Allogeneic hematopoietic stem cell transplantation at the first remission for younger adults with  FLT3 ‐internal tandem duplication AML: The JALSG AML209‐FLT3‐SCT study

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Abstract

In this phase II multicenter study (JALSG AML209‐FLT3‐SCT), we aimed to prospectively elucidate the role of allogeneic hematopoietic stem cell transplantation (allo‐HSCT) at first complete remission (CR1) for FLT3‐internal tandem duplication (ITD)‐positive AML. Newly diagnosed de novo AML patients with FLT3‐ITD were enrolled at the achievement of CR1 and received allo‐HSCT as soon as possible after the first consolidation therapy. Mutations of 57 genes in AML cells at diagnosis were also analyzed. Among 48 eligible patients with a median age of 38.5 (17‐49) years, 36 (75%) received allo‐HSCT at a median of 108 days after CR1. The median follow‐up was 1726 days. The primary end‐point, 3‐year disease‐free survival (DFS) based on an intent to treat analysis, was 43.8% (95% confidence interval [CI], 30%‐57%), suggesting the efficacy of this treatment because the lower limit of the 95% CI exceeded the threshold response rate of 20%. The 3‐year overall survival, post‐transplant DFS, and non‐relapse mortality rates were 54.2% (95% CI, 39%‐67%), 58.3% (95% CI, 41%‐72%), and 25.0% (95% CI, 12%‐40%), respectively. The median ITD allelic ratio (AR) was 0.344 (0.006‐4.099). Neither FLT3‐ITD AR nor cooccurring genetic alterations was associated with a poor DFS. This prospective study indicated the efficacy and safety of allo‐HSCT for FLT3‐ITD AML patients in CR1. This study was registered at: www.umin.ac.jp/ctr/ as #UMIN000003433.

Abstract

Kaplan‐Meier estimates of disease‐free survival (A) and overall survival (B) in 48 AML patients with FLT3 internal tandem duplication.

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Most cited references 32

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Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia.

Richard F Schlenk, Konstanze Döhner, Jürgen Krauter … (2008)

Mutations occur in several genes in cytogenetically normal acute myeloid leukemia (AML) cells: the nucleophosmin gene (NPM1), the fms-related tyrosine kinase 3 gene (FLT3), the CCAAT/enhancer binding protein alpha gene (CEPBA), the myeloid-lymphoid or mixed-lineage leukemia gene (MLL), and the neuroblastoma RAS viral oncogene homolog (NRAS). We evaluated the associations of these mutations with clinical outcomes in patients. We compared the mutational status of the NPM1, FLT3, CEBPA, MLL, and NRAS genes in leukemia cells with the clinical outcome in 872 adults younger than 60 years of age with cytogenetically normal AML. Patients had been entered into one of four trials of therapy for AML. In each study, patients with an HLA-matched related donor were assigned to undergo stem-cell transplantation. A total of 53% of patients had NPM1 mutations, 31% had FLT3 internal tandem duplications (ITDs), 11% had FLT3 tyrosine kinase-domain mutations, 13% had CEBPA mutations, 7% had MLL partial tandem duplications (PTDs), and 13% had NRAS mutations. The overall complete-remission rate was 77%. The genotype of mutant NPM1 without FLT3-ITD, the mutant CEBPA genotype, and younger age were each significantly associated with complete remission. Of the 663 patients who received postremission therapy, 150 underwent hematopoietic stem-cell transplantation from an HLA-matched related donor. Significant associations were found between the risk of relapse or the risk of death during complete remission and the leukemia genotype of mutant NPM1 without FLT3-ITD (hazard ratio, 0.44; 95% confidence interval [CI], 0.32 to 0.61), the mutant CEBPA genotype (hazard ratio, 0.48; 95% CI, 0.30 to 0.75), and the MLL-PTD genotype (hazard ratio, 1.56; 95% CI, 1.00 to 2.43), as well as receipt of a transplant from an HLA-matched related donor (hazard ratio, 0.60; 95% CI, 0.44 to 0.82). The benefit of the transplant was limited to the subgroup of patients with the prognostically adverse genotype FLT3-ITD or the genotype consisting of wild-type NPM1 and CEBPA without FLT3-ITD. Genotypes defined by the mutational status of NPM1, FLT3, CEBPA, and MLL are associated with the outcome of treatment for patients with cytogenetically normal AML. Copyright 2008 Massachusetts Medical Society.

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Differential impact of allelic ratio and insertion site in FLT3-ITD-positive AML with respect to allogeneic transplantation.

Richard F Schlenk, Sabine Kayser, Lars Bullinger … (2014)

The objective was to evaluate the prognostic and predictive impact of allelic ratio and insertion site (IS) of internal tandem duplications (ITDs), as well as concurrent gene mutations, with regard to postremission therapy in 323 patients with FLT3-ITD-positive acute myeloid leukemia (AML). Increasing FLT3-ITD allelic ratio (P = .004) and IS in the tyrosine kinase domain 1 (TKD1, P = .06) were associated with low complete remission (CR) rates. After postremission therapy including intensive chemotherapy (n = 121) or autologous hematopoietic stem cell transplantation (HSCT, n = 17), an allelic ratio ≥ 0.51 was associated with an unfavorable relapse-free (RFS, P = .0008) and overall survival (OS, P = .004); after allogeneic HSCT (n = 93), outcome was significantly improved in patients with a high allelic ratio (RFS, P = .02; OS, P = .03), whereas no benefit was seen in patients with a low allelic ratio (RFS, P = .38; OS, P = .64). Multivariable analyses revealed a high allelic ratio as a predictive factor for the beneficial effect of allogeneic HSCT; ITD IS in TKD1 remained an unfavorable factor, whereas no prognostic impact of concurrent gene mutations was observed. The clinical trials described herein were previously published or are registered as follows: AMLHD93 and AMLHD98A, previously published; AML SG 07-04, ClinicalTrials.gov identifier #NCT00151242. © 2014 by The American Society of Hematology.

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Prognostic implication of FLT3 and N-RAS gene mutations in acute myeloid leukemia.

C Shimazaki, S Yokota, T Naoe … (1999)

Internal tandem duplication of the FLT3 gene and point mutations of the N-RAS gene are the most frequent somatic mutations causing aberrant signal-transduction in acute myeloid leukemia (AML). However, their prognostic importance is unclear. In this study, their prognostic significance was analyzed in 201 newly diagnosed patients with de novo AML except acute promyelocytic leukemia. Three patients had mutations in both genes, 43 had only the FLT3 gene mutation, 25 had only the N-RAS gene mutation, and 130 had neither. These mutations seemed to occur independently. Both mutations were related to high peripheral white blood cell counts, and the FLT3 gene mutation was infrequently observed in the French-American-British (FAB)-M2 type. AML cases with wild FLT3/mutant N-RAS had a lower complete remission (CR) rate than those with wild FLT3/wild N-RAS, whereas the presence of mutant FLT3 did not affect the CR rate. Univariate analysis showed that unfavorable prognostic factors for overall survival were age 60 years or older (P =.0002), cytogenetic data (P =.002), FAB types other than M2 (P =.002), leukocytosis over 100 +/- 10(9)/L (P =.003), and the FLT3 gene mutation (P =.004). However, the N-RAS gene mutation was only a marginal prognostic factor (P =.06). For the subjects under 60 years old, multivariate analysis showed that the FLT3 gene mutation was the strongest prognostic factor (P =.008) for overall survival. The FLT3 gene mutation, whose presence is detectable only by genomic polymerase chain reaction amplification and gel electrophoresis, might serve as an important molecular marker to predict the prognosis of patients with AML.

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Author and article information

Contributors

Hitoshi Kiyoi:

ORCID: https://orcid.org/0000-0001-6382-9498

kiyoi@med.nagoya-u.ac.jp

Journal

Journal ID (nlm-ta): Cancer Sci

Journal ID (iso-abbrev): Cancer Sci

Journal ID (doi): 10.1111/(ISSN)1349-7006

Journal ID (publisher-id): CAS

Title: Cancer Science

Publisher: John Wiley and Sons Inc. (Hoboken )

ISSN (Print): 1347-9032

ISSN (Electronic): 1349-7006

Publication date (Electronic): 29 May 2020

Publication date (Print): July 2020

Volume: 111

Issue: 7 ( doiID: 10.1111/cas.v111.7 )

Pages: 2472-2481

Affiliations

[ ¹ ] Department of Hematology and Oncology Nagoya University Graduate School of Medicine Nagoya Japan

[ ² ] Japanese Data Center for Hematopoietic Cell Transplantation Nagoya Japan

[ ³ ] Department of Hematology and Oncology Anjo Kosei Hospital Anjo Japan

[ ⁴ ] Department of Hematology Japanese Red Cross Nagoya First Hospital Nagoya Japan

[ ⁵ ] Department of Hematology Nakagami Hospital Okinawa Japan

[ ⁶ ] Department of Hematology and Oncology JA Aichi Konan Kosei Hospital Konan Japan

[ ⁷ ] Department of Hematology Fujita Health University School of Medicine Toyoake Japan

[ ⁸ ] Department of Hemato‐Oncology International Medical Center Saitama Medical University Hidaka Japan

[ ⁹ ] Department of Hematology Chiba University Hospital Chiba Japan

[ ¹⁰ ] Department of Hematology NTT Medical Center Tokyo Tokyo Japan

[ ¹¹ ] Department of Hematology and Clinical Immunology Yokohama City University Hospital Yokohama Japan

[ ¹² ] Department of Hematology Kanagawa Cancer Center Yokohama Japan

[ ¹³ ] The Division of Medical Oncology and Hematology Department of Medicine Kobe University Hospital Kobe Japan

[ ¹⁴ ] Department of Hematology and Oncology Japanese Red Cross Nagoya Daini Hospital Nagoya Japan

[ ¹⁵ ] Kanazawa University Kanazawa Japan

[ ¹⁶ ] Department of Hematology and Rheumatology Faculty of Medicine Kindai University Osaka Japan

[ ¹⁷ ] Department of Hematology Atomic Bomb Disease Institute Nagasaki University Graduate School of Biomedical Sciences Nagasaki Japan

[ ¹⁸ ] Department of Hematology National Hospital Organization Nagoya Medical Center Nagoya Japan

Author notes

[*] [* ] Correspondence

Hitoshi Kiyoi, Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Email: kiyoi@ 123456med.nagoya-u.ac.jp

Author information

Shigeki Ohtake https://orcid.org/0000-0003-0112-6564

Itaru Matsumura https://orcid.org/0000-0003-2818-4270

Hitoshi Kiyoi https://orcid.org/0000-0001-6382-9498

Article

Publisher ID: CAS14448

DOI: 10.1111/cas.14448

PMC ID: 7484840

PubMed ID: 32391628

SO-VID: 64c507ac-9ad0-4c4d-9266-1a13524d75b8

License:

This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

History

Date received : 27 January 2020

Date revision received : 16 April 2020

Date accepted : 03 May 2020

Page count

Figures: 5, Tables: 2, Pages: 10, Words: 7298

Funding

Funded by: Japan Agency for Medical Research and Development , open-funder-registry 10.13039/100009619;

Award ID: 19ck0106251

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source-schema-version-number 2.0

cover-date July 2020

details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_JATSPMC version:5.9.0 mode:remove_FC converted:11.09.2020

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: acute myeloid leukemia,allogeneic hematopoietic stem cell transplantation,flt3‐itd

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: acute myeloid leukemia, allogeneic hematopoietic stem cell transplantation, flt3‐itd

Allogeneic hematopoietic stem cell transplantation at the first remission for younger adults with FLT3‐internal tandem duplication AML: The JALSG AML209‐FLT3‐SCT study

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Most cited references 32

Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia.

Differential impact of allelic ratio and insertion site in FLT3-ITD-positive AML with respect to allogeneic transplantation.

Prognostic implication of FLT3 and N-RAS gene mutations in acute myeloid leukemia.

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