Allogeneic Transplantation in First Remission Improves Outcomes Irrespective of FLT3-ITD Allelic Ratio in FLT3-ITD-Positive Acute Myelogenous Leukemia

Betül Oran, Jorge Cortes, Amer Beitinjaneh, Hsiang Chun Chen, Marcos de Lima, Keyur Patel, Farhad Ravandi, Xuemei Wang, Mark Brandt, Borje S. Andersson, Stefan Ciurea, Fabio P. Santos, Leandro de Padua Silva, Elizabeth J. Shpall, Richard E. Champlin, Hagop Kantarjian, Gautam Borthakur

Research output: Contribution to journalArticle

Abstract

The adverse prognosis of internal tandem duplication in the FMS-like tyrosine kinase 3 gene(s) (FLT3-ITD) in patients with acute myelogenous leukemia (AML) may depend on allelic burden. We compared postremission treatment with chemotherapy and hematopoietic stem cell transplantation (HSCT) in 169 FLT3-ITDmut intermediate cytogenetic risk AML patients with allelic ratio evaluable at diagnosis who achieved first complete remission (CR1) with induction therapy. To minimize selection bias, the analysis was limited to patients who remained in CR1 for at least 4 months (median time to HSCT) after achieving CR1, and propensity score matching was implemented. Sensitivity analysis including patients who remained in CR1 for at least 3 months was applied as well. HSCT in CR1 was associated with longer relapse-free survival (RFS) and overall survival (OS), with 3-year estimated rates of 18% and 24%, respectively (P < .001), for patients receiving chemotherapy and 46% and 54%, respectively (P < .001), for those undergoing HSCT. Multivariate regression models showed that HSCT remained statistically significant with improved RFS and OS independent of FLT3-ITD allelic ratio and NPM1 status. Irrespective of postremission therapy, relapse remains the main reason for treatment failure, with a 3-year incidence of 68% in chemotherapy recipients versus 41% in HSCT recipients. Allogeneic HSCT improved disease outcomes compared with chemotherapy after propensity score matching was applied. The improvement observed for RFS (hazard ratio [HR], 0.55; P = .09) and OS (HR, 0.58; P = .10) with HSCT as postremission therapy in patients who remained in CR1 for at least 4 months did not reach statistical significance; however, the sensitivity analyses including patients who remained in CR1 for at least 3 months showed significant improvement in both RFS (HR, 0.31; P = .002) and OS (HR, 0.27; P = .02) after propensity score matching. Our results indicate that HSCT in CR1 for AML FLT3-ITDmut patients is associated with longer RFS and OS. Innovative transplantation strategies to improve relapse incidence are urgently needed.

Original languageEnglish (US)
Pages (from-to)1218-1226
Number of pages9
JournalBiology of Blood and Marrow Transplantation
Volume22
Issue number7
DOIs
StatePublished - Jul 1 2016
Externally publishedYes

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Homologous Transplantation
Hematopoietic Stem Cell Transplantation
Acute Myeloid Leukemia
Survival
Recurrence
Propensity Score
Drug Therapy
Selection Bias
Incidence
Therapeutics
Treatment Failure
Cytogenetics
Protein-Tyrosine Kinases
Transplantation

Keywords

  • Allogeneic stem cell transplantation
  • AML
  • FLT3-ITD mutation
  • Postremission therapy

ASJC Scopus subject areas

  • Hematology
  • Transplantation

Cite this

Allogeneic Transplantation in First Remission Improves Outcomes Irrespective of FLT3-ITD Allelic Ratio in FLT3-ITD-Positive Acute Myelogenous Leukemia. / Oran, Betül; Cortes, Jorge; Beitinjaneh, Amer; Chen, Hsiang Chun; de Lima, Marcos; Patel, Keyur; Ravandi, Farhad; Wang, Xuemei; Brandt, Mark; Andersson, Borje S.; Ciurea, Stefan; Santos, Fabio P.; de Padua Silva, Leandro; Shpall, Elizabeth J.; Champlin, Richard E.; Kantarjian, Hagop; Borthakur, Gautam.

In: Biology of Blood and Marrow Transplantation, Vol. 22, No. 7, 01.07.2016, p. 1218-1226.

Research output: Contribution to journalArticle

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', Biology of Blood and Marrow Transplantation, vol. 22, no. 7, pp. 1218-1226. https://doi.org/10.1016/j.bbmt.2016.03.027
Oran, Betül ; Cortes, Jorge ; Beitinjaneh, Amer ; Chen, Hsiang Chun ; de Lima, Marcos ; Patel, Keyur ; Ravandi, Farhad ; Wang, Xuemei ; Brandt, Mark ; Andersson, Borje S. ; Ciurea, Stefan ; Santos, Fabio P. ; de Padua Silva, Leandro ; Shpall, Elizabeth J. ; Champlin, Richard E. ; Kantarjian, Hagop ; Borthakur, Gautam. / Allogeneic Transplantation in First Remission Improves Outcomes Irrespective of FLT3-ITD Allelic Ratio in FLT3-ITD-Positive Acute Myelogenous Leukemia. In: Biology of Blood and Marrow Transplantation. 2016 ; Vol. 22, No. 7. pp. 1218-1226.
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abstract = "The adverse prognosis of internal tandem duplication in the FMS-like tyrosine kinase 3 gene(s) (FLT3-ITD) in patients with acute myelogenous leukemia (AML) may depend on allelic burden. We compared postremission treatment with chemotherapy and hematopoietic stem cell transplantation (HSCT) in 169 FLT3-ITDmut intermediate cytogenetic risk AML patients with allelic ratio evaluable at diagnosis who achieved first complete remission (CR1) with induction therapy. To minimize selection bias, the analysis was limited to patients who remained in CR1 for at least 4 months (median time to HSCT) after achieving CR1, and propensity score matching was implemented. Sensitivity analysis including patients who remained in CR1 for at least 3 months was applied as well. HSCT in CR1 was associated with longer relapse-free survival (RFS) and overall survival (OS), with 3-year estimated rates of 18{\%} and 24{\%}, respectively (P < .001), for patients receiving chemotherapy and 46{\%} and 54{\%}, respectively (P < .001), for those undergoing HSCT. Multivariate regression models showed that HSCT remained statistically significant with improved RFS and OS independent of FLT3-ITD allelic ratio and NPM1 status. Irrespective of postremission therapy, relapse remains the main reason for treatment failure, with a 3-year incidence of 68{\%} in chemotherapy recipients versus 41{\%} in HSCT recipients. Allogeneic HSCT improved disease outcomes compared with chemotherapy after propensity score matching was applied. The improvement observed for RFS (hazard ratio [HR], 0.55; P = .09) and OS (HR, 0.58; P = .10) with HSCT as postremission therapy in patients who remained in CR1 for at least 4 months did not reach statistical significance; however, the sensitivity analyses including patients who remained in CR1 for at least 3 months showed significant improvement in both RFS (HR, 0.31; P = .002) and OS (HR, 0.27; P = .02) after propensity score matching. Our results indicate that HSCT in CR1 for AML FLT3-ITDmut patients is associated with longer RFS and OS. Innovative transplantation strategies to improve relapse incidence are urgently needed.",
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AU - Oran, Betül

AU - Cortes, Jorge

AU - Beitinjaneh, Amer

AU - Chen, Hsiang Chun

AU - de Lima, Marcos

AU - Patel, Keyur

AU - Ravandi, Farhad

AU - Wang, Xuemei

AU - Brandt, Mark

AU - Andersson, Borje S.

AU - Ciurea, Stefan

AU - Santos, Fabio P.

AU - de Padua Silva, Leandro

AU - Shpall, Elizabeth J.

AU - Champlin, Richard E.

AU - Kantarjian, Hagop

AU - Borthakur, Gautam

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N2 - The adverse prognosis of internal tandem duplication in the FMS-like tyrosine kinase 3 gene(s) (FLT3-ITD) in patients with acute myelogenous leukemia (AML) may depend on allelic burden. We compared postremission treatment with chemotherapy and hematopoietic stem cell transplantation (HSCT) in 169 FLT3-ITDmut intermediate cytogenetic risk AML patients with allelic ratio evaluable at diagnosis who achieved first complete remission (CR1) with induction therapy. To minimize selection bias, the analysis was limited to patients who remained in CR1 for at least 4 months (median time to HSCT) after achieving CR1, and propensity score matching was implemented. Sensitivity analysis including patients who remained in CR1 for at least 3 months was applied as well. HSCT in CR1 was associated with longer relapse-free survival (RFS) and overall survival (OS), with 3-year estimated rates of 18% and 24%, respectively (P < .001), for patients receiving chemotherapy and 46% and 54%, respectively (P < .001), for those undergoing HSCT. Multivariate regression models showed that HSCT remained statistically significant with improved RFS and OS independent of FLT3-ITD allelic ratio and NPM1 status. Irrespective of postremission therapy, relapse remains the main reason for treatment failure, with a 3-year incidence of 68% in chemotherapy recipients versus 41% in HSCT recipients. Allogeneic HSCT improved disease outcomes compared with chemotherapy after propensity score matching was applied. The improvement observed for RFS (hazard ratio [HR], 0.55; P = .09) and OS (HR, 0.58; P = .10) with HSCT as postremission therapy in patients who remained in CR1 for at least 4 months did not reach statistical significance; however, the sensitivity analyses including patients who remained in CR1 for at least 3 months showed significant improvement in both RFS (HR, 0.31; P = .002) and OS (HR, 0.27; P = .02) after propensity score matching. Our results indicate that HSCT in CR1 for AML FLT3-ITDmut patients is associated with longer RFS and OS. Innovative transplantation strategies to improve relapse incidence are urgently needed.

AB - The adverse prognosis of internal tandem duplication in the FMS-like tyrosine kinase 3 gene(s) (FLT3-ITD) in patients with acute myelogenous leukemia (AML) may depend on allelic burden. We compared postremission treatment with chemotherapy and hematopoietic stem cell transplantation (HSCT) in 169 FLT3-ITDmut intermediate cytogenetic risk AML patients with allelic ratio evaluable at diagnosis who achieved first complete remission (CR1) with induction therapy. To minimize selection bias, the analysis was limited to patients who remained in CR1 for at least 4 months (median time to HSCT) after achieving CR1, and propensity score matching was implemented. Sensitivity analysis including patients who remained in CR1 for at least 3 months was applied as well. HSCT in CR1 was associated with longer relapse-free survival (RFS) and overall survival (OS), with 3-year estimated rates of 18% and 24%, respectively (P < .001), for patients receiving chemotherapy and 46% and 54%, respectively (P < .001), for those undergoing HSCT. Multivariate regression models showed that HSCT remained statistically significant with improved RFS and OS independent of FLT3-ITD allelic ratio and NPM1 status. Irrespective of postremission therapy, relapse remains the main reason for treatment failure, with a 3-year incidence of 68% in chemotherapy recipients versus 41% in HSCT recipients. Allogeneic HSCT improved disease outcomes compared with chemotherapy after propensity score matching was applied. The improvement observed for RFS (hazard ratio [HR], 0.55; P = .09) and OS (HR, 0.58; P = .10) with HSCT as postremission therapy in patients who remained in CR1 for at least 4 months did not reach statistical significance; however, the sensitivity analyses including patients who remained in CR1 for at least 3 months showed significant improvement in both RFS (HR, 0.31; P = .002) and OS (HR, 0.27; P = .02) after propensity score matching. Our results indicate that HSCT in CR1 for AML FLT3-ITDmut patients is associated with longer RFS and OS. Innovative transplantation strategies to improve relapse incidence are urgently needed.

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