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.
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 |
| . | 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 |
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 |
| 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.
Hunger:Sigma Tau: Consultancy; Jazz Pharmaceuticals: Consultancy; Merck: Equity Ownership; Spectrum Pharmaceuticals: Consultancy.
Author notes
Asterisk with author names denotes non-ASH members.
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