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

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 1Patient CharacteristicsAALL1131AALL0932DS-ALLNon-DS ALLDS-ALLNon-DS ALLN11726892075619Median Age at Diagnosis (Years)10.510.34.84.5GenderMale6215111172981Female551178902637Table 2Treatment-Related Mortality Case CharacteristicsCaseAgeGenderTreatment PhaseSite of InfectionOrganismAALL1131 (High Risk)115FInduction D#29 (RER)Pneumonia, ARDSHMPV (pre-treatment)221FInduction D#29 (SER)Sepsis317FInduction D#22 (SER)Sepsis, typhlitisEscherichia coli412MInduction D#16 (RER)Sepsis, pneumonia (+baseline CHD, AV canal s/p repair 2003)Influenza B519MConsolidation D#18SepsisCitrobacter62FDelayed Intensification D#101ARDS/capillary leak (+baseline CHD)Rhinovirus715FDelayed Intensification D#45Sepsis, pneumoniaKlebsiella, enterovirus, rhinovirus827MDelayed Intensification D#52SepsisGram negative bacillus914MDelayed Intensification D#22SepsisAALL0932 (Standard Risk)17.3MInductionFebrile neutropenia, hypotension, cardiorespiratory failureNone reported23.0FInductionFebrile neutropenia, sepsis, liver failureViridans group Strepococcus coagulase negative staphylococcus HSV, EBV and HHV33.4MConsolidationMeningitis, brainstem infarctionNone reported49.7FInterim Maintenance ISepsis, Stevens Johnson syndrome/TENNone reported57.2MInterim Maintenance IIDeath NOSNone reportedRER, 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. DisclosuresHunger:Sigma Tau: Consultancy; Jazz Pharmaceuticals: Consultancy; Merck: Equity Ownership; Spectrum Pharmaceuticals: Consultancy.