Introduction
Acute myeloid leukaemia (AML) is an aggressive haematological malignancy affecting mainly adults. The use of combination chemotherapy is effective and curative in some patients. The standard induction chemotherapy is a combination of an anthracycline and standard-dose cytosine arabinoside (Ara-C, 100–200 mg/m2/day), which results in a complete remission (CR) rate of 60–70%. Consolidation or post-remission chemotherapy, with or without haematopoietic stem cell transplantation (HSCT), further improves the outcome by decreasing relapses.
However, in primary refractory or relapsed AML, the prognosis is generally unfavourable, with salvage chemotherapy giving a remission rate of merely 10–40%. Factors predicting a poor outcome include advanced age, adverse cytogenetic or molecular findings and a short duration of prior remission in relapsed cases [
1].
High-dose Ara-C (1–6 g/m
2/day) alone or in combination with other drugs is often employed as a salvage strategy for AML. An intriguing concept in the use of high-dose Ara-C involves the pre-administration of the purine analogue fludarabine. In the FLAG regimen (fludarabine, high-dose Ara-C), fludarabine is first administered, which activates deoxycytidine kinase, thus enhancing the intracellular conversion of other purine analogues to their active metabolites. Thereafter, when Ara-C is administered, a higher intracellular concentration of its active metabolite Ara-CTP is attained, providing a putative mechanism of “biochemical modulation” whereby cell killing is increased [
2]. Variations of the FLAG regimen, including FLAG-IDA (idarubicin), result in a remission rate of 30–50% in relapsed and refractory AML [
3,
4].
Clofarabine (2-chloro-2′-fluoro-deoxy-9-β-
d-arabinofuranosyladenosine) is a purine analogue designed to combine the favourable properties of fludarabine and 2-chlorodeoxyadenosine [
5]. Clofarabine alone or in combination chemotherapy has been shown to be effective in induction therapy of adult AML, especially in the elderly population [
6‐
8]. In relapsed or refractory AML, clofarabine had also shown activity [
9]. Because of the structural similarity between purine analogues, a putative synergism between clofarabine and Ara-C, similar to that between fludarabine and Ara-C, has been postulated [
10,
11].
In this study, we examined the efficacy and safety of sequential clofarabine and high-dose Ara-C in relapsed and refractory AML.
Discussion
The effectiveness of clofarabine alone or in combination with other chemotherapeutic drugs has been shown in induction treatment for adult AML, especially in elderly patients [
6‐
8]. Besides induction therapy, phase 1 and phase 2 clinical trials had examined the efficacy of clofarabine alone [
9], or combined with Ara-C and/or idarubicin, in relapsed or refractory AML [
10,
11]. In a phase 2 study, treatment of refractory and relapsed AML with clofarabine alone resulted in a CR rate of 41.9% [
9]. Another phase 1/2 study of clofarabine (40 mg/m
2/day × 5) plus Ara-C (1 g/m
2/day × 5) in relapsed and refractory AML showed an overall response (including CR without platelet recovery, CRp) rate of 40% [
10]. These results indicated that clofarabine had significant activity in newly diagnosed and refractory or relapsed AML. On the other hand, a recent study by the Southwest Oncology Group in patients with refractory or relapsed acute lymphoblastic leukaemia showed that clofarabine (40 mg/m
2/day × 5) and Ara-C (1 g/m
2/day × 5) resulted in a CR rate of merely 17% [
13]. Hence, the usefulness of clofarabine and Ara-C appears to be maximal in AML.
Our study showed a high efficacy of clofarabine plus high-dose Ara-C in refractory or relapsed AML. All our cases were heavily pre-treated, many with unfavourable karyotypes. Other traditional salvage regimens were generally regarded to be ineffective for these patients, and without innovative regimens, most cases were candidates for palliative treatment only. On an intention-to-treat basis, CR was achieved in a remarkable 43% of patients. Interestingly, Ara-C at 2 g/m
2/day appeared to result in better outcome than 1 g/m
2/day. The importance of Ara-C in combination with clofarabine was shown in another phase 1 study of refractory or relapsed AML, where clofarabine (15–30 mg/m
2/day × 5) plus idarubicin (12 mg/m
2/day × 3) resulted in a CR + CRp rate of 22%, whereas the addition of Ara-C (1 g/m
2/day × 5) improved the CR rate to 48% [
11]. Notably, all of our patients were previously refractory to or had relapsed from regimens containing Ara-C at standard to high doses. Moreover, of four cases where FLAG had failed (Table
1), there was one CR to clofarabine/Ara-C. Hence, clofarabine/Ara-C appeared to be still effective in cases otherwise considered to be refractory to Ara-C. However, further studies may be required to define the optimal dose of Ara-C to be used in combination with clofarabine and the actual margin of clinical benefit derived from the clofarabine/Ara-C combination as compared with each of the drugs alone.
The main toxicity of our regimen was myelosuppression. Two patients died of septicaemia. Therefore, routine use of myeloid growth factors and aggressive treatment of any signs of sepsis are needed.
In conclusion, clofarabine plus high-dose Ara-C is a feasible, safe and efficacious therapy for refractory or relapsed adult AML. Future studies are needed to examine the effectiveness of this regimen in induction therapy, and whether higher doses of Ara-C can be administered safely and more efficaciously.