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More precisely defining risk peri-HCT in pediatric ALL: pre- vs post-MRD measures, serial positivity, and risk
Peter Bader1, Emilia Salzmann-Manrique1, Adriana Balduzzi2
1Division for Stem Cell Transplantation and Immunology, Department for Children and Adolescents, University Hospital Frankfurt, Goethe University, Frankfurt am Main, Germany.
Abstract:
Detection of minimal residual disease (MRD) pre- and post-hematopoietic cell transplantation (HCT) for pediatric acute lymphoblastic leukemia (ALL) has been associated with relapse and poor survival. Published studies have had insufficient numbers to: (1) compare the prognostic value of pre-HCT and post-HCT MRD; (2) determine clinical factors post-HCT associated with better outcomes in MRD+ patients; and (3) use MRD and other clinical factors to develop and validate a prognostic model for relapse in pediatric patients with ALL who undergo allogeneic HCT. To address these issues, we assembled an international database including sibling (n = 191), unrelated (n = 259), mismatched (n = 56), and cord blood (n = 110) grafts given after myeloablative conditioning. Although high and very high MRD pre-HCT were significant predictors in univariate analysis, with bivariate analysis using MRD pre-HCT and post-HCT, MRD pre-HCT at any level was less predictive than even low-level MRD post-HCT. Patients with MRD pre-HCT must become MRD low/negative at 1 to 2 months and negative within 3 to 6 months after HCT for successful therapy. Factors associated with improved outcome of patients with detectable MRD post-HCT included acute graft-versus-host disease. We derived a risk score with an MRD cohort from Europe, North America, and Australia using negative predictive characteristics (late disease status, non-total body irradiation regimen, and MRD [high, very high]) defining good, intermediate, and poor risk groups with 2-year cumulative incidences of relapse of 21%, 38%, and 47%, respectively. We validated the score in a second, more contemporaneous cohort and noted 2-year cumulative incidences of relapse of 13%, 26%, and 47% (P < .001) for the defined risk groups.
Insights
Post-transplant minimal residual disease (MRD) is more predictive of relapse than pre-transplant MRD in pediatric acute lymphoblastic leukemia (ALL) patients undergoing hematopoietic cell transplantation (HCT). Achieving MRD negativity post-HCT is crucial for successful outcomes.
Area of Science:
- Hematology
- Pediatric Oncology
- Immunology
Background:
- Minimal residual disease (MRD) detection post-hematopoietic cell transplantation (HCT) for pediatric acute lymphoblastic leukemia (ALL) is linked to relapse and survival outcomes.
- Previous studies lacked sufficient data to compare pre- and post-HCT MRD prognostic value or develop predictive models.
Purpose of the Study:
- To compare the prognostic significance of pre- and post-HCT MRD in pediatric ALL patients undergoing allogeneic HCT.
- To identify clinical factors associated with better outcomes in MRD-positive patients post-HCT.
- To develop and validate a prognostic model for relapse risk using MRD and clinical factors.
Main Methods:
- Assembled an international database of pediatric ALL patients receiving allogeneic HCT with various graft types (sibling, unrelated, mismatched, cord blood) after myeloablative conditioning.
- Conducted univariate and bivariate analyses to assess the predictive value of pre- and post-HCT MRD.
- Derived and validated a risk score incorporating MRD status and clinical factors (disease status, conditioning regimen, graft type).
Main Results:
- Post-HCT MRD, even at low levels, was more predictive of relapse than any level of pre-HCT MRD.
- Achieving MRD negativity within 3-6 months post-HCT is essential for successful treatment.
- Acute graft-versus-host disease was associated with improved outcomes in patients with detectable post-HCT MRD.
- A validated risk score stratified patients into good, intermediate, and poor relapse risk groups with distinct 2-year cumulative incidences of relapse (13-47%).
Conclusions:
- Post-HCT MRD is a critical determinant of relapse risk in pediatric ALL patients undergoing allogeneic HCT.
- A novel prognostic model integrating MRD and clinical factors can effectively stratify relapse risk.
- Early MRD monitoring and timely intervention are crucial for improving outcomes in pediatric ALL patients post-HCT.
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