Infectious complications in patients with acute leukemia according to the duration of neutropenia

Introduction. Patients with hematological malignancies undergoing chemotherapy (CT) have high incidence of infections which profile is affected by various factors including neutropenia.

Objective was to evaluate incidence and type of infections in patients with de novo acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) according to neutropenia duration.

Materials and methods. Prospective study (2013–2015) included 110 patients (66 AML, 44 ALL) that received 480 CT cycles throughout 6 month.

Results. Neutropenia with median duration of 15 (2–55) days was in 288 (60 %) of CT cycles. Infections occurred in 242 (50 %) of CT cycles and predominated in neutropenic compared to non-neutropenic patients (80 % vs 6 %, p <0.0001). Infections prevailed in patients with AML compared to ALL patients (93 % vs 18 %, p <0.0001) as in patients with neutropenia (96 % vs 45 %, p <0.0001) and without neutropenia (27 % vs 4 %, p = 0.02). Prolongation of neutropenia from 1–7 days to ≥22 days was associated with increase of infections rate from 52 to 96 % (p <0.0001). Incidence of infections in AML patients was high (92–100 %) regardless of neutropenia duration, whereas in ALL patients it increased from 25–33 to 91 % if neutropenia lengthened from 2 weeks to ≥22 days. During neutropenia the probability of fever of unknown origin was 33.9 %, clinically documented infection – 31.3 %, bacteremia – 17.2 %. They predominated in the first 2 weeks of neutropenia. Probability of invasive aspergillosis (IA) increased after 28 days of neutropenia and reached 66 % on the 55th day. First case of IA in patients with ALL was on 28th day of neutropenia whilst in AML patients – 4 (44 %) of 9 occurred more early (6–16 days of neutropenia). Nine (6 %) of 110 patients died, 4 (4 %) of them due to infection.

Conclusions. Neutropenia was a predictor of infectious complications in patients with AML and ALL. Correlation between duration of neutropenia and incidence of infections was in patients with ALL, whereas in AML patients the rate of infections was high regardless of neutropenia duration. In patients with neutropenia for 2 weeks the most common types of infection were fever of unknown origin, clinically documented infection and bacteremia whilst IA predominated if neutropenia duration was ≥28 days.

1. Klyasova G.A., Okhmat V.A. Antimicrobial therapy. In: Algorithms of diagnosing and protocols of treatment of blood system diseases. Ed.: V.G. Savchenko. Vol. 2. M.: Praktika 2018. Р.1067–114. (In Russ.).

2. Savchenko V.G., Parovichnikova E.N., Afanasyev B.V. et al. National clinical guidelines for the diagnosis and treatment of acute myeloid leukemia in adults. Gematologiya i Transfusiologiya = Hematology and Transfusiology 2014;59(S2):2–29. (In Russ.).

3. Parovichnikova E.N., Klyasova G.A., Isaev V.G. et al. Pilot results of therapy of adult Ph-negative acute lymphoblastic leukemia according to the protocol of Research Group of Russian Hematological Centers ALL-2009. Terapevticheskiy Arkhiv = Therapeutic archive 2011;83(7):11–7. (In Russ.).

4. De Pauw B., Walsh T.J., Donnelly J.P. et al. Revised definitions of invasive fungal disease from the European organization for research and treatment of cancer/invasive fungal infections cooperative group and the national institute of allergy and infectious diseases mycoses study group (EORTC/MSG) consensus group. Clin Infect Dis 2008;46(12):1813–21. DOI: 10.1086/588660. PMID: 18462102.

5. Bodey G.P., Buckley M., Sathe Y.S., Freireich E.J. Quantitative relationships between circulating leukocytes and infection in patients with acute leukemia. Ann Intern Med 1966;64(2):328–40. DOI: 10.7326/0003-4819-64-2-328. PMID: 5216294.

6. Di Blasi R., Cattaneo C., Lewis R.E. et al. Febrile events in acute lymphoblastic leukemia: a prospective observational multicentric SEIFEM study (SEIFEM-2012/B ALL). Ann Hematol 2018;97(5):791–8. DOI: 10.1007/s00277-018-3252-6. PMID: 29411126.

7. Gerson S.L., Talbot G.H., Hurwitz S. et al. Prolonged granulocytopenia: the major risk factor for invasive pulmonary aspergillosis in patients with acute leukemia. Ann Intern Med 1984;100(3):345–51. DOI: 10.7326/0003-4819-100-3-345. PMID: 6696356.

8. Portugal R.D., Garnica M., Nucci M. Index to predict invasive mold infection in high-risk neutropenic patients based on the area over the neutrophil curve. J Clin Oncol 2009;27(23):3849–54. DOI: 10.1200/JCO.2008.21.0856. PMID: 19597026.

9. Kaya S., Gençalioğlu E., Sönmez M., Köksal I. The importance of risk factors for the prediction of patients with invasive pulmonary aspergillosis. Rev Assoc Med Bras 2017;63(9):764–70. DOI: 10.1590/1806-9282.63.09.764. PMID: 29239468.