In contrast, the rate of grade 3/5 hypoxia reported in an analysis of results of 2 clinical trials involving a similar patient population was 6%. “A discordance likely related to under recognition of respiratory adverse events in prior multi-institutional cohort analyses,” the researchers commented.

Notably, although fluid overload was found to occur in 28.6% (n=30) of patients, half of these events occurred within 24 hours of hospitalization, often prior to initiation of chemotherapy; whereas the other half occurred 10 or more days after treatment initiation. On multivariate analysis adjusted for age, race/ethnicity, platelet count, and infection, fluid overload was associated with increased risk of a respiratory adverse event both before day 10 (hazard ratio [HR], 5.5; 95% CI, 2.3-12.8) and from day 10 and beyond (HR, 13.0; 95% CI, 4.1-41.8).

“Fluid overload is an iatrogenic and modifiable risk factor, yet the construct of fluid overload is not included in the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) versions 4.0 and 5.0” the researchers pointed out.

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In addition, respiratory infections occurred in 39% (n=41) of patients; a positive infection status at 10 or more days following treatment initiation was also independently associated with the development of respiratory adverse events (HR, 14.9; 95% CI, 5.4-41.6).

Five patients (4.8%) died during induction chemotherapy. The deaths were attributed to ARDS in 2 patients and hypoxia not otherwise specified in 1 patient (with each of those 3 patients experiencing invasive fungal infection), as well as apnea secondary to left frontal intraparenchymal hemorrhage in 1 patient, and uncal herniation in a patient with coagulopathy.

Limitations of this study included challenges associated with retrospective assessment of fluid overload and the omission of incidences of fever of unknown origin as well as nonpulmonary infections.

Nevertheless, the study authors concluded that these “data support a need for the prospective management of fluid overload and systemic or pulmonary infection as risk factors for respiratory adverse event development during the initial pediatric AML course. Cooperative and institutional protocols should consider providing explicit fluid management guidelines directed to recognition of fluid overload, maintenance of net-neutral fluid balance, and standardization of grading and reporting of fluid overload status.”

The study authors suggest scheduled incentive spirometry, positive expiratory pressure, and early frequent ambulation for all children and adolescents with AML.


Miller LH, Keller F, Mertens A, et al. Impact of fluid overload and infection on respiratory adverse event development during induction therapy for childhood acute myeloid leukemia [published online September 10, 2019]. Pediatr Blood Cancer. doi: 10.1002/pbc.27975