Abstract
Background:
Hematological adverse events (HAEs) are common during treatment for glioblastoma (GBM), usually associated with temozolomide (TMZ). Their clinical value is uncertain, as few investigations have focused on outcomes for HAEs during GBM treatment.
Methods:
We combined data from two randomized clinical trials, RTOG 0525 and RTOG 0825, to analyze HAEs during treatment for GBM. We investigated differences between chemoradiation and adjuvant therapy, and by regimen received during adjuvant treatment.
Results:
1454 patients participated in these trials, of which 1154 (79.4%) developed HAEs. During chemoradiation, 44.4% of patients developed HAEs (54% involving more than one cell line), and were most commonly lymphopenia (50.6%), and thrombocytopenia (47.5%). During adjuvant treatment, 45% of patients presented HAEs (78.6% involving more than one cell line), and were more commonly leukopenia (62.7%), and thrombocytopenia (62.3%). Median overall survival (OS) and progression free survival (PFS) were longer in patients with HAEs (OS 19.4 months and PFS 9.9 months) compared to those with other or no adverse events (OS 14.1 months and PFS 5.9 months). There was no significant difference in survival between grade 1 and/or 2 versus grade 3 and/or 4 HAEs. History of HAEs during chemoradiation was a protective factor for presentation of HAEs during adjuvant therapy.
Conclusion:
HAEs are common during GBM treatment, and often involve more than one cell line (more likely during adjuvant therapy). HAEs may be associated with prolonged OS and PFS, particularly during adjuvant therapy. HAEs during chemoradiation was a protective factor for HAEs during adjuvant therapy.
Keywords: Hematologic adverse events, glioblastoma, management, temozolomide, bevacizumab, outcomes
INTRODUCTION
The recommended medical regiment for glioblastoma (GBM) includes an initial phase with concurrent radiation for 6 weeks, followed by at least 6 cycles of adjuvant temozolomide (TMZ) after the initial surgical resection(1). From 1998 to 2011, over 50% of newly diagnosed GBM patients in the United States received chemotherapy alone, and around 40% received a combination of chemotherapy, radiation, and surgery(2). This multimodality approach has become more common in recent years. In an analysis from 2005 to 2015, over 49% of WHO grade IV brain tumors were treated with chemotherapy, radiation, and surgery as initial therapy(3).
Hematological adverse events (HAEs) are associated with temozolomide, bevacizumab, and with radiation. Hematologic toxicity from TMZ is a significant and emerging concern, with reports of severe myelosuppression(4–6). Clinical data on HAEs of TMZ is limited. Severe myelotoxicity has been reported in 3–4% of patients in randomized clinical trials(1). Single nucleotide polymorphisms in the O6-methylguanine-DNA-methyltransferase (MGMT) could be implicated in higher risk of TMZ-induced myelosuppression(6). Moreover, severe myelosuppression has been associated with inactivation of the MGMT gene in peripheral blood mononuclear cells or in bone-marrow stem cells(7). Bevacizumab, a monoclonal antibody against vascular endothelial growth factor has also been associated with HAEs, particularly neutropenia and thrombocytopenia, more frequently when combined with chemotherapy(8, 9). Due to limited options for GBM treatment, discontinuing or holding chemotherapy requires careful consideration, and early prognostic indicators may be helpful in deciding further management.
Radiation Therapy Oncology Group (RTOG) 0525 and RTOG 0825 represent the largest studies published for GBM. RTOG 0525 demonstrated prognostic significance for the methylated status of the MGMT gene in GBM(10), while RTOG 0825 demonstrated that TMZ alone was not different from TMZ plus bevacizumab during maintenance(11). Grade 3 and 4 lymphopenia were common toxicities in the trials (10–12% of patients). Other common events included serious (grade 3 and 4) thrombocytopenia and neutropenia, which were more frequent in patients receiving bevacizumab. Even though there were no significant opportunistic infections, neutropenia resulted in one treatment related death(11, 10). We combined data from RTOG 0525 and RTOG 0825 to expand the evaluation of HAEs during GBM treatment and their association with clinical determinants and outcomes.
In the Stupp et al. trial in 2005 where it was initially proved that temozolomide increased survival benefits(1), TMZ-associated grade 3 or 4 hematologic toxicity was seen in less than 5% of patients. During chemoradiation, grade 3 or 4 thrombocytopenia was reported in 11% and grade 3 or 4 neutropenia was reported in 4% of patients; whereas during adjuvant treatment grade 3 or 4 neutropenia was reported in 4% of patients(12).
METHODS
We requested data from RTOG 0525 and RTOG 0825 through the National Clinical Trials Network. Hematological toxicities (anemia, leukopenia, lymphopenia, neutropenia, and thrombocytopenia) were analyzed. In these trials, patients underwent weekly complete blood counts during chemoradiation, and on days 21 and 28 of each cycle during maintenance. HAEs were graded with the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 in both trials, and were grouped as mild (grade 1 or 2) or severe (grade 3 or 4) in our analyses.
In patients that had more than one episode of individual hematological toxicities (i.e. more than one episode of anemia, leukopenia, lymphopenia, neutropenia, or thrombocytopenia), the highest grade was taken for the analyses. Our analysis was separated into two time points; chemoradiation and adjuvant TMZ, based on the standard of care for GBM(1), and the treatment received in the trials.
All patients in RTOG 0525 and 0825 received concurrent chemoradiation therapy with a 75 mg/m2 daily dose of TMZ for a total of 42 doses until the radiation component was completed. Clinical characteristics of the participants, along with inclusion and exclusion criteria for participation are described in published trials(11, 10). Active infections requiring antibiotics were an exclusion criteria for both trials.
Patients were further divided according to the TMZ regimen received during adjuvant therapy (standard, dose-dense, or temozolomide plus bevacizumab). The standard TMZ group (sTMZ) was defined by combining arm 1 of RTOG 0525 and arm 1 of RTOG 0825, the dose dense TMZ (ddTMZ) group was defined as arm 2 of RTOG 0525, and the TMZ and bevacizumab (TMZ+Bev) group was defined as arm 2 of RTOG 0825 (Figure 1).
Figure 1.
Adjuvant therapy group distribution diagram
ddTMZ, dose dense temozolomide; sTMZ, standard temozolomide; TMZ+Bev, temozolomide and bevacizumab
The duration of TMZ was calculated from randomization to first HAE occurrence. Outcomes such as overall survival (OS) and progression free survival (PFS) were estimated using Kaplan-Meier and tested using log-rank test(13, 14). OS was defined as the interval from random assignment to death as a result of any cause, or the last follow-up date on which the patient was reported alive. PFS was defined as the interval from random assignment to progression or death or being censored at the last clinical or radiology assessment date on which the patient was reported alive without progression.
Variables available for our review included age, gender, MGMT methylation status, randomized arm, adverse events, and cause of treatment termination. Antibiotic prophylaxis or treatment after adverse events was not available for our review.
Logistic regression was performed to assess risk factors for developing HAEs and mortality. History of HAEs during evaluation of cases during adjuvant therapy was defined as having HAEs during chemoradiation. Statistical analyses were performed with SPSS 14 software (SPSS, Inc. Chicago, IL, USA) and SAS 9.4 (Cary, NC). A two-sided p-value of less than 0.05 was considered significant.
RESULTS
1454 patients were included in the current analysis, of which 1154 (79.4%) presented with any HAE during treatment. Patients that presented with HAEs had a median age of 57 years and 58.9% were male (Table 1). MGMT was non-methylated in 64.9% of patients and methylated in 28.9%. Treatment was completed per protocol in 24.3%. The reason for stopping treatment was progression in 60.2%, AE/Complications in 24.1%, study refusal/withdrawal in 7.3%, other in 4.3%, and death in 2.9% of patients. Ten patients were taken off protocol and one patient decided to receive alternative therapy.
Table 1.
Demographics of glioblastoma patients that presented HAEs during treatment with temozolomide
| TMZ standard (N = 552) | ddTMZ (N=363) | TMZ +Bev (N=239) | All (N=1154) | p-value | ||
|---|---|---|---|---|---|---|
| Age | Median (Range) | 56 (19–84) | 58 (21–84) | 59 (26–82) | 57 (19–84) | 0.013 |
| Gender | Male | 332 (60.1%) | 208 (57.3%) | 140 (58.6%) | 680 (58.9%) | 0.688 |
| Female | 220 (39.9%) | 155 (42.7%) | 99 (41.4%) | 474 (41.1%) | ||
| Age group | ≤50 years | 170 (30.8%) | 108 (29.8%) | 49 (20.5%) | 327 (28.3%) | 0.01 |
| > 50 years | 382 (69.2%) | 255 (70.2%) | 190 (79.5%) | 827 (71.7%) | ||
| MGMT | Methylated | 159 (28.8%) | 108 (29.8%) | 66 (27.6%) | 333 (28.9%) | 0.015 |
| Non-methylated | 354 (64.1%) | 226 (62.3%) | 169 (70.7%) | 749 (64.9%) | ||
| Indeterminate | 39 (7.1%) | 29 (8.0%) | 4 (1.7%) | 72 (6.2%) | ||
| Treatment termination | Treatment completed per protocol | 126 (22.8%) | 77 (21.2%) | 77 (32.2%) | 280 (24.3%) | <0.0001 |
| Progression | 290 (52.5%) | 161 (44.4%) | 55 (23.0%) | 506 (43.8%) | ||
| Adverse event | 61 (11.1%) | 75 (20.7%) | 67 (28.0%) | 203 (17.6%) | ||
| Death | 11 (2.0%) | 8 (2.2%) | 5 (2.1%) | 24 (2.1%) | ||
| Withdrawal/refusal during protocol | 25 (4.5%) | 20 (5.6%) | 16 (6.7%) | 61 (5.3%) | ||
| Alternative therapy | 0 | 0 | 1 (0.4%) | 1 (0.1%) | ||
| Patient off protocol | 4 (0.7%) | 6 (1.7%) | 0 | 10 (0.9%) | ||
| Other | 17 (3.1%) | 9 (2.5%) | 10 (4.2%) | 36 (3.1%) |
Statistical analyses were performed using the chi-squared test, F-test, or Fisher’s exact test.
ddTMZ, dose dense temozolomide; sTMZ, standard temozolomide; TMZ+Bev, temozolomide and bevacizumab
The percentage of patients that presented with HAEs by adjuvant group was 76.6% for sTMZ, 86.01% for ddTMZ, and 76.6% for TMZ+Bev. There was a higher percentage of patients older than 50 years in the TMZ+Bev group. The percentage of patients that completed treatment per protocol was higher in the TMZ+Bev group, with a higher percentage of patients where treatment was stopped due to adverse events. Progression was the cause of treatment termination in 52.5% of patients in the sTMZ group, compared to 44.4% in the ddTMZ group, and 23.0% in the TMZ+ Bev group.
CHEMORADIATION
Overall, 646 (44.4%) patients presented with HAEs during chemoradiation, of which 348 (53.9%) had more than one HAE. The most common HAE during chemoradiation was lymphopenia (50.62%), followed by thrombocytopenia (47.5%), and anemia (43.0%). Severe HAEs (Grade 3 or 4) occurred in 224 (34.7%) patients while mild HAEs (grade 1 or 2) were reported in 573 (88.7%). The most common severe HAE was lymphopenia (68.8%), followed by thrombocytopenia (34.4%). The most common of mild HAEs was anemia (47.5%), followed by thrombocytopenia (40.1%).
During chemoradiation, neutropenia and thrombocytopenia were most common in the TMZ+Bev group, while lymphopenia was most common in the ddTMZ and sTMZ groups. The percentage of patients presenting with anemia, and leukopenia was similar among groups (Table 2 and supplementary table 1). Neutropenia and thrombocytopenia were more frequent in the TMZ+Bev group during chemoradiation (Table 2 and supplementary table 1). The median number of days on temozolomide prior to HAEs was numerically longer for leukopenia (39 days) and neutropenia (37 days). Overall, the days prior to HAEs were numerically shorter in the TMZ+Bev group (see Supplemental table 3).
Table 2.
Hematological adverse events during chemoradiation in patients receiving temozolomide for glioblastoma
| TMZ standard | ddTMZ | TMZ +Bev | All | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| G1-2 N=270 | G3-4 N=97 | All N=299 | G1-2 N=140 | G3-4 N=63 | All N=168 | G1-2 N=163 | G3-4 N=64 | All N=179 | G1-2 N=573 | G3-4 N=224 | All N=646 | |
| N (%) | N (%) | N (%) | N (%) | N (%) | N (%) | N (%) | N (%) | N (%) | N (%) | N (%) | N (%) | |
| Patients with more than one HAE | 158 (52.84%) | 85 (50.59%) | 105 (58.65%) | 348 (53.86%) | ||||||||
| Individual events (percentage of patients) | ||||||||||||
| Anemia | 132 (48.89%) | 1 (1.03%) | 133 (44.48%) | 71 (50.71%) | 3 (4.76%) | 74 (44.05%) | 69 (42.33%) | 2 (3.13%) | 71 (39.66%) | 272 (47.47%) | 6 (2.68%) | 278 (43.03%) |
| Leukopenia | 86 (31.85%) | 12 (12.37%) | 98 (32.78%) | 43 (30.71%) | 10 (15.87%) | 53 (31.55%) | 40 (24.54%) | 14 (21.88%) | 54 (30.17%) | 169 (29.49%) | 36 (16.07%) | 205 (31.73%) |
| Lymphopenia | 90 (33.33%) | 67 (69.07%) | 157 (52.51%) | 42 (30.0%) | 50 (79.37%) | 92 (54.76%) | 41 (25.15%) | 37 (57.81%) | 78 (43.58%) | 173 (30.19%) | 154 (68.75%) | 327 (50.62%) |
| Neutropenia | 28 (10.37%) | 16 (16.49%) | 44 (14.72%) | 15 (10.71%) | 6 (9.52%) | 21 (12.50%) | 26 (15.95%) | 21 (32.81%) | 47 (26.26%) | 69 (12.04%) | 43 (19.20%) | 112 (17.34%) |
| Thrombocytopenia | 103 (38.15%) | 35 (36.08%) | 138 (46.15%) | 46 (32.86%) | 14 (22.22%) | 60 (35.71%) | 81 (49.69%) | 28 (43.75%) | 109 (60.89%) | 230 (40.14%) | 77 (34.38%) | 307 (47.52%) |
ADJUVANT THERAPY
Overall, 687 (47.3%) patients presented with HAEs during adjuvant temozolomide, of which 521 (75.6%) presented with more than one event. The most common HAE was leukopenia (62.7%), followed by thrombocytopenia (62.3%), and lymphopenia (56.0%) (Table 3). Severe HAE accounted for 264 (38.13%) patients, while mild HAE occurred in 647 (94.17%) patients.
Table 3.
Hematological adverse events during adjuvant therapy in patients receiving temozolomide for glioblastoma
| TMZ standard | ddTMZ | TMZ +Bev | All | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| G1-2 N=295 | G3-4 N=109 | All N=310 | G1-2 N=192 | G3-4 N=108 | All N=212 | G1-2 N=160 | G3-4 N=47 | All N=165 | G1-2 N=647 | G3-4 N=264 | All N=687 | |
| N (%) | N (%) | N (%) | N (%) | N (%) | N (%) | N (%) | N (%) | N (%) | N (%) | N (%) | N (%) | |
| Patients with more than one HAE | 235 (78.33%) | 168 (79.25%) | 118 (78.15%) | 521 (78.58%) | ||||||||
| Individual events (percentage of patients) | ||||||||||||
| Anemia | 159 (53.90%) | 3 (2.75%) | 162 (52.26%) | 95 (49.48%) | 2 (1.85%) | 97 (45.75%) | 58 (36.25%) | 3 (6.38%) | 61 (36.97%) | 312 (48.22%) | 8 (3.03%) | 320 (46.58%) |
| Leukopenia | 161 (54.88%) | 30 (27.52%) | 191 (61.61%) | 130 (67.71%) | 24 (22.22%) | 154 (72.64%) | 72 (45.0%) | 14 (29.79%) | 86 (52.12%) | 363 (56.11%) | 68 (25.76%) | 431 (62.74%) |
| Lymphopenia | 108 (36.61%) | 69 (63.30%) | 177 (57.10%) | 33 (17.19%) | 97 (89.81%) | 130 (61.32%) | 53 (33.13%) | 25 (53.19%) | 78 (47.27%) | 194 (29.98%) | 191 (72.35%) | 385 (56.04%) |
| Neutropenia | 90 (30.51%) | 27 (24.77%) | 117 (37.74%) | 54 (28.13%) | 19 (17.59%) | 73 (34.43%) | 41 (25.63%) | 17 (36.17%) | 58 (35.13%) | 185 (28.59%) | 63 (23.86%) | 248 (36.10%) |
| Thrombocytopenia | 162 (54.92%) | 36 (33.03%) | 198 (63.87%) | 94 (48.96%) | 7 (6.48%) | 101 (47.64%) | 112 (70.0%) | 17 (36.17%) | 129 (78.18%) | 368 (56.88%) | 60 (22.73%) | 428 (62.30%) |
During this time, thrombocytopenia was more common in the TMZ+Bev group (p<0.0001) (supplementary table 2). During adjuvant therapy the median number of days on temozolomide prior to HAEs was numerically larger for neutropenia in all treatment groups (63 days), for all other HAEs, the median number of days prior to HAEs was numerically larger on the ddTMZ group (supplementary table 4).
SURVIVAL
Median overall survival and progression free survival were longer in patients presenting with HAEs (OS 19.4 months and PFS 9.9 months) compared to those who presented with other AEs or no AEs (OS of 14.1 months and PFS of 5.9 months) (Figure 2a and 2b). There was no statistically significant difference in survival (OS and PFS) in patients that had HAEs compared to other AEs (Supplemental figures 1a and 1b).
Figure 2.
a. Overall survival (OS) comparison between patients that developed hematological adverse events (HAE) versus all other adverse events (AEs) and no adverse events (AEs) (p<0.0001). 2b. Progression free survival (PFS) between patients that developed HAE versus all other AEs and no AEs (p<0.0001)
OS, Overall survival; HAEs, Hematological adverse events; AEs, Adverse events; PFS, Progression free survival
Median survival was 18.6 months for patients presenting with anemia, 20.7 months for leukopenia, 18.5 months for lymphopenia, 19.5 months for neutropenia, and 16.5 months for thrombocytopenia (Supplemental figure 2). There was no significant difference in survival (OS and PFS) between mild and severe HAEs in the overall cohort (Figure 3). In patients presenting with leukopenia, severe HAE was associated with increased OS (Supplemental figure 3). There was no significant difference in OS or PFS between sTMZ, ddTMZ, and TMZ+Bev groups (Supplemental figure 4).
Figure 3.
a. Overall survival (OS) comparison between grade 1–2 versus grade 3–4 for all patients with hematological adverse events (HAEs) (overall) (p=0.281). 3b. Progression free survival (PFS) comparison between grade 1–2 versus grade 3–4 for all patients with HAEs (overall) (p=0.421)
OS, Overall survival; HAEs, Hematological adverse events; PFS, Progression free survival
During chemoradiation, median progression free survival did not vary between mild and severe HAEs for anemia, leukopenia, and lymphopenia. Patients with mild neutropenia and thrombocytopenia had a longer PFS compared to severe HAEs (p=0.01 and p=0.007, respectively). In the TMZ+Bev group, mild anemia and neutropenia were also associated with increased PFS (p=0.012). In the sTMZ and ddTMZ groups, there were no differences in PFS while comparing mild versus severe HAEs (see Supplemental table 5).
Overall survival was significantly higher in mild anemia, neutropenia, and thrombocytopenia (p=0.004, 0.004, 0.024, respectively) during chemoradiation. In the TMZ+Bev there was also a significant survival benefit in patients with mild anemia compared to severe (p=0.009). Mild thrombocytopenia and mild anemia were also associated with significant survival benefit in the ddTMZ group. There were no significant differences in overall survival between mild and severe HAEs in the sTMZ group (Supplemental table 6). During maintenance chemotherapy there were no significant differences in PFS or OS by HAE grade (Supplemental tables 7 and 8).
RISK FACTORS
Gender, age, and MGMT methylation status of GBM were not associated with increased risk of presenting HAEs. History of HAEs during chemoradiation was a protective factor for presenting HAEs during maintenance (Supplemental table 9). Age older than 50 years was a risk factor for mortality in patients presenting with HAEs. MGMT methylated GBM decreased the risk of overall mortality (Supplemental table 10).
DISCUSSION
HAEs are common during glioblastoma treatment, with studies describing 42% of patients having lymphopenia even before starting treatment(15), and 75% developing lymphopenia after finishing chemoradiation(16). Over 79% of patients presented with HAEs during treatment in our analysis; 44% during chemoradiation, and 47.3% during adjuvant therapy. The incidence of HAEs in our study is significantly higher compared to a prospective study by Lombardi et al(17). However, differences in the timing of taking complete blood counts, grading definitions, and sample size may explain the differences; as these events are usually mild and reversed after discontinuation or decreased TMZ dose without the need for further intervention. Analyzing the data from two randomized clinical trials provides the opportunity to evaluate clinical outcomes and incidence in a homogenized patient population, with close follow up and similar times of laboratory studies. This approach removes some of the confounders that have limited the conclusions from previous studies.
Lymphopenia, thrombocytopenia, and anemia were the most common HAEs during chemoradiation. Leukopenia and lymphopenia were the most common during adjuvant therapy. Age and gender were not associated with risk of HAEs in our study. Previous studies have described a higher incidence of HAEs in females during their first cycle of TMZ (12.4%) compared to males (6.3%)(6), and an overall higher risk of myelotoxicity in females(17, 5, 18). MGMT methylation has also been associated with increased risk of HAEs, as bone marrow precursors have low levels of MGMT, making them susceptible to HAE(19). Previous investigations suggested that inactivated MGMT in peripheral blood mononuclear cells during the pre-treatment period is associated with thrombocytopenia and neutropenia(7). MGMT methylated GBM was not associated with HAEs in our analyses.
While comparing adjuvant therapy groups, the TMZ+Bev group had a slightly older population. The percentage of patients that stopped treatment due to progression was lower in the ddTMZ and the TMZ+Bev groups, but the percentage of patients stopping therapy due to adverse events was higher in the TMZ+Bev group. While comparing type of HAEs, neutropenia and thrombocytopenia were more common in the TMZ+Bev group. However, thrombocytopenia and neutropenia were also more common during chemoradiation in this group (before receiving bevacizumab). During adjuvant therapy, the most common HAEs in the TMZ+Bev use was thrombocytopenia. Bevacizumab has been previously associated with neutropenia and immune mediated thrombocytopenia(8, 9). While comparing sTMZ and ddTMZ groups, there was a higher rate of leukopenia in ddTMZ, with smaller percentages of anemia, and thrombocytopenia.
From our analysis, anemia occurred in 43% of patients with HAEs during chemoradiation, and 47% during maintenance TMZ, and was rarely graded as severe (6 patients during chemoradiation and 8 during maintenance). Literature on anemia and temozolomide is scarce, mostly associated with case reports directly related to temozolomide(20, 21), or to hemolysis due to other causes(22, 23). The FDA issued a Drug Safety Newsletter in 2007, citing 18 cases of aplastic anemia in patients treated with TMZ from August 1999 to November 2006(24). In an analysis of the FDA MedWatch database from 1997 to 2008, 76 cases of aplasia/aplastic anemia were reported(4). Thrombocytopenia and neutropenia have shown a positive impact on survival in GBM patients(25–27). Radiation (dose dependent), and medications used during GBM treatment may also impact blood counts, such as steroids, that are associated neutrophilia and leukocytosis, and increased mortality in GBM patients(25). Interestingly, the clearance of TMZ is not influenced by drugs such as dexamethasone, phenytoin, and ondansetron(28), that are commonly used during GBM treatment.
Overall, HAEs were associated with improved OS and PFS when compared to patients that presented other AEs or no AEs, particularly during adjuvant therapy. However, there was no OS or PFS benefit while comparing HAEs to all other AEs. The decreased OS and PFS in patients with other AEs or no AEs may be due to decreased effect of temozolomide, tumor resistance, short duration of therapy, or other severe adverse events associated with higher mortality.
While analyzing HAEs during chemoradiation, there was no association with mortality. HAEs during chemoradiation were a protective factor for presentation of HAEs during adjuvant therapy. There was no difference in OS while comparing individuals events. PFS was overall longer in patients presenting mild neutropenia or thrombocytopenia during chemoradiation. OS was longer in patients presenting mild anemia, neutropenia, and thrombocytopenia during chemoradiation. There was no difference in survival when comparing severity during adjuvant therapy.
Immunosuppression and myelosuppression during chemoradiation is a poor prognostic factor in some cancers including GBM(29), and the presence of circulating lymphocytes has been associated with favorable clinical response(30–32). Overall, a decrease in white blood cells and thrombocytopenia during chemoradiation have been associated with OS and PFS benefits in patients with GBM, based on data from retrospective studies(25, 26). Myelosuppression may be associated with survival by serving as a marker for tumor response to temozolomide, suggesting cancer stem cell suppression(33, 25), but also may be useful as an assessment for correct dosing due to differences in metabolism and DNA repair function(25, 34). In future studies, it would be interesting to see if molecular profiling is associated with myelosuppression. In our data, MGMT methylation was not associated with HAEs, but no other tumor marker was included. This is similar to prior reports, where MGMT methylation did not correlate with white blood cell counts(25). GBM has been associated with sequestration of T cells into the bone marrow(35). This would be important to elucidate in future studies, particularly with the development of immunotherapy.
Other factors that may influence mortality include duration of the hematologic event, and use of specific therapy to treat HAEs (granulocyte colony stimulating factors(36, 37)). We were unable to include the duration of HAEs or the treatment related to them in our study, as the data was not available for our review. Prolonged TMZ-related HAEs, especially prolonged lymphopenia (more than a year), have been associated with chemoradiation or longer duration of adjuvant chemotherapy(38).
It is interesting to mention that for other cancer types, there has been reported a higher risk of neutropenic infections in single center studies compared to clinical trials (39, 40). We do not know if patients enrolled in RTOG 0525 and RTOG 0825 had infections after their cytopenias.
Some of the limitations of our study include the lack of genetic profiling (only MGMT methylation was included), clinical characteristics, symptoms associated with HAEs, the impact of Tumor Treating Fields (TTFields), and duration of events as discussed above. In addition, hematologic history was not available for our review and may had been a confounding factor for some patients. However, the use of data from clinical trials indicates that these patients did not have severe comorbidities, significantly abnormal baseline labs, and were overall stable prior to starting therapy, as per the eligibility criteria of each trial. Our study provides a comprehensive review for TMZ-associated HAEs, combining data from two large phase 3 trials. HAEs are common and may be associated with increased PFS and OS, particularly during maintenance chemotherapy. No difference in OS or PFS among the different grades of HAEs was identified.
Supplementary Material
Acknowledgement
Our investigation would not be possible without data support from RTOG central office, along with RTOG 0525 and 0825 investigators and the many participating patients.
Funding:
Supported by the Biostatistics and Bioinformatics Shared Resource of the University of Kentucky Markey Cancer Center (P30 CA177558).
Footnotes
Conflict of Interest: None of the authors has any conflicts to declare.
Ethical approval: This article does not contain any studies with human participants performed by any of the authors. Data was requested through the National Clinical Trials Network.
DECLARATIONS
Compliance with Ethical Standards
Publisher's Disclaimer: This AM is a PDF file of the manuscript accepted for publication after peer review, when applicable, but does not reflect postacceptance improvements, or any corrections. Use of this AM is subject to the publisher’s embargo period and AM terms of use. Under no circumstances may this AM be shared or distributed under a Creative Commons or other form of open access license, nor may it be reformatted or enhanced, whether by the Author or third parties. See here for Springer Nature’s terms of use for AM versions of subscription articles: https://www.springernature.com/gp/open-research/policies/accepted-manuscript-terms
Data availability:
Data sharing not applicable to this article. Data was requested through the National Clinical Trials Network.
REFERENCES:
- 1.Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352:987–96. [DOI] [PubMed] [Google Scholar]
- 2.Dressler EV, Liu M, Garcia CR, et al. Patterns and disparities of care in glioblastoma. Neurooncol Pract 2019;6:37–46. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Garcia CR, Slone SA, Dolecek TA, et al. Primary central nervous system tumor treatment and survival in the United States, 2004–2015. J Neurooncol 2019;144:179–91. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Villano JL, Letarte N, Yu JM, et al. Hematologic adverse events associated with temozolomide. Cancer Chemother Pharmacol 2012;69:107–13. [DOI] [PubMed] [Google Scholar]
- 5.Gerber DE, Grossman SA, Zeltzman M, et al. The impact of thrombocytopenia from temozolomide and radiation in newly diagnosed adults with high-grade gliomas. Neuro Oncol 2007;9:47–52. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Armstrong TS, Cao Y, Scheurer ME, et al. Risk analysis of severe myelotoxicity with temozolomide: the effects of clinical and genetic factors. Neuro Oncol 2009;11:825–32. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Sabharwal A, Waters R, Danson S, et al. Predicting the myelotoxicity of chemotherapy: the use of pretreatment O6-methylguanine-DNA methyltransferase determination in peripheral blood mononuclear cells. Melanoma Res 2011;21:502–8. [DOI] [PubMed] [Google Scholar]
- 8.Dior M, Coriat R, Mir O, et al. A rare hematological adverse event induced by bevacizumab: severe thrombocytopenia. Am J Med 2012;125:828–30. [DOI] [PubMed] [Google Scholar]
- 9.Schutz FA, Jardim DL, Je Y, et al. Haematologic toxicities associated with the addition of bevacizumab in cancer patients. Eur J Cancer 2011;47:1161–74. [DOI] [PubMed] [Google Scholar]
- 10.Gilbert MR, Wang M, Aldape KD, et al. Dose-dense temozolomide for newly diagnosed glioblastoma: a randomized phase III clinical trial. J Clin Oncol 2013;31:4085–91. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Gilbert MR, Dignam JJ, Armstrong TS, et al. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med 2014;370:699–708. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Stupp R, Dietrich PY, Ostermann Kraljevic S, et al. Promising survival for patients with newly diagnosed glioblastoma multiforme treated with concomitant radiation plus temozolomide followed by adjuvant temozolomide. J Clin Oncol 2002;20:1375–82. [DOI] [PubMed] [Google Scholar]
- 13.Kaplan EL, Meier P. Nonparametric Estimation from Incomplete Observations. Journal of the American Statistical Association 1958;53:457–81. [Google Scholar]
- 14.Mantel N Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 1966;50:163–70. [PubMed] [Google Scholar]
- 15.Kim WJ, Dho YS, Ock CY, et al. Clinical observation of lymphopenia in patients with newly diagnosed glioblastoma. J Neurooncol 2019;143:321–8. [DOI] [PubMed] [Google Scholar]
- 16.Campian JL, Piotrowski AF, Ye X, et al. Serial changes in lymphocyte subsets in patients with newly diagnosed high grade astrocytomas treated with standard radiation and temozolomide. J Neurooncol 2017;135:343–51. [DOI] [PubMed] [Google Scholar]
- 17.Lombardi G, Rumiato E, Bertorelle R, et al. Clinical and Genetic Factors Associated With Severe Hematological Toxicity in Glioblastoma Patients During Radiation Plus Temozolomide Treatment: A Prospective Study. Am J Clin Oncol 2015;38:514–9. [DOI] [PubMed] [Google Scholar]
- 18.Dixit S, Baker L, Walmsley V, et al. Temozolomide-related idiosyncratic and other uncommon toxicities: a systematic review. Anticancer Drugs 2012;23:1099–106. [DOI] [PubMed] [Google Scholar]
- 19.Gerson SL, Phillips W, Kastan M, et al. Human CD34+ hematopoietic progenitors have low, cytokine-unresponsive O6-alkylguanine-DNA alkyltransferase and are sensitive to O6-benzylguanine plus BCNU. Blood 1996;88:1649–55. [PubMed] [Google Scholar]
- 20.Batalini F, Kaufmann MR, Aleixo GF, et al. Temozolomide-induced aplastic anaemia and incidental low-grade B-cell non-Hodgkin lymphoma in a geriatric patient with glioblastoma multiforme. BMJ Case Rep 2019;12. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Vandraas K, Tjonnfjord GE, Johannesen TB, et al. Persistent bone marrow depression following short-term treatment with temozolomide. BMJ Case Rep 2016;2016. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Murphy AG, Grossman SA. Acute hemolysis in a patient with a newly diagnosed glioblastoma. CNS Oncol 2016;5:125–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Lewis JA, Petty WJ, Harmon M, et al. Hemolytic anemia in two patients with glioblastoma multiforme: A possible interaction between vorinostat and dapsone. J Oncol Pharm Pract 2015;21:220–3. [DOI] [PubMed] [Google Scholar]
- 24.FDA. Temozolomide (marketed as Temodar): Aplastic Anemia. In: Consumer Update. Fall, 2007. Accessed February 2018. [Google Scholar]
- 25.Vaios EJ, Nahed BV, Muzikansky A, et al. Bone marrow response as a potential biomarker of outcomes in glioblastoma patients. J Neurosurg 2017;127:132–8. [DOI] [PubMed] [Google Scholar]
- 26.Williams M, Liu ZW, Woolf D, 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 2012;138:1683–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Saito T, Sugiyama K, Hama S, et al. Prognostic importance of temozolomide-induced neutropenia in glioblastoma, IDH-wildtype patients. Neurosurg Rev 2018;41:621–8. [DOI] [PubMed] [Google Scholar]
- 28.Trinh VA, Patel SP, Hwu WJ. The safety of temozolomide in the treatment of malignancies. Expert Opin Drug Saf 2009;8:493–9. [DOI] [PubMed] [Google Scholar]
- 29.Mendez JS, Govindan A, Leong J, et al. Association between treatment-related lymphopenia and overall survival in elderly patients with newly diagnosed glioblastoma. J Neurooncol 2016;127:329–35 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Ku GY, Yuan J, Page DB, et al. Single-institution experience with ipilimumab in advanced melanoma patients in the compassionate use setting: lymphocyte count after 2 doses correlates with survival. Cancer 2010;116:1767–75 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Hiraoka K, Miyamoto M, Cho Y, et al. Concurrent infiltration by CD8+ T cells and CD4+ T cells is a favourable prognostic factor in non-small-cell lung carcinoma. Br J Cancer 2006;94:275–80. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Lohr J, Ratliff T, Huppertz A, et al. Effector T-cell infiltration positively impacts survival of glioblastoma patients and is impaired by tumor-derived TGF-beta. Clin Cancer Res 2011;17:4296–308. [DOI] [PubMed] [Google Scholar]
- 33.Rocconi RP, Matthews KS, Kemper MK, et al. Chemotherapy-related myelosuppression as a marker of survival in epithelial ovarian cancer patients. Gynecol Oncol 2008;108:336–41. [DOI] [PubMed] [Google Scholar]
- 34.Ho KG, Uhlmann EN, Wong ET, et al. Leukopenia is a biomarker for effective temozolomide dosing and predicts overall survival of patients with glioblastoma. Mol Clin Oncol 2020;13:80. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Chongsathidkiet P, Jackson C, Koyama S, et al. Sequestration of T cells in bone marrow in the setting of glioblastoma and other intracranial tumors. Nat Med 2018;24:1459–68. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Bunn PA Jr., Crowley J, Kelly K, et al. Chemoradiotherapy with or without granulocyte-macrophage colony-stimulating factor in the treatment of limited-stage smallcell lung cancer: a prospective phase III randomized study of the Southwest Oncology Group. J Clin Oncol 1995;13:1632–41. [DOI] [PubMed] [Google Scholar]
- 37.Staar S, Rudat V, Stuetzer H, et al. Intensified hyperfractionated accelerated radiotherapy limits the additional benefit of simultaneous chemotherapy--results of a multicentric randomized German trial in advanced head-and-neck cancer. Int J Radiat Oncol Biol Phys 2001;50:1161–71. [DOI] [PubMed] [Google Scholar]
- 38.Lin AJ, Campian JL, Hui C, et al. I Impact of concurrent versus adjuvant chemotherapy on the severity and duration of lymphopenia in glioma patients treated with radiation therapy. J Neurooncol 2018;136:403–11. [DOI] [PubMed] [Google Scholar]
- 39.Chan A, Fu WH, Shih V, et al. Impact of colony-stimulating factors to reduce febrile neutropenic events in breast cancer patients receiving docetaxel plus cyclophosphamide chemotherapy. Support Care Cancer 2011;19:497–504. [DOI] [PubMed] [Google Scholar]
- 40.Chan A, Lee CP, Chiang J, et al. Breakthrough febrile neutropenia and associated complications among elderly cancer patients receiving myelosuppressive chemotherapy for solid tumors and lymphomas. Support Care Cancer 2013;21:2137–43. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Data sharing not applicable to this article. Data was requested through the National Clinical Trials Network.