Skip to main content
  • Bone Marrow Response as a Potential Biomarker of Outcomes in Glioblastoma Patients

    Final Number:

    Eugene John Vaios BA; Brian V. Nahed MD, MSc; Alona Muzikansky; Amir Fathi; Jorg Dietrich MD, PhD

    Study Design:

    Subject Category:

    Meeting: Congress of Neurological Surgeons 2016 Annual Meeting

    Introduction: Glioblastoma (GBM) is a highly aggressive malignancy which requires a multi-disciplinary therapeutic approach of surgery, chemotherapy and radiation therapy, but is frequently limited by treatment-related side-effects. The most common adverse effect of chemotherapy with temozolomide (TMZ) is myelosuppression. It remains unclear whether the degree of bone marrow suppression might serve as a biomarker for treatment outcome. The aim of the current study was to investigate whether the degree of bone-marrow toxicity in patients treated with TMZ correlates with overall survival (OS) and MRI-based time to progression (PFS).

    Methods: Complete blood counts and clinical and radiographic information were collected retrospectively from 86 malignant glioma patients who had completed both radiation therapy and at least 6 monthly cycles of chemotherapy with TMZ.

    Results: Using a multivariate cox proportional hazard model, it was observed that treatment-induced leukopenia, MGMT promotor methylation, wild-type EGFR, and younger patient age at diagnosis were associated with improved OS. The 2-year survival rate was 25% and 58% for patients with leukocytosis and leukopenia, respectively, over 6 months of TMZ treatment. Consistent with the literature, IDH mutation and MGMT promotor methylation were associated with better PFS and OS. IDH mutation and MGMT promotor methylation were not correlated with changes in peripheral red blood cell or white blood cell counts.

    Conclusions: Bone marrow suppression, specifically leukopenia, might serve as a potential biomarker for OS and PFS in malignant glioma patients treated with chemoradiation and temozolomide. It remains unclear whether treatment induced leukopenia correlates with drug induced anti-tumor activity, or represents an independent factor of altered systemic and tumor microenvironment. Additional studies will be needed to determine a dose-dependence for chemotherapy based upon peripheral blood counts.

    Patient Care: Given the routine and reliable sampling of peripheral blood counts in GBM patients receiving conventional therapies, leukopenia could serve as a valuable biomarker for monitoring of treatment response and predicting clinical outcomes. It could enhance the clinical utility of emerging liquid biopsy techniques that monitor circulating tumor cells and tumor DNA. If changes in white blood cell counts can serve as a correlate marker for in vivo TMZ levels and efficacy, this could help in the optimization of dosing and scheduling of chemotherapy, accounting for variability in drug metabolism. This study sets the foundation for a larger prospective study to validate and characterize the prognostic and predictive value of alterations in white blood cell counts in GBM patients treated with TMZ.

    Learning Objectives: By the conclusion of this session, participants should be able to: 1) Describe the importance of leukopenia as an independent prognostic marker associated with improved OS in GBM patients receiving TMZ. 2) Discuss, in small groups, whether the temporal relationship between changes in peripheral white blood cell counts during adjuvant TMZ treatment and clinical outcomes may be a reflection of plasma TMZ levels, and thus a surrogate marker of therapeutic efficacy. Currently, TMZ dosing is based solely on patient BSA and does not account for variability in resistance mechanisms and drug metabolism, raising the possibility that some patients may be dosed sub-therapeutically. Inadequate dosing may partially contribute to the observed resistance to cytotoxic treatment and ultimately tumor recurrence. If changes in white blood cell counts can serve as a correlate marker for in vivo TMZ levels and efficacy, this could help in the optimization of dosing and scheduling of chemotherapy, accounting for variability in drug metabolism. 3) Identify an effective treatment protocol for GBM patients in which TMZ dosing accounts for inter-patient differences in resistance mechanisms or drug metabolism. Adequate dosing, guided by changes in white blood cell counts, may overcome causes of treatment failure and improve survival.

    References: 1. Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB, et al: Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444:756-760, 2006 2. Bastien JI, McNeill KA, Fine HA: Molecular characterizations of glioblastoma, targeted therapy, and clinical results to date. Cancer 121:502-516, 2015 3. Batchelor TT, Mulholland P, Neyns B, Nabors LB, Campone M, Wick A, et al: Phase III randomized trial comparing the efficacy of cediranib as monotherapy, and in combination with lomustine, versus lomustine alone in patients with recurrent glioblastoma. J Clin Oncol 31:3212-3218, 2013 4. Best MG, Sol N, Zijl S, Reijneveld JC, Wesseling P, Wurdinger T: Liquid biopsies in patients with diffuse glioma. Acta Neuropathol 129:849-865, 2015 5. Bettegowda C, Sausen M, Leary RJ, Kinde I, Wang Y, Agrawal N, et al: Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med 6:224ra224, 2014 6. Chamberlain MC: Treatment of newly diagnosed malignant glioma in the elderly people: new trials that impact therapy. Int J Clin Pract 67:1225-1227, 2013 7. Chan KC, Jiang P, Zheng YW, Liao GJ, Sun H, Wong J, et al: Cancer genome scanning in plasma: detection of tumor-associated copy number aberrations, single-nucleotide variants, and tumoral heterogeneity by massively parallel sequencing. Clin Chem 59:211-224, 2013 8. Chinot OL, Wick W, Mason W, Henriksson R, Saran F, Nishikawa R, et al: Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med 370:709-722, 2014 9. Ellingson BM, Wen PY, van den Bent MJ, Cloughesy TF: Pros and cons of current brain tumor imaging. Neuro Oncol 16 Suppl 7:vii2-11, 2014 10. Ellis HP, Greenslade M, Powell B, Spiteri I, Sottoriva A, Kurian KM: Current Challenges in Glioblastoma: Intratumour Heterogeneity, Residual Disease, and Models to Predict Disease Recurrence. Front Oncol 5:251, 2015 11. Esteller M, Garcia-Foncillas J, Andion E, Goodman SN, Hidalgo OF, Vanaclocha V, et al: Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. N Engl J Med 343:1350-1354, 2000 12. Gilbert MR, Dignam JJ, Armstrong TS, Wefel JS, Blumenthal DT, Vogelbaum MA, et al: A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med 370:699-708, 2014 13. Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, et al: MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352:997-1003, 2005 14. Idbaih A, Omuro A, Ducray F, Hoang-Xuan K: Molecular genetic markers as predictors of response to chemotherapy in gliomas. Curr Opin Oncol 19:606-611, 2007 15. Kanzawa T, Bedwell J, Kondo Y, Kondo S, Germano IM: Inhibition of DNA repair for sensitizing resistant glioma cells to temozolomide. J Neurosurg 99:1047-1052, 2003 16. Khwaja FW, Reed MS, Olson JJ, Schmotzer BJ, Gillespie GY, Guha A, et al: Proteomic identification of biomarkers in the cerebrospinal fluid (CSF) of astrocytoma patients. J Proteome Res 6:559-570, 2007 17. Kros JM, Mustafa DM, Dekker LJ, Sillevis Smitt PA, Luider TM, Zheng PP: Circulating glioma biomarkers. Neuro Oncol 17:343-360, 2015 18. Leary RJ, Sausen M, Kinde I, Papadopoulos N, Carpten JD, Craig D, et al: Detection of chromosomal alterations in the circulation of cancer patients with whole-genome sequencing. Sci Transl Med 4:162ra154, 2012 19. Liu G, Yuan X, Zeng Z, Tunici P, Ng H, Abdulkadir IR, et al: Analysis of gene expression and chemoresistance of CD133+ cancer stem cells in glioblastoma. Mol Cancer 5:67, 2006 20. Lonardi S, Tosoni A, Brandes AA: Adjuvant chemotherapy in the treatment of high grade gliomas. Cancer Treat Rev 31:79-89, 2005 21. Macarthur KM, Kao GD, Chandrasekaran S, Alonso-Basanta M, Chapman C, Lustig RA, et al: Detection of brain tumor cells in the peripheral blood by a telomerase promoter-based assay. Cancer Res 74:2152-2159, 2014 22. Marchesi F, Turriziani M, Tortorelli G, Avvisati G, Torino F, De Vecchis L: Triazene compounds: mechanism of action and related DNA repair systems. Pharmacol Res 56:275-287, 2007 23. McPherson CM, Gerena-Lewis M, Breneman JC, Warnick RE: Results of phase I study of a multi-modality treatment for newly diagnosed glioblastoma multiforme using local implantation of concurrent BCNU wafers and permanent I-125 seeds followed by fractionated radiation and temozolomide chemotherapy. J Neurooncol 108:521-525, 2012 24. Miknyoczki S, Chang H, Grobelny J, Pritchard S, Worrell C, McGann N, et al: The selective poly(ADP-ribose) polymerase-1(2) inhibitor, CEP-8983, increases the sensitivity of chemoresistant tumor cells to temozolomide and irinotecan but does not potentiate myelotoxicity. Mol Cancer Ther 6:2290-2302, 2007 25. Mourad PD, Farrell L, Stamps LD, Chicoine MR, Silbergeld DL: Why are systemic glioblastoma metastases rare? Systemic and cerebral growth of mouse glioblastoma. Surg Neurol 63:511-519; discussion 519, 2005 26. Muller C, Holtschmidt J, Auer M, Heitzer E, Lamszus K, Schulte A, et al: Hematogenous dissemination of glioblastoma multiforme. Sci Transl Med 6:247ra101, 2014 27. Murtaza M, Dawson SJ, Tsui DW, Gale D, Forshew T, Piskorz AM, et al: Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA. Nature 497:108-112, 2013 28. Newlands ES, Stevens MF, Wedge SR, Wheelhouse RT, Brock C: Temozolomide: a review of its discovery, chemical properties, pre-clinical development and clinical trials. Cancer Treat Rev 23:35-61, 1997 29. Ostrom QT, Gittleman H, Liao P, Rouse C, Chen Y, Dowling J, et al: CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2007-2011. Neuro Oncol 16 Suppl 4:iv1-63, 2014 30. Peschillo S, Caporlingua A, Diana F, Caporlingua F, Delfini R: New therapeutic strategies regarding endovascular treatment of glioblastoma, the role of the blood-brain barrier and new ways to bypass it. J Neurointerv Surg, 2015 31. Preusser M: Neuro-oncology: a step towards clinical blood biomarkers of glioblastoma. Nat Rev Neurol 10:681-682, 2014 32. Purow BW, Schiff D: Glioblastoma genetics: in rapid flux. Discov Med 9:125-131, 2010 33. Roos WP, Batista LF, Naumann SC, Wick W, Weller M, Menck CF, et al: Apoptosis in malignant glioma cells triggered by the temozolomide-induced DNA lesion O6-methylguanine. Oncogene 26:186-197, 2007 34. Snuderl M, Fazlollahi L, Le LP, Nitta M, Zhelyazkova BH, Davidson CJ, et al: Mosaic amplification of multiple receptor tyrosine kinase genes in glioblastoma. Cancer Cell 20:810-817, 2011 35. Stommel JM, Kimmelman AC, Ying H, Nabioullin R, Ponugoti AH, Wiedemeyer R, et al: Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted therapies. Science 318:287-290, 2007 36. Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, et al: Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 10:459-466, 2009 37. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, et al: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987-996, 2005 38. Sullivan JP, Nahed BV, Madden MW, Oliveira SM, Springer S, Bhere D, et al: Brain tumor cells in circulation are enriched for mesenchymal gene expression. Cancer Discov 4:1299-1309, 2014 39. Szerlip NJ, Pedraza A, Chakravarty D, Azim M, McGuire J, Fang Y, et al: Intratumoral heterogeneity of receptor tyrosine kinases EGFR and PDGFRA amplification in glioblastoma defines subpopulations with distinct growth factor response. Proc Natl Acad Sci U S A 109:3041-3046, 2012 40. Tabatabai G, Stupp R, van den Bent MJ, Hegi ME, Tonn JC, Wick W, et al: Molecular diagnostics of gliomas: the clinical perspective. Acta Neuropathol 120:585-592, 2010 41. Tanaka S, Louis DN, Curry WT, Batchelor TT, Dietrich J: Diagnostic and therapeutic avenues for glioblastoma: no longer a dead end? Nat Rev Clin Oncol 10:14-26, 2013 42. Thomas AA, Brennan CW, DeAngelis LM, Omuro AM: Emerging therapies for glioblastoma. JAMA Neurol 71:1437-1444, 2014 43. Villano JL, Seery TE, Bressler LR: Temozolomide in malignant gliomas: current use and future targets. Cancer Chemother Pharmacol 64:647-655, 2009 44. von Deimling A, Korshunov A, Hartmann C: The next generation of glioma biomarkers: MGMT methylation, BRAF fusions and IDH1 mutations. Brain Pathol 21:74-87, 2011 45. Williams M, Liu ZW, Woolf D, Hargreaves S, Michalarea V, Menashy R, et al: Change in platelet levels during radiotherapy with concurrent and adjuvant temozolomide for the treatment of glioblastoma: a novel prognostic factor for survival. J Cancer Res Clin Oncol 138:1683-1688, 2012 46. Wilson TA, Karajannis MA, Harter DH: Glioblastoma multiforme: State of the art and future therapeutics. Surg Neurol Int 5:64, 2014 47. Ziegler DS, Kung AL, Kieran MW: Anti-apoptosis mechanisms in malignant gliomas. J Clin Oncol 26:493-500, 2008

We use cookies to improve the performance of our site, to analyze the traffic to our site, and to personalize your experience of the site. You can control cookies through your browser settings. Please find more information on the cookies used on our site. Privacy Policy