Induction Treatment In Elderly Patients with Acute Myeloid Leukemia (AML): Randomized Comparison of Intermediate-Dose Cytarabine Plus Mitoxantrone (IMA) Versus Standard-Dose Cytarabine Plus Daunorubicin (DA) In 492 AML Patients >60 Years – Results From the SAL 60plus Trial

The majority of patients diagnosed with Acute Myeloid Leukemia (AML) are older than 60 years. Although intensive induction chemotherapy is still the standard practice and a prerequisite for long-term survival, elderly patients have a higher risk of treatment related morbidity and lower remission rates than younger AML patients. An optimized induction treatment would combine high complete remission (CR) rates with tolerable toxicity. The combination of intermediate-dose cytarabine plus mitoxantrone (IMA) has recently been reported to result in high CR rates (73.5%) with acceptable toxicity in 86 elderly AML patients (Niederwieser et al., Blood 2002, abstr. 1337). We present the results of a randomized-controlled trial (RCT) comparing efficacy and tolerability of IMA with the standard 7+3 induction regimen consisting of daunorubicin plus cytarabine (DA).

In the 60plus trial of the Study Alliance Leukemia (SAL, former DSIL), AML patients >60 years considered medically fit for chemotherapy were randomized to receive either intermediate-dose cytarabine (1000 mg/m² BID days 1,3,5,7) plus mitoxantrone (10 mg/m² days 1–3) (IMA) or standard induction therapy with cytarabine (100 mg/m² continuously days 1–7) plus daunorubicin (45 mg/m² days 3–5) (DA). All patients who achieved a CR received cytarabine based consolidation treatment (2+5/MAMAC). Primary endpoint was the CR rate with an expected difference of 15% based on the results of the study named above. Secondary endpoints were the incidence of serious adverse events (SAEs), time to relapse (TTR), disease-free survival (DFS), and overall survival (OS).

A total of 492 patients with a median age of 69 years (range, 61–84) were enrolled between 2003 and 2009 by 29 German centers. 248 were randomized to receive IMA and 244 to receive DA. Patient characteristics were similar in the two treatment arms. In the intention-to-treat analysis, the CR rate was 59.3% (95% CI, 53.1–65.2) in the IMA arm and 51.2% (95%CI, 45.0–57.4) in the DA arm (p= 0.085). Mortality during the first 2 months after the start of study treatment was 18.1% and 18.4% in the IMA and the DA arm, respectively. Forty-five SAEs and grade-4 non hematological toxicities in 43 patients (19%) were reported in the IMA arm, while there were 57 SAEs in 52 patients in the DA arm (23%; p=0.1866). After a median follow-up time of 25.7 months (2.1 years), the median TTR is 10.3 months for IMA and 11.1 months for DA (p=0.328), the median DFS is 10.2 versus 11.7 months (p=0.11) and the median OS is 9.7 versus 10.8 months for IMA versus DA (p=0.945). This results in a 1-year OS of 43.6% in the IMA arm and 46.9% in the DA arm.

Our current results show an equal efficacy and toxicity of both induction regimens. The trend for a higher CR rate after IMA does not translate into a survival advantage. Thus, our study indicates that elderly AML patients do not benefit from a dose escalation of cytarabine in induction therapy.

No relevant conflicts of interest to declare.