Use of Minimal Residual Disease Assessment to Redefine Induction Failure in Pediatric Acute Lymphoblastic Leukemia
David O'Connor1, Anthony V Moorman1, Rachel Wade1
1David 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.
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.
Insights
End-of-induction minimal residual disease (MRD) assessment improves pediatric acute lymphoblastic leukemia (ALL) induction failure identification. Integrating MRD with morphology refines patient stratification and identifies genetic targets like EBF1-PDGFRB fusions.
Area of Science:
- Pediatric Oncology
- Hematology
- Molecular Biology
Background:
- Acute lymphoblastic leukemia (ALL) is the most common childhood cancer.
- Accurate identification of induction failure is crucial for treatment stratification in pediatric ALL.
- Minimal residual disease (MRD) assessment is an emerging tool in leukemia management.
Purpose of the Study:
- To evaluate the role of end-of-induction (EOI) MRD assessment in identifying and stratifying induction failure in pediatric ALL.
- To identify genetic abnormalities associated with induction failure in pediatric ALL.
- To refine the definition of induction failure using both morphological and MRD criteria.
Main Methods:
- Analysis of 3,113 pediatric ALL patients from the UKALL2003 multicenter trial.
- Standardized real-time quantitative PCR for MRD measurement at end-of-induction.
- Morphological assessment of bone marrow and genetic testing for gene fusions.
Main Results:
- Morphologic induction failure occurred in 1.9% of patients, with significantly lower event-free survival (EFS).
- Patients in morphologic remission with high EOI MRD (≥ 5%) had EFS similar to those with morphologic failure.
- Redefining induction failure to include MRD ≥ 5% identified 3.9% of patients, with a 5-year EFS of 48.0%.
- T-ALL and B-other ALL (lacking known abnormalities) showed higher rates of induction failure.
- EBF1-PDGFRB gene fusions were identified in nearly one-third of B-other ALL cases.
Conclusions:
- End-of-induction MRD assessment, integrated with morphology, provides a more precise identification of induction failure in pediatric ALL.
- A revised definition incorporating MRD ≥ 5% improves stratification of high-risk patients.
- The prevalence of EBF1-PDGFRB fusions in B-other ALL underscores the need for genetic screening to identify potential therapeutic targets.
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