Sequential high-dose cytarabine and mitoxantrone (S-HAM) versus standard double induction in acute myeloid leukemia-a phase 3 study

Abstract

Dose-dense induction with the S-HAM regimen was compared to standard double induction therapy in adult patients with newly diagnosed acute myeloid leukemia. Patients were centrally randomized (1:1) between S-HAM (2nd chemotherapy cycle starting on day 8 = "dose-dense") and double induction with TAD-HAM or HAM(-HAM) (2nd cycle starting on day 21 = "standard"). 387 evaluable patients were randomly assigned to S-HAM (N = 203) and to standard double induction (N = 184). The primary endpoint overall response rate (ORR) consisting of complete remission (CR) and incomplete remission (CR_i) was not significantly different (P = 0.202) between S-HAM (77%) and double induction (72%). The median overall survival was 35 months after S-HAM and 25 months after double induction (P = 0.323). Duration of critical leukopenia was significantly reduced after S-HAM (median 29 days) versus double induction (median 44 days)-P < 0.001. This translated into a significantly shortened duration of hospitalization after S-HAM (median 37 days) as compared to standard induction (median 49 days)-P < 0.001. In conclusion, dose-dense induction therapy with the S-HAM regimen shows favorable trends but no significant differences in ORR and OS compared to standard double induction. S-HAM significantly shortens critical leukopenia and the duration of hospitalization by 2 weeks.

Fig. 1

Flow chart of protocol treatment

Fig. 2

Study flow diagram (CONSORT)

Fig. 3

Overall survival and event-free survival. Overall survival of all patients (a), of patients younger than <60 years (b), of patients older than ≥60 years (c). Event-free survival of all patients (d), of patients younger than <60 years (e), of patients older than ≥60 years (f)—always biological age as defined in “Patients and methods”

Fig. 4

Duration of leukopenia. Duration of critical leukopenia (<1.000 leukocytes/µl) in all patients (a), in patients younger than <60 years (b), in patients older than ≥60 years (c). Duration of critical leukopenia was calculated from the start of therapy until recovery of peripheral blood counts and was presented as inverse Kaplan–Meier curves. In (c) please note the “bump” in the standard group (blue line), which is due to the fact that one subgroup of patients received only one cycle of HAM (positive selection because of adequate blast clearance in the day 16 bone marrow aspirate) and the other subgroup received two cycles of HAM (negative selection because of residual blasts in the day 16 bone marrow aspirate). Comparison of the duration of critical leukopenia (<1.000 leukocytes/µl) of all S-HAM patients older than ≥60 years versus those standard arm patients who received only one cycle of HAM (positive selection because of adequate blast clearance in the day 16 bone marrow aspirate) (d), of all S-HAM patients older than ≥60 years versus those standard arm patients who received two cycles of HAM (negative selection because of residual blasts in the day 16 bone marrow aspirate) (e)

Fig. 5

Duration of hospitalization. Duration of hospitalization in all patients (a), in patients younger than <60 years (b), in patients older than ≥60 years (c). Duration of hospitalization was calculated from the start of therapy until the day of discharge and was presented as inverse Kaplan–Meier curves. In (c) please note the “bump” in the standard group (blue line), which is due to the fact that one subgroup of patients received only one cycle of HAM (positive selection because of adequate blast clearance in the day 16 bone marrow aspirate) and the other subgroup received two cycles of HAM (negative selection because of residual blasts in the day 16 bone marrow aspirate). Comparison of the duration of hospitalization of all S-HAM patients older than ≥60 years versus those standard arm patients who received only one cycle of HAM (positive selection because of adequate blast clearance in the day 16 bone marrow aspirate) (d), of all S-HAM patients older than ≥60 years versus those standard arm patients who received two cycles of HAM (negative selection because of residual blasts in the day 16 bone marrow aspirate) (e)