Monitoring of fusion gene transcripts to predict relapse in pediatric acute myeloid leukemia

Hidemasa Matsuo, Yuka Iijima-Yamashita, Miho Yamada, Takao Deguchi, Nobutaka Kiyokawa, Akira Shimada, Akio Tawa, Daisuke Tomizawa, Takashi Taga, Akitoshi Kinoshita, Souichi Adachi, Keizo Horibe

Research output: Contribution to journalArticle

Abstract

Background: In acute myeloid leukemia (AML), accurate detection of minimal residual disease (MRD) enables better risk-stratified therapy. There are few studies, however, on the monitoring of multiple fusion transcripts and evaluation of their accuracy as indicators of MRD at multiple time points. Methods: We retrospectively examined RNA obtained from 82 pediatric AML patients enrolled in the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) AML-05 study. The expression of six important fusion transcripts (AML1(RUNX1)-ETO, CBFB-MYH11, MLL(KMT2A)-AF9, MLL-ELL, MLL-AF6, and FUS-ERG) was analyzed at five time points 30–40 days apart following diagnosis. Results: In patients with AML1-ETO (n = 36 at time point 5), all six patients with >3,000 copies and four of 30 patients with ≤3,000 copies relapsed. AML1-ETO transcripts persisted during treatment even in patients without relapse, as well as CBFB-MYH11 transcripts. In contrast, in patients with MLL-AF9 (n = 9 at time point 5), two patients were positive for MLL-AF9 expression (>50 copies) and both relapsed. Only one of seven MLL-AF9-negative patients relapsed. In the AML1-ETO group, MRD-positive patients (>3,000 copies at time point 5) had significantly lower relapse-free survival (RFS; P < 0.0001) and overall survival (OS; P = 0.009) than MRD-negative patients. Similarly, in the MLL-AF9 group, MRD-positive patients (>50 copies at time point 5) had significantly lower RFS (P = 0.002) and OS (P = 0.002) than MRD-negative patients. Conclusions: Detection of MLL-AF9 transcripts on real-time quantitative polymerase chain reaction is a promising marker of relapse in pediatric AML. In contrast, the clinical utility of detecting AML1-ETO and CBFB-MYH11 expression is limited, although higher AML1-ETO expression can be a potential predictor of relapse when assessed according to an optimal threshold.

Original languageEnglish
Pages (from-to)41-46
Number of pages6
JournalPediatrics International
Volume60
Issue number1
DOIs
Publication statusPublished - Jan 1 2018

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Gene Fusion
Acute Myeloid Leukemia
Pediatrics
Recurrence
Residual Neoplasm
Real-Time Polymerase Chain Reaction
Lymphoma
Leukemia
RNA
Survival

Keywords

  • acute myeloid leukemia
  • fusion gene
  • minimal residual disease
  • polymerase chain reaction
  • prognosis

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health

Cite this

Matsuo, H., Iijima-Yamashita, Y., Yamada, M., Deguchi, T., Kiyokawa, N., Shimada, A., ... Horibe, K. (2018). Monitoring of fusion gene transcripts to predict relapse in pediatric acute myeloid leukemia. Pediatrics International, 60(1), 41-46. https://doi.org/10.1111/ped.13440

Monitoring of fusion gene transcripts to predict relapse in pediatric acute myeloid leukemia. / Matsuo, Hidemasa; Iijima-Yamashita, Yuka; Yamada, Miho; Deguchi, Takao; Kiyokawa, Nobutaka; Shimada, Akira; Tawa, Akio; Tomizawa, Daisuke; Taga, Takashi; Kinoshita, Akitoshi; Adachi, Souichi; Horibe, Keizo.

In: Pediatrics International, Vol. 60, No. 1, 01.01.2018, p. 41-46.

Research output: Contribution to journalArticle

Matsuo, H, Iijima-Yamashita, Y, Yamada, M, Deguchi, T, Kiyokawa, N, Shimada, A, Tawa, A, Tomizawa, D, Taga, T, Kinoshita, A, Adachi, S & Horibe, K 2018, 'Monitoring of fusion gene transcripts to predict relapse in pediatric acute myeloid leukemia', Pediatrics International, vol. 60, no. 1, pp. 41-46. https://doi.org/10.1111/ped.13440
Matsuo, Hidemasa ; Iijima-Yamashita, Yuka ; Yamada, Miho ; Deguchi, Takao ; Kiyokawa, Nobutaka ; Shimada, Akira ; Tawa, Akio ; Tomizawa, Daisuke ; Taga, Takashi ; Kinoshita, Akitoshi ; Adachi, Souichi ; Horibe, Keizo. / Monitoring of fusion gene transcripts to predict relapse in pediatric acute myeloid leukemia. In: Pediatrics International. 2018 ; Vol. 60, No. 1. pp. 41-46.
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abstract = "Background: In acute myeloid leukemia (AML), accurate detection of minimal residual disease (MRD) enables better risk-stratified therapy. There are few studies, however, on the monitoring of multiple fusion transcripts and evaluation of their accuracy as indicators of MRD at multiple time points. Methods: We retrospectively examined RNA obtained from 82 pediatric AML patients enrolled in the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) AML-05 study. The expression of six important fusion transcripts (AML1(RUNX1)-ETO, CBFB-MYH11, MLL(KMT2A)-AF9, MLL-ELL, MLL-AF6, and FUS-ERG) was analyzed at five time points 30–40 days apart following diagnosis. Results: In patients with AML1-ETO (n = 36 at time point 5), all six patients with >3,000 copies and four of 30 patients with ≤3,000 copies relapsed. AML1-ETO transcripts persisted during treatment even in patients without relapse, as well as CBFB-MYH11 transcripts. In contrast, in patients with MLL-AF9 (n = 9 at time point 5), two patients were positive for MLL-AF9 expression (>50 copies) and both relapsed. Only one of seven MLL-AF9-negative patients relapsed. In the AML1-ETO group, MRD-positive patients (>3,000 copies at time point 5) had significantly lower relapse-free survival (RFS; P < 0.0001) and overall survival (OS; P = 0.009) than MRD-negative patients. Similarly, in the MLL-AF9 group, MRD-positive patients (>50 copies at time point 5) had significantly lower RFS (P = 0.002) and OS (P = 0.002) than MRD-negative patients. Conclusions: Detection of MLL-AF9 transcripts on real-time quantitative polymerase chain reaction is a promising marker of relapse in pediatric AML. In contrast, the clinical utility of detecting AML1-ETO and CBFB-MYH11 expression is limited, although higher AML1-ETO expression can be a potential predictor of relapse when assessed according to an optimal threshold.",
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T1 - Monitoring of fusion gene transcripts to predict relapse in pediatric acute myeloid leukemia

AU - Matsuo, Hidemasa

AU - Iijima-Yamashita, Yuka

AU - Yamada, Miho

AU - Deguchi, Takao

AU - Kiyokawa, Nobutaka

AU - Shimada, Akira

AU - Tawa, Akio

AU - Tomizawa, Daisuke

AU - Taga, Takashi

AU - Kinoshita, Akitoshi

AU - Adachi, Souichi

AU - Horibe, Keizo

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Background: In acute myeloid leukemia (AML), accurate detection of minimal residual disease (MRD) enables better risk-stratified therapy. There are few studies, however, on the monitoring of multiple fusion transcripts and evaluation of their accuracy as indicators of MRD at multiple time points. Methods: We retrospectively examined RNA obtained from 82 pediatric AML patients enrolled in the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) AML-05 study. The expression of six important fusion transcripts (AML1(RUNX1)-ETO, CBFB-MYH11, MLL(KMT2A)-AF9, MLL-ELL, MLL-AF6, and FUS-ERG) was analyzed at five time points 30–40 days apart following diagnosis. Results: In patients with AML1-ETO (n = 36 at time point 5), all six patients with >3,000 copies and four of 30 patients with ≤3,000 copies relapsed. AML1-ETO transcripts persisted during treatment even in patients without relapse, as well as CBFB-MYH11 transcripts. In contrast, in patients with MLL-AF9 (n = 9 at time point 5), two patients were positive for MLL-AF9 expression (>50 copies) and both relapsed. Only one of seven MLL-AF9-negative patients relapsed. In the AML1-ETO group, MRD-positive patients (>3,000 copies at time point 5) had significantly lower relapse-free survival (RFS; P < 0.0001) and overall survival (OS; P = 0.009) than MRD-negative patients. Similarly, in the MLL-AF9 group, MRD-positive patients (>50 copies at time point 5) had significantly lower RFS (P = 0.002) and OS (P = 0.002) than MRD-negative patients. Conclusions: Detection of MLL-AF9 transcripts on real-time quantitative polymerase chain reaction is a promising marker of relapse in pediatric AML. In contrast, the clinical utility of detecting AML1-ETO and CBFB-MYH11 expression is limited, although higher AML1-ETO expression can be a potential predictor of relapse when assessed according to an optimal threshold.

AB - Background: In acute myeloid leukemia (AML), accurate detection of minimal residual disease (MRD) enables better risk-stratified therapy. There are few studies, however, on the monitoring of multiple fusion transcripts and evaluation of their accuracy as indicators of MRD at multiple time points. Methods: We retrospectively examined RNA obtained from 82 pediatric AML patients enrolled in the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) AML-05 study. The expression of six important fusion transcripts (AML1(RUNX1)-ETO, CBFB-MYH11, MLL(KMT2A)-AF9, MLL-ELL, MLL-AF6, and FUS-ERG) was analyzed at five time points 30–40 days apart following diagnosis. Results: In patients with AML1-ETO (n = 36 at time point 5), all six patients with >3,000 copies and four of 30 patients with ≤3,000 copies relapsed. AML1-ETO transcripts persisted during treatment even in patients without relapse, as well as CBFB-MYH11 transcripts. In contrast, in patients with MLL-AF9 (n = 9 at time point 5), two patients were positive for MLL-AF9 expression (>50 copies) and both relapsed. Only one of seven MLL-AF9-negative patients relapsed. In the AML1-ETO group, MRD-positive patients (>3,000 copies at time point 5) had significantly lower relapse-free survival (RFS; P < 0.0001) and overall survival (OS; P = 0.009) than MRD-negative patients. Similarly, in the MLL-AF9 group, MRD-positive patients (>50 copies at time point 5) had significantly lower RFS (P = 0.002) and OS (P = 0.002) than MRD-negative patients. Conclusions: Detection of MLL-AF9 transcripts on real-time quantitative polymerase chain reaction is a promising marker of relapse in pediatric AML. In contrast, the clinical utility of detecting AML1-ETO and CBFB-MYH11 expression is limited, although higher AML1-ETO expression can be a potential predictor of relapse when assessed according to an optimal threshold.

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