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 
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 
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) 
15 Induction D#29 (RER) Pneumonia, ARDS HMPV (pre-treatment) 
21 Induction D#29 (SER) Sepsis  
17 Induction D#22 (SER) Sepsis, typhlitis Escherichia coli 
12 Induction D#16 (RER) Sepsis, pneumonia (+baseline CHD, AV canal s/p repair 2003) Influenza B 
19 Consolidation D#18 Sepsis Citrobacter 
Delayed Intensification D#101 ARDS/capillary leak (+baseline CHD) Rhinovirus 
15 Delayed Intensification D#45 Sepsis, pneumonia Klebsiella, enterovirus, rhinovirus 
27 Delayed Intensification D#52 Sepsis Gram negative bacillus 
14 Delayed Intensification D#22 Sepsis  
AALL0932 (Standard Risk) 
7.3 Induction Febrile neutropenia, hypotension, cardiorespiratory failure None reported 
3.0 Induction Febrile neutropenia, sepsis, liver failure Viridans group Strepococcus coagulase negative staphylococcus
HSV, EBV and HHV 
3.4 Consolidation Meningitis, brainstem infarction None reported 
9.7 Interim Maintenance I Sepsis, Stevens Johnson syndrome/TEN None reported 
7.2 Interim Maintenance II Death NOS None reported 
Case Age Gender Treatment Phase Site of Infection Organism 
AALL1131 (High Risk) 
15 Induction D#29 (RER) Pneumonia, ARDS HMPV (pre-treatment) 
21 Induction D#29 (SER) Sepsis  
17 Induction D#22 (SER) Sepsis, typhlitis Escherichia coli 
12 Induction D#16 (RER) Sepsis, pneumonia (+baseline CHD, AV canal s/p repair 2003) Influenza B 
19 Consolidation D#18 Sepsis Citrobacter 
Delayed Intensification D#101 ARDS/capillary leak (+baseline CHD) Rhinovirus 
15 Delayed Intensification D#45 Sepsis, pneumonia Klebsiella, enterovirus, rhinovirus 
27 Delayed Intensification D#52 Sepsis Gram negative bacillus 
14 Delayed Intensification D#22 Sepsis  
AALL0932 (Standard Risk) 
7.3 Induction Febrile neutropenia, hypotension, cardiorespiratory failure None reported 
3.0 Induction Febrile neutropenia, sepsis, liver failure Viridans group Strepococcus coagulase negative staphylococcus
HSV, EBV and HHV 
3.4 Consolidation Meningitis, brainstem infarction None reported 
9.7 Interim Maintenance I Sepsis, Stevens Johnson syndrome/TEN None reported 
7.2 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.

Author notes

*

Asterisk with author names denotes non-ASH members.