Distinct clinico-biological features in AML patients with low allelic ratio FLT3-ITD: role of allogeneic stem cell transplantation in first remission

Tien, Feng‐Ming; Tsai, Chiao-Ling; Huang, Sheng‐Chuan; Liu, Jia-Hau; Chen, Chien-Yuan; Kuo, Yueh‐Hsiung; Chuang, Yi‐Kuang; Tseng, Mei‐Hsuan; Peng, Yuting; Liu, Ming-Chih; Liu, Chia-Wen; Liao, Xiu‐Wen; Lin, Liang-In; Wu, Yu-Sin; Hou, Mei-Fang; Wu, Shang‐Ju; Hsu, Szu-Chun; Ko, Bor‐Sheng; Chou, Wen‐Chien; Yao, Ming; Hou, Hsin‐An; Tang, Jih‐Luh; Tien, Hwei‐Fang

doi:10.1038/s41409-021-01454-z

Cited by 10 publications

(9 citation statements)

References 41 publications

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“…Second, among patients with intermediate-risk genotypes, FLT3-ITD high allelic ratio was significantly more prevalent among younger patients without MDS-R mutations than among those with MDS-R mutations (P = 0.033, Supplementary Table 2). Although all these patients had concurrent NPM1 mutations, their prognosis might still be worse than that of patients with wild-type NPM1 and FLT3, as reported previously [24,25]. Furthermore, because of the enrollment timeframe, many patients with FLT3-ITD in our cohort did not receive FLT3 inhibitor treatment upfront, which also compromised their outcomes.…”

Section: − −mentioning

confidence: 66%

Poor prognostic implications of myelodysplasia-related mutations in both older and younger patients with de novo AML

Tsai

Sun

et al. 2023

Blood Cancer J.

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A set of myelodysplasia-related (MDS-R) gene mutations are incorporated into the 2022 European LeukemiaNet risk classification as adverse genetic factors for acute myeloid leukemia (AML) based on their poor prognostic impact on older patients. The impact of these mutations on younger patients (age < 60 years) remains elusive. In the study of 1213 patients with de novo non-M3 AML, we identified MDS-R mutations in 32.7% of the total cohort, 44.9% of older patients and 23.4% of younger patients. The patients with MDS-R mutations had a significantly lower complete remission rate in both younger and older age groups. With a median follow-up of 9.2 years, the MDS-R group experienced shorter overall survival (P = 0.034 for older and 0.035 for younger patients) and event-free survival (P = 0.004 for older and 0.042 for younger patients). Furthermore, patients with MDS-R mutations more frequently harbored measurable residual disease that was detectable using next generation sequencing at morphological CR than those without MDS-R mutations. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) might ameliorate the negative impact of MDS-R mutations. In summary, AML patients with MDS-R mutations have significantly poorer outcomes regardless of age. More intensive treatment, such as allo-HSCT and/or novel therapies, is warranted for AML patients with MDS-R mutations.

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Section: − −mentioning

confidence: 66%

Poor prognostic implications of myelodysplasia-related mutations in both older and younger patients with de novo AML

Tsai

Sun

et al. 2023

Blood Cancer J.

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“…Cytogenetic analyses were performed as described previously and interpreted according to the International System for Human Cytogenetic Nomenclature 26,27 . TruSight myeloid sequencing panel (Illumina, San Diego, CS, USA) and the HiSeq platform (Illumina, San Diego, CA, USA) were adopted to analyze the gene alterations and mutant allele burdens of 54 myeloid‐neoplasm relevant genes 28 (Table S1), as previously described 13,29 . The library preparation and sequencing were performed in accordance with the manufacturer's instructions.…”

Section: Methodsmentioning

confidence: 99%

“…26,27 TruSight myeloid sequencing panel (Illumina, San Diego, CS, USA) and the HiSeq platform (Illumina, San Diego, CA, USA) were adopted to analyze the gene alterations and mutant allele burdens of 54 myeloid-neoplasm relevant genes 28 (Table S1), as previously described. 13,29 The library preparation and sequencing were performed in accordance with the manufacturer's instructions. The median reading depth was 10 550x.…”

Section: Methodsmentioning

confidence: 99%

Effect of mutation allele frequency on the risk stratification of myelodysplastic syndrome patients

et al. 2022

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Myelodysplastic syndrome (MDS) is a heterogeneous group of clonal myeloid malignancies. Though several recurrent mutations are closely correlated with clinical outcomes, data concerning the association between mutation variant allele frequencies (VAF) and prognosis are limited. In this study, we performed comprehensive VAF analyses of relevant myeloid-malignancy related mutations in 698 MDS patients and correlated the results with their prognosis. Mutation VAF in DNMT3A, TET2, ASXL1, EZH2, SETBP1, BCOR, SFSF2, ZRSR2, and TP53 mutations correlated with outcomes.In multivariable analysis, DNMT3A and ZRSR2 mutations with high VAF and mutant IDH2, CBL, U2AF1, and TP53 were independent poor prognostic factors for overall survival. A substantial portion of patients in each revised International Prognostic Scoring System (IPSS-R) risk group could be adjusted to different prognostic groups based on the integrated VAF and mutational profiles. Patients with these unfavorable mutations in each IPSS-R risk subgroup had survivals worse than other patients of the same risk but similar to those in the next higher-risk subgroup. Furthermore, patients harboring U2AF1 mutation might benefit from hypomethylating agents. This study demonstrated the critical role of VAF of mutations for risk stratification in MDS patients and may be incorporated in novel scoring systems.

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“…22,24 While the data are less convincing for alloHCT in those with low allelic ratio (<0.5, FLT3-ITD low ), it is still common practice to perform allogeneic transplants following first remission in eligible patients, regardless of cytogenetic risk group, concurrent mutations, or negative minimal residual disease (MRD). 25 Other factors impacting relapse risk and survival in patients with FLT3-ITD AML include the presence of increased ITD fragment length or measurable residual disease by FLT3 sequencing prior to alloHCT. [26][27][28][29] FLT3-TKD mutations may have less influence on overall survival (OS) and disease-free survival; however, there is a suggestion this may differ among ethnicities, with more favorable outcomes in Asian patients compared to Caucasians.…”

Section: Prognostic Impact Of Flt3-itd Amlmentioning

confidence: 99%

FLT3 Inhibitors as Maintenance Therapy after Allogeneic Stem-Cell Transplantation

Blackmon¹,

Aldoss²,

Ball³

2022

BLCTT

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Mutations in the FLT3 gene are associated with poor prognosis in patients with AML, even after consolidation with allogeneic hematopoietic cell transplantation (alloHCT) in first remission. Treatment failure in FLT3 -mutated AML is largely driven by excessive risk of relapse compared to other genetic subtypes, including in patients post-alloHCT. As a result, there is substantial interest in studying posttransplant maintenance therapy in FLT3 -mutated AML as an approach to optimize disease control and improve long-term outcomes. Clinical trials utilizing posttransplant FLT3 inhibitors, such as sorafenib and midostaurin, have shown feasibility, safety, and encouraging posttransplant outcomes, and there are ongoing studies using newer-generation tyrosine-kinase inhibitors as posttransplant maintenance therapy. Here, we review the toxicities and efficacy of FLT3 inhibitors as posttransplant maintenance, recommendations on the use of FLT3 inhibitors by international consensus guidelines, and highlight key remaining questions.

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Distinct clinico-biological features in AML patients with low allelic ratio FLT3-ITD: role of allogeneic stem cell transplantation in first remission

Cited by 10 publications

References 41 publications

Poor prognostic implications of myelodysplasia-related mutations in both older and younger patients with de novo AML

Poor prognostic implications of myelodysplasia-related mutations in both older and younger patients with de novo AML

Effect of mutation allele frequency on the risk stratification of myelodysplastic syndrome patients

FLT3 Inhibitors as Maintenance Therapy after Allogeneic Stem-Cell Transplantation

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