Excess treatment reduction including anthracyclines results in higher incidence of relapse in core binding factor acute myeloid leukemia in children

Tomizawa, Daisuke; Tawa, Akio; Watanabe, Tetsu; Saito, Akiko; Kudo, Kazuko; Taga, Takashi; Iwamoto, Shotaro; Shimada, Akira; Terui, Kiminori; Moritake, Hiroshi; Kinoshita, Akitoshi; Takahashi, Hiroyuki; Nakayama, Hideki; Koh, Katsuyoshi; Kigasawa, Hisato; Kosaka, Yoshiyuki; Miyachi, Hayato; Horibe, Keizo; Nakahata, Tatsutoshi; Adachi, Souichi

doi:10.1038/leu.2013.153

Cited by 60 publications

(69 citation statements)

References 12 publications

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“…Core binding factor (CBF)‐AML patients were assigned to the low‐risk group; those with unfavorable cytogenetics (−7, 5q‐, t(16;21)(p11;q22), Philadelphia chromosome [Ph1], Fms‐like tyrosine kinase 3 ‐internal tandem duplications [ FLT3 ‐ITD]) and poor induction responders were assigned to the high‐risk group; the remaining patients were assigned to the intermediate‐risk group. Details of the patient disposition and treatment have been described previously . The study was conducted in accordance with the principles set down in the Declaration of Helsinki, and was approved by the Ethics Committees of all participating institutions.…”

Section: Methodsmentioning

confidence: 99%

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

Matsuo

Iijima-Yamashita

Yamada

et al. 2018

Pediatrics International

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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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Section: Methodsmentioning

confidence: 99%

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

Matsuo

Iijima-Yamashita

Yamada

et al. 2018

Pediatrics International

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“…Details of the patient disposition, treatment schedules and risk stratification have been described previously. 19, 20 In the present study, morphology was diagnosed prospectively using a central review system. Cytogenetic tests were performed in regional laboratories, but the reports were reviewed centrally.…”

Section: Methodsmentioning

confidence: 99%

Prognostic implications of CEBPA mutations in pediatric acute myeloid leukemia: a report from the Japanese Pediatric Leukemia/Lymphoma Study Group

Matsuo

Kajihara

Tomizawa

et al. 2014

Blood Cancer Journal

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CCAAT/enhancer-binding protein alpha (CEBPA) mutations are a favorable prognostic factor in adult acute myeloid leukemia (AML) patients; however, few studies have examined their significance in pediatric AML patients. Here we examined the CEBPA mutation status and clinical outcomes of pediatric AML patients treated in the AML-05 study. We found that 47 (14.9%) of the 315 evaluable patients harbored mutations in CEBPA; 26 cases (8.3%) harbored a single mutation (CEBPA-single) and 21 (6.7%) harbored double or triple mutations (CEBPA-double). After excluding core-binding factor-AML cases, patients harboring CEBPA mutations showed better overall survival (OS; P=0.048), but not event-free survival (EFS; P=0.051), than wild-type patients. Multivariate analysis identified CEBPA-single and CEBPA-double as independent favorable prognostic factors for EFS in the total cohort (hazard ratio (HR): 0.47 and 0.33; P=0.02 and 0.01, respectively). CEBPA-double was also an independent favorable prognostic factor for OS (HR: 0.30; P=0.04). CEBPA-double remained an independent favorable factor for EFS (HR: 0.28; P=0.04) in the normal karyotype cohort. These results suggest that CEBPA mutations, particularly CEBPA-double, are an independent favorable prognostic factor in pediatric AML patients, which will have important implications for risk-stratified therapy.

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“…Following the excellent outcomes of the AML99 study, a nationwide multicenter study (termed the AML‐05 study, UMIN000000511) was conducted by a new national collaboration established in 2003, the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG), to further optimize risk‐stratified therapies for childhood AML; in which the four existing pediatric leukemia study groups (TCCSG, JACLS, KYCCSG, and CCLSG) were merged …”

Section: De Novo Amlmentioning

confidence: 99%

“…The 3 year EFS and OS rates were 54.2% and 73.1%, respectively, which was similar to the outcomes of the AML99 study. The key findings of the AML‐05 study were as follows: (i) the EFS for CBF leukemia was worse than in the AML99 study due to excessive treatment reduction, especially with anthracyclines; (ii) the outcome for non‐CBF AML was similar to that in the AML99 study, even with the reduction of treatment courses and restriction of HSCT indication at first remission; (iii) serious pulmonary complications in infants frequently occurred during induction therapy and dose reduction would be needed for this group; (iv) the outcome for AML with myelodysplastic syndrome (MDS)‐related changes was poor; and (v) the outcome for FLT3 ‐ITD‐positive AML could not be improved even with escalation to HR because of poor treatment response to induction therapy before HSCT.…”

Section: De Novo Amlmentioning

confidence: 99%

Acute myeloid leukemia in children: Current status and future directions

Taga

Tomizawa

Takahashi

et al. 2016

Pediatrics International

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Acute myeloid leukemia (AML) accounts for 25% of pediatric leukemia and affects approximately 180 patients annually in Japan. The treatment outcome for pediatric AML has improved through advances in chemotherapy, hematopoietic stem cell transplantation (HSCT), supportive care, and optimal risk stratification. Currently, clinical pediatric AML studies are conducted separately according to the AML subtypes: de novo AML, acute promyelocytic leukemia (APL), and myeloid leukemia with Down syndrome (ML-DS). Children with de novo AML are treated mainly with anthracyclines and cytarabine, in some cases with HSCT, and the overall survival (OS) rate now approaches 70%. Children with APL are treated with an all-trans retinoic acid (ATRA)-combined regimen with an 80-90% OS. Children with ML-DS are treated with a less intensive regimen compared with non-DS patients, and the OS is approximately 80%. HSCT in first remission is restricted to children with high-risk de novo AML only. To further improve outcomes, it will be necessary to combine more accurate risk stratification strategies using molecular genetic analysis with assessment of minimum residual disease, and the introduction of new drugs in international collaborative clinical trials.

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Excess treatment reduction including anthracyclines results in higher incidence of relapse in core binding factor acute myeloid leukemia in children

Abstract: Individualized intervention guided by BCR-ABL transcript levels after HLA-identical sibling donor transplantation improves HSCT outcomes for subjects with chronic myeloid leukemia.

Cited by 60 publications

References 12 publications

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

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

Prognostic implications of CEBPA mutations in pediatric acute myeloid leukemia: a report from the Japanese Pediatric Leukemia/Lymphoma Study Group

Acute myeloid leukemia in children: Current status and future directions

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