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

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.