Effectiveness of Supportive Care Measurements to Reduce Infections during Induction for Children with Acute Myeloid Leukemia: A Report from the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG)

BACKGROUND: Current intensive chemotherapy for pediatric acute myeloid leukemia (AML) in conjunction with supportive care has increased survival rate up to 70%, and yet infections are still responsible for considerable morbidity and most treatment-related deaths. These factors have led to much interest in supportive care measurements to reduce infections and infectious mortality. The Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) trial AML-05 was a phase 2 study that included children with de novo AML treated with intensive chemotherapy. We surveyed participating JPLSG sites to assess the effect of each supportive care measurements on Induction I infection risk and non-relapse mortality for children in AML-05 study.

METHODS: Between November 2006 and December 2010, JPLSG AML-05, registered at http://www.umin.ac.jp/ctr/ as UMIN000000511, recruited 447 eligible children (age <18 years) with de novo AML. AML-05 used 5 courses of intensive chemotherapy with Induction I consisting of etoposide 150mg/m2/dose intravenous (IV) every 24 h on day 1-5; cytarabine 200 mg/m2/dose intravenous (IV) every 12 h on days 6-12; mitoxantrone 5 mg/m2/dose IV on days 6-10; triple intrathecal treatment (methotrexate/ cytarabine/ hydrocortisone) (ECM 5+7+5). Data of Infectious complications were collected prospectively and monitored in real-time to optimize reporting accuracy. In this analysis, infectious events were limited to Induction I. Non-relapse mortality was defined as any induction death within 40 days of being taken off study due to non-disease related causes. The survey included questions on implementations in each patient participated in AML-05 study for antibacterial prophylaxis, antifungal prophylaxis, intestinal sterilization, use of HEPA-filter, surveillance culture, and use of G-CSF until count recovery.

RESULTS: The survey response rate from the JPLSG sites was 359/447 (80.3%). In multiple regression, anti-bacterial prophylaxis reduced the development of febrile neutropenia during induction chemotherapy (Odds ratio [OR] 0.56, 95% confidence interval [CI] 0.39-0.88; p = 0.013). Sterile site bacterial infections increased in younger age group (OR 2.0, 95% CI, 1.09-3.66; p = 0.025) but decreased in patients who were routinely carried out surveillance culture (OR 0.5, 95% CI, 0.27-0.96; p = 0.038). Fungal infection during induction chemotherapy was associated with intestinal sterilization (OR 0.21, 95% CI, 0.61-0.70; p = 0.011) and the use of G-CSF (OR 3.83, 95% CI, 1.10-13.32; p = 0.035). Prophylactic antifungal agent had a tendency to reduce the frequency and duration of pyrexia, and the peak value of CRP. Nonetheless, routine prophylaxis with these agents did not impact non-relapse mortality.

CONCLUSIONS: Prophylactic use of antibiotics was associated with less development of febrile neutropenia. Routine prophylaxis with these agents may be associated with incidence and severity of infectious complications, but did not impact non-relapse mortality during induction chemotherapy in childhood AML.