ALBERT

Description: 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.

Description: Background: Approximately 45% of AML patients have a normal karyptype (NK-AML) and an intermediate clinical prognosis. As only 20–42% of these patients show long-term survival, it is important to identify prognostic markers to distinguish patients’ outcome more precisely. Mutations in the FLT3 gene such as internal tandem duplications (ITD) in the juxtamembrane domain and point mutations in the tyrosine kinase domain (TKD) are the second most common abnormalties in AML patients. For FLT3-ITD it is well known that patients have an unfavourable prognosis. Up to now there are not enough reliable data to determine the prognostic impact of FLT3-TKD mutations. Patients and Methods: We have investigated the prevalence of FLT3-TKD mutations in a cohort of 803 cytogenetically normal AML (NK-AML) patients and its possible prognostic significance. At diagnosis the mutation status of FLT3 (ITD and TKD) and the NPM1 gene were analyzed by routine molecular techniques. Results: The median age of all patients was 60 years and the median observation time of survivors 23.2 months. Results of the mutation status’ of FLT3-ITD, FLT3-TKD and NPM1 were available in 757/803 (94.3%), 683/803 (85.1%) and 696/803 (86.7%) patients, respectively. FLT3-ITD, FLT3-TKD and NPM1 mutations were found in 222 (29.3%), 46 (6.7%) and 354 (50.9%) of all analyzed patients, respectively. We could not detect any influence of the FLT3-TKD mutation on OS (p= 0.753), RFS (p= 0.229), EFS (p= 0.835), CR (p= 0.168) and on d16 blast count (p= 0.696). In most patients FLT3-ITD and TKD mutations were mutually exclusive, although a minority of 8/674 patients (1.2%) carried both mutations. FLT3-TKD mutations were more frequently found in patients with NPM1 mutations compared to NPM1-negative patients (9.04% vs. 3.74%; p= 0.008). In contrast to FLT3-ITD mutations FLT3-TKD mutation had no prognostic impact in NPM1 positive AML cases. Conclusions: In our study in a large cohort of 803 NK-AML patients we could not detect any prognostic impact of FLT3-TKD mutations. Although FLT3-ITD and TKD mutations have both transforming potential in vitro and in vivo mouse models, the clinical impact of both mutations shows striking differences. Further studies with FLT3-PTK inhibitors will clarify the pathogenetic relevance of these mutations in AML.