Cancer Chemother Pharmacol (1989)23:373-376 ancer hemotherapy and LP harmacology © Spring~-Verlag 1989 Treatment of relapsed and refractory acute leukaemia with high-dose cytosine arabinoside and etoposide Martin Gore, Ray Powles, Anil Lakhani, Sarah Milan, Jennifer Maitland, Glen Goss, Ann Nandi, Timothy Perren, Garry Forgeson, Jennifer Treleaven, Ayed Zuiable, and Fulvio Porta Leukaemia Unit, Royal Marsden Hospital and Institute of Cancer Research, Sutton, Surrey, U. K Summary. A total of 65 patients under the age of 55 with acute leukaemia received high-dose cytosine arabinoside (Ara-C) in combination with high-dose etoposide without an anthracycline. Complete remission rates for patients with relapsed or refractory acute myelogenous leukaemia (AML) were 15/25 (60%) and 11/16 (69%), respectively. The complete remission rate for patients with refractory or relapsed acute lymphoblastic leukaemia (ALL) was 10/18 (56%). The treatment-related mortality was 17%. Nine pa- tients whose leukaemia relapsed after matched alloge- neic, sibling bone-marrow transplantation (BMT) were al- so treated in this way; the treatment-related mortality in this group was high (7/9) and the duration of remission in the two patients who responded, too short to justify this in- tensive treatment in such patients. Similarly, patients who underwent BMT after achieving a complete remission with high-dose Ara-C and etoposide did very poorly, only one patient surviving well and disease-free at 8 months. The important finding in this study was the high complete re- mission rate rapidly obtained in patients with relapsed or refractory AML without using an anthracycline. Introduction Cytosine arabinoside (Ara-C) given in conventional doses to previously untreated patients with acute myelogenous leukaemia (AML) results in a 25% complete remission rate when given as a single agent over 5-7 clays [3, 6, 10, 12, 29, 30]. Turnout cells may become resistant to low concen- trations of Ara-C, but in vitro studies suggest that some of the proposed mechanisms of resistance can be overcome by exposing the cells to higher concentrations of drug [28]; the dose of Ara-C may need to be 10-100 times greater than that which is effective against Ara-C-sensitive cell lines [8, 9, 20, 21]. In vivo studies of Ara-C toxicity in man have shown that it is possible to obtain these high concen- trations safely by the administration of equivalently large doses [11, 27], and such treatment has been shown to be ef- fective against acute leukaemia that is resistant to conven- tional doses of Ara-C [27]. In the last 5 years a number of groups have used high doses of Ara-C alone and in combination with other drugs to treat relapsed leukaemia or leukaemia that is refractory Offprint requests to: Martin Gore to conventional therapy [1, 4, 5, 13-15, 19, 23, 26, 31]. The complete remission rates in these studies vary widely and for patients with AML, rates of 25%-70% are reported [15, 23]. In these studies several drugs have been used in combination with high-dose Ara-C: doxorubicin [13], daunorubicin [31], asparaginase [1, 5] mAMSA [15, 16] and mitoxantrone [19]. However, no randomised trials have been done to compare single-agent Ara-C with any of these combinations and no one particular combination appears to be superior. Etoposide has activity against acute leukaemia when given as a single agent [7], and pre-clinical studies have shown that there is synergism between Ara-C and etopo- side [25]. There have been no reports of any large series of patients treated with a combination of etoposide and high- dose Ara-C for AML, although a report has been publish- ed in which this combination was used in a small group of 15 patients with acute lymphoblastic leukaemia (ALL) [22]. We present our experience of treating AML and ALL at relapse and when refractory to conventional therapy with high doses of Ara-C in combination with high-dose etoposide. Materials and methods Between January 1984 and June 1986, 65 patients at the Royal Marsden Hospital, Sutton, Surrey, received high- dose Ara-C with etoposide for 68 episodes of acute leu- kaemia (AML or ALL). In all, 38 patients (19 men and 19 women aged 1-47; median age, 29) were treated for 41 episodes of AML, 18 (11 men and 7 women aged 3-52; median age, 24) were treated for ALL, and 9 (6 men and 3women aged 10-48; median age, 27) were treated for relapsed leukaemia following bone marrow transplan- tation (BMT). Patients were entered into the study only if they had ei- ther failed conventional leukaemia induction therapy (ini- tial failures) or were in first or subsequent relapse (re- lapsed patients). All individuals had previously received anthracycline-containing combination chemotherapy. Pa- tients gave fully informed consent as laid down by the Eth- ics Committee of the Royal Marsden Hospital. Ara-C was infused i.v. at a dose of 2 g/m 2 over 3 h twice daily for 5 consecutive days, and 100 mg/m 2 etopo- side was given i.v. over 1 h either once (etoposide o.d.) or twice (etoposide b.i.d.) daily for 5 days. Patients received one cycle of this treatment. Table 1 shows the treatment