Measurable residual disease detection by high-throughput sequencing improves risk stratification for pediatric B-ALL

Brent Wood, David Wu, Beryl Crossley, Yunfeng Dai, David Williamson, Charles Gawad, Michael J. Borowitz, Meenakshi Devidas, Kelly W. Maloney, Eric Larsen, Naomi Winick, Elizabeth Raetz, William L. Carroll, Stephen P. Hunger, Mignon L. Loh, Harlan Robins, Ilan Kirsch

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Early response to induction chemotherapy is an important prognostic factor in B-lymphoblastic leukemia (B-ALL). Here, we compare high-throughput sequencing (HTS) of IGH and TRG genes vs flow cytometry (FC) for measurable residual disease (MRD) detection at the end of induction chemotherapy in pediatric patients with newly diagnosed B-ALL. Six hundred nineteen paired pretreatment and end-of-induction bone marrow samples from Children’s Oncology Group studies AALL0331 (clinicaltrials.gov #NCT00103285) (standard risk [SR]; with MRD by FC at any level) and AALL0232 (clinicaltrials.gov #NCT00075725) (high risk; with day 29 MRD <0.1% by FC) were evaluated by HTS and FC for event-free (EFS) and overall survival (OS). HTS and FC showed similar 5-year EFS and OS for MRD-positive and -negative patients using an MRD threshold of 0.01%. However, there was a high discordant rate with HTS identifying 55 (38.7%) more patients MRD positive at this threshold. These discrepant patients have worse outcomes than FC MRD-negative patients. In addition, the increased analytic sensitivity of HTS permitted identification of 19.9% of SR patients without MRD at any detectable level who had excellent 5-year EFS (98.1%) and OS (100%). The higher analytic sensitivity and lower false-negative rate of HTS improves upon FC for MRD detection in pediatric B-ALL by identifying a novel subset of patients at end of induction who are essentially cured using current chemotherapy and identifying MRD at 0.01% in up to one-third of patients who are missed at the same threshold by FC.

Original languageEnglish (US)
Pages (from-to)1350-1359
Number of pages10
JournalBlood
Volume131
Issue number12
DOIs
StatePublished - Mar 22 2018

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Pediatrics
Flow cytometry
Throughput
Flow Cytometry
Chemotherapy
Induction Chemotherapy
Survival
Oncology
Gene Flow
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Bone
Genes
Bone Marrow
Drug Therapy

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Wood, B., Wu, D., Crossley, B., Dai, Y., Williamson, D., Gawad, C., ... Kirsch, I. (2018). Measurable residual disease detection by high-throughput sequencing improves risk stratification for pediatric B-ALL. Blood, 131(12), 1350-1359. https://doi.org/10.1182/blood-2017-09-806521

Measurable residual disease detection by high-throughput sequencing improves risk stratification for pediatric B-ALL. / Wood, Brent; Wu, David; Crossley, Beryl; Dai, Yunfeng; Williamson, David; Gawad, Charles; Borowitz, Michael J.; Devidas, Meenakshi; Maloney, Kelly W.; Larsen, Eric; Winick, Naomi; Raetz, Elizabeth; Carroll, William L.; Hunger, Stephen P.; Loh, Mignon L.; Robins, Harlan; Kirsch, Ilan.

In: Blood, Vol. 131, No. 12, 22.03.2018, p. 1350-1359.

Research output: Contribution to journalArticle

Wood, B, Wu, D, Crossley, B, Dai, Y, Williamson, D, Gawad, C, Borowitz, MJ, Devidas, M, Maloney, KW, Larsen, E, Winick, N, Raetz, E, Carroll, WL, Hunger, SP, Loh, ML, Robins, H & Kirsch, I 2018, 'Measurable residual disease detection by high-throughput sequencing improves risk stratification for pediatric B-ALL', Blood, vol. 131, no. 12, pp. 1350-1359. https://doi.org/10.1182/blood-2017-09-806521
Wood, Brent ; Wu, David ; Crossley, Beryl ; Dai, Yunfeng ; Williamson, David ; Gawad, Charles ; Borowitz, Michael J. ; Devidas, Meenakshi ; Maloney, Kelly W. ; Larsen, Eric ; Winick, Naomi ; Raetz, Elizabeth ; Carroll, William L. ; Hunger, Stephen P. ; Loh, Mignon L. ; Robins, Harlan ; Kirsch, Ilan. / Measurable residual disease detection by high-throughput sequencing improves risk stratification for pediatric B-ALL. In: Blood. 2018 ; Vol. 131, No. 12. pp. 1350-1359.
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title = "Measurable residual disease detection by high-throughput sequencing improves risk stratification for pediatric B-ALL",
abstract = "Early response to induction chemotherapy is an important prognostic factor in B-lymphoblastic leukemia (B-ALL). Here, we compare high-throughput sequencing (HTS) of IGH and TRG genes vs flow cytometry (FC) for measurable residual disease (MRD) detection at the end of induction chemotherapy in pediatric patients with newly diagnosed B-ALL. Six hundred nineteen paired pretreatment and end-of-induction bone marrow samples from Children’s Oncology Group studies AALL0331 (clinicaltrials.gov #NCT00103285) (standard risk [SR]; with MRD by FC at any level) and AALL0232 (clinicaltrials.gov #NCT00075725) (high risk; with day 29 MRD <0.1{\%} by FC) were evaluated by HTS and FC for event-free (EFS) and overall survival (OS). HTS and FC showed similar 5-year EFS and OS for MRD-positive and -negative patients using an MRD threshold of 0.01{\%}. However, there was a high discordant rate with HTS identifying 55 (38.7{\%}) more patients MRD positive at this threshold. These discrepant patients have worse outcomes than FC MRD-negative patients. In addition, the increased analytic sensitivity of HTS permitted identification of 19.9{\%} of SR patients without MRD at any detectable level who had excellent 5-year EFS (98.1{\%}) and OS (100{\%}). The higher analytic sensitivity and lower false-negative rate of HTS improves upon FC for MRD detection in pediatric B-ALL by identifying a novel subset of patients at end of induction who are essentially cured using current chemotherapy and identifying MRD at 0.01{\%} in up to one-third of patients who are missed at the same threshold by FC.",
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AU - Wood, Brent

AU - Wu, David

AU - Crossley, Beryl

AU - Dai, Yunfeng

AU - Williamson, David

AU - Gawad, Charles

AU - Borowitz, Michael J.

AU - Devidas, Meenakshi

AU - Maloney, Kelly W.

AU - Larsen, Eric

AU - Winick, Naomi

AU - Raetz, Elizabeth

AU - Carroll, William L.

AU - Hunger, Stephen P.

AU - Loh, Mignon L.

AU - Robins, Harlan

AU - Kirsch, Ilan

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N2 - Early response to induction chemotherapy is an important prognostic factor in B-lymphoblastic leukemia (B-ALL). Here, we compare high-throughput sequencing (HTS) of IGH and TRG genes vs flow cytometry (FC) for measurable residual disease (MRD) detection at the end of induction chemotherapy in pediatric patients with newly diagnosed B-ALL. Six hundred nineteen paired pretreatment and end-of-induction bone marrow samples from Children’s Oncology Group studies AALL0331 (clinicaltrials.gov #NCT00103285) (standard risk [SR]; with MRD by FC at any level) and AALL0232 (clinicaltrials.gov #NCT00075725) (high risk; with day 29 MRD <0.1% by FC) were evaluated by HTS and FC for event-free (EFS) and overall survival (OS). HTS and FC showed similar 5-year EFS and OS for MRD-positive and -negative patients using an MRD threshold of 0.01%. However, there was a high discordant rate with HTS identifying 55 (38.7%) more patients MRD positive at this threshold. These discrepant patients have worse outcomes than FC MRD-negative patients. In addition, the increased analytic sensitivity of HTS permitted identification of 19.9% of SR patients without MRD at any detectable level who had excellent 5-year EFS (98.1%) and OS (100%). The higher analytic sensitivity and lower false-negative rate of HTS improves upon FC for MRD detection in pediatric B-ALL by identifying a novel subset of patients at end of induction who are essentially cured using current chemotherapy and identifying MRD at 0.01% in up to one-third of patients who are missed at the same threshold by FC.

AB - Early response to induction chemotherapy is an important prognostic factor in B-lymphoblastic leukemia (B-ALL). Here, we compare high-throughput sequencing (HTS) of IGH and TRG genes vs flow cytometry (FC) for measurable residual disease (MRD) detection at the end of induction chemotherapy in pediatric patients with newly diagnosed B-ALL. Six hundred nineteen paired pretreatment and end-of-induction bone marrow samples from Children’s Oncology Group studies AALL0331 (clinicaltrials.gov #NCT00103285) (standard risk [SR]; with MRD by FC at any level) and AALL0232 (clinicaltrials.gov #NCT00075725) (high risk; with day 29 MRD <0.1% by FC) were evaluated by HTS and FC for event-free (EFS) and overall survival (OS). HTS and FC showed similar 5-year EFS and OS for MRD-positive and -negative patients using an MRD threshold of 0.01%. However, there was a high discordant rate with HTS identifying 55 (38.7%) more patients MRD positive at this threshold. These discrepant patients have worse outcomes than FC MRD-negative patients. In addition, the increased analytic sensitivity of HTS permitted identification of 19.9% of SR patients without MRD at any detectable level who had excellent 5-year EFS (98.1%) and OS (100%). The higher analytic sensitivity and lower false-negative rate of HTS improves upon FC for MRD detection in pediatric B-ALL by identifying a novel subset of patients at end of induction who are essentially cured using current chemotherapy and identifying MRD at 0.01% in up to one-third of patients who are missed at the same threshold by FC.

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