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Clinical characterization and cytokine profile of fatigue in hematologic malignancy patients with chronic graft-versus-host disease

Bone Marrow Transplantation volume 56, pages 2934–2939 (2021)Cite this article

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Abstract

Limited information is available regarding clinical and biological properties of fatigue in patients with chronic graft-versus-host disease (cGvHD). Patients with moderate-to-severe cGvHD per NIH criteria were enrolled on a cross-sectional study and categorized as “fatigued” if SF-36 vitality score was <40. Clinical and laboratory parameters of fatigued (n = 109) and nonfatigued patients (n = 72) were compared. In univariate analysis, walk velocity, NIH joint-fascia score, human activity profile, and SF-36 physical and mental health self-report scales were correlates of fatigue. No cGvHD biomarkers were associated with fatigue. NIH joint score, Lee sleep and depression questions, and PG-SGA activities and function score jointly predicted fatigue. Though higher rates of depression and insomnia were reported in the fatigued group, antidepressant or sleep aid use did not differ between groups. Survival ratio was not significantly different by fatigue status. Pathophysiology of fatigue in patients with cGvHD is complex and may involve mechanisms unrelated to disease activity. Patients with cGvHD experiencing fatigue had higher rates of untreated depression and insomnia, highlighting the need to focus clinical management of these conditions to improve health-related quality of life.

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Fig. 1: Levels of potential cGvHD biomarkers in fatigued and nonfatigued individuals.
Fig. 2: Overall survival in fatigued vs nonfatigued patients.

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References

  1. El-Jawahri A, Pidala J, Khera N, Wood WA, Arora M, Carpenter PA, et al. Impact of psychological distress on quality of life, functional status, and survival in patients with chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2018;24:2285–92.

    Article  PubMed  Google Scholar 

  2. Jagasia MH, Greinix HT, Arora M, Williams KM, Wolff D, Cowen EW, et al. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group report. Biol Blood Marrow Transplant. 2015;21:389–401.e381.

    Article  PubMed  Google Scholar 

  3. Lee SJ, Onstad L, Chow EJ, Shaw BE, Jim HSL, Syrjala KL, et al. Patient-reported outcomes and health status associated with chronic graft-versus-host disease. Haematologica. 2018;103:1535–41.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Miklos D, Cutler CS, Arora M, Waller EK, Jagasia M, Pusic I, et al. Ibrutinib for chronic graft-versus-host disease after failure of prior therapy. Blood. 2017;130:2243–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Cutler C, Pavletic SZ. NCCN guidelines: pretransplant recipient evaluation and management of graft-versus-host disease. J Natl Compr Cancer Netw. 2020;18:645–7.

    Article  Google Scholar 

  6. Lynch Kelly D, Lyon DE, Ameringer SA, Elswick RK. Symptoms, Cytokines, and Quality of Life in Patients Diagnosed with Chronic Graft-Versus-Host Disease Following Allogeneic Hematopoietic Stem Cell Transplantation. Oncol Nurs Forum. 2015;42:265–75.

    Article  PubMed  Google Scholar 

  7. Park J, Wehrlen L, Mitchell SA, Yang L, Bevans MF. Fatigue predicts impaired social adjustment in survivors of allogeneic hematopoietic cell transplantation (HCT). Support Care Cancer. 2019;27:1355–63.

    Article  PubMed  Google Scholar 

  8. Pidala J, Kurland B, Chai X, Majhail N, Weisdorf DJ, Pavletic S, et al. Patient-reported quality of life is associated with severity of chronic graft-versus-host disease as measured by NIH criteria: report on baseline data from the Chronic GVHD Consortium. Blood. 2011;117:4651–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Esser P, Kuba K, Mehnert A, Schwinn A, Schirmer L, Schulz-Kindermann F, et al. Investigating the temporal course, relevance and risk factors of fatigue over 5 years: a prospective study among patients receiving allogeneic HSCT. Bone Marrow Transplant. 2017;52:753–8.

    Article  CAS  PubMed  Google Scholar 

  10. Jim HS, Sutton SK, Jacobsen PB, Martin PJ, Flowers ME, Lee SJ. Risk factors for depression and fatigue among survivors of hematopoietic cell transplantation. Cancer. 2016;122:1290–7.

    Article  PubMed  Google Scholar 

  11. Berger AM, Mooney K, Alvarez-Perez A, Breitbart WS, Carpenter KM, Cella D, et al. Cancer-related fatigue, version 2.2015. J Natl Compr Cancer Netw. 2015;13:1012–39.

    Article  Google Scholar 

  12. Ghazikhanian SE, Dorfman CS, Somers TJ, O’Sullivan ML, Fisher HM, Edmond SN, et al. Cognitive problems following hematopoietic stem cell transplant: relationships with sleep, depression and fatigue. Bone Marrow Transplant. 2017;52:279–84.

    Article  CAS  PubMed  Google Scholar 

  13. Saligan LN, Olson K, Filler K, Larkin D, Cramp F, Yennurajalingam S, et al. The biology of cancer-related fatigue: a review of the literature. Support Care Cancer. 2015;23:2461–78.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Feng LR, Nguyen Q, Ross A, Saligan LN. Evaluating the role of mitochondrial function in cancer-related fatigue. J Vis Exp. 2018;135:e57736.

    Google Scholar 

  15. Tariman JD, Dhorajiwala S. Genomic variants associated with cancer-related fatigue: a systematic review. Clin J Oncol Nurs. 2016;20:537–46.

    Article  PubMed  Google Scholar 

  16. Shaw BE, Syrjala KL, Onstad LE, Chow EJ, Flowers ME, Jim H, et al. PROMIS measures can be used to assess symptoms and function in long-term hematopoietic cell transplantation survivors. Cancer. 2018;124:841–9.

    Article  PubMed  Google Scholar 

  17. Im A, Mitchell SA, Steinberg SM, Curtis L, Berger A, Baird K, et al. Prevalence and determinants of fatigue in patients with moderate to severe chronic GvHD. Bone Marrow Transplant. 2016;51:705–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Wolff D, Greinix H, Lee SJ, Gooley T, Paczesny S, Pavletic S, et al. Biomarkers in chronic graft-versus-host disease: quo vadis? Bone Marrow Transplant. 2018;53:832–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Kitko CL, Levine JE, Storer BE, Chai X, Fox DA, Braun TM, et al. Plasma CXCL9 elevations correlate with chronic GVHD diagnosis. Blood. 2014;123:786–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Yu J, Storer BE, Kushekhar K, Abu Zaid M, Zhang Q, Gafken PR, et al. Biomarker panel for chronic graft-versus-host disease. J Clin Oncol. 2016;34:2583–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Goklemez S, Im AP, Cao L, Pirsl F, Steinberg SM, Curtis LM, et al. Clinical characteristics and cytokine biomarkers in patients with chronic graft-vs-host disease persisting seven or more years after diagnosis. Am J Hematol. 2020. https://doi.org/10.1002/ajh.25717.

  22. Lee S, Cook EF, Soiffer R, Antin JH. Development and validation of a scale to measure symptoms of chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2002;8:444–52.

    Article  PubMed  Google Scholar 

  23. McQuellon RP, Russell GB, Cella DF, Craven BL, Brady M, Bonomi A, et al. Quality of life measurement in bone marrow transplantation: development of the functional assessment of cancer therapy-bone marrow transplant (FACT-BMT) scale. Bone Marrow Transplant. 1997;19:357–68.

    Article  CAS  PubMed  Google Scholar 

  24. Davidson M, de Morton N. A systematic review of the human activity profile. Clin Rehabil. 2007;21:151–62.

    Article  PubMed  Google Scholar 

  25. Baker F, Haffer SC, Denniston M. Health-related quality of life of cancer and noncancer patients in Medicare managed care. Cancer. 2003;97:674–81.

    Article  PubMed  Google Scholar 

  26. Bjorner JB, Wallenstein GV, Martin MC, Lin P, Blaisdell-Gross B, Tak Piech C, et al. Interpreting score differences in the SF-36 vitality scale: using clinical conditions and functional outcomes to define the minimally important difference. Curr Med Res Opin. 2007;23:731–9.

    Article  PubMed  Google Scholar 

  27. Bauer J, Capra S, Ferguson M. Use of the scored patient-generated subjective global assessment (PG-SGA) as a nutrition assessment tool in patients with cancer. Eur J Clin Nutr. 2002;56:779–85.

    Article  CAS  PubMed  Google Scholar 

  28. Pidala J, Anasetti C, Jim H. Quality of life after allogeneic hematopoietic cell transplantation. Blood. 2009;114:7–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Wan JJ, Qin Z, Wang PY, Sun Y, Liu X. Muscle fatigue: general understanding and treatment. Exp Mol Med. 2017;49:e384.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Morris G, Berk M, Galecki P, Walder K, Maes M. The neuro-immune pathophysiology of central and peripheral fatigue in systemic immune-inflammatory and neuro-immune diseases. Mol Neurobiol. 2016;53:1195–219.

    Article  CAS  PubMed  Google Scholar 

  31. Kaltsas G, Vgontzas A, Chrousos G. Fatigue, endocrinopathies, and metabolic disorders. PM R. 2010;2:393–8.

    Article  PubMed  Google Scholar 

  32. Golomb BA, Evans MA, Dimsdale JE, White HL. Effects of statins on energy and fatigue with exertion: results from a randomized controlled trial. Arch Intern Med. 2012;172:1180–2.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Knutsen KV, Brekke M, Gjelstad S, Lagerløv P. Vitamin D status in patients with musculoskeletal pain, fatigue and headache: a cross-sectional descriptive study in a multi-ethnic general practice in Norway. Scand J Prim Health Care. 2010;28:166–71.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Smith SR, Haig AJ, Couriel DR. Musculoskeletal, neurologic, and cardiopulmonary aspects of physical rehabilitation in patients with chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2015;21:799–808.

    Article  PubMed  Google Scholar 

  35. Kuba K, Esser P, Mehnert A, Hinz A, Johansen C, Lordick F, et al. Risk for depression and anxiety in long-term survivors of hematologic cancer. Health Psychol. 2019;38:187–95.

    Article  PubMed  Google Scholar 

  36. Irwin MR, Olmstead RE, Ganz PA, Haque R. Sleep disturbance, inflammation and depression risk in cancer survivors. Brain, Behav, Immun. 2013;30:S58–67.

    Article  Google Scholar 

  37. Nelson AM, Jim HSL, Small BJ, Nishihori T, Gonzalez BD, Cessna JM, et al. Sleep disruption among cancer patients following autologous hematopoietic cell transplantation. Bone Marrow Transplant. 2018;53:307–14.

    Article  CAS  PubMed  Google Scholar 

  38. Andrykowski MA, Carpenter JS, Greiner CB, Altmaier EM, Burish TG, Antin JH, et al. Energy level and sleep quality following bone marrow transplantation. Bone Marrow Transplant. 1997;20:669–79.

    Article  CAS  PubMed  Google Scholar 

  39. Espie CA, Fleming L, Cassidy J, Samuel L, Taylor LM, White CA, et al. Randomized controlled clinical effectiveness trial of cognitive behavior therapy compared with treatment as usual for persistent insomnia in patients with cancer. J Clin Oncol. 2008;26:4651–8.

    Article  PubMed  Google Scholar 

  40. Fleming L, Randell K, Harvey CJ, Espie CA. Does cognitive behaviour therapy for insomnia reduce clinical levels of fatigue, anxiety and depression in cancer patients? Psycho-Oncology. 2014;23:679–84.

    Article  PubMed  Google Scholar 

  41. Cramer H, Lauche R, Klose P, Lange S, Langhorst J, Dobos GJ. Yoga for improving health-related quality of life, mental health and cancer-related symptoms in women diagnosed with breast cancer. Cochrane Database Syst Rev. 2017;1:Cd010802.

    PubMed  Google Scholar 

  42. Ostuzzi G, Matcham F, Dauchy S, Barbui C, Hotopf M. Antidepressants for the treatment of depression in people with cancer. Cochrane Database Syst Rev. 2015;2015:Cd011006.

    PubMed Central  Google Scholar 

  43. Breitbart W, Alici Y. Pharmacologic treatment options for cancer-related fatigue: current state of clinical research. Clin J Oncol Nurs. 2008;12:27–36.

    Article  PubMed  Google Scholar 

  44. Moss EL, Simpson JS, Pelletier G, Forsyth P. An open-label study of the effects of bupropion SR on fatigue, depression and quality of life of mixed-site cancer patients and their partners. Psycho-Oncology. 2006;15:259–67.

    Article  PubMed  Google Scholar 

  45. Hakim FT, Memon S, Jin P, Imanguli MM, Wang H, Rehman N, et al. Upregulation of IFN-inducible and damage-response pathways in chronic graft-versus-host disease. J Immunol. 2016;197:3490–503.

    Article  CAS  PubMed  Google Scholar 

  46. Carroll TJ, Taylor JL, Gandevia SC. Recovery of central and peripheral neuromuscular fatigue after exercise. J Appl Physiol. 2017;122:1068–76.

    Article  CAS  PubMed  Google Scholar 

  47. Klimas NG, Broderick G, Fletcher MA. Biomarkers for chronic fatigue. Brain, Behav, Immun. 2012;26:1202–10.

    Article  CAS  Google Scholar 

  48. Dirou S, Chambellan A, Chevallier P, Germaud P, Lamirault G, Gourraud PA, et al. Deconditioning, fatigue and impaired quality of life in long-term survivors after allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant. 2018;53:281–90.

    Article  CAS  PubMed  Google Scholar 

  49. Fiuza-Luces C, Simpson RJ, Ramírez M, Lucia A, Berger NA. Physical function and quality of life in patients with chronic GvHD: a summary of preclinical and clinical studies and a call for exercise intervention trials in patients. Bone Marrow Transplant. 2016;51:13–26.

    Article  CAS  PubMed  Google Scholar 

  50. Wiskemann J, Dreger P, Schwerdtfeger R, Bondong A, Huber G, Kleindienst N, et al. Effects of a partly self-administered exercise program before, during, and after allogeneic stem cell transplantation. Blood. 2011;117:2604–13.

    Article  CAS  PubMed  Google Scholar 

  51. Krupski C, Jagasia M. Quality of life in the chronic GVHD Consortium Cohort: lessons learned and the long road ahead. Curr Hematol Malig Rep. 2015;10:183–91.

    Article  PubMed  Google Scholar 

  52. Berger AM, Mitchell SA, Jacobsen PB, Pirl WF. Screening, evaluation, and management of cancer-related fatigue: ready for implementation to practice? CA Cancer J Clin. 2015;65:190–211.

    Article  PubMed  Google Scholar 

  53. Brown LF, Kroenke K, Theobald DE, Wu J. Comparison of SF-36 vitality scale and fatigue symptom inventory in assessing cancer-related fatigue. Support Care Cancer. 2011;19:1255–9.

    Article  PubMed  Google Scholar 

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Acknowledgements

The authors thank all the patients and their families for their participation in the National Institutes of Health chronic GVHD natural history study. This work was supported by the Intramural Research Program of the National Institutes Health, Center for Cancer Research, National Cancer Institute. The views expressed in this work are of the authors and do not represent the official views of the National Institutes of Health or the US Government.

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Author notes

  1. Sencer Goklemez

    Present address: University of Cincinnati Medical Center, Cincinnati, OH, USA

Authors and Affiliations

  1. Immune Deficiency and Cellular Therapy Program, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, USA

    Sencer Goklemez, Filip Pirsl, Noa G. Holtzman, Alen Ostojic, Frances T. Hakim, Jeremy J. Rose, Zhigang Kang, Yunkai Yu, Liang Cao & Steven Z. Pavletic

  2. National Institute of Nursing Research, NIH, Bethesda, MD, USA

    Leorey N. Saligan

  3. Department of Internal Medicine, University Hospital Center Zagreb, Zagreb, Croatia

    Alen Ostojic

  4. Biostatistics and Data Management Section, NCI, NIH, Bethesda, MD, USA

    Seth M. Steinberg

  5. Division of Cancer Control and Population Sciences, NCI, NIH, Bethesda, MD, USA

    Sandra A. Mitchell

  6. Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, PA, USA

    Annie Im

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Contributions

SG: conceptualization, investigation, and writing original draft, YY and ZK: data curation and resources, SMS: statistical analysis, FTH: data curation and methodology, SZP: conceptualization, investigation, editing, and supervision, and all coauthors: review and editing.

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Correspondence to Steven Z. Pavletic.

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Goklemez, S., Saligan, L.N., Pirsl, F. et al. Clinical characterization and cytokine profile of fatigue in hematologic malignancy patients with chronic graft-versus-host disease. Bone Marrow Transplant 56, 2934–2939 (2021). https://doi.org/10.1038/s41409-021-01419-2

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