Additional Induction Intrathecal Cytarabine for Patients with CNS2 Disease at Diagnosis Is Not Beneficial for Patients with B-ALL Treated on Children's Oncology Group Protocols AALL0932 and AALL1131
Bibliographic record
Abstract
Background: Children's Oncology Group (COG) trials AALL0932 and AALL1131 enrolled children with newly diagnosed National Cancer Institute (NCI) standard-risk (SR) and high-risk (HR) B-ALL from 2010-2019 and 2012-2019, respectively. In 2016, COG amended these trials to incorporate additional induction intrathecal (IT) therapy for patients with B-ALL and CNS2 status [CSF <5/μL WBCs and cytospin positive for blasts; or traumatic lumbar puncture (LP) with ≥5/μL WBCs and cytospin positive for blasts that was negative by Steinherz/Bleyer algorithm]. Based on data demonstrating worse outcomes for CNS2 patients enrolled on prior COG B-ALL trials compared to those without CNS disease at diagnosis (CNS1), COG added IT cytarabine on day 4, maintained day 8 IT methotrexate, then continued twice weekly IT cytarabine until 3 consecutive LPs returned negative cerebrospinal fluid (CSF) results. Methods: Event free survival (EFS), overall survival (OS), and cumulative incidence of relapse (CIR) were compared among CNS2 pre- vs post-amendment patients, stratified by NCI risk group. Multivariable models were also constructed to adjust for demographic and disease variables. Results: When stratified by trial, pre- and post-amendment patients did not differ significantly by demographic or disease factors, including age at diagnosis, end of induction bone marrow MRD status, and blast cytogenetics. For patients with NCI SR B-ALL and CNS2 enrolled on AALL0932 (8% of study population, n=535 pre-amendment, n=207 post-amendment), the 5-year EFS pre- vs post-amendment was 86.7% (SE, 1.5%) vs 88.9% (SE, 2.3%), p=0.44, and 5-year OS pre- vs post-amendment was 95.5% (SE, 0.9%) vs 96.0% (SE, 1.5%), p=0.50. The 5-year CIR for isolated CNS relapse was 3.6% (SE, 0.8%) vs 4.0% (SE, 1.4%) pre- vs post-amendment, p=0.71, and for combined marrow and CNS relapses was 1.0% (SE, 0.4%) vs 1.0% (SE, 0.7%), p=0.71. Among post-amendment NCI SR patients (CNS1 n=2033, CNS2 n=207), the adverse impact of CNS2 status remained statistically significant, with 5-year EFS of 93.2% (SE, 0.6%) vs 88.9% (SE, 2.3%) for CNS1 vs CNS2, p=0.025. For patients with NCI HR B-ALL and CNS2 status (16.6% of study population, n=488 pre-amendment, n=313 post-amendment), the 5-year EFS pre- vs post-amendment was 66.5% (SE, 2.4%) vs 73.5% (SE, 3.4%), p=0.095 and OS pre- vs post-amendment was 80.2% (SE, 2.0%) vs 84.0% (SE, 2.8%), p=0.20. The 5-year CIR for isolated CNS relapse was 5.9% (SE, 1.1%) vs 5.6% (SE, 1.4%) pre- vs post-amendment, p=0.92, and for combined marrow and CNS relapses was 2.7% (SE, 0.8%) vs 0.7% (SE, 0.5%) pre- vs post-amendment, p=0.068. The post-amendment impact of CNS status on outcomes remained significant for NCI HR patients (CNS1 n=1326, CNS2 n=313), with 5-year EFS of 78.4% (SE 1.5%) vs 73.5% for CNS1 vs CNS2, p=0.049. In multivariable analyses conducted separately for AALL0932 and AALL1131 and adjusting for disease prognosticators and race/ethnicity, treatment post-amendment was not significantly associated with any difference in EFS (AALL0932: hazard ratio 0.99, 95CI 0.6-1.6, p=0.95; AALL1131: hazard ratio 0.80, 95CI 0.6-1.1, p=0.14). Additional analyses evaluating subgroups defined by cytogenetics (favorable, neutral, unfavorable) or disease response did not find any subpopulation that significantly benefited from extra IT chemotherapy. The additional therapy was not associated with an increase in toxicity. Conclusions: Additional IT cytarabine during induction for patients with CNS2 disease on AALL0932 and AALL1131 did not improve outcomes or mitigate the adverse prognostic impact of CNS2 status. Rates of CNS2 status and impact on outcome vary greatly between cooperative groups, and factors such as variability in CSF analysis and post-induction therapy need to be considered in order to identify this population accurately and treat accordingly. Given these results showing lack of improvements in outcome and concerns surrounding repeated anesthesia exposure, future frontline B-ALL COG studies will not include additional IT cytarabine for the CNS2 population. Alternative methods of improving outcomes for CNS2 patients are needed.
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 | 0.002 | 0.006 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".