Relative Monocytopenia, A Proposed Correlate Of Decreased Vasculogenesis, Is Associated With Improved Survival In Patients With Glioblastoma Multiforme

Lymphocytopenia is a known risk factor for poor survival in patients with glioblastoma multiforme (GBM). Conversely, preclinical models of GBM have demonstrated that the influx of bone marrow derived myelomonocytic cells to the tumor bed promotes vasculogenesis required for tumor recurrence after chemoradiation therapy (CRT). We evaluated the association of circulating monocyte and lymphocyte levels with overall survival in patients with GBM. We hypothesized that a low monocyte count, as a potential correlate for decreased vasculogenesis, is associated with improved survival. We retrospectively reviewed 125 patients with GBM, with available MGMT promoter methylation status, treated from 2005 - 2012. The mean, minimum and maximum absolute monocyte counts (AMC) and absolute lymphocyte counts (ALC) were obtained prior to CRT and at 7, 15, 45, 90, and 180 days after the start of CRT. Patients who did not undergo either chemotherapy or RT (n = 18) or for whom a CRT start date was unavailable (n = 3), had time 0 defined at 4 weeks after either biopsy or resection (if craniotomy performed). Cox proportional hazards analyzed factors predictive (p < 0.05) of overall survival (OS). Of 125 tumors, 57 (46%) and 68 (54%) were positive (MGMT+) and negative (MGMT-) for promoter hypermethylation of MGMT. Median follow-up for MGMT+ and MGMT- patients was 21.3 and 10.0 months, respectively. Of the 107 of 125 patients who received first line CT, 106 (85%) received Temozolomide, and 100 (80%) received concurrent radiation therapy. Median OS of MGMT+ and MGMT- patients were 25.5 and 10.5 months, respectively (p < 0.001). Among MGMT- patients, higher mean and maximum AMC values at days (d) 7, 15, 45, 90 and 180 were significantly associated with poorer OS with greatest hazard ratios (HR) observed at later time points (HR for maximum AMC: d7 4.3, d15 4.2, d45 5.8, d90 7.7, d180 6.9; all p < 0.04). In contrast, higher mean ALC was associated with improved overall survival in MGMT- patients at day 7 (HR = 0.4, p = 0.03), day 15 (HR = 0.3, p = 0.02) and were nearly significant at days 45 (HR = 0.4, p = 0.06) and 90 (HR = 0.4, p = 0.05). Although not statistically significant, HR trended similarly for both mean AMC and ALC in MGMT+ patients at these time points (e.g., day 15 HR = 3.8 (p = 0.2) and HR = 0.5 (p = 0.3) respectively). Age at diagnosis, extent of surgical resection, and treatment with CRT were significantly associated with survival (all p < 0.02). In multivariate analyses incorporating all significant variables, neither AMC nor ALC remained significant. Higher AMC and lower ALC during therapy are significantly associated with poorer overall survival in patients with MGMT- GBM. While larger sample sizes and further investigation are needed, these data suggest AMC during therapy is a potentially modifiable risk factor for poor survival, which may be positively affected by myelosuppressive therapy.