Dose-Dense Induction (Sequential-HAM) in Primary Acute Myeloid Leukemia - A Pilot Study of the AML-CG.

Background: Dose intensity is considered one of the prime determinants of antileukemic efficacy in induction treatment of acute myeloid leukemia (AML) - as demonstrated by the superior long-term results of double induction versus conventional induction. In an attempt to further pursue this historically successful strategy an ongoing phase II study of the AML-CG pilots the feasibility of the S-HAM regimen (HD-AraC 3g/m2/12h d1,2,8,9; Mitoxantrone 10mg/m2 d3,4,10,11) in first-line treatment of de-novo AML. In this regimen the interval between the two induction cycles is reduced from 17 days (double induction) to a minimum of 3 days (S-HAM) - thereby increasing dose-intensity more than 2-fold in the critical early phase of treatment.

Results: In the past 18 months 99 patients have been recruited into the trial with a median age of 52 years (range 18 – 78). Of 93 patients evaluable for response the following results were achieved: CR 62%, CRp 24%, PL 6%, ED 8% - resulting in an overall response rate (ORR) of 86%. The early death rate (ED) of 8% and the toxicity profile compared favourably with a historical control group within the AML-CG 1999 study (subgroup: de-novo AML, age less than 60 years, HAM-HAM double induction) with an ED rate of 14% (ORR 68%, persistent leukemia (PL) 18%). The high antileukemic efficacy of S-HAM was also demonstrated by the fact that 88% of patients had a bone marrow blast count of < 10% one week after therapy as compared to less than 48% of patients of the HAM-HAM double induction group. If patients had an adequate blast clearance on day 18 pegylated G-CSF was applied every 10 days until neutrophil recovery. The median time to neutrophil recovery was 30 days after start of treatment with S-HAM which was substantially shorter than following either TAD-HAM or HAM-HAM double induction in the AML-CG 1999 trial (both with a median of 45 days). Since the S-HAM regimen has proven feasible at the present dose level a dose escalation was performed with an additional day of HD-AraC and Mitoxantrone in the first cycle of the sequential regimen.

Conclusion: In the future the appropriate dose level of the S-HAM regimen will then constitute the experimental arm for a randomized comparison of a dose-intensified regimen S-HAM - combining a promising antileukemic activity with significantly reduced duration of critical neutropenia - versus standard double induction for patients younger than 60–70 years in the next generation of the AML-CG studies.