-transplant FLT3/ITD status predicts outcome in FLT3-mutated acute myeloid leukemia following allogeneic stem cell transplantation

Authors: Grzegorz Helbig, Anna Koclęga, Agata Wieczorkiewicz-Kabut, Krzysztof Woźniczka, Anna Kopińska, Kinga Boral, Iwona Grygoruk-Wiśniowska, Małgorzata Stachowicz, Agnieszka Karolczyk

Published in: Annals of Hematology | Issue 8/2020

Login to get access

Abstract

Acute myeloid leukemia (AML) with fetal liver tyrosine kinase 3 (FLT3) internal tandem duplication (ITD) is associated with poor prognosis, and allogeneic stem cell transplantation (Allo-SCT) seems to be the preferred therapeutic approach. However, the predictors of post-transplant outcomes were not well-defined. The aim of the study was to evaluate the significance of FLT3/ITD mutation by polymerase chain reaction as minimal residual disease (MRD) marker of outcomes after transplantation. We identified 43 patients (28 females and 15 males) with FLT3-mutated AML at the median age of 45 years who were allografted between 2009 and 2019. Hematological status at transplant was as follows: the first complete remission (CR1) in 29 patients, CR2 in 5, and 9 patients were transplanted in marrow aplasia (MA). Twenty-seven patients were FLT3 MRD negative at transplant. Median time from diagnosis to transplant was 16.7 months. Post-allograft CR rate was 88%. The relapse incidence (RI) was lower for patients who were FLT3 MRD negative at transplant when compared with those with FLT3 MRD positivity (41% vs 59%; p = 0.01). The patients who eradicated FLT3/ITD at day + 30 after transplant had lower RI than those with detectable FLT3/ITD (23% vs 76%; p = <0.001). The 2-year LFS and OS were 53% and 54%, with the median OS and LFS of 28 months and 27 months, respectively. Patients with CR1/2 and FLT3 MRD(−) had a 2-year OS of 80%. The FLT3 MRD negativity at transplant prolonged LFS in multivariate analysis (HR 5.3 95%CI 1.97–14.2); p < 0.001), whereas FLT3 MRD negativity and unrelated donor predicted favorable OS.
Literature
1.
go back to reference Stirewalt DL, Radich JP (2003) The role of FLT3 in hematopoietic malignancies. Nat Rev Cancer 3:650–665CrossRef Stirewalt DL, Radich JP (2003) The role of FLT3 in hematopoietic malignancies. Nat Rev Cancer 3:650–665CrossRef
2.
go back to reference Frӧhling S, Schlenk RF, Breitruck J et al (2002) 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. 100:4372–4380CrossRef Frӧhling S, Schlenk RF, Breitruck J et al (2002) 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. 100:4372–4380CrossRef
3.
go back to reference Rombouts WJ, Blokland I, Lowenberg B et al (2000) Biological characteristics and prognosis of adult acute myeloid leukemia with internal tandem duplications in the Flt3 gene. Leukemia. 14:675–683CrossRef Rombouts WJ, Blokland I, Lowenberg B et al (2000) Biological characteristics and prognosis of adult acute myeloid leukemia with internal tandem duplications in the Flt3 gene. Leukemia. 14:675–683CrossRef
4.
go back to reference Dӧhner H, Estey E, Grimwade D et al (2017) Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 129:424–447CrossRef Dӧhner H, Estey E, Grimwade D et al (2017) Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 129:424–447CrossRef
5.
go back to reference Bornhauser M, Illmer T, Schaich M et al (2007) Improved outcome after stem-cell transplantation in FLT3-ITD positive AML. Blood. 109:2264–2265CrossRef Bornhauser M, Illmer T, Schaich M et al (2007) Improved outcome after stem-cell transplantation in FLT3-ITD positive AML. Blood. 109:2264–2265CrossRef
6.
go back to reference Lin PH, Lin CC, Yang HI, Li LY, Bai LY, Chiu CF, Liao YM, Lin CY, Hsieh CY, Lin CY, Ho CM, Yang SF, Peng CT, Tsai FJ, Yeh SP (2013) Prognostic impact of allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia patients with internal tandem duplication of FLT3. Leuk Res 37:287–292CrossRef Lin PH, Lin CC, Yang HI, Li LY, Bai LY, Chiu CF, Liao YM, Lin CY, Hsieh CY, Lin CY, Ho CM, Yang SF, Peng CT, Tsai FJ, Yeh SP (2013) Prognostic impact of allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia patients with internal tandem duplication of FLT3. Leuk Res 37:287–292CrossRef
7.
go back to reference Gale RE, Hills R, Kottaridis PD et al (2005) 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. 106:5658–5665 Gale RE, Hills R, Kottaridis PD et al (2005) 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. 106:5658–5665
8.
go back to reference Brunet S, Labopin M, Esteve J, Cornelissen J, Socié G, Iori AP, Verdonck LF, Volin L, Gratwohl A, Sierra J, Mohty M, Rocha V (2012) 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 30:735–741CrossRef Brunet S, Labopin M, Esteve J, Cornelissen J, Socié G, Iori AP, Verdonck LF, Volin L, Gratwohl A, Sierra J, Mohty M, Rocha V (2012) 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 30:735–741CrossRef
9.
go back to reference Gaballa S, Saliba R, Oran B, Brammer JE, Chen J, Rondon G, Alousi AM, Kebriaei P, Marin D, Popat UR, Andersson BS, Shpall EJ, Jabbour E, Daver N, Andreeff M, Ravandi F, Cortes J, Patel K, Champlin RE, Ciurea SO (2017) Relapse risk and survival in patients with FLT3 mutated acute myeloid leukemia undergoing stem cell transplantation. Am J Hematol 92:331–337CrossRef Gaballa S, Saliba R, Oran B, Brammer JE, Chen J, Rondon G, Alousi AM, Kebriaei P, Marin D, Popat UR, Andersson BS, Shpall EJ, Jabbour E, Daver N, Andreeff M, Ravandi F, Cortes J, Patel K, Champlin RE, Ciurea SO (2017) Relapse risk and survival in patients with FLT3 mutated acute myeloid leukemia undergoing stem cell transplantation. Am J Hematol 92:331–337CrossRef
10.
go back to reference Huang Q, Chen W, Gaal KK et al A rapid, one step assay for simultaneous detection of FLT3/ITD and NPM1 mutations in AML with normal cytogenetics. Br J Haematol 142:489–492 Huang Q, Chen W, Gaal KK et al A rapid, one step assay for simultaneous detection of FLT3/ITD and NPM1 mutations in AML with normal cytogenetics. Br J Haematol 142:489–492
11.
go back to reference Dohner H, Estey EH, Amadori S et al (2010) Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood. 115:453–474CrossRef Dohner H, Estey EH, Amadori S et al (2010) Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood. 115:453–474CrossRef
12.
go back to reference Ma Y, Wu Y, Shen Z et al (2015) Is allogeneic transplantation really the best treatment for FLT3/ITD-positive acute myeloid leukemia? A systemic review. Clin Transpl 29:149–160CrossRef Ma Y, Wu Y, Shen Z et al (2015) Is allogeneic transplantation really the best treatment for FLT3/ITD-positive acute myeloid leukemia? A systemic review. Clin Transpl 29:149–160CrossRef
13.
go back to reference DeZern AE, Sung A, Kim S, Smith BD, Karp JE, Gore SD, Jones RJ, Fuchs E, Luznik L, McDevitt M, Levis M (2011) 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 17:1404–1409CrossRef DeZern AE, Sung A, Kim S, Smith BD, Karp JE, Gore SD, Jones RJ, Fuchs E, Luznik L, McDevitt M, Levis M (2011) 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 17:1404–1409CrossRef
14.
go back to reference Oran B, Cortes J, Beitinjaneh A, Chen HC, de Lima M, Patel K, Ravandi F, Wang X, Brandt M, Andersson BS, Ciurea S, Santos FP, de Padua Silva L, Shpall EJ, Champlin RE, Kantarjian H, Borthakur G (2016) Allogeneic transplantation in first remission improves outcomes irrespective of FLT3-ITD allelic ratio in FLT3-ITD-positive acute myelogenous leukemia. Biol Blood Marrow Transplant 22:1218–1226CrossRef Oran B, Cortes J, Beitinjaneh A, Chen HC, de Lima M, Patel K, Ravandi F, Wang X, Brandt M, Andersson BS, Ciurea S, Santos FP, de Padua Silva L, Shpall EJ, Champlin RE, Kantarjian H, Borthakur G (2016) Allogeneic transplantation in first remission improves outcomes irrespective of FLT3-ITD allelic ratio in FLT3-ITD-positive acute myelogenous leukemia. Biol Blood Marrow Transplant 22:1218–1226CrossRef
15.
go back to reference Nazha A, Cortes J, Faderl S, Pierce S, Daver N, Kadia T, Borthakur G, Luthra R, Kantarjian H, Ravandi F (2012) Activating internal tandem duplication mutations of the fms-like tyrosine kinase-3 (FLT3-ITD) at complete remission and relapse in patients with acute myeloid leukemia. Haematologica. 97:1242–1245CrossRef Nazha A, Cortes J, Faderl S, Pierce S, Daver N, Kadia T, Borthakur G, Luthra R, Kantarjian H, Ravandi F (2012) Activating internal tandem duplication mutations of the fms-like tyrosine kinase-3 (FLT3-ITD) at complete remission and relapse in patients with acute myeloid leukemia. Haematologica. 97:1242–1245CrossRef
16.
go back to reference Grunwald MR, Tseng LH, Lin MT et al (2004) Improved FLT3/ITD PCR assay predicts outcome following allogenic transplant for AML. Biol Blood Marrow Transplant 20:1989–1995CrossRef Grunwald MR, Tseng LH, Lin MT et al (2004) Improved FLT3/ITD PCR assay predicts outcome following allogenic transplant for AML. Biol Blood Marrow Transplant 20:1989–1995CrossRef
17.
go back to reference Zhao X, Wang Z, Ruan G, Liu Y, Wang Y, Zhang X, Xu L, Huang X, Chang Y (2018) Impact of pre-transplantation minimal residual disease determined by multiparameter flow cytometry on the outcome of AML patients with FLT3-ITD after allogeneic stem cell transplantation. Ann Hematol 97:967–975CrossRef Zhao X, Wang Z, Ruan G, Liu Y, Wang Y, Zhang X, Xu L, Huang X, Chang Y (2018) Impact of pre-transplantation minimal residual disease determined by multiparameter flow cytometry on the outcome of AML patients with FLT3-ITD after allogeneic stem cell transplantation. Ann Hematol 97:967–975CrossRef
18.
go back to reference Stone RM, Mandrekar SJ, Sanford BL, Laumann K, Geyer S, Bloomfield CD, Thiede C, Prior TW, Döhner K, Marcucci G, Lo-Coco F, Klisovic RB, Wei A, Sierra J, Sanz MA, Brandwein JM, de Witte T, Niederwieser D, Appelbaum FR, Medeiros BC, Tallman MS, Krauter J, Schlenk RF, Ganser A, Serve H, Ehninger G, Amadori S, Larson RA, Döhner H (2017) Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med 377:454–464CrossRef Stone RM, Mandrekar SJ, Sanford BL, Laumann K, Geyer S, Bloomfield CD, Thiede C, Prior TW, Döhner K, Marcucci G, Lo-Coco F, Klisovic RB, Wei A, Sierra J, Sanz MA, Brandwein JM, de Witte T, Niederwieser D, Appelbaum FR, Medeiros BC, Tallman MS, Krauter J, Schlenk RF, Ganser A, Serve H, Ehninger G, Amadori S, Larson RA, Döhner H (2017) Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med 377:454–464CrossRef
19.
go back to reference Bazarbachi A, Labopin M, Battipaglia G et al (2019) Allogeneic stem cell transplantation for FLT3-mutated acute myeloid leukemia: in vivo T-cell depletion and posttransplant sorafenib maintenance improve survival. A retrospective acute leukemia working party- European Society for Blood and Marrow Transplant Study. Clin Hematol Int 1:58–74CrossRef Bazarbachi A, Labopin M, Battipaglia G et al (2019) Allogeneic stem cell transplantation for FLT3-mutated acute myeloid leukemia: in vivo T-cell depletion and posttransplant sorafenib maintenance improve survival. A retrospective acute leukemia working party- European Society for Blood and Marrow Transplant Study. Clin Hematol Int 1:58–74CrossRef
20.
go back to reference Maziarz RT, Patnaik MM, Scott BL, et al. (2018) Radius: a phase 2 randomized trial investigating standard of care +/− midostaurin after allogeneic stem cell transplantation in FLT3/ITD-mutated AML. 60th ASH Annual Meeting and Exposition, San Diego, CA. Abstract 633 Maziarz RT, Patnaik MM, Scott BL, et al. (2018) Radius: a phase 2 randomized trial investigating standard of care +/− midostaurin after allogeneic stem cell transplantation in FLT3/ITD-mutated AML. 60th ASH Annual Meeting and Exposition, San Diego, CA. Abstract 633
21.
go back to reference Burchert A, Bug G, Finke J, et al. (2018) Sorafenib as maintenance therapy post allogeneic stem cell transplantation for FLT3-ITD positive AML: results from the randomized, double-blind, placebo-controlled multicenter Sormain Trial. . 60th ASH Annual Meeting and Exposition, San Diego, CA. Abstract 661 Burchert A, Bug G, Finke J, et al. (2018) Sorafenib as maintenance therapy post allogeneic stem cell transplantation for FLT3-ITD positive AML: results from the randomized, double-blind, placebo-controlled multicenter Sormain Trial. . 60th ASH Annual Meeting and Exposition, San Diego, CA. Abstract 661
22.
go back to reference Di Stasi A, Milton DR, Poon LM et al (2014) Similar transplantation outcome for acute myeloid leukemia and myelodysplastic syndrome patients with haploidentical versus 10/10 human leukocyte antigen-matched unrelated and related donors. Biol Blood Marrow Transplant 20:1975–1981CrossRef Di Stasi A, Milton DR, Poon LM et al (2014) Similar transplantation outcome for acute myeloid leukemia and myelodysplastic syndrome patients with haploidentical versus 10/10 human leukocyte antigen-matched unrelated and related donors. Biol Blood Marrow Transplant 20:1975–1981CrossRef
23.
go back to reference Fleischmann M, Schnetzke U, Schrenk KG, Schmidt V, Sayer HG, Hilgendorf I, Hochhaus A, Scholl S (2017) Outcome of FLT3-ITD-positive acute myeloid leukemia: impact of allogeneic stem cell transplantation and tyrosine kinase inhibitor treatment. J Cancer Res Clin Oncol 143:337–345CrossRef Fleischmann M, Schnetzke U, Schrenk KG, Schmidt V, Sayer HG, Hilgendorf I, Hochhaus A, Scholl S (2017) Outcome of FLT3-ITD-positive acute myeloid leukemia: impact of allogeneic stem cell transplantation and tyrosine kinase inhibitor treatment. J Cancer Res Clin Oncol 143:337–345CrossRef
24.
go back to reference Poire X, Labopin M, Polge E et al (2018) 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. Haematologica. 103:256–265CrossRef Poire X, Labopin M, Polge E et al (2018) 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. Haematologica. 103:256–265CrossRef
Metadata
Title
Pre-transplant FLT3/ITD status predicts outcome in FLT3-mutated acute myeloid leukemia following allogeneic stem cell transplantation
Authors
Grzegorz Helbig
Anna Koclęga
Agata Wieczorkiewicz-Kabut
Krzysztof Woźniczka
Anna Kopińska
Kinga Boral
Iwona Grygoruk-Wiśniowska
Małgorzata Stachowicz
Agnieszka Karolczyk
Publication date
01-08-2020
Publisher
Springer Berlin Heidelberg
Published in
Annals of Hematology / Issue 8/2020
Print ISSN: 0939-5555
Electronic ISSN: 1432-0584
DOI
https://doi.org/10.1007/s00277-020-04026-1

Other articles of this Issue 8/2020

Annals of Hematology 8/2020 Go to the issue
Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.