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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 Loh, Harlan Robins and Ilan Kirsch

Key points

  • HTS identifies MRD at the conventional clinical cutoff in more patients than FC and these patients have worse outcomes.

  • A subset of B-ALL patients essentially cured using current chemotherapy is identified at end-of-induction by HTS.

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 versus flow cytometry (FC) for measurable residual disease (MRD) detection at the end of induction chemotherapy in pediatric patients with newly diagnosed B-ALL. 619 paired pretreatment and end of induction bone marrow samples from Children's Oncology Group (COG) studies AALL0331 (clinicaltrials.gov NCT00103285) (standard-risk; SR with MRD by FC at any level) and AALL0232 (clinicaltrials.gov NCT00075725) (high-risk; HR 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. Additionally, 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 measurable residual disease detection in pediatric B lymphoblastic leukemia 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.

  • Submitted September 14, 2017.
  • Accepted December 12, 2017.