Outcomes in children and adolescents with down syndrome and B-lymphoblastic leukemia: A report from Children's oncology group study AALL1731
Bibliographic record
Abstract
Abstract Background: Individuals with DS have a 20-fold increased risk of B-ALL, and experience increased rates of both relapse and treatment-related mortality (TRM). Those with high-risk (HR) disease requiring intensified therapy have shown the greatest disparities in both TRM and relapse rates compared to patients without DS, and thus may benefit most from treatment incorporating blinatumomab due to its anti-leukemic efficacy and favorable toxicity profile. Here, we report outcomes for patients with DS and B-ALL with HR features enrolled on COG trial AALL1731 from 2019-2022, receiving a regimen of modified chemotherapy plus 3 cycles of 28-day continuous intravenous blinatumomab, versus comparable patients with DS and B-ALL enrolled on the prior trial, AALL1131, treated with chemotherapy alone. Methods: Eligible patients had DS and de novo B-ALL, age 1-30 years, NCI HR and/or other HR features (CNS3 status, testicular involvement, steroid pretreatment, unfavorable cytogenetics, or end of induction [EOI] minimal residual disease [MRD]>0.01%). HR DS patients on AALL1131 received a chemotherapy regimen with DS-specific modifications: leucovorin rescue after intrathecal methotrexate (MTX), reduced induction anthracycline, intermediate-dose MTX, and enhanced supportive care. HR DS patients on AALL1731 were assigned to a single arm cohort termed DS-High. AALL1731 DS-High patients received the same treatment modifications as on AALL1131, and additionally omitted all induction anthracycline and the second month of delayed intensification (DI). AALL1731 DS-High patients also received 3 non-sequential cycles of blinatumomab intercalated between chemotherapy courses. The DS-High cohort was suspended to accrual on 4/29/2022 and subsequently permanently closed; patients meeting DS-High criteria at EOI after this date were taken off protocol therapy. Results: AALL1731 enrolled 134 patients with DS and B-ALL with HR features (85 classified as HR at diagnosis and 49 classified as HR post-induction). As of 06/2025, with a median follow-up time of 4.1 years (interquartile range 3.6-4.7 years), there were 3 deaths in induction and 7 deaths in remission (DIR). Induction death rate was not different between AALL1731 and AALL1131 (3.5% vs 3.6%). Ninety-three AALL1731 patients (69 classified as HR at diagnosis and 24 classified post-induction) received DS-High on protocol therapy post-induction (22 came off protocol due to protocol closure, and 19 for other reasons), with a 4-year disease-free survival (DFS) of 84.8+4.9%. A post-consolidation comparison of HR DS patients treated on AALL1731 (n=85) and AALL1131 (n=235) showed no significant difference in 4-year DFS (84.7+5.4% vs 77.6+2.8%, p=0.21); overall survival (OS) (88.2+4.8% vs 89.2+2.1%, p=0.71); or cumulative incidence (CI) of DIR (8.2+3.0% vs 4.7+1.4%, p=0.22). Post-consolidation DIR on AALL1731 occurred in DI (n=4), maintenance (n=2), and off therapy (n=1), 5 with an infectious component. Importantly, DS-High patients treated on AALL1731 showed a significantly lower 4-year CI of relapse compared with AALL1131 (4.7+2.3% vs 16.9+2.5%, p=0.006). Indeed, among the AALL1731 DS-High cohort, more post-Consolidation treatment failures were due to DIR (N=7) than due to relapse (N=4), in contrast to similar patients on AALL1131 (DIR=12, relapse=52). Among the AALL1731 DS-High cohort as of the 06/25 data cutoff, no relapse was seen later than 2.7 years from diagnosis. Three relapses on AALL1731 were CD19-positive (2 isolated extramedullary, one combined marrow/CNS) and one was CD19-negative. Conclusions: Patients with DS and B-ALL continue to have inferior outcomes compared to those without DS due to both relapse and TRM. At a median follow-up of 4 years, DFS and OS on AALL1731 were preserved but not improved compared to AALL1131 with use of 3 cycles of blinatumomab and moderately de-intensified chemotherapy. However, the CI of relapse is significantly lower on AALL1731 and to date, late relapses seen in previous cohorts of DS patients have not been observed. As 25% of DS relapses on AALL1131 occurred more than 4 years from diagnosis, AALL1731 DFS may demonstrate superiority with longer follow-up time. Nevertheless, unacceptable risk of TRM persists for patients with DS and B-ALL. Our findings suggest that strategies further reducing chemotherapy and/or further incorporating immunotherapy are warranted in future trials to improve outcomes for this high-risk, vulnerable population.
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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 | 0.001 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.002 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.000 | 0.001 |
| 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".