Commentary: dose intensive chemotherapy in acute myeloid leukemia

Abstract

Therapy for adults with acute myeloid leukemia (AML) generally includes cytarabine (Ara-C) and an anthracycline. Escalation of the Ara-C dose, either during the post-remission phase of therapy, or, during induction has improved survival for some patients with AML, those under age 60 and particularly those with favorable cytogenetic changes, t(8:21) and inv (16) [1,2]. An enhanced efficacy of higher doses of anthracyclines is less clearly established. In this issue, Thomas et al. report on a study evaluating the feasibility of using higher than standard doses of mitoxantrone in combination with Ara-C and etoposide in patients with relapsed or refractory AML [3]. Mitoxantrone, an anthracenedione, has demonstrated antileukemic activity similar to that of the anthracyclines when given in comparable myelosuppressive doses [4]. A dose of 12 mg/m daily for 3 days in combination with Ara-C (cumulative dose 700–1000 mg/m) has been considered the standard dose of mitoxantrone. The rationale for escalation of the dose of mitoxantrone has been documented both in vitro and in phase I clinical and pharmacokinetic trials. Studies in ovarian cancer and leukemic cells have demonstrated a steep dose response curve in clonogenic assays and an enhancement of apoptotic cell death has been observed in leukemic cells exposed to increasing concentrations of mitoxantrone [5–7]. A phase I study demonstrated that up to 80 mg/m could be given with Ara-C as induction therapy for adults with AML and that high concentrations of mitoxantrone were achievable in vivo, equivalent to levels shown to be highly cytotoxic in vitro [8]. In the study reported by Thomas et al., mitoxantrone at a dose of 36–60 mg/m was administered in combination with an intermediate dose of Ara-C( 500 mg/ m×6 doses) and etoposide 200 mg/m×3 doses as salvage therapy for patients with AML. Overall, this regimen was well tolerated with only one reported induction death in the 24 patients treated. Apart from severe myelosuppression, which was seen in all patients, mucositis and gastrointestinal toxicity was moderate and not dose limiting. Reversible hepatic dysfunction and cardiac toxicity manifested by a dimunition in left ventricular ejection fraction was reported as the dose limiting toxicity in patients receiving 60 mg/m of mitoxantrone. Although the earlier dose-escalation study with mitoxantrone in acute leukemia had established a maximally tolerated dose (MTD) at 80 mg/m in combination with intermediate dose Ara-C in earlier treated as well as untreated patients [8], variability in patient characteristics, i.e cumulative dose of anthracyclines received prior to treatment with the high-dose mitoxantrone-based regimen, may have accounted for the differences in MTD’s observed. Nevertheless, the Thomas study confirms the feasibility of delivering a higher than standard dose of mitoxantrone in patients with acute leukemia. This study also confirms the experience that intensive induction therapy is effective in AML. Although a small pilot study, the response rate of 67% in the salvage setting reported by Thomas et al. is impressive. Most of the efforts to intensify induction therapy in AML have focused on the escalation of the dose of Ara-C. This regimen differs in that it includes a relatively lower cumulative dose of Ara-C (3 gm/m) compared with other high-dose Ara-C-based regimens (24–36 gm/m), but instead delivers a higher than standard dose of mitoxantrone and includes a second topoisomerase II inhibitor, etoposide. The dose-dependant efficacy of Ara-C is well established, but what is E-mail address: ejf2001@mail.med.cornell.edu (E.J. Feldman).