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Clinical article
Bone marrow response as a potential biomarker of
outcomes in glioblastoma patients
*Eugene J. Vaios, AB,1,5 Brian V. Nahed, MD, MSc,1,5 Alona Muzikansky, MA,2 Amir T. Fathi, MD,1,3
and Jorg Dietrich, MD, PhD1,4
Harvard Medical School; and Departments of 2Biostatistics, 3Hematology-Oncology, 4Neuro-Oncology, and 5Neurosurgery,
Massachusetts General Hospital, Boston, Massachusetts
1
Objective Glioblastoma (GBM) is a highly aggressive malignancy that requires a multidisciplinary therapeutic approach of surgery, chemotherapy, and radiation therapy, but therapy is frequently limited by 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 (progression-free survival [PFS]).
Methods Complete blood counts and clinical and imaging information were collected retrospectively from 86 cases
involving GBM 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 MGMT promoter methylation,
wild-type EGFR, younger patient age at diagnosis, and treatment-induced decreases in white blood cell counts were
associated with improved OS. The 2-year survival rate was 25% and 58% for patients with increases and decreases,
respectively, in white blood cell counts from baseline over 6 months of TMZ treatment. Consistent with the literature, IDH
mutation and MGMT promoter methylation were associated with better PFS and OS. IDH mutation and MGMT promoter
methylation were not correlated with changes in peripheral red blood cell or white blood cell counts.
Conclusions Decreases in white blood cell counts might serve as a potential biomarker for OS and PFS in malignant glioma patients treated with radiation therapy and TMZ. It remains unclear whether treatment-induced changes in
white blood cell counts correlate with drug-induced antitumor activity or represent an independent factor of the altered
local and systemic tumor environment. Additional studies will be needed to determine dose dependence for chemotherapy based upon peripheral blood counts.
http://thejns.org/doi/abs/10.3171/2016.7.JNS16609
Key Words glioblastoma; temozolomide; bone marrow; biomarker; overall survival; oncology
G
(GBM) is the most common and
most aggressive primary brain tumor, with few
therapeutic advances over the last 20 years.1 The
standard of care includes surgery with a goal of maximal
safe resection, followed by a combination of radiation and
chemotherapy.16 Chemoradiation includes radiotherapy 5
lioblastoma
days per week over 6 weeks in combination with daily
temozolomide (TMZ), followed by at least 6 monthly
cycles of TMZ administered on 5 consecutive days per
28-day cycle.8,16 Patients may continue on TMZ for up to
12 months at some institutions unless there are intolerable
side effects such as myelosuppression. Despite standard
Abbreviations EGFR = epidermal growth factor receptor; GBM = glioblastoma; OS = overall survival; PFS = progression-free survival; TMZ = temozolomide.
SUBMITTED March 18, 2016. ACCEPTED July 25, 2016.
include when citing Published online October 14, 2016; DOI: 10.3171/2016.7.JNS16609.
* Drs. Nahed and Dietrich contributed equally to this work.
©AANS, 2016
J Neurosurg October 14, 2016
1
E. J. Vaios et al.
treatment, GBM remains incurable, with a median survival of less than 19 months and only a 30% probability
of survival 2 years after diagnosis.1,19
The genetic heterogeneity of GBM and the emergence
of various resistance mechanisms are proposed limitations of standardized therapies.1,18 However, MGMT promoter methylation and IDH1 mutation have been identified in genome-wide association studies as robust genetic
markers for improved clinical outcomes in patients treated
with standard chemoradiation.1,18 While IDH status is considered an independent biomarker for clinical outcomes,
MGMT promoter methylation is associated with improved
response to TMZ and radiation and thus serves as a predictive biomarker of more favorable treatment outcomes.
This observed relationship between the molecular-genetic
tumor signature and treatment response has elevated the
importance of noninvasive biomarkers that enable realtime selection and adjustment of personalized therapies.
The unique role of the local and systemic tumor environment is increasingly recognized in overall tumor biology
and treatment outcome.18,23 The identification of a peripheral biomarker for treatment response and overall survival
(OS) would improve patient management and perhaps
alter chemotherapy (e.g., TMZ) dosing protocols, which
currently do not account for individual pharmacogenetics,
pharmacokinetics, or pharmacodynamics.2
The use of circulating blood counts as a marker of
drug activity and clinical outcomes is an emerging area
of investigation. The current understanding of the effect
of chemotherapeutic agents suggests that greater toxicity
to various organ systems, such as the bone marrow, might
reflect increased potency and, conversely, be associated
with a more favorable antitumor profile.11,12 For instance,
in patients with renal cell carcinoma, leukopenia induced
by the tyrosine kinase inhibitor sunitinib was identified
as an independent and prognostic marker for improved
response rate and progression-free survival (PFS).4 This
finding was further supported by work from Zhu et al.,24
suggesting that sunitinib-induced decreases in neutrophils, monocytes, and platelets were associated with improved progression and survival outcomes in patients with
hepatocellular carcinoma.
TMZ therapy, in combination with radiotherapy, significantly improves OS in GBM patients.15 However, dosing is based solely on patient body surface area and does
not account for variability in resistance mechanisms and
drug metabolism, raising the possibility that some patients
may be dosed subtherapeutically. Inadequate dosing may
partially contribute to the observed resistance to cytotoxic treatment and ultimately tumor recurrence. One of
the most common adverse effects of chemotherapy with
TMZ is myelosuppression, including thrombocytopenia
and leukopenia. It remains unclear whether patients who
do not show a notable decrease in blood counts in response to TMZ are treated subtherapeutically. Therefore,
we hypothesized that changes in circulating blood counts
may be predictive of clinical outcomes, with alterations in
blood counts indicative of myelosuppression being associated with improved OS and PFS.
2
J Neurosurg October 14, 2016
Methods
We conducted a retrospective, chart-review analysis of
clinical and demographic data from patients who previously underwent surgery and treatment for primary GBM
at the Massachusetts General Hospital between 2007 and
2014. Patient data were obtained from a Massachusetts
General Hospital institutional database. This time interval
allowed enough time for diagnosis and to follow a complete blood count throughout the patient’s disease course.
This study received institutional review board approval
from Massachusetts General Hospital for all activities.
Eligibility
All patients were treated at the Massachusetts General
Hospital and met the following eligibility criteria: newly
diagnosed with GBM (WHO Grade IV) between January 1, 2007, and July 30, 2014; 18 years of age or older at
the time of diagnosis; surgical biopsy/resection after initial presentation; and treatment with at least 6 cycles of
monthly TMZ. Patients who did not complete 6 months
of TMZ therapy for any reason were excluded from the
study.
Variables
Descriptive information, including age, sex, and steroid
use, was collected. Steroid use was defined as exposure to
steroids (e.g., dexamethasone) at any given time during the
course of chemotherapy. Genetic information including
chromosomal abnormalities, point mutations, and gene
methylation was recorded. This included known prognostic markers for gliomas such as epidermal growth factor
receptor (EGFR) amplification, MGMT promoter methylation, IDH mutation, and 1p/19q co-deletion. The genetic
characteristics of the sample are reported as the percentage of those patients for whom that genetic variable was
tested. Absolute peripheral blood platelet, red blood cell,
white blood cell, eosinophil, basophil, lymphocyte, neutrophil, and monocyte count measurements were recorded
at a maximum of 15 discrete time points during the course
of treatment. Time points included before surgery, after
surgery, before chemoradiation, and before each monthly
TMZ treatment cycle. PFS and OS were also assessed.
Statistics
The primary outcome measure was OS, which was defined as the length of time from the date of initial diagnosis to time of death or last date known to be alive for those
who were censored. The secondary outcome measure was
PFS, which was defined as the length of time from initial
diagnosis to the time of first progression based on radiology report and clinician notes indicating a switch in therapy or last date known to be progression free for censored
patients. The effect of changes in peripheral blood counts
on clinical outcomes was assessed during the interval
between baseline measurement (before chemoradiation)
and Cycle 6 of monthly TMZ, as this time interval had
the greatest sample size and was controlled for the immunosuppressive effect of steroid use during surgery and
chemoradiation. Baseline and 6-month blood counts were
Bone marrow response as a potential biomarker
performed closest to the time of chemoradiation or TMZ
initiation, but no earlier than 2 weeks prior. Changes in
blood counts are reported as the percentage change from
baseline to Cycle 6 of monthly TMZ.
Genetic variables known to be strong prognostic markers were compared with clinical outcomes using logistic
regression or Pearson’s chi-square test. Spearman or Pearson correlation coefficients were estimated to measure
the relation between baseline demographic variables and
clinical outcome measures. Wilcoxon rank-sum tests and
Kruskal-Wallis tests by ranks were used to examine differences in mean blood count changes between groups
of patients stratified by IDH mutation and MGMT promoter methylation. Univariate and multivariate Cox proportional hazards models were used to evaluate variables
for association with PFS and OS. Variables were chosen for multivariate analysis using the backward selection method based on statistical significance in univariate analysis. Percentage changes from baseline in white
blood cell and red blood cell counts were included in the
multivariate model as dichotomized variables, indicating
either an increase or a decrease in that blood count from
baseline. IDH mutation was excluded from the multivariate analysis due to a sample size less than 10. A Wilcoxon
rank-sum test was performed to assess the association between changes in neutrophils and steroid use. Neutrophil
counts at Cycle 6 of TMZ were compared between patients with and without steroid treatment using a 2-sample
t-test. Changes in neutrophil counts were excluded from
the multivariate analysis as they were confounded by steroid use. Survival probabilities were compared between
patient groups, stratified by the dichotomous white blood
cell variable, using the log-rank test. In subgroup analysis, patients with a decreased peripheral white blood cell
count from baseline were subdivided into groups based on
the degree of change, using either quartiles or the median
decrease. Here too the log-rank test was used to compare
survival curves between these patient subgroups. All reported p values were 2-sided, and statistical significance
was considered as p < 0.05.
Results
Descriptive Data Analysis
In total, 86 patients diagnosed with GBM were included in this study. Their median age at diagnosis was 55
years; 32 patients (37%) were women and 54 (63%) were
men. Nineteen patients (22%) were still alive at the time
of data cutoff for analysis. The median OS for the entire
group was 800 days, and the median PFS was 453 days.
Baseline and 6-month peripheral blood counts are listed
in Table 1. Mutation frequencies in the patient cohort are
reported in Table 2.
Univariate and Multivariate Analysis of Biomarker Impact
on OS
By univariate analysis, MGMT promoter methylation
and IDH mutation were associated with better OS and
PFS, consistent with the literature (Table 3 and Supplemental Table 1A). EGFR amplification, changes in neutro-
phil counts, changes in peripheral red and white blood cell
parameters, steroid use, and patient age at diagnosis were
also associated with OS (Table 3). As predicted, patients
receiving steroids during TMZ therapy had worse OS, with
a 2-year survival rate of 51% compared with 71% in patients who were not treated with steroids (p = 0.0051). Additionally, changes in neutrophil counts differed between
patients with and without steroid use (p = 0.0032), and
patients receiving steroids had significantly greater neutrophil counts at 6 months of TMZ compared with those who
never received steroids (p = 0.0031). Changes in neutrophil
counts were not associated with OS in patients who never
received steroids (p = 0.300). On multivariate analysis,
MGMT promoter methylation, a decreased white blood
cell count from baseline, and wild-type EGFR status (i.e.,
EGFR not amplified) were significantly associated with
improved OS (Table 4). These associations remained significant on multivariate analysis that incorporated patient
age and steroid use, despite our observation that steroid use
was associated with increased white blood cells counts (p
= 0.0585). On subgroup analysis, decreases in white blood
cell counts remained associated with improved OS with
hazard ratios of 0.410 (p = 0.053) and 0.109 (p = 0.066) in
patients with and without steroid use.
Association of MGMT and IDH With Alterations in
Circulating Blood Cell Counts
MGMT promoter methylation and IDH1 mutation are
known to be robust prognostic markers for OS in GBM patients.1,18 Regarding the association of these genetic markers with alterations in circulating biomarkers that were
significant on univariate analysis, we report that MGMT
promoter methylation was not correlated with changes in
peripheral red blood cell or white blood cell (p = 0.4492)
counts. Similarly, IDH mutation was not correlated with
changes in peripheral red blood cell (p = 0.2198) or white
blood cell (p = 0.3447) counts during the course of treatment.
Association of Changes in White Blood Cell Counts
With OS
The Kaplan-Meier estimated 2-year survival rate for
patients with a decrease in white blood cell counts from
baseline was 58% and that for patients with an increase
relative to baseline was 25% (p = 0.0019; Fig. 1). Patients
with decreases in white blood cell counts had a median
OS of 850 days (95% CI 691–1097 days) compared with
627 days (95% CI 454–745 days) for those with increases
in white blood cell counts from baseline. We found no significant differences in OS between subgroups of patients
with decreased white blood cell counts during treatment,
when the data were stratified by quartile or median decrease.
Discussion
We here demonstrate that treatment-associated myelosuppression, as manifested by a decrease in circulating white blood cell counts from baseline during adjuvant
J Neurosurg October 14, 2016
3
E. J. Vaios et al.
TABLE 1. Patient blood counts
Hematology
Baseline
Platelets (×10 9 /L)
Mean (SD)
Range
Red blood cells (×1012 /L)
Mean (SD)
Range
White blood cells (×10 9 /L)
Mean (SD)
Range
Eosinophils (×10 9 /L)
Mean (SD)
Range
Basophils (×10 9 /L)
Mean (SD)
Range
Lymphocytes (×10 9 /L)
Mean (SD)
Range
Neutrophils (×10 9 /L)
Mean (SD)
Range
Monocytes (×10 9 /L)
Mean (SD)
Range
6-mo adjuvant TMZ*
Platelets (×10 9 /L)
Mean (SD)
Range
Red blood cells (×1012 /L)
Mean (SD)
Range
White blood cells (×10 9 /L)
Mean (SD)
Range
Eosinophils (×10 9 /L)
Mean (SD)
Range
Basophils (×10 9 /L)
Mean (SD)
Range
Lymphocytes (×10 9 /L)
Mean (SD)
Range
Neutrophils (×10 9 /L)
Mean (SD)
Range
Monocytes (×10 9 /L)
Mean (SD)
Range
TABLE 2. Summary of patient characteristics
Value
279.28 (97.59)
95.00–589.00
4.28 (0.43)
3.27–5.16
8.69 (3.29)
3.27–20.00
0.11 (0.11)
0.00–0.58
0.03 (0.03)
0.00–0.20
1.67 (0.73)
0.52–3.93
6.21 (2.90)
2.16–15.43
0.46 (0.24)
0.14–1.51
188.74 (65.76)
80.00–400.00
4.13 (0.45)
3.24–5.29
5.68 (2.50)
3.00–14.10
0.12 (0.10)
0.00–0.45
0.02 (0.02)
0.00–0.15
0.99 (0.41)
0.35–2.10
3.97 (2.21)
0.02–11.30
0.40 (0.18)
0.02–1.02
* Blood counts obtained at the time of the 6th monthly cycle of TMZ treatment.
4
J Neurosurg October 14, 2016
Characteristic
Sex
Male
Female
Age at diagnosis, yrs
Mean (SD)
Range
OS, days
Mean (SD)
Range
PFS, days
Mean (SD)
Range
Genetic mutation
EGFR
MGMT
IDH
Steroid use
Deceased
Value
54 (63%)
32 (37%)
55.37 (12.55)
18.00–80.00
915.09 (476.37)
324.00–2660.00
622.10 (487.02)
12.00–2660.00
37 (50.00%)
39 (54.17%)
6 (8.96%)
62 (72.09%)
67 (77.91%)
Values represent n (%) unless otherwise indicated.
TMZ therapy, might serve as a potential prognostic marker for clinical outcomes in patients with GBM. Our serial assessment of peripheral blood counts and additional
laboratory and radiographic data found that a decrease
in white blood cells from baseline during adjuvant TMZ
therapy predicts significantly improved OS.
Our institutional survival data for patients with decreases in white blood cells compares favorably with data
from the original EORTC/NCIC trial, which reported a
median survival of 14.6 months and a 2-year survival rate
of 26.5% for patients receiving radiotherapy plus TMZ.16
The present findings are consistent with findings of previous studies demonstrating an association of MGMT
promoter methylation and IDH1 mutation with improved
clinical outcomes.3,5,6,17,21 Interestingly, we found that
MGMT promoter methylation and IDH mutation did not
correlate with changes in white blood cell counts, suggesting that these changes may serve as an independent prognostic factor.
Despite these robust findings, our study is limited by
its modest sample size and retrospective nature. Nevertheless, our exploratory analysis of hematological parameters
identified that treatment-related changes in white blood
cell counts are associated with OS, with decreases in white
blood cell counts from baseline serving as a biomarker for
improved OS. This association was maintained on multivariate analysis, even after controlling for other known
prognostic variables, including age at the time of diagnosis, steroid use, EGFR amplification status, and MGMT
promoter methylation status. On subgroup analysis, decreases in white blood cell counts from baseline maintained a strong association with improved OS regardless of
whether a patient used steroids during TMZ therapy. Notably, an increase in white blood cell counts from baseline
was also considered an important biomarker for worse OS,
suggesting that changes in white blood cell counts play an
Bone marrow response as a potential biomarker
TABLE 3. Univariate analysis for OS
Covariate
Sex
Male
Female
Age
Genetic mutations
EGFR
MGMT
IDH
Percent change in
Platelets
Red blood cells
White blood cells
Eosinophils
Basophils
Lymphocytes
Neutrophils
Monocytes
Steroids
Used
Not used
TABLE 4. Multivariate analysis for OS
HR
95% CI
p Value*
0.685
—
1.021
0.418–1.124
—
1.000–1.042
0.1346
—
0.0470
1.818
0.353
0.100
1.074–3.078
0.203–0.615
0.014–0.726
0.0261
0.0002
0.0228
1.163
0.074
3.133
0.979
0.938
1.330
1.856
1.407
0.443–3.051
0.007–0.787
1.489–6.591
0.895–1.070
0.678–1.296
0.675–2.621
1.218–2.828
0.873–2.270
0.7588
0.0308
0.0026
0.6340
0.6973
0.4102
0.0040
0.1610
2.286
—
1.262–4.142
0.0064
—
* Based on log-rank test.
important biological role in the tumor microenvironment
independent of chemotherapy.
We were unable to identify an association between
changes in the peripheral platelet count and clinical outcomes, as described by Williams et al.22 This finding suggests that decreases in white blood cell counts, rather than
general “bone marrow suppression,” might be a predictor
of improved OS. However, we did not observe a statistically significant association between white blood cell
changes and PFS in our multivariate model, when controlling for steroid use and other markers that were significant on univariate analysis (Supplemental Data). Our
findings, however, indicate that patient age and MGMT
promoter methylation are important predictors of PFS.
Changes in neutrophils were also significantly associated with OS and PFS, with neutrophil increases from
baseline predicting worse outcomes. However, given the
association of neutrophil counts with medications (e.g.,
steroid use), infections, and environmental factors, these
findings remain more challenging to interpret. Neutrophil
counts were likely confounded by steroid use, perhaps indicative of more aggressive tumor growth necessitating
steroid administration for the management of edema. Consistent with the literature, our study found that steroid use
was associated with elevated neutrophil counts and worse
outcomes. In patients who did not receive steroids, we did
not observe an association between neutrophil counts and
OS. Therefore, this hematological parameter was excluded
from our multivariate analysis.
The observed relationship between a decrease in white
blood cell counts and clinical outcomes is possibly due to
higher in vivo drug concentrations of TMZ, resulting from
differences in drug metabolism. TMZ activity is dose and
schedule dependent and induces cytotoxicity primarily by
Covariate
HR
95% CI
p Value*
Age
MGMT
EGFR
White blood cells
Increase
Decrease
Red blood cells
Increase
Decrease
Steroids
Used
Not used
1.064
0.106
1.779
1.033–1.096
0.043–0.259
0.978–3.247
<0.0001
<0.0001
0.0594
3.040
—
1.245–7.407
—
0.0147
—
1.065
—
0.578–1.961
—
0.8390
—
1.196
—
0.575–2.494
—
0.6317
—
IDH was excluded due to inadequate sample size.
* Based on log-rank test.
causing O6-meG lesions, which deplete the repair enzyme
MGMT, leading to double-strand DNA breaks and tumor
cell apoptosis.7,13,14,25 TMZ is administered orally and has
a half-life of 1.8 hours, reaching concentrations in the CSF
that are 30%–40% of plasma concentrations. The clinical efficacy of TMZ and its active metabolite depends on
MGMT activity; the integrity of the mismatch repair system, which recognizes O6-meG lesions in template DNA
strands; and function of the base excision repair system,
which corrects highly lethal N3-meA lesions via poly
(ADP-ribose) polymerase.9,10,20 There are no guidelines for
dose adjustment based on the tumor genetic signature or
in the context of severe renal or hepatic impairment. Since
Fig. 1. Kaplan-Meier analysis of OS in patients stratified by increase
(dotted line) or decrease (solid line) in white blood cell counts from baseline. A significant survival benefit is noted for patients with a decrease in
white blood cells relative to baseline (log-rank p = 0.0019).
J Neurosurg October 14, 2016
5
E. J. Vaios et al.
current dosing guidelines do not factor interpatient differences in resistance mechanisms or patient-specific drug
metabolism, it is possible that some patients are treated
subtherapeutically.
Given the routine and reliable assessment of peripheral blood counts in GBM patients receiving conventional
therapies, white blood cell counts could serve as a valuable
biomarker of treatment response and for predicting clinical outcomes. Future prospective studies should address
whether blood cell counts could serve as a correlate biomarker for in vivo TMZ levels and drug activity as well as
a predictor of clinical outcomes, which in turn could help
to optimize dosing and scheduling of chemotherapy by accounting for variability in drug metabolism.
Conclusions
We report a temporal relationship between changes in
peripheral white blood cell counts during adjuvant TMZ
treatment and clinical outcomes. Specifically, depression
of white blood cell counts appears to be an independent
prognostic factor and was associated with improved OS.
This relationship may be a reflection of plasma TMZ levels
and, in time, may serve as a surrogate marker of therapeutic efficacy. These findings warrant further investigation in
prospective studies, including correlations with the degree
of change in white blood cell counts and pharmacokinetics of TMZ in individual patients. It also remains unclear
whether treatment-associated changes in white blood cell
counts correlate with drug-induced antitumor activity or
represent an independent factor of the altered local and
systemic tumor environment.
Acknowledgments
This work was supported by the 2015 Neurosurgical Research
and Education Foundation (NREF) Medical Student Summer
Research Fellowship (Eugene J. Vaios) and the Harvard Medical
School Scholars in Medicine Office (Eugene J. Vaios).
Jorg Dietrich received support from the American Academy of
Neurology, the American Cancer Society, and generous gifts from
the family foundations of Bryan Lockwood, Ronald Tawil, and
Sheila McPhee.
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Disclosures
The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this
paper.
Author Contributions
Conception and design: Vaios, Nahed, Dietrich. Acquisition of
data: Vaios. Analysis and interpretation of data: Vaios, Nahed,
Muzikansky, Dietrich. Drafting the article: Vaios. Critically revising the article: Vaios, Nahed, Fathi, Dietrich. Reviewed submitted
version of manuscript: all authors. Approved the final version of
the manuscript on behalf of all authors: Vaios. Statistical analysis:
Vaios, Muzikansky. Administrative/technical/material support:
Nahed, Dietrich. Study supervision: Nahed, Dietrich.
Supplemental Information
Online-Only Content
Supplemental material is available with the online version of the
article.
Supplemental Tables 1A and B. http://thejns.org/doi/
suppl/0.3171/2016.7.JNS16609.
Correspondence
Eugene John Vaios, Vanderbilt Hall Box 099, 107 Ave. Louis
Pasteur, Boston, MA 02115. email: [email protected].
edu.
J Neurosurg October 14, 2016
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