Induction Therapy by Ara-C Plus Daunorubicin Versus Ara-C Plus Gemtuzumab Ozogamicin: Interim Analysis of a Randomized Phase II Trial of the SAL In Elderly Patients with Acute Myeloid Leukemia

Standard chemotherapy for elderly patients with acute myeloid leukemia (AML) results in a median overall survival of only </= 1 year. Considerable numbers of elderly patients with AML present with cardiac comorbidity rendering the use of daunorubicin (DNR) containing chemotherapy regimens hazardous. Gemtuzumab ozogamicin (GO) is active in elderly (=/> 60 years) patients with relapsed AML and shows low cardiac toxicity. The purpose of the randomized phase II study reported here was to compare the antileukemic activity of a standard combination of ara-C (100 mg/m²/day c.i., days 1–7) and DNR (60 mg/m² i.v., on days 3–5) (7+3) versus ara-C plus GO (6 mg/m² i.v. on days 1 and 8) (7+GO) as the first course of induction therapy in AML patients at the age of 60 years and older.

On the basis of the data from the AMLCG (JCO 27: 61–69, 2009) the study was powered to detect an increase of median event free survival (EFS) from 90 to 160 days and a prolongation of the median overall survival (OS) from 9 to >16 months with a power of 80% (alpha= .05), in order to obtain information as a basis for potential further phase III randomized studies. Primary objectives of the study were the achievement of blast clearance (< 5%) on day 16 after induction therapy onset and EFS. OS, complete response (CR) and tolerability were among the secondary objectives. 112 pts. entered the study, suffering from de novo AML, treatment-related secondary AML, AML with a history of MDS, and high-risk MDS. Median age of the patients was 69 years (range 60–83). Study protocol outlined a second induction course 7+3 in those pts. without blast clearance on day 16 and 2 courses of consolidation therapy with high-dose ara-C (1 g/m² q 12 hours i.v., days 1, 3, 5) for patients in CR. We looked for balance of AML standard risk factors between both arms of the study.

The study was approved by the Ethical Board of the University of Muenster and the other participating institutions and written informed consent was obligatory by every pt. prior to entry on study. 58 pts. were randomized to induction therapy with 7+3 as the first course, whereas 54 pts. were randomized to receive 7+GO. All parameters evaluated are for the intent-to-treat population. There were no statistically significant differences between treatment arms in blast clearance (< 5%) on day 16 after treatment onset (7+3: 18 pts., 7+GO: 19 pts.), complete response (CR) rate (7+3: 53.5%, 7+GO: 61.1%), EFS (median for 7+3: 67 days, median for 7+GO: 172 days), or OS (median for 7+3: 9 months, median for 7+GO: 15 months). Toxicity profiles of the protocols were different with 4 pts. developing severe veno-occlusive disease in the 7+GO group.

The study did not show a significant advantage of 7+GO over 7+3 as the first course of induction treatment in elderly pts. with AML. Ara-C and GO and ara-C and DNR have comparable antileukemic activity as the first course of induction. Ara-C and GO may represent an alternative, replacing non-targeted anthracyclines for induction therapy of elderly AML patients e.g. with significant cardiac comorbidities.

Berdel:Wyeth: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Mylotarg as first-line treatment in AML.