title: Use of Minimal Residual Disease Assessment to Redefine Induction Failure in Pediatric Acute Lymphoblastic Leukemia.
abstract: Purpose Our aim was to determine the role of end-of-induction (EOI) minimal residual disease (MRD) assessment in the identification and stratification of induction failure in patients with pediatric acute lymphoblastic leukemia (ALL) and to identify genetic abnormalities that drive disease in these patients. Patients and Methods Analysis included 3,113 patients who were treated in the Medical Research Council UKALL2003 multicenter randomized trial (NCT00222612) between 2003 and 2011. MRD was measured by using standardized real-time quantitative PCR. Median follow-up was 5 years 9 months. Results Fifty-nine patients (1.9%) had morphologic induction failure with 5-year event-free survival (EFS) of 50.7% (95% CI, 37.4 to 64.0) and 5-year overall survival of 57.7% (95% CI, 44.2 to 71.2). Of these, a small proportion of patients with M2 marrow (6 of 44) and a low EOI MRD level (< 0.01%) had 5-year EFS of 100%. Conversely, among patients with morphologic remission 2.3% (61 of 2,633) had high MRD (≥ 5%) and 5-year EFS of 47.0% (95% CI, 32.9 to 61.1), which was similar to those with morphologic induction failure. Redefining induction failure to include morphologic induction failure and/or MRD ≥ 5% identified 3.9% (120 of 3,133 patients) of the trial cohort with 5-year EFS of 48.0% (95% CI, 39.3 to 58.6). Induction failure (morphologic or MRD ≥ 5%) occurred most frequently in T-ALL (10.1%; 39 of 386 T-ALL cases) and B-other ALL, that is, lacking established chromosomal abnormalities (5.6%; 43 of 772 B-other cases). Genetic testing within the B-other group revealed the presence of PDGFRB gene fusions, particularly EBF1-PDGFRB, in almost one third of B-other ALL cases. Conclusion Integration of EOI MRD level with morphology identifies induction failure more precisely than morphology alone. Prevalence of EBF1-PDGFRB fusions in this group highlights the importance of genetic screening to identify abnormalities that may be targets for novel agents.
authors.affiliation: David O'Connor, Ronald M.R. Tan, Jack Bartram, and Sujith Samarasinghe, Great Ormond Street Hospital for Children NHS Foundation Trust; Rachael Hough, University College London Hospitals NHS Foundation Trust, London; Anthony V. Moorman, Claire Schwab, and Christine J. Harrison, Newcastle University, Newcastle Upon Tyne; Rachel Wade, University of Oxford, Oxford; Jeremy Hancock, North Bristol NHS Trust; John Moppett, Royal Hospital for Children, Bristol; Ajay Vora and Katharine Patrick, Sheffield Children's NHS Foundation Trust, Sheffield, United Kingdom; and Nick Goulden, Trapehade, Monferran Plaves, France.
authors.forename: David
authors.initials: D
authors.lastname: O'Connor
authors.affiliation: David O'Connor, Ronald M.R. Tan, Jack Bartram, and Sujith Samarasinghe, Great Ormond Street Hospital for Children NHS Foundation Trust; Rachael Hough, University College London Hospitals NHS Foundation Trust, London; Anthony V. Moorman, Claire Schwab, and Christine J. Harrison, Newcastle University, Newcastle Upon Tyne; Rachel Wade, University of Oxford, Oxford; Jeremy Hancock, North Bristol NHS Trust; John Moppett, Royal Hospital for Children, Bristol; Ajay Vora and Katharine Patrick, Sheffield Children's NHS Foundation Trust, Sheffield, United Kingdom; and Nick Goulden, Trapehade, Monferran Plaves, France.
authors.forename: Anthony V
authors.initials: AV
authors.lastname: Moorman
authors.affiliation: David O'Connor, Ronald M.R. Tan, Jack Bartram, and Sujith Samarasinghe, Great Ormond Street Hospital for Children NHS Foundation Trust; Rachael Hough, University College London Hospitals NHS Foundation Trust, London; Anthony V. Moorman, Claire Schwab, and Christine J. Harrison, Newcastle University, Newcastle Upon Tyne; Rachel Wade, University of Oxford, Oxford; Jeremy Hancock, North Bristol NHS Trust; John Moppett, Royal Hospital for Children, Bristol; Ajay Vora and Katharine Patrick, Sheffield Children's NHS Foundation Trust, Sheffield, United Kingdom; and Nick Goulden, Trapehade, Monferran Plaves, France.
authors.forename: Rachel
authors.initials: R
authors.lastname: Wade
authors.affiliation: David O'Connor, Ronald M.R. Tan, Jack Bartram, and Sujith Samarasinghe, Great Ormond Street Hospital for Children NHS Foundation Trust; Rachael Hough, University College London Hospitals NHS Foundation Trust, London; Anthony V. Moorman, Claire Schwab, and Christine J. Harrison, Newcastle University, Newcastle Upon Tyne; Rachel Wade, University of Oxford, Oxford; Jeremy Hancock, North Bristol NHS Trust; John Moppett, Royal Hospital for Children, Bristol; Ajay Vora and Katharine Patrick, Sheffield Children's NHS Foundation Trust, Sheffield, United Kingdom; and Nick Goulden, Trapehade, Monferran Plaves, France.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Hancock
authors.affiliation: David O'Connor, Ronald M.R. Tan, Jack Bartram, and Sujith Samarasinghe, Great Ormond Street Hospital for Children NHS Foundation Trust; Rachael Hough, University College London Hospitals NHS Foundation Trust, London; Anthony V. Moorman, Claire Schwab, and Christine J. Harrison, Newcastle University, Newcastle Upon Tyne; Rachel Wade, University of Oxford, Oxford; Jeremy Hancock, North Bristol NHS Trust; John Moppett, Royal Hospital for Children, Bristol; Ajay Vora and Katharine Patrick, Sheffield Children's NHS Foundation Trust, Sheffield, United Kingdom; and Nick Goulden, Trapehade, Monferran Plaves, France.
authors.forename: Ronald M R
authors.initials: RM
authors.lastname: Tan
authors.affiliation: David O'Connor, Ronald M.R. Tan, Jack Bartram, and Sujith Samarasinghe, Great Ormond Street Hospital for Children NHS Foundation Trust; Rachael Hough, University College London Hospitals NHS Foundation Trust, London; Anthony V. Moorman, Claire Schwab, and Christine J. Harrison, Newcastle University, Newcastle Upon Tyne; Rachel Wade, University of Oxford, Oxford; Jeremy Hancock, North Bristol NHS Trust; John Moppett, Royal Hospital for Children, Bristol; Ajay Vora and Katharine Patrick, Sheffield Children's NHS Foundation Trust, Sheffield, United Kingdom; and Nick Goulden, Trapehade, Monferran Plaves, France.
authors.forename: Jack
authors.initials: J
authors.lastname: Bartram
authors.affiliation: David O'Connor, Ronald M.R. Tan, Jack Bartram, and Sujith Samarasinghe, Great Ormond Street Hospital for Children NHS Foundation Trust; Rachael Hough, University College London Hospitals NHS Foundation Trust, London; Anthony V. Moorman, Claire Schwab, and Christine J. Harrison, Newcastle University, Newcastle Upon Tyne; Rachel Wade, University of Oxford, Oxford; Jeremy Hancock, North Bristol NHS Trust; John Moppett, Royal Hospital for Children, Bristol; Ajay Vora and Katharine Patrick, Sheffield Children's NHS Foundation Trust, Sheffield, United Kingdom; and Nick Goulden, Trapehade, Monferran Plaves, France.
authors.forename: John
authors.initials: J
authors.lastname: Moppett
authors.affiliation: David O'Connor, Ronald M.R. Tan, Jack Bartram, and Sujith Samarasinghe, Great Ormond Street Hospital for Children NHS Foundation Trust; Rachael Hough, University College London Hospitals NHS Foundation Trust, London; Anthony V. Moorman, Claire Schwab, and Christine J. Harrison, Newcastle University, Newcastle Upon Tyne; Rachel Wade, University of Oxford, Oxford; Jeremy Hancock, North Bristol NHS Trust; John Moppett, Royal Hospital for Children, Bristol; Ajay Vora and Katharine Patrick, Sheffield Children's NHS Foundation Trust, Sheffield, United Kingdom; and Nick Goulden, Trapehade, Monferran Plaves, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Schwab
authors.affiliation: David O'Connor, Ronald M.R. Tan, Jack Bartram, and Sujith Samarasinghe, Great Ormond Street Hospital for Children NHS Foundation Trust; Rachael Hough, University College London Hospitals NHS Foundation Trust, London; Anthony V. Moorman, Claire Schwab, and Christine J. Harrison, Newcastle University, Newcastle Upon Tyne; Rachel Wade, University of Oxford, Oxford; Jeremy Hancock, North Bristol NHS Trust; John Moppett, Royal Hospital for Children, Bristol; Ajay Vora and Katharine Patrick, Sheffield Children's NHS Foundation Trust, Sheffield, United Kingdom; and Nick Goulden, Trapehade, Monferran Plaves, France.
authors.forename: Katharine
authors.initials: K
authors.lastname: Patrick
authors.affiliation: David O'Connor, Ronald M.R. Tan, Jack Bartram, and Sujith Samarasinghe, Great Ormond Street Hospital for Children NHS Foundation Trust; Rachael Hough, University College London Hospitals NHS Foundation Trust, London; Anthony V. Moorman, Claire Schwab, and Christine J. Harrison, Newcastle University, Newcastle Upon Tyne; Rachel Wade, University of Oxford, Oxford; Jeremy Hancock, North Bristol NHS Trust; John Moppett, Royal Hospital for Children, Bristol; Ajay Vora and Katharine Patrick, Sheffield Children's NHS Foundation Trust, Sheffield, United Kingdom; and Nick Goulden, Trapehade, Monferran Plaves, France.
authors.forename: Christine J
authors.initials: CJ
authors.lastname: Harrison
authors.affiliation: David O'Connor, Ronald M.R. Tan, Jack Bartram, and Sujith Samarasinghe, Great Ormond Street Hospital for Children NHS Foundation Trust; Rachael Hough, University College London Hospitals NHS Foundation Trust, London; Anthony V. Moorman, Claire Schwab, and Christine J. Harrison, Newcastle University, Newcastle Upon Tyne; Rachel Wade, University of Oxford, Oxford; Jeremy Hancock, North Bristol NHS Trust; John Moppett, Royal Hospital for Children, Bristol; Ajay Vora and Katharine Patrick, Sheffield Children's NHS Foundation Trust, Sheffield, United Kingdom; and Nick Goulden, Trapehade, Monferran Plaves, France.
authors.forename: Rachael
authors.initials: R
authors.lastname: Hough
authors.affiliation: David O'Connor, Ronald M.R. Tan, Jack Bartram, and Sujith Samarasinghe, Great Ormond Street Hospital for Children NHS Foundation Trust; Rachael Hough, University College London Hospitals NHS Foundation Trust, London; Anthony V. Moorman, Claire Schwab, and Christine J. Harrison, Newcastle University, Newcastle Upon Tyne; Rachel Wade, University of Oxford, Oxford; Jeremy Hancock, North Bristol NHS Trust; John Moppett, Royal Hospital for Children, Bristol; Ajay Vora and Katharine Patrick, Sheffield Children's NHS Foundation Trust, Sheffield, United Kingdom; and Nick Goulden, Trapehade, Monferran Plaves, France.
authors.forename: Nick
authors.initials: N
authors.lastname: Goulden
authors.affiliation: David O'Connor, Ronald M.R. Tan, Jack Bartram, and Sujith Samarasinghe, Great Ormond Street Hospital for Children NHS Foundation Trust; Rachael Hough, University College London Hospitals NHS Foundation Trust, London; Anthony V. Moorman, Claire Schwab, and Christine J. Harrison, Newcastle University, Newcastle Upon Tyne; Rachel Wade, University of Oxford, Oxford; Jeremy Hancock, North Bristol NHS Trust; John Moppett, Royal Hospital for Children, Bristol; Ajay Vora and Katharine Patrick, Sheffield Children's NHS Foundation Trust, Sheffield, United Kingdom; and Nick Goulden, Trapehade, Monferran Plaves, France.
authors.forename: Ajay
authors.initials: A
authors.lastname: Vora
authors.affiliation: David O'Connor, Ronald M.R. Tan, Jack Bartram, and Sujith Samarasinghe, Great Ormond Street Hospital for Children NHS Foundation Trust; Rachael Hough, University College London Hospitals NHS Foundation Trust, London; Anthony V. Moorman, Claire Schwab, and Christine J. Harrison, Newcastle University, Newcastle Upon Tyne; Rachel Wade, University of Oxford, Oxford; Jeremy Hancock, North Bristol NHS Trust; John Moppett, Royal Hospital for Children, Bristol; Ajay Vora and Katharine Patrick, Sheffield Children's NHS Foundation Trust, Sheffield, United Kingdom; and Nick Goulden, Trapehade, Monferran Plaves, France.
authors.forename: Sujith
authors.initials: S
authors.lastname: Samarasinghe
mesh_terms: D000293:Adolescent; D001853:Bone Marrow / Q000473:pathology; D002648:Child; D005260:Female; D006801:Humans; D008297:Male; D015337:Multicenter Studies as Topic; D018365:Neoplasm, Residual; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D016032:Randomized Controlled Trials as Topic; D060888:Real-Time Polymerase Chain Reaction; D012074:Remission Induction; D017211:Treatment Failure