Treatment Intensification Does Not Improve Outcome for Children with Myeloid Leukemia of Down Syndrome (ML-DS) Who Are MRD-Positive after Induction Therapy: A Report from the Children's Oncology Group
Bibliographic record
Abstract
Background . Myeloid leukemia of Down syndrome (ML-DS) is a distinct form of pediatric AML that is treated with DS-specific reduced intensity chemotherapy with a resulting favorable prognosis (5-year EFS 89.9%). In contrast, non-responders and patients with relapsed ML-DS have a dismal outcome. The aim of Children's Oncology Group (COG) study AAML1531 was introduce risk stratification of chemotherapy intensity for patients with ML-DS based on measurable residual disease by multi-parameter flow cytometry at the end of the first course of induction (EOI-1 MRD), which is used to risk stratify treatment intensity for non-DS pediatric AML patients and was prognostic in the preceding ML-DS trial, AAML0431. Methods . AAML1531 enrolled 280 patients with ML-DS between November 2015 and April 2022. All patients received the same first course of induction therapy (Induction I): daunorubicin, cytarabine, 6-thioguanine (DAT). Those with EOI-1 MRD <0.05% were classified as Standard Risk (SR, Arm A) and treated with reduced-intensity chemotherapy based on the historical control, AAML0431, but with elimination of the second induction course of AAML0431 therapy, which consisted of high-dose cytarabine/asparaginase, to reduce infectious events. Patients with EOI-1 MRD >0.05% were classified as High Risk (HR, Arm B) and had their subsequent treatment intensified to a level consistent with that of pediatric non-DS AML (Induction II: mitoxantrone/high-dose cytarabine; Intensification I: cytarabine/etoposide; Intensification II: high-dose cytarabine/asparaginase) with the aim of reducing the number of relapse events. Cytogenetic results were centrally reviewed and MRD was measured by multidimensional flow cytometry in a reference laboratory (Hematologics, Inc., Seattle, WA). Results.We previously reported outcomes for the SR group (n=114) (Hitzler et al. Blood 2021). We now report outcomes of patients in the ML-DS HR group (n=41). Efficacy: Intensification of chemotherapy for EOI-1 MRD-positive patients did not significantly improve the 2-year EFS compared to that of the AAML0431 EOI-1 MRD-positive cohort (AAML1531: 80.5 + 12.4% vs. AAML0431: 76%, p=0.247). OS also did not differ significantly (AAML1531: 80.5 + 12.4% vs. AAML0431: 76.2 + 18.6%, p=0.819). There were 7 relapses and 1 death as first event. Of the 7 patients with relapse, 6 did not survive (2-year-OS 14.3 + 26.5% after relapse). Adverse events: Febrile neutropenia (FN) occurred in 25.4% of all AAML1531 patients during the common Induction I phase. During intensified post-induction therapy on the HR arm, the course-specific proportions of FN were 31.7% of 41 patients (Induction II), 27.5% of 40 patients (Intensification I) and 26.3% of 38 patients (Intensification II). The corresponding proportions on the reduced-intensity SR arm were significantly lower than on the HR arm: 3.7% of 108 patients (Induction II, p<0.001), 6.9% of 101 patients (Induction III, no corresponding HR course), 6.1% of 98 patients (Intensification I, p=0.001) and 8.6% of 93 patients (Intensification II, p=0.008). Sepsis grade 3 or greater was reported in 9.8% of 41 patients (Induction II, p=0.005) treated on HR arm compared to none treated on the SR (Ind II, n=108), and in 3.3% in the common Induction phase (Induction I). Conclusions. Intensification of chemotherapy for patients with ML-DS with positive EOI-1 MRD neither improved EFS nor OS and resulted in more FN and a greater number of sepsis events. While EOI-1 flow cytometric MRD detected ML-DS patients whose outcomes were poorer than those without MRD (Taub et al. Blood 2017), intensification of chemotherapy was not beneficial to the MRD-positive group. Overall, results of AAML1531 demonstrate that stratification of treatment intensity according to flow cytometric EOI-1 MRD did not did not improve outcomes for patients with ML-DS. Alternative approaches such as mutational profiling of ML-DS blasts should be evaluated with regard to prognostication, risk stratification and identification of targets for novel agents to improve the overall outcome for this disease.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.001 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| 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".