Treatment-Related Mortality (TRM) in Children with Down Syndrome (DS) and B-Lymphoblastic Leukemia (B-ALL): An Interim Report from the Children's Oncology Group Trials AALL0932 and AALL1131
Bibliographic record
Abstract
Abstract Background: Children with DS and B-ALL have historically experienced excessive TRM, primarily from infection. Here we provide an interim report on TRM in children with DS and newly diagnosed B-ALL enrolled on Children's Oncology Group (COG) trials for NCI standard risk (SR) (AALL0932) and high risk (HR) B-ALL (AALL1131). Methods: As of 06/30/2015, 203 SR DS-ALL patients have completed Induction on AALL0932 with 146 receiving post-Induction treatment on AALL0932. Eighty-eight HR DS patients have completed Induction on AALL1131, with 80 receiving post-Induction treatment on AALL1131. An additional 26 SR DS patients with poor early response received post-Induction therapy on AALL1131. Adverse events were graded according to NCI CTCAE v4.0, with enhanced data collection for targeted toxicities including infectious toxicities, and enhanced supportive care recommendations. Results: Patient characteristics are summarized in Table 1. TRM on AALL0932 occurred during Induction in 2/203 (1.0%) and post-Induction in 3/146 (2.1%), compared to 17/5528 (0.3%) and 12/3119 (0.4%) in non-DS SR patients (Fisher exact p=0.14 for Induction and p=0.03 for post-Induction). TRM on AALL1131 occurred during Induction in 4/88 (4.5%) and post-Induction in 5/106 (4.7%), compared to 34/2116 (1.6%) and 13/1258 (1.0%) in non-DS AALL1131 patients (p=0.06 for Induction and p=0.01 for post-Induction). Timing, cause, and other circumstances surrounding TRM are provided in Table 2. Gram-negative organisms accounted for the majority of fatal bacterial infections in patients with HR DS-ALL. Conclusion: TRM continues to be higher on current COG trials for patients with DS-ALL compared to non-DS patients. Most of the toxic deaths occur during intensive treatment phases due to infection in the context of profound neutropenia. Patients with HR B-ALL have a higher incidence of toxic death, notably in patients over 15 years of age. Based on our findings, hospitalization and antimicrobial prophylaxis during intensive treatment phases should be considered in children with DS-ALL due to their increased risk of infection-related mortality. Table 1. Patient Characteristics AALL1131 AALL0932 DS-ALL Non-DS ALL DS-ALL Non-DS ALL N 117 2689 207 5619 Median Age at Diagnosis (Years) 10.5 10.3 4.8 4.5 Gender Male 62 1511 117 2981 Female 55 1178 90 2637 Table 2. Treatment-Related Mortality Case Characteristics Case Age Gender Treatment Phase Site of Infection Organism AALL1131 (High Risk) 1 15 F Induction D#29 (RER) Pneumonia, ARDS HMPV (pre-treatment) 2 21 F Induction D#29 (SER) Sepsis 3 17 F Induction D#22 (SER) Sepsis, typhlitis Escherichia coli 4 12 M Induction D#16 (RER) Sepsis, pneumonia (+baseline CHD, AV canal s/p repair 2003) Influenza B 5 19 M Consolidation D#18 Sepsis Citrobacter 6 2 F Delayed Intensification D#101 ARDS/capillary leak (+baseline CHD) Rhinovirus 7 15 F Delayed Intensification D#45 Sepsis, pneumonia Klebsiella, enterovirus, rhinovirus 8 27 M Delayed Intensification D#52 Sepsis Gram negative bacillus 9 14 M Delayed Intensification D#22 Sepsis AALL0932 (Standard Risk) 1 7.3 M Induction Febrile neutropenia, hypotension, cardiorespiratory failure None reported 2 3.0 F Induction Febrile neutropenia, sepsis, liver failure Viridans group Strepococcus coagulase negative staphylococcus HSV, EBV and HHV 3 3.4 M Consolidation Meningitis, brainstem infarction None reported 4 9.7 F Interim Maintenance I Sepsis, Stevens Johnson syndrome/TEN None reported 5 7.2 M Interim Maintenance II Death NOS None reported RER, rapid early responder; SER, slow early responder; CHD, congenital heart disease; AV, atrioventricular; ARDS, acute respiratory distress syndrome; HMPV, human metapneumovirus; TEN, toxic epidermal necrolysis; HSV, herpes simplex virus; EBV, Epstein-Barr virus; HHV, human herpesvirus. Disclosures Hunger: Sigma Tau: Consultancy; Jazz Pharmaceuticals: Consultancy; Merck: Equity Ownership; Spectrum Pharmaceuticals: Consultancy.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".