Cytarabine is a cytosine derivative that is a common component of chemotherapy regimens for blood cancers such as acute myeloid leukaemia (AML), and because it can cross the blood–brain barrier, it is useful in the treatment of central nervous system lymphomas. However, the response is variable, and resistance commonly develops via multiple mechanisms. Its activity is dependent on the intracellular concentrations of the active phosphorylated form, and one of the main mechanisms of resistance involves the deficiency of the transporter molecule hENT1 that carries it into the cells. As a result, Clavis Pharma developed a lipophilic ester derivative, elacytarabine, whose cellular uptake is not hENT1-dependent.1
The drug was given to 61 patients with advanced AML as monotherapy, with doses of 2000mg/m2/day being given continuously via intravenous drip for the first five days of a three-week cycle.2 The remission rate was 18%, compared with 4% in controls, with a 43% six-month survival rate, and a median overall survival time of 5.3 months, compared with 1.5 months for the controls. The most common adverse events were febrile neutropoenia, hypokalaemia and hyponatraemia, fatigue, dyspnoea and pyrexia. Ten of the patients were referred for stem cell transplantation after their treatment finished.
Another, ongoing, Phase II study is looking at its activity in combination with idarubicin for second course remission induction in AML patients who had failed cytarabine/anthracycline treatment.3 Subjects were given continuous intravenous doses of 1000mg/m2/day on the first five days of the cycle in combination with 12mg/m2/day of idarubicin for the first three of those days. Subjects could continue after this part of the trial with 2000mg/m2/day elacytarabine monotherapy cycles. Initial results show that 18 of the 40 evaluable patients (out of 47 that had been enrolled at that point) achieved complete remission, or complete remission with incomplete blood count recovery. About half the patients had low hENT1 expression, and preliminary data indicated that the response rate was higher in this group. Fatigue hypokalaemia, hypoalbuminaemia, hypoxia, infections and sepsis were the most commonly observed non-haematological adverse events. Trials continue.
References
1. C.M. Kuiper et al. Proc. Am. Assoc. Cancer Res. 1998, 39
2. S. O’Brien et al. Br. J. Haematol. 2012, 158, 1365
3. D.A. Rizzieri et al. 54th ASH Annual Meeting 2012 (Atlanta, 8–11 Dec), Abst. 46
