ORLANDO, Florida ― The aggressive chemotherapy regimen given to children with acute lymphocytic leukemia (ALL) during the induction phase, which aims to push the disease into remission, also depletes their immune system and leaves them highly vulnerable to infection. Giving them prophylactic antibiotics during the whole induction phase reduces infections, a new study shows.
"Children who develop bacterial infections during induction can become severely ill and often need to be admitted to the intensive care unit," said senior author Lewis Silverman, MD, clinical director of the Hematologic Malignancy Center at the Dana Farber Cancer Institute (DFCI), Boston. Infections are the primary cause of treatment-related mortality during the induction phase and lead to prolonged hospitalization, as well as delays and dose modifications in planned chemotherapy, which can reduce its impact on the leukemia.
The new study, presented here at the American Society of Hematology (ASH) 57th Annual Meeting, suggests that giving these children prophylactic antibiotics can more than halve the incidence of bacterial infections, although this result comes from a comparison with historical controls.
Although acknowledging that larger randomized trials are needed to confirm the findings, Dr Silverman described the results as "very exciting.... The use of antibacterial prophylaxis appears to have made a profound difference to our patients."
Approached for an outside comment, Richard Bram, MD, PhD, professor of pediatrics at the Mayo Clinic, in Rochester, Minnesota, said: "We usually do not use antibacterial prophylaxis for ALL induction because we have been concerned about the overuse of antibiotics and possible risk of Clostridium difficile colitis.
"This interesting new study suggests it is safe and decreases the risk of infection," he told Medscape Medical News. "Once it is repeated, it is worth considering prophylactic antibiotics for all children receiving induction therapy for ALL."
Infections Were Halved
The study was conducted by the DFCI All Consortium clinical trials group, which involves nine sites across the United States and Canada. "As a group, we realized that there was a great variability among our institutions in terms of management of leukemia patients who developed a fever," Dr Silverman commented in a statement.
"The study was designed to ask whether uniform guidelines for antibiotic prophylaxis and fever management could prevent infection-related morbidity and mortality in our patients," he explained. "It was not clear, prior to starting the study, whether such a strategy would succeed or whether the use of prophylaxis might increase the incidence of antibiotic-resistant infections or the frequency of fungal infections."
The results show that it did succeed.
The new strategy of antibiotic prophylaxis was used in the 11-001 treatment protocol for pediatric ALL. Results for 229 newly diagnosed patients treated from 2012 to 2015 were presented here at the meeting by Maria-Luisa Sulis, MD, from Columbia University College of Physicians and Surgeons, New York City. All patients received antibiotics throughout the induction phase, whether or not they developed a fever.
The median age of these ALL patients was 5 years (range, 1 - 20.9 years).
The induction therapy included vincristine, methylprednisolone, doxorubicin, low-dose methotrexate, and pegylated L-asparaginase.
Just more than a third of the patients (86 of 229 [37.5%]) were afebrile on diagnosis. Fluoroquinolone prophylaxis was started at the time of initiation of therapy and was continued until count recovery at the end of induction. Of the 86 patients who were afebrile and who received prophylaxis therapy, 37 (43%) subsequently developed fever and were switched to broad-spectrum antibiotics (eg, cefepime).
The rest of the patients (141 of 229 [61.6%]) had fever at diagnosis. They were started on broad-spectrum antibiotics rather than fluoroquinolone and either remained on broad-spectrum antibiotics or were switched to fluoroquinolone prophylaxis until count recovery, at the discretion of the treating clinician, Dr Sulis explained.
The results in this group were compared with historical controls, children who had been treated under the 05-001 protocol, through which they received antibiotics only when they developed a fever.
Infections were halved with the new protocol, Dr Sulis reported.
Under the new protocol of antibiotic prophylaxis, 13.1% of patients had at least one infection, compared with 26.6% under the old protocol. The incidence of bacterial infections was 9.9% with the new protocol, compared with 24.7% with the old protocol.
The observed reduction was due to a decrease in the incidence of bacterial infection (9.9% vs 24.7%; P < .0001). Of note, there were significantly fewer episodes of bacteremia caused by Gram-negative rods,Staphylococcus aureus, and Streptococcus viridans under the new protocol, Dr Sulis reported.
There were no significant differences in the rates of other treatment-related mortality, fungal infection, or infections with Clostridium difficile between the groups.
The induction death rate on the new protocol was 0.9%, compared with 2% on the old protocol. The incidence of fungal infection was 4.5% vs 3.9% (P = .32). Dr Sulis noted that 20 of the 229 patients (9%) on the new protocol developed C difficile colitis (16 patients, grade 2; 3 patients, grade 3; 1 patient, grade 4).
The authors have disclosed no relevant financial relationships.
American Society of Hematology (ASH) 57th Annual Meeting. Abstract 249. Presented December 6, 2015.
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