Combination of Cytarabine and Topotecan Improves Response Rate for Patients Treated for Acute Myeloid Leukemia with Persistent Disease After Frontline Induction

Achievement of first complete response (CR) is the objective of frontline treatment for patients treated for acute myeloid leukemia (AML). After a first course of induction chemotherapy, 30 to 40% of the patients do not achieve CR. The association of anthracyclins and intermediate dose cytarabine (IDAC) allow 50 to 60% of patients with persistent AML to achieve CR when given as early as day 14 (Lioure ASH 2006). Previous studies have shown that topotecan had a significant activity in AML patients and could be safely combined with IDAC (Kantarjian cancer 2006). We hypothesize that switching from anthracyclins to another class of topo-isomerase inhibitor for patients with persistent AML at day 14 of induction may be useful to improve tolerance and efficacy of the salvage regimen.

This is a retrospective single center study. Patients had (1) a diagnosis of de novo or therapy related AML excluding APL, (2) received an initial 3+7 induction regimen with 60mg/m2/d of daunorubicin, (3) had a bone marrow aspirate at day 14 with ≥5% marrow blast. We evaluated the combination of IDAC (1000mg/m2/12h day14-17) and topotecan (TA, 1.25mg/m2/d CIV day 14–17) in 31 consecutive AML and compared its results in terms of CR rate and survival with a series of 54 patients treated with IDAC (1000mg/m2/12h day14-17) + anthracyclins (AA group, daunorubicin 35 mg/m2/d day 14–15 or idarubicin 8 mg/m2/d day 14–15).

Pretreatment patient's characteristics were comparable between TA and AA groups including median age (48y vs 45y, p=0.34), cytogenetic risk stratification (with low/intermediate/high risk in 3/65/32% vs 2/52/46% of patients,p=0.44), median WBC count at diagnosis (11G/l vs 7 G/l), and median day 14 bone marrow blast count (21% vs 35%, p=0.23). Median follow-up was 51 months. Induction death rate (6%), neutropenia duration (38 days), thrombocytopenia duration (37 days), and frequency of microbiologically documented infections (47%) were comparable between the 2 groups. In univariate analysis, TA regimen was associated with a better CR rate (81% vs 59%, p=0.04), a better probability of overall survival (2-years estimate 66% vs 33%, p=0.03) and a better cumulative incidence of relapse (2-years estimate 38% vs 67%, p=0.002) as compared with AA. Our analysis also showed that high WBC count (more than 30G/L) and presence of adverse cytogenetics were associated with a lower frequency of CR. Adverse cytogenetics had also a negative impact on CIR and OS. The potential benefit of TA regimen was confirmed in the multivariate model for CR (HR=3.3, 95%CI [1.02–10.6], p=0.04), OS (HR=0.5, 95%CI [0.28–0.91], p=0.02), and CIR (HR=0.26, 95%CI [0.11–0.6], p=0.001). Patients in the TA group were more frequently allo-transplanted in CR1 as compared with AA (9/32 in AA group vs 17/25 in TA group, p=0.002) but survival results were confirmed if we censored patients at the time of allogeneic transplantation for CIR (p=0.002) whereas only a trend was shown for OS (p=0.057).

This work shows that the substitution of anthracyclins by topotecan in combination with IDAC for second induction is safe and is associated with a better efficacy for AML patients with persistent leukemia after induction. The use of topotecan may be especially interesting in the context of high dose anthracyclins induction regimen in order to introduce an alternative drug in diseases selected with high resistance to chemotherapy and to limit the cumulative dose of anthracyclins administered.

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