Headache in bone marrow donors and oncohematological patients, who taking granulocyte colony-stimulating factor: incidence and clinical features

The aim of the study was to assess the incidence and clinical features of headache associated with the use of granulocyte colony-stimulating factor (G-CSF) for stem cell mobilization or neutropenia treatment among oncohematological patients and bone marrow donors.
Material and methods. A prospective observational uncontrolled study included 39 participants: 20 bone marrow donors (group 1) and 19 oncohematological patients (group 2). We evaluated the incidence and clinical features of headache after subcutaneous administration of G-CSF (filgrastim) at doses of 5 to 10 μg/kg for 2 to 5 days.
Results. Headache occurred in bone marrow donors more often compared to patients with hematological malignancies (78.9% vs 35.0%; p = 0.006). There were no significant differences in the time of headache onset, its duration, intensity, features, and localization between two groups. Gender, age, dose of G-CSF, and duration of its use were not associated with headache development in both groups.
Conclusion. Headache occurs more often in bone marrow donors than in patients with hematological malignancies. The phenotype of headache associated with G-CSF exposure is not drug-specific and requires further studies on its semiotics.

1. Karagiannidis I., Salataj E., Said Abu Egal E., Beswick E.J. G-CSF in tumors: Aggressiveness, tumor microenvironment and immune cell regulation. Cytokine. 2021;142:155479. https://doi.org/10.1016/j.cyto.2021.155479

2. Schmitt M., Hoffmann J.M., Lorenz K., Publicover A., Schmitt A., Nagler A. Mobilization of autologous and allogeneic peripheral blood stem cells for transplantation in haematological malignancies using biosimilar G-CSF. Vox Sang. 2016;111(2):178–186. https://doi.org/10.1111/vox.12397

3. Brockmann F., Kramer M., Bornhäuser M., Ehninger G., Hölig K. Efficacy and side effects of granulocyte collection in healthy donors. Transfus Med Hemother. 2013;40(4):258–264. https://doi.org/10.1159/000354093

4. Государственный реестр лекарственных средств. https://grls.rosminzdrav.ru/Grls_View_v2.aspx?routingGuid=4741199ef54f-4bcb-8798d0cc3095f783&t=%20(accessed%20Apr.%2009,%202021

5. Headache Classification Committee of the International Headache Society (IHS) The International Classification of Headache Disorders, 3rd edition. Cephalalgia. 2018;38(1):1–211. https://doi.org/10.1177/0333102417738202

6. Moog R. Donor tolerance and results of stimulation with G-CSF alone or in combination with dexamethasone for the collection of granulocytes. J Clin Apher. 2004;19(3):115–118. https://doi.org/10.1002/jca.20013

7. Kröger N., Renges H., Sonnenberg S., Krüger W., Gutensohn K., Dielschneider T. et al. Stem cell mobilisation with 16 microg/ kg vs 10 microg/kg of G-CSF for allogeneic transplantation in healthy donors. Bone Marrow Transplant. 2002;29(9):727–730. https://doi.org/10.1038/sj.bmt.1703509

8. Reik R.A., Noto T.A., Fernandez H.F. Safety of large-volume leukapheresis for collection of peripheral blood progenitor cells. J Clin Apher. 1997;12(1):10–13. https://doi.org/10.1002/(sici)1098-1101(1997)12:1<10::aid-jca3>3.0.co;2-d

9. Cesaro S., Marson P., Gazzola M.V., De Silvestro G., Destro R., Pillon M. et al. The use of cytokine-stimulated healthy donors in allogeneic stem cell transplantation. Haematologica. 2002;87(8 Suppl):35–41.

10. Kröger N., Zander A.R. Dose and schedule effect of G-GSF for stem cell mobilization in healthy donors for allogeneic transplantation. Leuk Lymphoma. 2002;43(7):1391–1394. https://doi.org/10.1080/10428190290033323

11. Kröger N., Renges H., Krüger W., Gutensohn K., Löliger C., Carrero I. et al. A randomized comparison of once versus twice daily recombinant human granulocyte colony-stimulating factor (filgrastim) for stem cell mobilization in healthy donors for allogeneic transplantation. British journal of haematology. 2000:111(3);761–765.

12. Nakamura J., Nishi T.M., Yamashita S., Nakamura H., Sato K., Oda Y. et al. Pegfilgrastim-associated large-vessel vasculitis developed during adjuvant chemotherapy for breast cancer: A case report and review of the literature. J Oncol Pharm Pract. 2020;26(7):1785–1790. https://doi.org/10.1177/1078155220910800

13. Gong Y., Hoover-Plow J. The plasminogen system in regulating stem cell mobilization. J Biomed Biotechnol. 2012;2012:437920. https://doi.org/10.1155/2012/437920

14. Goadsby P.J., Holland P.R., Martins-Oliveira M., Hoffmann J., Schankin C., Akerman S. Pathophysiology of Migraine: A Disorder of Sensory Processing. Physiol Rev. 2017;97(2):553–622. https://doi.org/10.1152/physrev.00034.2015

15. Noseda R., Copenhagen D., Burstein R. Current understanding of photophobia, visual networks and headaches. Cephalalgia. 2019;39(13):1623–1634. https://doi.org/10.1177/0333102418784750

16. Burstein R., Noseda R., Fulton A.B. Neurobiology of Photophobia. J Neuroophthalmol. 2019;39(1):94–102. https://doi.org/10.1097/WNO.0000000000000766

17. Young N.P., Elrashidi M.Y., McKie P.M., Ebbert J.O. Neuroimaging utilization and findings in headache outpatients: Significance of red and yellow flags. Cephalalgia. 2018;38(12):1841–1848. https://doi.org/10.1177/0333102418758282

18. Singh N.N., Sahota P. Sleep-related headache and its management. Curr Treat Options Neurol. 2013;15(6):704–722. https://doi.org/10.1007/s11940-013-0258-1

19. Ahn A.H. Southern Headache Society supplement: the neurobiology of throbbing pain in migraine. Headache. 2012;52(Suppl.1):12–14. https://doi.org/10.1111/j.1526-4610.2012.02136.x

20. Meseeha M.G., Attia M. Throbbing headache is not always migraine; it can be serious. J Community Hosp Intern Med Perspect. 2016;6(5):32361. Published 2016 Oct 26. https://doi.org/10.3402/jchimp.v6.32361

21. Brusadelli T., Carnovale C., Gentili M., Borsadoli C., Speziali A., Perrone V. et al. Throbbing headache associated with enoxaparin administration: a case report, a review of pharmacovigilance databases for similar cases and possible mechanisms. J Clin Pharm Ther. 2015;40(3):342–344. https://doi.org/10.1111/jcpt.12257

22. Eyles J.L., Roberts A.W., Metcalf D., Wicks I.P. Granulocyte colony-stimulating factor and neutrophils-forgotten mediators of inflammatory disease. Nat Clin Pract Rheumatol. 2006;2(9):500–510. https://doi.org/10.1038/ncprheum0291

23. Castellani S., D’Oria S., Diana A., Polizzi A.M., Di Gioia S., Mariggiò M.A. et al. G-CSF and GM-CSF Modify Neutrophil Functions at Concentrations found in Cystic Fibrosis. Sci Rep. 2019;9(1):12937. Published 2019 Sep 10. https://doi.org/10.1038/s41598-019-49419-z

24. McColl S.R., Paquin R., Ménard C., Beaulieu A.D. Human neutrophils produce high levels of the interleukin 1 receptor antagonist in response to granulocyte/macrophage colonystimulating factor and tumor necrosis factor alpha. J Exp Med. 1992;176(2):593–598. https://doi.org/10.1084/jem.176.2.593

25. Rambe A.S., Sjahrir H., Machfoed M.H. Tumour Necrosis Factor-Α, Interleukin-1 and Interleukin-6 Serum Levels and Its Correlation with Pain Severity in Chronic Tension-Type Headache Patients: Analysing Effect of Dexketoprofen Administration. Open Access Maced J Med Sci. 2017;5(1):54–57. https://doi.org/10.3889/oamjms.2017.024

26. Koçer A., Memişoğullari R., Domaç F.M., Ilhan A., Koçer E., Okuyucu S. et al. IL-6 levels in migraine patients receiving topiramate. Pain Pract. 2009;9(5):375–379. https://doi.org/10.1111/j.1533-2500.2009.00301.x

27. Conti P., D’Ovidio C., Conti C., Gallenga C.E., Lauritano D., Caraffa A. et al. Progression in migraine: Role of mast cells and proinflammatory and anti-inflammatory cytokines. Eur J Pharmacol. 2019;844:87–94. https://doi.org/10.1016/j.ejphar.2018.12.004

28. Han D. Association of Serum Levels of Calcitonin Gene-related Peptide and Cytokines during Migraine Attacks. Ann Indian Acad Neurol. 2019;22(3):277–281. https://doi.org/10.4103/aian.AIAN_371_18

29. Messlinger K., Russo A.F. Current understanding of trigeminal ganglion structure and function in headache. Cephalalgia. 2019;39(13):1661–1674. https://doi.org/10.1177/0333102418786261

30. Gong Q., Lin Y., Lu Z., Xiao Z. Microglia-Astrocyte Cross Talk through IL-18/IL-18R Signaling Modulates Migrainelike Behavior in Experimental Models of Migraine. Neuroscience. 2020;451:207–215. https://doi.org/10.1016/j.neuroscience.2020.10.019

31. He W., Long T., Pan Q., Zhang S., Zhang Y., Zhang D. et al. Microglial NLRP3 inflammasome activation mediates IL-1β release and contributes to central sensitization in a recurrent nitroglycerin-induced migraine model. J Neuroinflammation. 2019;16(1):78. Published 2019 Apr 10. https://doi.org/10.1186/s12974-019-1459-7

32. Zhang X.C., Kainz V., Burstein R., Levy D. Tumor necrosis factor-α induces sensitization of meningeal nociceptors mediated via local COX and p38 MAP kinase actions. Pain. 2011;152(1):140–149. https://doi.org/10.1016/j.pain.2010.10.002

33. Bowen E.J., Schmidt T.W., Firm C.S, Russo A.F, Durham P.L. Tumor necrosis factor-alpha stimulation of calcitonin generelated peptide expression and secretion from rat trigeminal ganglion neurons. J Neurochem. 2006;96(1):65–77. https://doi.org/10.1111/j.1471-4159.2005.03524.x

34. Yan J., Melemedjian O.K., Price T.J., Dussor G. Sensitization of dural afferents underlies migraine-related behavior following meningeal application of interleukin-6 (IL-6). Mol Pain. 2012;8:6. Published 2012 Jan 24. https://doi.org/10.1186/1744-8069-8-6