Temozolomide-induced aplastic anaemia and incidental low-grade B-cell non-Hodgkin lymphoma in a geriatric patient with glioblastoma multiforme

Abstract

Glioblastoma multiforme is an astrocyte-derived tumour representing the most aggressive primary brain malignancy. The median overall survival is 10–12 months, but it drops to 3–8.5 months for the cohort with more than 65 years old, which account to half of all patients. Initial management in this patient population aims to balance overall patient survival and quality of life with the inherent risks of treatment intervention, which include maximal safe tumour resection, radiation and temozolomide (TMZ) chemotherapy. This is accomplished through risk stratification as a function of patient age, functional status, comorbidities, tumour location and methylguanine methyltransferase promoter methylation status. We describe the care of a patient with prolonged febrile neutropaenia, with a rare but fatal complication from TMZ-induced idiosyncratic reaction, leading to aplastic anaemia and a provoking diagnosis of low-grade B-cell non-Hodgkin’s lymphoma.

Background

Glioblastoma multiforme (GBM) is an astrocyte-derived tumour representing the most aggressive primary brain malignancy. Once diagnosed, median overall survival is 10–12 months,¹ and old age is one of the most important negative prognostic factors on overall survival at the time of diagnosis.² Half of all patients with GBM are at age 65 or older,³ and median overall survival in this cohort is between 3 and 8.5 months.⁴ Initial management in this patient population aims to balance overall patient survival and quality of life with the inherent risks of treatment intervention, which include various permutations of tumour resection, radiation and temozolomide (TMZ) chemotherapy. This is accomplished through evidence-based risk stratification notably as a function of patient age, functional status, medical comorbidities, tumour location and methylguanine methyltransferase promoter methylation status.⁵ Our case describes the care of a patient with prolonged febrile neutropaenia, who had a rare but fatal complication from TMZ-induced idiosyncratic reaction, leading to aplastic anaemia and an intriguing diagnosis of low-grade B-cell non-Hodgkin’s lymphoma.

Case presentation

The patient is an 89-year-old man with history of GBM, monoclonal gammopathy of undetermined significance, vitamin B₁₂ deficiency and peripheral neuropathy who presented to hospital with a 2-week history of fatigue. Three months prior to admission, he was found to have a 0.8 cm mass in the right frontal lobe suspicious for GBM. Tissue obtained from brain biopsy and maximal safe resection confirmed GBM. He received chemoradiation with 60 Gy in 30 fractions over 6 weeks and concurrent TMZ at a dose of 75 mg/m². In light of age >70 and favourable Karnofsky Performance Status >70, he was started on the adjuvant TMZ at a dose of 150 mg/m², started 3 weeks prior to admission and given for 5 consecutive days.^{6 7} In light of its low incidence,⁸ and considering the patient’s preference for a lower pill burden, prophylaxis for Pneumocystis jirovecii pneumonia was not used. The patient felt well after his most recent TMZ treatment, he was independent, living by himself, raking leaves and cooking for himself. However, 1 week after treatment, he began to experience fatigue, dyspnoea on exertion, significant hyporexia, xerostomia, tremulousness and lack of energy to dress himself or cut his food during mealtimes. His symptoms progressed continuously for 2 weeks, prompting him to present to the hospital.

On initial presentation, the patient was febrile ≥38°C for >1 hour, and he had pancytopaenia with an absolute neutrophil count (ANC) of 0, total white cell count of 0.3×10⁹/L, haemoglobin (Hb) of 72 g/L and platelets of 14 ×10⁹/L. Infectious workup with chest radiograph, urine and blood cultures were negative. He was started on empiric broad-spectrum antibiotic coverage with cefepime and subsequently admitted to the inpatient medicine service for severe febrile neutropaenia (agranulocytosis). The patient continued to spike fevers despite being on antibiotics for more than 48 hours. Therefore, granulocyte colony stimulation factor (G-CSF) therapy was initiated at 5 µg/kg per day based on American Society of Clinical Oncology and National Comprehensive Cancer Network guidelines⁹: profound neutropaenia (<100 cells/µL), age >65 and being hospitalised at the time the fever developed. The patient continued to spike saw-tooth-patterned fevers in the 100–101°F range for 3 weeks every 1–2 days. During this time, the patient’s ANC failed to rise above 0.44 cells/µL, and the haematology/oncology consult believed G-CSF treatment was contributing to the patient’s fatigue and bone pain, so it was discontinued.

Investigations

Repeat laboratory tests (including galactomannan and parvovirus serologies) and imaging studies 1–2 weeks after admission were unremarkable. However, serum beta-D-glucan was positive; therefore, treatment for invasive fungal infection with intravenous micafungin was added to the patient’s antimicrobial regimen. During this time, the patient also complained of dental pain in a left mandibular incisor with corresponding mild erythema on examination representing possible oral source for fever. Head CT was negative for abscess formation. Oral surgery consult confirmed this finding and believed the dental pain was secondary to dental caries without evidence of abscess formation.

During this prolonged hospitalisation, he required frequent supportive measures including numerous leuko-reduced red cell and platelet transfusions when Hb <70 g/L and platelets <20 ×10⁹/L, respectively. Because aplastic anaemia is a rare but previously documented side effect of TMZ therapy in patients with GBM, a bone marrow biopsy was recommended for evaluation of myelosuppression. The patient and family initially declined the biopsy but accepted 1 month into the patient’s hospital course with no signs of bone marrow recovery. The bone marrow biopsy (figure 1) and flow cytometry analysis of the aspirate (figure 2) revealed the presence of a low-grade B-cell non-Hodgkin’s lymphoma and concurrent trilineage hypoplasia. The haematology/oncology consult believed the lymphoma was an incidental finding in the setting of the patient’s aplastic anaemia rather than secondary to TMZ therapy and that the lymphoma did not contribute to his myelosuppressed state. The conclusion was that this complicated presentation of prolonged pancytopaenia, fevers of unknown origin refractory to broad-spectrum antibiotic coverage including an antifungal and agranulocytosis refractory to G-CSF therapy, presenting 25 days after his last TMZ treatment was consistent with this drug’s rare but serious adverse effect of iatrogenic aplastic anaemia.^10–17 The pathology consult concurred with this reasoning since the bone marrow biopsy results demonstrated trilineage hypoplasia; a finding more consistent with aplastic anaemia than low-grade B-cell non-Hodgkin’s lymphoma. Notably, although the patient’s recent levetiracetam use could have induced haematotoxicity, it would most commonly manifest itself as agranulocytosis rather than pancytopaenia, making TMZ the more likely culprit of this patient’s iatrogenic aplastic anaemia.¹⁸ Pancytopaenia from levetiracetam has been reported but not aplastic anaemia.^19–21 This is consistent with Villano et al’s report of aplastic anaemia in the setting of concomitant TMZ and anticonvulsant use.²²

Figure 1.

Bone marrow biopsy revealing trilineage hypoplasia and aggregates of lymphocytes.

Figure 2.

Flow cytometry analysis revealed that lymphocytes are comprised of mixed CD79a+CD20+ B cells and CD3+T cells. The B-cells comprise 50% of total cellularity based on CD79a stain. There are increased CD138+ plasma cells, comprising 10% of total cellularity. CD34 stain showed blasts comprising less than 5% of total cells. Concurrent flow cytometry analysis detected a monoclonal CD5–CD10 kappa-restricted B-cell population. The overall findings were consistent with involvement by a low-grade B-cell non-Hodgkin’s lymphoma.

Outcome and follow-up

A meeting to establish goals of care was held with patient and family, palliative care, haematology/oncology and the primary inpatient medicine teams. At the end of the meeting, the patient and family decided to pursue comfort measures only, without planned antibiotic therapy, phlebotomy or transfusions, and the patient was discharged to a hospice care nursing facility, where he passed away shortly thereafter.

Discussion

TMZ is an oral alkylating agent that is a pro-drug of the intravenous drug dacarbazide. In comparison with the later, the former has the advantage of being an oral formulation, as opposed to intravenous. In a randomised-controlled trial of 562 geriatric patients (age range: 65–90, mean age: 73), Perry et al found prolonged median overall survival (9.3 months vs 7.6 months; HR for death, 0.67; 95% CI 0.56 to 0.80; p<0.001), progression-free survival (5.3 months vs 3.9 months; HR for disease progression or death, 0.50; 95% CI, 0.41 to 0.60; p<0.001) and decreased risk of death and disease progression with dual radiotherapy plus TMZ compared with radiotherapy alone (HR=0.50; 95% CI 0.41 to 0.60; p<0.001).¹⁶ These data would seem to support TMZ treatment survival benefit for our patient. However, this study also reports a slightly increased adverse event rate in patients who underwent dual radiotherapy and TMZ treatment versus radiotherapy alone. The most common events were indeed haematological, namely pancytopaenia.¹⁶

Drug adverse events usually develop from different possible mechanisms, such as direct drug toxicity, autoimmunity through mimicry or idiosyncrasy, in which the reaction widely varies in an unpredictable form, depending more on a patient’s biology than on pharmacodynamics.¹⁵

Although rare, TMZ-induced aplastic anaemia has recently been reported.^10–17 Kopecký et al report prolonged fatal pancytopaenia complicated by infection in a 61-year-old female patient with GBM.¹² Singhal et al report two treatment-naïve middle-aged patients with GBM without significant comorbidities who developed febrile neutropaenia and prolonged pancytopaenia within 4–5 weeks of TMZ treatment.¹⁷ George et al describe a 65-year-old female patient with GBM who developed fatigue and easy bruising 14 days after adjuvant TMZ therapy and diagnosed with TMZ-induced aplastic anaemia by bone marrow biopsy.¹⁰ Morris et al report TMZ-induced severe aplastic anaemia successfully treated with a matched unrelated bone marrow transplant in an adolescent female patient with GBM.¹³ All of these reports established TMZ as the direct cause of aplastic anaemia in these patients.

These data support the impression of our haematology/oncology consultant who suggested that the patient suffered TMZ-induced delayed and prolonged pancytopaenia, which commonly presents 25 days after last treatment, keeping with the patient’s symptom timeline and presentation. Ultimately, we speculate that our patient’s advanced age likely increased his susceptibility to these adverse events. This report further adds to the growing body of literature pointing to this lethal complication. The diagnosis of low grade B-cell lymphoma in the setting of TMZ-induced aplastic anaemia is intriguing, and attention should be given to future cases before an investigation of the nature of this association is pursued.

Learning points.

• Temozolomide (TMZ) is used for the treatment of glioblastoma multiforme, is generally well tolerated but is associated with rare and fatal adverse events.

• In a patient with febrile neutropaenia, antifungal coverage is to be started after 5–7 days of persistent fevers refractory to broad-spectrum antibiotics.

• Idiosyncratic reactions does not depend on pharmacodynamics and are unpredictable in occurrence and severity.

• TMZ is known to rarely induce bone marrow aplasia, and attention must be paid to the development of lymphoma.