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  • br a Department of Medicine University Health Network


    a Department of Medicine, University Health Network, Toronto, Canada
    b Department of Medicine, University of Toronto, Toronto, Canada
    c Institute of Health Policy, Management, and Evaluation, University of Toronto, Toronto, Canada
    d Biostatistics Research Unit, University Health Network, Toronto, Canada
    e Department of Psychiatry, University Health Network, Toronto, Canada
    f Division of Neurology, Department of Medicine, University of Alberta, Edmonton, Canada
    Article history:
    Received in revised form 20 February 2019 Accepted 9 April 2019 Available online xxxx
    Acute myeloid leukemia
    Cancer-related fatigue
    Quality of life
    Tumor necrosis factor
    Objectives: We determined whether cytokines are a potential target to improve cancer-related fatigue (CRF) and quality of life (QOL) in acute myeloid leukemia (AML).
    Methods: 219 patients age 18+ undergoing intensive chemotherapy for AML were assessed at up to 4 time points (pre-treatment, 1 month, 6 months, 12 months). CRF and QOL were assessed with validated patient-reported outcome measures with minimum clinically important differences (MCID) of 4 and 10 points, respectively. A panel of 31 plasma cytokines was measured. CRF and QOL were regressed against scaled cytokine values, adjusting for age, gender, time, remission status, and Fasudil in linear models.
    Results: 498 cytokine samples were available. For CRF, the model R2 was 25.3%, with cytokines explaining 6.9% of the variance. For QOL, corresponding values were 27.9% and 7.4%, respectively. A shift from the 30th to 70th centile distribution of all cytokines was associated with an improvement in CRF by 5.2 points and a 10.2-point improvement in QOL. A shift from 5th to 95th centile in TNF-α but no other single cytokine was associated with a change of NMCID in CRF, but there was no similar association with QOL. Cytokines had greater explanatory power for CRF in older versus younger adults and the most influential cytokines differed by age, particularly TNF-α.
    Conclusion: Cytokines explain a relatively small amount of CRF and QOL scores in patients with AML and effects differ by age group. For cytokine-targeted therapies to improve either outcome, multiple cytokines may need to be substantially altered and therapeutic targets may vary with age. © 2019 Elsevier Ltd. All rights reserved.
    1. Introduction
    Acute myeloid leukemia (AML) is an aggressive hematological ma-lignancy with a poor prognosis [1]. For younger and otherwise fit older adults, initial treatment of AML consists of four to five weeks of in-hospital induction chemotherapy followed by several cycles of con-solidation chemotherapy after complete remission has been achieved. In addition to the significant toxicities and mortality risk from chemo-therapy [2,3], cancer-related fatigue (CRF) is one of the most common symptoms and negatively impacts on quality of life (QOL) [4–6]. Com-pared to usual fatigue, CRF is a more severe and enduring fatigue that
    Corresponding author at: University Health Network, 200 Elizabeth Street Room EN14-214, Toronto, Ontario M5G 2C4, Canada.
    E-mail address: [email protected] (S.M.H. Alibhai).
    may persist for months to years after cancer treatment and is not allevi-ated by rest or adequate sleep [7,8].
    Previous studies of CRF in patients with AML have shown that over 90% of patients reported fatigue at every time point between the time of diagnosis and completion of intensive chemotherapy (IC) [9]. Fur-thermore, improvements in CRF were relatively small over the next six months [9,10]. Increasing CRF was associated with both worse QOL and worse daily function [9].
    Although the etiology of CRF is complex and treatment approaches to date remain limited [11–13], changes in the immune system may contribute to the initiation and persistence of CRF. In particular, the “sickness behavior model” suggests that non-specific behavioral symp-toms such as fatigue, sleep disturbance, and cognitive changes are due to inflammation associated with chronic medical conditions such as cancer [7,14]. Sickness behaviors are thought to arise from increased
    Please cite this article as: S.M.H. Alibhai, H. Breunis, J. Matelski, et al., Age-related cytokine effects on cancer-related fatigue and quality of life in acute myeloid leukemia, J Geriatr Oncol,
    expression of pro-inflammatory cytokines, associated with Th1 cell-mediated immunity [15].
    Five small studies have examined cytokines and patient-reported outcomes in AML [16–20]. Sample sizes ranged from 7 to 74, and asso-ciations with several pro- and anti-inflammatory cytokines were identi-fied. Although no single cytokine association was consistently replicated for either CRF or QOL across all studies, the most consistent relation-ships appeared to be with interleukin (IL)-6, IL-1 receptor antagonist (IL-1RA), and tumor necrosis factor (TNF)-α with CRF [16].