Minimal Residual Disease–Guided Treatment Deintensification for Children With Acute Lymphoblastic Leukemia: Results From the Malaysia-Singapore Acute Lymphoblastic Leukemia 2003 Study

Yeoh, Allen Eng Juh; Ariffin, Hany; Chai, Elaine Li Leng; Kwok, Cecilia; Chan, Yiong Huak; Kuperan, Ponnudurai; Campana, Dario; Tan, Poh Lin; Chan, Mei Yoke; Kham, Shirley Kow Yin; Chong, Lee Ai; Tan, Ah Moy; Lin, Hai; Quah, Thuan Chong

doi:10.1200/jco.2011.40.5936

Cited by 121 publications

(137 citation statements)

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“…Included in this study were 231 children with newly diagnosed ALL treated in Ma-Spore frontline ALL clinical trials (Yeoh et al 2012). Gross cytogenetics and common translocations were determined at the time of diagnosis (i.e., BCR-ABL1, ETV6-RUNX1, TCF3-PBX1, STIL-TAL1, MLL rearrangement, and hyperdiploid karyotype) by karyotyping and reverse transcription PCR in the reference laboratory at National University Hospital, Singapore (Yeoh et al 2012).…”

Section: Patients and Samplesmentioning

confidence: 99%

“…Gross cytogenetics and common translocations were determined at the time of diagnosis (i.e., BCR-ABL1, ETV6-RUNX1, TCF3-PBX1, STIL-TAL1, MLL rearrangement, and hyperdiploid karyotype) by karyotyping and reverse transcription PCR in the reference laboratory at National University Hospital, Singapore (Yeoh et al 2012). Subjects were selected based on sample availability.…”

Section: Patients and Samplesmentioning

confidence: 99%

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Whole-transcriptome sequencing identifies a distinct subtype of acute lymphoblastic leukemia with predominant genomic abnormalities of EP300 and CREBBP

et al. 2016

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Chromosomal translocations are a genomic hallmark of many hematologic malignancies. Often as initiating events, these structural abnormalities result in fusion proteins involving transcription factors important for hematopoietic differentiation and/or signaling molecules regulating cell proliferation and cell cycle. In contrast, epigenetic regulator genes are more frequently targeted by somatic sequence mutations, possibly as secondary events to further potentiate leukemogenesis. Through comprehensive whole-transcriptome sequencing of 231 children with acute lymphoblastic leukemia (ALL), we identified 58 putative functional and predominant fusion genes in 54.1% of patients (n = 125), 31 of which have not been reported previously. In particular, we described a distinct ALL subtype with a characteristic gene expression signature predominantly driven by chromosomal rearrangements of the ZNF384 gene with histone acetyltransferases EP300 and CREBBP. ZNF384-rearranged ALL showed significant up-regulation of CLCF1 and BTLA expression, and ZNF384 fusion proteins consistently showed higher activity to promote transcription of these target genes relative to wild-type ZNF384 in vitro. Ectopic expression of EP300-ZNF384 and CREBBP-ZNF384 fusion altered differentiation of mouse hematopoietic stem and progenitor cells and also potentiated oncogenic transformation in vitro. EP300-and CREBBP-ZNF384 fusions resulted in loss of histone lysine acetyltransferase activity in a dominant-negative fashion, with concomitant global reduction of histone acetylation and increased sensitivity of leukemia cells to histone deacetylase inhibitors. In conclusion, our results indicate that gene fusion is a common class of genomic abnormalities in childhood ALL and that recurrent translocations involving EP300 and CREBBP may cause epigenetic deregulation with potential for therapeutic targeting.

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Section: Patients and Samplesmentioning

confidence: 99%

Section: Patients and Samplesmentioning

confidence: 99%

Whole-transcriptome sequencing identifies a distinct subtype of acute lymphoblastic leukemia with predominant genomic abnormalities of EP300 and CREBBP

et al. 2016

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“…10 Many other pediatric ALL trials incorporate MRD into their treatment strategies. [11][12][13][14][15] Though our initial studies only assessed the prognostic significance of MRD without intervention, in 2003, we began using MRD as one variable to determine the intensity of postinduction therapy. Here, we report the effect of MRD on the outcome of subjects with NCI high-risk (HR) ALL treated on COG trial AALL0232 (NCT00075725).…”

Section: Introductionmentioning

confidence: 99%

Prognostic significance of minimal residual disease in high risk B-ALL: a report from Children’s Oncology Group study AALL0232

Borowitz

Wood

Devidas

et al. 2015

Blood

303

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• MRD measured by flow cytometry is prognostic in childhood B-ALL even with more effective high-dose methotrexate therapy.• Intensive therapy in MRDpositive patients altered the timing of relapse but did not overcome the poor prognostic significance of MRD.Minimal residual disease (MRD) is highly prognostic in pediatric B-precursor acute lymphoblastic leukemia (B-ALL). In Children's Oncology Group high-risk B-ALL study AALL0232, we investigated MRD in subjects randomized in a 2 3 2 factorial design to receive either highdose methotrexate (HD-MTX) or Capizzi methotrexate (C-MTX) during interim maintenance (IM) or prednisone or dexamethasone during induction. Subjects with end-induction MRD ‡0.1% or those with morphologic slow early response were nonrandomly assigned to receive a second IM and delayed intensification phase. MRD was measured by 6-color flow cytometry in 1 of 2 reference labs, with excellent agreement between the two. Subjects with end-induction MRD <0.01% had a 5-year event-free survival (EFS) of 87% 6 1% vs 74% 6 4% for those with MRD 0.01% to 0.1%; increasing MRD amounts was associated with progressively worse outcome. Subjects converting from MRD positive to negative by end consolidation had a relatively favorable 79% 6 5% 5-year disease-free survival vs 39% 6 7% for those with MRD ‡0.01%. Although HD-MTX was superior to C-MTX, MRD retained prognostic significance in both groups (86% 6 2% vs 58% 6 4% for MRD-negative vs positive C-MTX subjects; 88% 6 2% vs 68% 6 4% for HD-MTX subjects). Intensified therapy given to subjects with MRD >0.1% did not improve either 5-year EFS or overall survival (OS). However, these subjects showed an early relapse rate similar to that seen in MRD-negative ones, with EFS/OS curves for patients with 0.1% to 1% MRD crossing those with 0.01% to 0.1% MRD at 3 and 4 years, thus suggesting that the intensified therapy altered the disease course of MRD-positive subjects. Additional interventions targeted at the MRD-positive group may further improve outcome. This trial was registered at www.clinicaltrials.gov as #NCT00075725. (Blood. 2015;126(8):964-971) IntroductionMinimal residual disease (MRD) is highly predictive of relapse in children, adolescents, and young adults treated for acute lymphoblastic leukemia (ALL). [1][2][3][4][5][6] MRD is typically measured either by assessment of clone-specific markers of immunoglobulin and/or T-cell receptor gene rearrangements using polymerase chain reaction (PCR) or by flow cytometry, taking advantage of the fact that leukemic cells have phenotypes that allow them to be distinguished from normal cells. The Children's Oncology Group (COG) has been assessing MRD by flow cytometry at the end of 4 weeks of induction therapy in subjects with newly diagnosed ALL since 1999, and has previously demonstrated that this is the most powerful predictor of outcome in children, adolescents, and young adults with B-precursor ALL (B-ALL). Because MRD is known to be such a strong prognostic factor, most studies of childhood ALL use this to deter...

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“…Pediatric oncologists treating children and adolescents with ALL have pioneered the use of MRD to monitor response to treatment, and all major pediatric oncology centers and cooperative groups worldwide now systematically use MRD levels to guide treatment decisions (Table 1). [8][9][10][11][12][13][14][15][16][17][18][19][20] Because precise measurements of MRD have important prognostic and therapeutic implications, it is essential to understand their clinical significance in the context of presenting clinical and biologic features, treatment regimen, and time interval at which MRD is measured.…”

Section: Introductionmentioning

confidence: 99%

Minimal residual disease–guided therapy in childhood acute lymphoblastic leukemia

Campana

Pui

2017

Blood

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A 3-year-old boy presented with a leukocyte count of 5.9 3 10 9 /L and was found to have near-haploid B-lineage acute lymphoblastic leukemia (ALL) with a 27, X, 1Y, 113, 118, 121 karyotype. He was enrolled in the St. Jude Children's Research Hospital Total Therapy XV study. After 19 days of remission induction therapy with 1 high dose of methotrexate, 14 days of prednisone, 2 doses of vincristine and daunorubicin, and 6 doses of Escherichia coli-derived asparaginase, flow cytometry examination of his bone marrow revealed the presence of minimal residual disease (MRD) amounting to 3 leukemic cells per 10 000 mononucleated cells (0.03%). Upon completion of the remaining remission induction therapy consisting of 1 dose of cyclophosphamide, 14 days of mercaptopurine, and 8 onceper-day doses of cytarabine, he attained a morphologic remission on day 46, with undetectable (,0.01%) MRD by flow cytometry and polymerase chain reaction. Because of the near-haploid ALL karyotype and negative day 46 MRD, he was assigned to receive intensive chemotherapy for 3 years. MRD remained undetectable throughout treatment. He has remained in continuous complete remission for 11.6 years. Case 2A 9-year-old boy presented with a 3-month history of progressive pallor and upper respiratory tract infection. He had no hepatosplenomegaly or mediastinal mass. An abnormal blood count with hemoglobin 3.4 g/dL, leukocytes 4.2 3 10 9 /L with 15% neutrophils, 52% lymphocytes, 33% blasts, and platelets 123 3 10 9 /L prompted a bone marrow examination which disclosed 96% replacement with leukemic lymphoblasts. By flow cytometry, the blasts expressed CD45, surface CD3, CD2, CD7, T-cell receptor g/d, CD11b, and CD13, with a subset of cells positive for CD56, a cell profile indicative of T-cell ALL. He was enrolled on the Total Therapy XV study and began remission induction therapy with high-dose methotrexate followed by prednisone once per day, vincristine once per week, daunorubicin once per week, and E coli-derived asparaginase 3 times per week. On day19 of treatment, 62.9% of bone marrow mononucleated cells were leukemic lymphoblasts by flow cytometry (31% of all cells were blasts by morphology). Three additional doses of asparaginase were given, and the remaining remission induction therapy consisted of cyclophosphamide, mercaptopurine, and cytarabine. On day 46, he attained morphologic remission (with 3% lymphoblasts), but MRD by flow cytometry was 5.82%. After consolidation treatment with 4 courses of high-dose methotrexate plus mercaptopurine as well as 1 course of re-intensification therapy with dexamethasone, etoposide, high-dose cytarabine, and asparaginase, MRD decreased to 0.18%. He attained MRD-negative status (,0.01%) after a second course of re-intensification treatment and subsequently underwent a matched-related allogeneic hematopoietic stem cell transplantation. He has remained in continuous complete remission for 11.9 years.

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Minimal Residual Disease–Guided Treatment Deintensification for Children With Acute Lymphoblastic Leukemia: Results From the Malaysia-Singapore Acute Lymphoblastic Leukemia 2003 Study

Abstract: Our results demonstrate significant progress over previous trials in the region. Three-drug remission-induction therapy combined with MRD-based risk stratification to identify poor responders is an effective strategy for childhood ALL.

Cited by 121 publications

References 23 publications

Whole-transcriptome sequencing identifies a distinct subtype of acute lymphoblastic leukemia with predominant genomic abnormalities of EP300 and CREBBP

Whole-transcriptome sequencing identifies a distinct subtype of acute lymphoblastic leukemia with predominant genomic abnormalities of EP300 and CREBBP

Prognostic significance of minimal residual disease in high risk B-ALL: a report from Children’s Oncology Group study AALL0232

Minimal residual disease–guided therapy in childhood acute lymphoblastic leukemia

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