Preneutropenic Fever in Patients With Hematological Malignancies: A Novel Target for Antimicrobial Stewardship

Many patients with hematological malignancy develop fever after chemotherapy/conditioning but before chemotherapy-induced neutropenia (preneutropenic fever [PNF]). The proportion of PNF with an infectious etiology is not well established.

We conducted a single-center, prospective observational substudy of PNF (neutrophils >0.5 cells/μL, ≥38.0°C) in adults receiving acute myeloid leukemia (AML) chemotherapy, or allogeneic hematopoietic cell transplant (allo-HCT) conditioning enrolled in a neutropenic fever randomized controlled trial between 1 January and 31 October 2018. Eligible patients had anticipated neutropenia ≥10 days and exclusions included concurrent infection and/or neutropenia prior to chemotherapy or conditioning. PNF rates and infections encountered were described. Associations between noninfectious etiologies and fever were explored. Antimicrobial therapy prescription across preneutropenic and neutropenic periods was examined.

Of 62 consecutive patients included (43 allo-HCT, 19 AML), 27 had PNF (44%) and 5 (19%) had an infective cause. Among allo-HCT, PNF occurred in 14 of 17 (82%) who received thymoglobulin; only 1 of 14 (7%) had infection. During AML chemotherapy, 18 of 19 received cytarabine, of which 8 of 18 (44%) had PNF and 3 of 8 (38%) had infection. Most patients with PNF had antimicrobial therapy continued into the neutropenic period (19/27 [70%]). Those with PNF were more likely to be escalated to broader antimicrobial therapy at onset/during neutropenic fever (5/24 [21%] vs 2/30 [7%]).

Rates of PNF were high, and documented infection low, leading to prolonged and escalating antimicrobial therapy. In the absence of infection, early cessation of empiric therapy after PNF is recommended as an important stewardship intervention.