Optimized treatment for pediatric patients with low-risk Acute Myeloid Leukemia: A report from the Children's oncology group study AAML1831
Bibliographic record
Abstract
Abstract Introduction: Prior comparison of low risk (LR) pediatric acute myeloid leukemia (AML) patients enrolled on Children’s Oncology Group (COG) Phase 3 trials AAML0531 and AAML1031 determined that removal of the 5th high-dose cytarabine cycle results in an increased relapse rate (RR) and inferior disease-free survival (DFS) for most patients except those with favorable genetics and negative (<0.05% by flow cytometry) end of induction 1 (EOI1) minimal residual disease (MRD). COG AAML1831 implemented 4 cycles for this favorable group (LR1) and 5 cycles for LR2 patients (not LR1, not high risk [HR]). AAML1831 also decreased anthracycline exposure for LR1 patients by replacing mitoxantrone/cytarabine (MA) in Cycle 4 with high-dose cytarabine/asparaginase (Capizzi). Here, we report the impact of these changes on outcomes of LR1 and LR2 patients enrolled on AAML1831. Methods: AAML1831 risk stratification criteria were applied retrospectively to AAML0531 Arm B and AAML1031 Arms A and B. To validate the necessity of a 5th cycle, we compared 2-year RR, DFS and overall survival (OS) of LR2 patients on AAML1831 (n=99, 5 cycles), AAML0531 (n=115, 5 cycles) and AAML1031 (n=319, 4 cycles). Similarly, we compared 2-year outcomes between LR1 patients on AAML0531 (n=116, 5 cycles)and AAML1831 (n=88, 4 cycles), and evaluated the impact of substitution of MA (AAML1031 [n=243, 4 cycles]) with Capizzi (AAML1831, 60% cumulative anthracycline reduction). Patients with activating FLT3 point mutations or internal tandem duplication with allelic ratio > 0.1 were not included in this analysis. Time dependent variable (TDV) analysis was used to evaluate the impact of a 5th chemotherapy course. Results: LR2 patients treated with 5 cycles on AAML1831 had a lower 2-year RR than those receiving 4 cycles on AAML1031 (24% vs 44%, p<0.001). Similarly, LR2 DFS was improved on AAML1831 compared to AAML1031 (74% vs 54%, p=0.001). There was no significant difference in OS for LR2 patients treated on AAML1831 vs AAML1031 (87% vs 81%, p=0.21) suggesting that the survival impact of omitting a 5th cycle could be partially mitigated with relapse therapy, including hematopoietic stem cell transplant. As expected, there was no significant difference in RR, DFS or OS for LR2 patients on AAML0531 and AAML1831 as these patients received 5 similar cycles on both studies. Multivariable analysis with cycle 5 as a TDV confirmed the importance of the 5th treatment cycle, with a significant difference in RR (p=0.032), DFS (0.004) and OS (p<0.001). For the most favorable LR1 group, RR and DFS were not significantly different when treated with 4 cycles on AAML1831 compared to 5 cycles on AAML0531 (RR 19% vs 15%, p=0.7; DFS 81% vs 78%, p=0.34). Omission of cycle 5 did not decrease OS, and those treated on AAML1831 had superior OS compared to those treated on AAML0531 (99% vs 90%, p=0.01). Importantly, we found that anthracycline could be safely removed from post-induction therapy for the favorable LR1 group. The 2-year RR and DFS were similar for those treated on AAML1831 and AAML1031 (RR: 19% vs 22%, p=0.33, DFS: 81% vs 75%, p=0.11). LR1 patients receiving high-dose cytarabine without anthracycline on AAML1831 also had superior OS compared to those receiving MA on AAML1031 (99% vs 92%, p=0.031). Multivariable analysis using cycle 5 as a TDV confirmed no survival benefit of a 5th cycle in the LR1 cohort given lack of significant difference in RR, DFS or OS across the 3 trials. Conclusion: Comparison of data from the most recent COG AML phase 3 studies demonstrates that a subgroup of pediatric AML patients (LR2) had superior outcomes with 5 chemotherapy cycles when compared to 4 cycles. The lowest-risk patients with favorable genetics and good disease response (LR1) had no significant difference in RR or DFS with 4 chemotherapy cycles on AAML1831 compared to 5 cycles on AAML0531. Furthermore, this study demonstrates that in LR1 patients, substantial therapy reduction, including a 60% decrease in anthracycline exposure, can be achieved with outstanding survival. These results set a new precedent for risk-adapted treatment to minimize short- and long-term toxicity for pediatric patients with LR AML. Acknowledgment: Astellas Pharma Inc. is a collaborator for AAML 1831, including study funding and clinical supply. Jazz Pharmaceuticals provided funding for AAML1831 and performed a courtesy medical review of the abstract.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".