Abstract
Cytarabine is a pyrimidine analogue that is used for the treatment of acute myeloid leukemia at different doses. Standard doses of cytarabine are used for induction therapy, while high doses are used for post-remission (consolidation) and relapsed/refractory treatment. One of the major side effects of its high doses is acute cerebellar toxicity occurring in 10 to 25% of patients. We report a case that developed this side effect after receiving two doses of high-dose cytarabine. The patient’s symptoms improved after withholding the drug. Thereafter, the patient tolerated treatment continuation with lower doses.
Introduction
Cytarabine or cytosine arabinoside is an antineoplastic agent that after entering into the cell gets converted to the active form (aracytidine triphosphate). This form of cytarabine is incorporated into the DNA structure that causes the inhibition of DNA synthesis. 1 Cytarabine is used for the treatment of acute myeloid leukemia (AML) at different doses. A standard dose of cytarabine (100–200 mg/m2) is used as induction therapy, while high doses of cytarabine (HiDAC) are used for post-remission and relapsed/refractory therapy of AML. Dosing regimen of HiDAC in these indications is 3 g/m2 q12 hour on days 1, 3, 5 or 1, 2, 3 for three to four cycles. 2 The major side effects of HiDAC are central nervous system (CNS), skin and ocular toxicities. CNS toxicity occurs in 8 to 37% of patients receiving HiDAC. The most important factors related to these toxicities are its dose and schedule. Doses more than 18 g/m2 per cycle increase the probability of CNS toxicity. One of the most common forms of CNS toxicity is cerebellar toxicity that is characterized by gait and coordination disorders, dysmetria and ataxia. 3 This type of toxicity is seen in 10 to 25% of patients. The exact pathogenesis of the cerebellar toxicity is not known, but it seems that the loss of Purkinje cells has an important role in its development. 4
Case presentation
A 22-year-old woman with chief complaints of fatigue and weakness was admitted in the Hematology–Oncology and Stem Cell Transplantation Research Center (HOSCRC) of Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran on March 2019. After work up, AML M2 with the t (8; 21) translocation was diagnosed. The induction treatment was 7 + 3 regimen (seven days of cytarabine and three days of idarubicine). After 28 days from starting induction chemotherapy, bone marrow aspiration (BMA) showed complete response. Since the patient met the remission criteria, HiDAC regimen was considered as the consolidation or post-remission treatment. Due to body surface area (BSA) of approximately 1.5 for the patient, the regimen was planned as 4500 mg of cytarabine (3 g/m2) twice a day on days 1, 3 and 5 (4500 mg diluted in 1000 ml N/S, infused over 3 h). At the time of HiDAC initiation, hepatic, renal and neurologic functions of the patient were normal. Other drugs that were administered to the patient included fluconazole, acyclovir and levofloxacin for the prophylaxis of the infections and also granisetrone, aprepitant, chlopheniramine, pantoprazole, calcium carbonate with vitamin D and betamethasone eye drop. After the second dose of cytarabine, the patient complained of imbalance and vertigo. Examination revealed dysmetria on the heel to shin and the finger to nose test, and the gait of the patient was ataxic.
Management and outcome
On the second day, the drug was withheld, and magnetic resonance imaging (MRI) was requested for the patient. The MRI was normal and her symptoms resolved completely. Therefore, her regimen was continued with a reduced dose of 1500 mg twice a day (1 g/m2) for three consecutive days (3, 4 and 5). The reduced dose of regimen was tolerated well by the patient without presenting any cerebellar toxicity symptoms. Three days after the last dose of chemotherapy, the patient was discharged, and her follow-up was continued in the clinic. In the outpatient setting, the AML1-ETO was checked for the patient and the result was undetectable, showing that the patient achieved complete molecular remission. Therefore, it was decided that the patient shall receive a reduced dose of HiDAC from the second cycle. The probability of this side effect was evaluated and calculated by the Naranjo adverse drug reaction scale and this scale showed the possibility is probable (score 8). 5
Discussion
HiDAC is used for the consolidation and refractory/relapsed treatment of AML which produces higher intracellular concentrations when compared to the lower doses. Although this dose of cytarabine is preferable to lower doses in clinical trials, sometimes its use in clinical practice has been limited due to its serious side effects such as cerebellar dysfunction. In the literature, a number of risk factors such as kidney or liver dysfunction, age more than 40 years, pre-existing neurologic disorders and cumulative dose more than 18 g/m2 per cycle have been mentioned for this side effect. 4 The cerebellar dysfunction has been reported as case reports and case series. This toxicity has been reported as a reversible dysfunction in most cases. Salinsky et al. have reported a HiDAC-induced cerebellar dysfunction after receiving 30 g of cytarabine by the patient. The patient’s symptoms included slurred speech, ataxia and wide-based gait. In the postmortem examination, the morphologic changes were seen in Purkinje cells. 6 Vaughn et al. reported acute cerebellar dysfunction in a woman with myelodysplastic syndrome. This case had received 2 g/m2 of cytarabine every 12 h for six days. The symptoms related to cerebellar dysfunction were developed after the last dose and improved after one week. In the MRI, cerebral changes and abnormalities were seen without cerebellar abnormalities. 7 Varghese et al. detected cerebellar dysfunction in a 44-year-old man with AML. The patient became ataxic and nystagmic on day 5 of HiDAC therapy. Methylprednisolone with a dose of 125 mg daily for three days had been administrated to improve the symptoms. 1 In our case, the patient developed cerebellar dysfunction after receiving the second dose which caused the treatment to be stopped until the symptoms were resolved. Soon after the detection of symptoms, MRI was requested for the patient. There was no abnormality seen in the imaging. After 24 h from the detection of symptoms, no abnormality was seen in neurologic examination. No intervention was taken to eliminate the symptoms. Due to the concern of reincidence of symptoms, the drug was started with a reduced dose of 1 g/m2 every 12 h on days 3, 4 and 5. In addition, previous studies had demonstrated that 1 to 1.5 g/m2 every 12 h of cytarabine for five days had similar rate of disease-free survival (DFS) and overall survival (OS) in comparison with 3 g/m2. 8 It should be noted that the patient had no serious neurologic problem on days 3 to 5. We report a 22-year-old woman with AML that developed cerebellar dysfunction after receiving two doses of HiDAC. To the best of our knowledge, the incidence of symptoms with this onset and also the recovery rate after the discontinuation of cytarabine have been less reported in previous case reports.
Conclusion
We reported a case where the patient developed cerebellar toxicity following only two doses of HiDAC. Since this side effect is dependent to cumulative dosing of cytarabine in each cycle of chemotherapy, its incidence was reported rarely in the early treatment. On the other hand, we followed up the patient and reduced the dose of HiDAC which is effective and safe in this setting.
Footnotes
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
