Evaluating hematologic parameters in newly diagnosed and recurrent glioblastoma: Prognostic utility and clinical trial implications of myelosuppression

Abstract

Background Glioblastoma patients are treated with radiation therapy, chemotherapy, and corticosteroids, which can cause myelosuppression. To understand the relative prognostic utility of blood-based biomarkers in GBM and its implications for clinical trial design, we examined the incidence, predictors, and prognostic value of lymphopenia, neutrophil-to-lymphocyte ratio (NLR) and platelet count during chemoradiation (CRT) and recurrence. Methods This cohort study included 764 newly diagnosed glioblastoma patients treated from 2005-2019 with blood counts prior to surgery, within 6 weeks of CRT and at first recurrence available for automatic extraction from the medical record. Logistic regression was used to evaluate exposures and Kaplan-Meier was used to evaluate outcomes. Results Among the cohort, median age was 60.3 years; 87% had Karnofsky performance status (KPS) ≥ 70, 37.5% had gross total resection, and 90% received temozolomide (TMZ). During CRT, 37.8% (248/656) patients developed grade 3 or higher lymphopenia. On multivariable analysis (MVA), high NLR during CRT remained an independent predictor for inferior survival (AHR=1.57, 95%CI=1.14-2.15) and shorter progression-free survival (PFS) (AHR= 1.42, 95%CI= 1.05-1.90). Steroid use was associated with lymphopenia (OR=2.66,1.20-6.00) and high NLR (OR=3.54,2.08-6.11). Female sex was associated with lymphopenia (OR=2.33,1.03-5.33). At first recurrence, 28% patients exhibited grade 3 or higher lymphopenia. High NLR at recurrence was associated with worse subsequent survival on MVA (AHR=1.69, 95%CI= 1.25-2.27). Conclusions High NLR is associated with worse outcomes in newly diagnosed and recurrent glioblastoma. Appropriate eligibility criteria and accounting and reporting of blood-based biomarkers are important in the design and interpretation of newly diagnosed and recurrent glioblastoma trials.

The need for paradigm shift: prognostic significance and implications of standard therapy-related systemic immunosuppression in glioblastoma for immunotherapy and oncolytic virotherapy

“…Similarly, Le Rhun et al. ( 29 ) reported that grade 3/4 lymphopenia during concomitant radiochemotherapy but not during maintenance temozolomide chemotherapy was significantly associated with inferior overall survival in univariate and multivariate analysis. Deng et al.…”

“…Sex is another confounding factor of therapy-related lymphopenia. In two large cohort studies (n>700 and n>2000), women were found to be more likely to develop lymphopenia than men ( 29 , 58 ). Remarkably, 21-47% of patients with glioblastoma/gliomas treated with radiochemotherapy developed long-lasting grade 3/4 lymphopenia ( 29 , 47 – 52 , 58 – 60 ), although there were studies reporting a less frequent occurrence of grade 3/4 lymphopenia during or after standard therapy (2.9-10%) ( 53 , 61 , 62 ).…”

“…In two large cohort studies (n>700 and n>2000), women were found to be more likely to develop lymphopenia than men ( 29 , 58 ). Remarkably, 21-47% of patients with glioblastoma/gliomas treated with radiochemotherapy developed long-lasting grade 3/4 lymphopenia ( 29 , 47 – 52 , 58 – 60 ), although there were studies reporting a less frequent occurrence of grade 3/4 lymphopenia during or after standard therapy (2.9-10%) ( 53 , 61 , 62 ). Moreover, patients with recurrent glioblastoma exhibited a significantly lower TLC compared with patients with newly diagnosed glioblastoma ( 63 ), and lymphopenia reached 76.5% for a standard temozolomide regimen in patients with recurrent glioblastoma ( 64 ).…”

Systemic and local immunosuppression in glioblastoma and its prognostic significance

“…Deng et al. reported that 11.9% (out of n=469) of patients with glioblastoma (median age: 60.3; range: 19–94) had grade 3/4 lymphopenia (<500 cells/µl) preoperatively and 15.4% (out of n=628) postoperatively and before standard radiochemotherapy ( 48 ). In the elderly group (median age: 71 years), only 57% (out of n=72) of patients had normal baseline total lymphocyte counts ( 49 ).…”

“…However, the independent prognostic significance of NLR remains debatable ( 55 ). High NLR during standard therapy was also associated with worse overall survival regardless of steroid use in multivariate analysis ( 48 ), and a decline of NLR during or post-therapy was associated with longer overall survival of patients with glioblastoma in multivariate analyses in prospective ( 53 ) and retrospective studies ( 57 , 119 , 134 ). NLR was prognostic in patients with recurrent glioblastoma ( 119 , 135 ).…”