Discussion:
GBM is one of the most commonly occurring Central Nervous System (CNS)
malignancies, with a prevalence of 5/100,000 people per annum (12). Most
of the patients are diagnosed between the ages of 75 to 84 years. The
prognosis is usually unfavorable, with a five-year survival rate of less
than 5 percent (12). Most frequent presentations include headache,
seizures, and focal neurological signs, including but not limited to;
memory problems, vision changes, motor deficits, and personality changes
(13). With advancements in the radiology and availability of Magnetic
Resonance Imaging (MRI), the diagnosis of GBM is not challenging
anymore. The tumor can be seen as a hypodense lesion on T1-weighted cuts
and increased signal intensity post-contrast (14). Biopsy with
histopathologic and genetic analysis can confirm the stage and type
(primary or secondary) (12).
Three primary modalities of treatment in GBM include surgery,
chemotherapy, and a combination of chemo-radiotherapy. Post-surgery
radiation was the standard treatment method until 2005; however,
currently, Temozolomide with radiation therapy is the gold standard
management modality, especially in younger patients (15). Other
treatments include Bevacizumab, immune therapy ( checkpoint inhibitors,
peptide vaccinations, adoptive cell therapy, viral immunotherapy, and
dendritic cell vaccinations) (15).
The landmark EORTC-NCIC trial paved the way for the use of combination
chemo-radiotherapy with Temozolomide in GBM (16). Temozolomide is an
alkylating agent, given at a dose of 75 mg/m2 with
radiation. Subsequent doses are 150 and 200 mg/m2 for
the first post-radiation cycle and subsequent cycles, respectively (1).
Unlike other alkylating agents, one of the rare adverse effects of
Temozolomide is aplastic anemia (2,4-11). Similar irreversible AA was
observed in our patient where discontinuation of the drug did not
resolve or improve AA.
The cases of AA secondary to Temozolomide are tabulated [Table 1].
Most of the patients reported having AA are females (9/10). Other
studies have also shown a slight female predominance for hematological
complications of Temozolomide (5). The median age of diagnosis of AA is
51 years. Most of the patients developed AA during CRT or after CRT and
before initiation of TMZ monotherapy. Another noteworthy observation is
AA’s irreversible nature, with only 3 out of 10 patients recovered or
improved to some extent by discontinuation of TMZ, supportive
transfusions, and Filgrastim.
The exact mechanism of AA secondary to TMZ is yet to be completely
understood and is thought to be immune-mediated (5). However, to
somewhat understand the pathophysiology behind the induction of AA
secondary to TMZ, it is vital first to appreciate the pharmacodynamics
of TMZ on molecular levels. TMZ is innately in its inactive form, and
once in the body, it is converted to its active metabolite, MTIC
[(methyl-triazene-1-yl)-imidazole-4-carboxamide] spontaneously (11).
MTIC “methylates the N7 and O6position of guanine and the O3 position of adenine”.
Subsequently, the cells’ auto-destruction occurs in an unsuccessful
attempt to repair the methylations by the mismatch repair genes (5). One
such mismatch repair gene, methylguanine-DNA methyltransferase (MGMT),
reverses the methylation at the guanine position and, as a result, the
effect of TMZ gets inactivated. Cells that are, by default, deficient in
MGMT are more susceptible to TMZ cytotoxicity, which is also the case
with hematopoietic precursor cells (11).
Although not a malignant hematological disease, aplastic anemia can have
a high mortality rate if left untreated. The most common causes of AA
include cytotoxic drugs and radiation therapy. However, usually, their
effect is dose-dependent and hence, reversible (17). Other uncommon
causes of AA include toxic chemicals such as Benzene and certain
pesticides and viruses such as hepatitis and human immunodeficiency
virus (18,19). The diagnosis depends on a careful history, focusing on
medication history, past medical conditions, and occupation. Relevant
tests must rule out other causes of bone marrow suppression before
confirming AA. Diagnosis can be confirmed by bone marrow biopsy, which
reveals a severely hypocellular marrow in the absence of malignant cells
or fibrosis (20).
The treatment of AA depends much on host factors as well as the degree
of AA. For patients younger than 40 years of age, the usual approach is
hematopoietic cell transplantation (HCT). For older patients, combined
immunosuppressive therapy with Anti-thymocyte globulin, Cyclosporine,
and Eltrombopag, is the first-line modality of treatment, given that the
patient is stable enough to tolerate the effects of the combination
therapy. For medically unfit patients, symptomatic management is the
current standard of care (21). Although treatment can be curative,
lethal complications can occur, making it a reasonably challenging
disease to tackle (22).