Abstract
Simple SummaryInternational Working Group (IWG) and European LeukemiaNet (ELN) adult response definitions are currently used to evaluate the efficacy of new agents for childhood acute myeloid leukemia (AML); however, the criteria are not consistent with consensus definitions used in pediatric trials or the common practice of intensifying treatment prior to full hematopoietic recovery of ANC ≥ 1000 cells/μL and platelets ≥ 100 cells/μL. This retrospective analysis of the two most recent Phase 3 AML trials in the Children’s Oncology Group assesses the incidence, timing, and prognostic significance of count recovery following induction chemotherapy in children with AML. These data confirm that awaiting count recovery to meet adult criteria does not reflect standard practice in pediatric AML and IWG/ELN-defined CR does not have a significant impact on survival in children. Continuing to use adult IWG/ELN count recovery definitions limits childhood AML drug development by underestimating response, and therefore, updated response criteria are needed for pediatric AML patients.International Working Group (IWG) and European LeukemiaNet (ELN) response definitions are utilized to evaluate the efficacy of new agents for childhood acute myeloid leukemia (AML) for regulatory purposes. However, these criteria are not consistent with definitions used in pediatric AML trials or with standard pediatric practice to proceed with subsequent therapy cycles prior to IWG/ELN-defined count recovery. We retrospectively analyzed data from the two most recent Phase 3 pediatric AML clinical trials conducted by the Children’s Oncology Group (COG) to assess the incidence, timing, and prognostic significance of count recovery following induction chemotherapy. Of the patients with fewer than 5% bone marrow blasts at the end of first induction, 21.5% of patients proceeded to a second induction cycle prior to achieving ANC ≥ 500 cells/μL and platelets ≥ 50,000 cells/μL, both well below the IWG/ELN thresholds of ANC > 1000 cells/μL and platelets > 100,000 cells/μL. In these two sequential childhood AML Phase 3 trials, neither ANC nor platelet recovery predicted survival. Intensification of treatment through the initiation of subsequent therapy cycles prior to attainment of IWG/ELN-defined CR is common practice in clinical trials for children with AML, suggesting that updated response definitions are needed for pediatric AML.
Highlights
Acute myeloid leukemia (AML) in children and adults represent a phenotypically heterogeneous and genetically complex subtype of hematopoietic malignancies
Among all patients with fewer than 5% bone marrow acute myeloid leukemia (AML) blasts by centralized ∆N flow cytometry (n = 1645), the proportion of patients who proceeded to Induction II prior to recovery of absolute neutrophil count (ANC) ≥ 500 cells/μL and platelet count ≥ 50,000 cells/μL was 21.5% (7.4% with ANC only + 8.3% with platelets only + 5.8% with neither ANC nor platelet recovery; Table 2)
Continuing to use adult International Working Group (IWG)/European LeukemiaNet (ELN) response assessment definitions places severe limitations on childhood AML drug development by classifying lack of complete response (CR) using these guidelines as treatment failure
Summary
Acute myeloid leukemia (AML) in children and adults represent a phenotypically heterogeneous and genetically complex subtype of hematopoietic malignancies. There are approximately 20,000 newly diagnosed cases of AML in the United States each year with an average age at diagnosis of 68 years; fewer than 500 of these cases occur in children under the age of 15. Given this differential age distribution [1], clinicians have long assumed that AML observed in older adults is distinct from that seen in children. Similar criteria are followed by the European LeukemiaNet (ELN) in adults with AML [7] These response criteria have remained the standard by which the efficacy of new drugs is measured in clinical trials in both adults and children
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