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).